biomarker_id biomarker assessed_biomarker_entity assessed_biomarker_entity_id assessed_entity_type condition condition_id exposure_agent exposure_agent_id best_biomarker_role specimen specimen_id loinc_code evidence_source evidence tag vocab_pattern biomarker_controlled_vocab component_group flags AN4559-1 ABCB1 I1145I mutation ABCB1 NCBI:5243 gene breast cancer DOID:1612 prognostic 74004-3 PubMed:22906996 A total of 57 women with HER2-positive metastatic breast cancer were analyzed after taxane plus trastuzumab chemotherapy. ABCB1 C3435T carriers had a longer progression-free survival (p = 0.039) along with a tendency toward a longer overall survival (p = 0.093). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I1145I sequence variation in gene ABCB1/NCBI:5243 604 check_entity AN4559-1 ABCB1 I1145I mutation ABCB1 NCBI:5243 gene breast cancer DOID:1612 prognostic 74004-3 CIViC:259 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I1145I sequence variation in gene ABCB1/NCBI:5243 604 check_entity AN4559-2 ABCB1 I1145I mutation ABCB1 NCBI:5243 gene lung non-small cell carcinoma DOID:3908 risk 74004-3 PubMed:22296372 The mutation at codon 3435 (C>T) correlated with a significantly higher response rate to platinum-based chemotherapy in patients with advanced non small cell lung cancer (NSCLC). 103 Chinese patients with NSCLC were evaluated in this study. However, there was not a significant correlation between the mutation and overall survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I1145I sequence variation in gene ABCB1/NCBI:5243 605 check_entity AN4559-2 ABCB1 I1145I mutation ABCB1 NCBI:5243 gene lung non-small cell carcinoma DOID:3908 risk 74004-3 CIViC:259 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I1145I sequence variation in gene ABCB1/NCBI:5243 605 check_entity AN4560-1 ABCB1 Overexpression ABCB1 NCBI:5243 gene chronic myeloid leukemia DOID:8552 risk 74004-3 PubMed:18191450 The BCR-ABL1 expressing imatinib-resistant cell line K562/D1-9 overexpresses P-glycoprotein (ABCB1), a known drug membrane transporter. Bafetinib (INNO-406) and dasatinib showed drastically higher IC50 values (970.3 nM and 91nM) in K562/D1-9 than the non-resistant K562 cell line (24.7 nM and 1.5nM), suggesting resistance in the presence of ABCB1 overexpression. The authors state that Bafetinib resistance is likely attributable to it being substrates of P-glycoprotein while nilotinib, which is unlikely to be a P-glycoprotein substrate, had a smaller change in IC50 between the two cell lines. Sensitivity was determined by assessing cell proliferation using the MTT assay. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ABCB1/NCBI:5243 606 AN4560-1 ABCB1 Overexpression ABCB1 NCBI:5243 gene chronic myeloid leukemia DOID:8552 risk 74004-3 CIViC:2784 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ABCB1/NCBI:5243 606 AN4560-2 ABCB1 Overexpression ABCB1 NCBI:5243 gene lung non-small cell carcinoma DOID:3908 risk 74004-3 PubMed:21883677 mRNA expression of ABCB1 in 17 NSCLC cell lines was associated with decreased response to paclitaxel (correlation of mRNA expression and paclitaxel IC50: r=0.5322, P=0.0279). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ABCB1/NCBI:5243 607 AN4560-2 ABCB1 Overexpression ABCB1 NCBI:5243 gene lung non-small cell carcinoma DOID:3908 risk 74004-3 PubMed:26870817 ALK fusion positive NSCLC cell lines with high expression of P-gp (ABCB1 gene) were found to be resistant to crizotinib and ceritinib. P-gp knockdown via shRNA increased the sensitivity of cells to crizotinib and ceritinib. A cell line developed to overexpress P-gp had increased resistance to crizotinib and ceritinib. These cells did not show increased resistance to alectinib and PF-06463922 (lorlatinib). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ABCB1/NCBI:5243 607 AN4560-2 ABCB1 Overexpression ABCB1 NCBI:5243 gene lung non-small cell carcinoma DOID:3908 risk 74004-3 CIViC:2784 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ABCB1/NCBI:5243 607 AN4561-1 ABCB1 S893A/T mutation ABCB1 NCBI:5243 gene breast cancer DOID:1612 prognostic 74004-3 PubMed:22906996 A total of 57 women with HER2-positive metastatic breast cancer were analyzed after taxane plus trastuzumab chemotherapy. ABCB1 G2677T carriers had a longer progression-free survival (p = 0.037) along with a tendency toward a longer overall survival (p = 0.057). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::s893a/t:mutation sequence variation in gene ABCB1/NCBI:5243 608 check_entity AN4561-1 ABCB1 S893A/T mutation ABCB1 NCBI:5243 gene breast cancer DOID:1612 prognostic 74004-3 CIViC:447 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::s893a/t:mutation sequence variation in gene ABCB1/NCBI:5243 608 check_entity AN4562-1 ABCB1 S893T mutation ABCB1 NCBI:5243 gene ovarian cancer DOID:2394 risk 74004-3 PubMed:16467099 The ABCB1 G2677T/A (S893T, rs2032582) homozygous variant was positively correlated with response to paclitaxel treatment in ovarian cancer patients. 51 epithelial and 2 fallopian tube frozen tumors were analyzed for this study. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S893T sequence variation in gene ABCB1/NCBI:5243 609 check_entity AN4562-1 ABCB1 S893T mutation ABCB1 NCBI:5243 gene ovarian cancer DOID:2394 risk 74004-3 CIViC:258 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S893T sequence variation in gene ABCB1/NCBI:5243 609 check_entity AN4563-1 ABCC10 Overexpression ABCC10 NCBI:89845 gene lung non-small cell carcinoma DOID:3908 risk PubMed:18445659 Increased expression of ABCC10 in 17 NSCLC cell lines was inversely correlated with paclitaxel sensitivity (r = 0.574; P < 0.05). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ABCC10/NCBI:89845 610 AN4563-1 ABCC10 Overexpression ABCC10 NCBI:89845 gene lung non-small cell carcinoma DOID:3908 risk CIViC:404 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ABCC10/NCBI:89845 610 AN4564-1 ABCC3 Amplification ABCC3 NCBI:8714 gene breast cancer DOID:1612 risk PubMed:18593940 44 cell lines and 145 patient samples were utilized in various aspects of this study. 31 breast cancer cell lines for in vitro sensitivity to paclitaxel and Monomethyl Auristatin E (MMAE). Genome wide amplification was assessed by Affymetrix SNP arrays and expression was assessed by Affymetrix gene expression arrays. ABCC3 amplification (and expression) in ERBB2 (HER2) amplified breast cancer cell lines was associated with resistance to paclitaxel and MMAE. Three independently derived EVSA-T cell lines overexpressing ABCC3 were at least 20-fold less sensitive to paclitaxel and MMAE based on EC50 values. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ABCC3/NCBI:8714 611 AN4564-1 ABCC3 Amplification ABCC3 NCBI:8714 gene breast cancer DOID:1612 risk CIViC:403 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ABCC3/NCBI:8714 611 AN4565-1 ABCG2 Q141K mutation ABCG2 NCBI:9429 gene ovarian cancer DOID:2394 prognostic PubMed:22112610 The ABCG2 Q141K variant was correlated with higher progression-free survival and overall survival in 511 ovarian cancer patients treated with platinum + taxane-based chemotherapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q141K sequence variation in gene ABCG2/NCBI:9429 612 check_entity AN4565-1 ABCG2 Q141K mutation ABCG2 NCBI:9429 gene ovarian cancer DOID:2394 prognostic CIViC:256 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q141K sequence variation in gene ABCG2/NCBI:9429 612 check_entity AN4566-1 ABL1 A397P mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:17264298 In this phase II multinational study, patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. Response rate among 60 imatinib-resistant patients with BCR-ABL mutations did not differ from the rate of the total population of 100 imatinib-resistant or -intolerant patients. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with A397P, 2/2 had MaHRs and 1/2 had MCyRs which were comparable to response rates among wild type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A397P sequence variation in gene ABL1/NCBI:25 613 check_entity AN4566-1 ABL1 A397P mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4723 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A397P sequence variation in gene ABL1/NCBI:25 613 check_entity AN4567-1 ABL1 BCR::ABL N331S ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with N331S evaluated, 1/1 had a major cytogenetic response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N331S sequence variation in gene ABL1/NCBI:25 614 check_entity AN4567-1 ABL1 BCR::ABL N331S ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:1437 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N331S sequence variation in gene ABL1/NCBI:25 614 check_entity AN4568-1 ABL1 BCR::ABL N336S ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:22371878 This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with N336S, 1/1 had a CHR and 0/1 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N336S sequence variation in gene ABL1/NCBI:25 615 check_entity AN4568-1 ABL1 BCR::ABL N336S ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:1548 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N336S sequence variation in gene ABL1/NCBI:25 615 check_entity AN4569-1 ABL1 BCR::ABL P480A ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with P480A evaluated, 1/1 had a major cytogenetic response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P480A sequence variation in gene ABL1/NCBI:25 616 check_entity AN4569-1 ABL1 BCR::ABL P480A ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:1445 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P480A sequence variation in gene ABL1/NCBI:25 616 check_entity AN4570-1 ABL1 BCR::ABL Q300R ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:22371878 This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with Q300R, 1/1 had a CHR and 1/1 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q300R sequence variation in gene ABL1/NCBI:25 617 check_entity AN4570-1 ABL1 BCR::ABL Q300R ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:1435 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q300R sequence variation in gene ABL1/NCBI:25 617 check_entity AN4571-1 ABL1 BCR::ABL S417Y ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:12623848 In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. A late-chronic phase (CP) patient had a complete hematologic response but acquired resistance 7 months after therapy initiation. At month 11, the L248V, G250E, S417Y, E459K variants were present in approximately 25, 25, 25, and 50% of transcripts, respectively. The patient died in accelerated phase at month 14. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S417Y sequence variation in gene ABL1/NCBI:25 618 check_entity AN4571-1 ABL1 BCR::ABL S417Y ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:1521 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S417Y sequence variation in gene ABL1/NCBI:25 618 check_entity AN4572-1 ABL1 BCR::ABL S438C ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16775234 Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with the S438C, K466E, and K466R secondary variants in 6/10, 1/10. and 1/10 bacterial clones generated using peripheral blood RNA. They had no best hematologic and no best cytogenetic responses to dasatinib which were poor compared to responses in patients with unmutated BCR-ABL1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S438C sequence variation in gene ABL1/NCBI:25 619 check_entity AN4572-1 ABL1 BCR::ABL S438C ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:2822 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S438C sequence variation in gene ABL1/NCBI:25 619 check_entity AN4573-1 ABL1 BCR::ABL T315V ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed reduced incorporation when treated with axitinib in fusions with the T315V variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 45nM vs. 823 nM), indicating the T315V variant induces sensitivity compared to BCR-ABL1 without secondary variants. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315V sequence variation in gene ABL1/NCBI:25 620 check_entity AN4573-1 ABL1 BCR::ABL T315V ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:2754 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315V sequence variation in gene ABL1/NCBI:25 620 check_entity AN4574-1 ABL1 BCR::ABL V298I ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16775234 Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with V289I, V289I/M388L, and G250E variants in 8/11, 1/11, and 1/11 clones, respectively. Clones were generated using peripheral blood RNA. The patient had minimal response as best cytogenetic response and complete response as best hematologic response to dasatinib which were comparable to responses in patients with unmutated BCR-ABL1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V298I sequence variation in gene ABL1/NCBI:25 621 check_entity AN4574-1 ABL1 BCR::ABL V298I ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:2821 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V298I sequence variation in gene ABL1/NCBI:25 621 check_entity AN4575-1 ABL1 BCR::ABL V379I ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16775234 Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in accelerated phase had the BCR-ABL1 fusion with E279K, V379I, and V379I/F317L/M351T variants in 3/11, 5/11, and 1/11 clones, respectively. Clones were generated using peripheral blood RNA. The patient had complete response as best cytogenetic response and no evidence of leukemia as best hematologic response to dasatinib which were improved compared to responses in patients with unmutated BCR-ABL1. An additional patient, in myeloid blast crisis, had V379I in 9/10 bacterial clones generated using peripheral blood RNA. They had complete response as best hematologic response and none as best cytogenetic response to dasatinib which were comparable to responses in patients with unmutated BCR-ABL1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V379I sequence variation in gene ABL1/NCBI:25 622 check_entity AN4575-1 ABL1 BCR::ABL V379I ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:17264298 In this phase II multinational study, patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. Response rate among 60 imatinib-resistant patients with BCR-ABL mutations did not differ from the rate of the total population of 100 imatinib-resistant or -intolerant patients. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with V379I, 3/4 had MaHRs and 2/4 had MCyRs which were comparable to response rates among wild type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V379I sequence variation in gene ABL1/NCBI:25 622 check_entity AN4575-1 ABL1 BCR::ABL V379I ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The V379I mutation was associated with resistance in 2 μM imatinib (2 clones recovered, ~1%). In a review of 20 publications, this mutation was previously described in imatinib resistant patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V379I sequence variation in gene ABL1/NCBI:25 622 check_entity AN4575-1 ABL1 BCR::ABL V379I ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:1517 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V379I sequence variation in gene ABL1/NCBI:25 622 check_entity AN4576-1 ABL1 BCR::ABL Y253F ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 PubMed:18191450 In an in vitro study, a Ba/F3 cell line stably expressing the Y253F mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with similar sensitivity to nilotinib, dasatinib, and bafetinib (INNO-406) treatment (IC50: 975.3 nM, 16.8 nM, and 490.8 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 642.3 nM, 87.6 nM, and 152.9 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y253F sequence variation in gene ABL1/NCBI:25 623 check_entity AN4576-1 ABL1 BCR::ABL Y253F ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 CIViC:1000 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y253F sequence variation in gene ABL1/NCBI:25 623 check_entity AN4576-1 ABL1 BCR::ABL Y253F ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 CIViC:2778 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y253F sequence variation in gene ABL1/NCBI:25 623 check_entity AN4576-2 ABL1 BCR::ABL Y253F ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19075254 A panel of 18 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The Y253F mutation was moderately resistant to imatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y253F sequence variation in gene ABL1/NCBI:25 624 check_entity AN4576-2 ABL1 BCR::ABL Y253F ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:15930265 In two cell-based studies, a panel of either 18 or 16 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The Y253F mutation was moderately resistant to imatinib . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y253F sequence variation in gene ABL1/NCBI:25 624 check_entity AN4576-2 ABL1 BCR::ABL Y253F ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with Y253F evaluated, 1/1 had a complete hematologic response and 0/1 had a major cytogenetic response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y253F sequence variation in gene ABL1/NCBI:25 624 check_entity AN4576-2 ABL1 BCR::ABL Y253F ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed increased incorporation when harboring fusions with the Y253F variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 1275nM vs. 823 nM), indicating resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y253F sequence variation in gene ABL1/NCBI:25 624 check_entity AN4576-2 ABL1 BCR::ABL Y253F ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:12623848 In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. An AP patient had a complete hematologic response. After 9 months of therapy, the patient progressed returning to chronic phase. Concurrently, the Y253F and E255V variants were found in ~50% and ~50% of BCR-ABL1 transcripts, respectively. Imatinib was withdrawn at 10 months and the patient died 14 months after treatment initiation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y253F sequence variation in gene ABL1/NCBI:25 624 check_entity AN4576-2 ABL1 BCR::ABL Y253F ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:1000 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y253F sequence variation in gene ABL1/NCBI:25 624 check_entity AN4576-2 ABL1 BCR::ABL Y253F ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:2778 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y253F sequence variation in gene ABL1/NCBI:25 624 check_entity AN4577-1 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene acute lymphoblastic leukemia DOID:9952 risk 55135-8 PubMed:16775234 Prior to dasatinib treatment, one imatinib-resistant patient with acute lymphoblastic leukemia had the BCR-ABL1 fusion with no secondary variants in at least ten bacterial clones generated using peripheral blood RNA. They had NEL (no evidence of leukemia) best hematologic and minor best cytogenetic responses to dasatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 625 check_entity AN4577-1 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene acute lymphoblastic leukemia DOID:9952 risk 55135-8 PubMed:17264298 In this phase II multinational study, patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. Response rate among 60 imatinib-resistant patients with BCR-ABL mutations did not differ from the rate of the total population of 100 imatinib-resistant or -intolerant patients. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with T315I, 0/5 had MaHRs and 0/5 had MCyRs which were lower than response rates among wild type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 625 check_entity AN4577-1 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene acute lymphoblastic leukemia DOID:9952 risk 55135-8 PubMed:25686603 Bone marrow mononuclear cells (BM MNCs) were isolated from three acute lymphoblastic leukemia patients with the BCR-ABL1 T315I variant who were pretreated with various chemotherapeutics and dasatinib. 2/3 patient's BM MNCs were considered sensitive to ponatinib and axitinib using drug sensitivity scoring of proliferation assays. Additionally, BCR-ABL T315I showed sensitivity to ponitinib and axitinib in Ba/F3 cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 625 check_entity AN4577-1 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene acute lymphoblastic leukemia DOID:9952 risk 55135-8 CIViC:1 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 625 check_entity AN4577-1 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene acute lymphoblastic leukemia DOID:9952 risk 55135-8 CIViC:4373 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 625 check_entity AN4577-1 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene acute lymphoblastic leukemia DOID:9952 risk 55135-8 CIViC:4431 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 625 check_entity AN4577-1 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene acute lymphoblastic leukemia DOID:9952 risk 55135-8 CIViC:4550 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 625 check_entity AN4577-2 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene acute myeloid leukemia DOID:9119 risk 55135-8 PubMed:12476305 BCR-ABL fusions have been found to contribute to imatinib resistance in AML cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 626 check_entity AN4577-2 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene acute myeloid leukemia DOID:9119 risk 55135-8 CIViC:1 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 626 check_entity AN4577-3 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 PubMed:15930265 A panel of 16 mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and evaluated for antiproliferative activity and substrate or auto-phosphorylation assays. The authors considered the M244V mutation sensitive to imatinib (IC50: 2000 vs. 260 nmol/L, 8x fold change, in a proliferative assay compared to Ba/F3 cells with unmutated BCR-ABL fusions). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 627 check_entity AN4577-3 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 PubMed:18191450 In an in vitro study, a Ba/F3 cell line stably expressing the M244V mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with similar sensitivity to dasatinib and nilotinib treatment (IC50: 93.1 nM and 891.4 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 87.6 nM and 642.3 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 627 check_entity AN4577-3 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 CIViC:4662 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 627 check_entity AN4577-3 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 CIViC:4555 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 627 check_entity AN4577-3 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 CIViC:4719 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 627 check_entity AN4577-3 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 CIViC:4373 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 627 check_entity AN4577-3 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 CIViC:4376 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 627 check_entity AN4577-3 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 CIViC:4556 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 627 check_entity AN4577-3 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 CIViC:4742 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 627 check_entity AN4577-3 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 CIViC:4381 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 627 check_entity AN4577-3 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 CIViC:4873 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 627 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 PubMed:25212276 Data from deep sequencing of a Ph-negative clone of a Ph-positive CML patient has found a driving mutation in DNMT3A that preceeded the BCR-ABL fusion, and may imply the possibility that BCR-ABL is not universally the initiating event in CML. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 PubMed:20537386 The presence of BCR-ABL fusion is considered the characterizing feature of chronic myeloid leukemia, and has been widely thought of as the initiating event in the disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 PubMed:16775234 Prior to dasatanib treatment, fifteen imatinib-resistant patients with chronic myeloid leukemia in various phases had the BCR-ABL1 fusion with no secondary variants in at least ten clones generated using peripheral blood RNA. They had no evidence of leukemia (n = 3), complete (9), minor (2), and no (1) best hematologic responses to dasatinib and complete (3), partial (3), minor (2), minimal (2), and no (5) best cytogenetic responses to dasatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 PubMed:18191450 In an in vitro study, six CML cell lines expressing the BCR-ABL1 fusion protein showed sensitivity to nilotinib (IC50: 24.3-84.5 nM), dasatinib (IC50: 1.5-10.9 nM), and bafetinib (IC50: 11.8-87.7 nM). When comparing potency of these treatments against the 6 CML cell lines, dasatinib, nilotinib and bafetinib were on average 98.6, 9.85 and 16.4 times more potent than imatinib. Sensitivity was determined by assessing cell proliferation using the MTT assay. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 PubMed:15194504 COS7 cell lines transfected with BCR-ABL constructs harboring E255K mutations were shown to be resistant to imatinib and exhibited increased kinase activity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 PubMed:18818391 BCR-ABL F317L has been shown to confer resistance to dasatinib in patients with CML. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 PubMed:24236021 Molecular dynamics simulations and calculated solvated interaction energies indicate BCR-ABL F317L mutations are Ponatinib sensitive. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 PubMed:25349473 Ponatinib has shown to be effective in patients with BCR-ABL kinase domain mutations including T315I. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 PubMed:23190221 Study describes a phase 1 clinical trial of ponatinib in treatment of 81 refractory Philadelphia chromosome-positive leukemias. 43 of these patients were considered to have chronic-phase CML. All 12 chronic-phase CML patients with a T315I mutation showed a complete hematologic response. Furthermore, 91% of these patients were estimated to remain in response at 1 year (95% CI, Kaplan-Meier analysis). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 PubMed:19075254 A panel of 18 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The F359V mutation was moderately resistant to imatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 PubMed:12623848 In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. An accelerated-phase (AP) patient improved to chronic phase. M351T, E255K, and F359V variants were each present in ~25% of transcripts beginning at 6, 11, and 14 months, respectively. At 20 months, the patient returned to accelerated phase with an increase in the proportion of E255K variants to ~75% of transcripts. Another AP patient had a complete hematologic response with the M351T variant present in ~25 to ~75% of transcripts and the F359V variant present in ~25% to ~50% of transcripts between 8 and 16 months after therapy initiation but prior to resistance. At 17 months, the patient progressed to myeloid blast crisis and there was cytogenetic evidence of a double Ph-chromosome. At that time, no secondary variants could be detected. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 PubMed:15930265 In two cell-based studies, a panel of either 18 or 16 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The F359V mutation was moderately resistant to imatinib . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 PubMed:16772610 In an in vitro study, a Ba/F3-p210BCR-ABL1 cell line was ENU-mutated and exposed to graded concentrations of imatinib, nilotinib or dasatinib to identify resistance mutations. The L248V mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance to 2 μM imatinib (3 clones recovered, ~2% of viable clones in this treatment), 50nM nilotinib (1 clone, ~2%), and 5nM dasatinib (3 clones, ~9%). In a review of 20 publications, this mutation was described in imatinib resistant patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with F359V evaluated, 6/6 had complete hematologic responses and 4/7 had major cytogenetic responses. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 PubMed:22371878 This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with F359V, 0/2 had a CHR and 1/2 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 PubMed:17264298 In this phase II multinational study, patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. Response rate among 60 imatinib-resistant patients with BCR-ABL mutations did not differ from the rate of the total population of 100 imatinib-resistant or -intolerant patients. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with F359V, 5/7 had MaHRs which was comparable to response rates among wild type patients, and 1/7 had MCyRs which which was lower than response rates among wild type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 PubMed:19779040 This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase) patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Of the 27 with F359V mutations, 14, 17, and 25 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed similar incorporation when harboring fusions with the F359V variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 933nM vs. 823 nM), indicating that the variant does not induce resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 PubMed:15705718 In an in vitro study, stochastic mutations in the ABL1 region of a stably expressed p210 BCR-ABL fusion were generated in Ba/F3 cell lines from five independently derived, mutagenized libraries. Dasatinib resistant subclones were identified using 50 nM dasatinib in liquid culture. 201 individual clones were identified representing 10 different mutations at 6 different residues. 60 of these clones had T315A mutations. To validate resistance to dasatinib, Ba/F3 cell lines stably expressing a T315A mutation in the ABL1 region of the BCR-ABL fusion were generated. T315A was associated with higher dasatinib IC50 of 125 nM vs 1.34 nM in wildtype as determined by dose response curves. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 PubMed:19652056 In this open-label, phase II registration trial, patients that were imatinib resistant or intolerant underwent nilotinib monotherapy. Within 12 months of nilotinib therapy, there was no significant difference in response to nilotinib treatment between patients with mutations in the Abl1 kinase domain versus without. However, the authors identify Y253H, E255K/V, and F359C/V variants as resistant as they had an IC50 of >150 nM. In patients with Y253H mutations prior to nilotinib treatment, complete hematologic response was achieved in 0 of 6 patients, major cytogenetic response in 1 of 8 patients, complete cytogenetic response in 0 of 8 patients, and major molecular response in 0 of 7 patients. After median follow-up of 15.5 months, 3 of 8 patients with this mutation progressed or died. The Y253H mutation was present in two patients at baseline and newly emerged in two patients at progression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:1 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4431 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4373 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4376 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4664 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4662 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4714 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4555 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4719 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4550 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4673 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4553 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4678 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4556 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4683 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4721 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4745 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4680 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4885 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4730 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4886 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4872 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4887 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4877 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4374 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4832 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4675 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4889 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4381 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4743 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4835 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4884 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4873 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4727 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4828 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4830 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4829 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4725 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4723 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4834 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4742 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4875 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4837 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4839 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4836 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4833 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4744 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4838 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4876 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4729 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4746 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4888 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4891 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4577-4 ABL1 BCR::ABL mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 diagnostic;risk 55135-8 CIViC:4890 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::ABL sequence variation in gene ABL1/NCBI:25 628 check_entity AN4578-1 ABL1 C475V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:22371878 This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with C475V, 1/1 had a CHR and 1/1 had a MCyR. 9 patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C475V sequence variation in gene ABL1/NCBI:25 629 check_entity AN4578-1 ABL1 C475V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:1547 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C475V sequence variation in gene ABL1/NCBI:25 629 check_entity AN4579-1 ABL1 CENPC::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 55135-8 PubMed:28408464 This study included 1389 cases of high-risk pediatric B-ALL, of which 284 were identified by TaqMan Low Density Array to have a BCR-ABL1-like (Ph-like) gene expression signature. RT-PCR or RNAseq performed on Ph-like, CRLF2 negative patients revealed 17 cases with ABL1 fusions with 8 different partner genes. There was one case of the CENPC-ABL1 fusion in a 15-year-old patient. Considering the previously confirmed Ph-like expression signature in the tested cases, the results suggest that the presence of the CENPC-ABL1 fusion in B-ALL indicates the BCR-ABL1-like (Ph-like) subtype of the disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CENPC::ABL1 sequence variation in gene ABL1/NCBI:25 630 check_entity AN4579-1 ABL1 CENPC::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 55135-8 CIViC:3139 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CENPC::ABL1 sequence variation in gene ABL1/NCBI:25 630 check_entity AN4580-1 ABL1 D276G mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19075254 A panel of 18 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The D276G mutation was moderately resistant to imatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D276G sequence variation in gene ABL1/NCBI:25 631 check_entity AN4580-1 ABL1 D276G mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with D276G evaluated, 1/1 had a complete hematologic responses and 0/1 had a major cytogenetic response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D276G sequence variation in gene ABL1/NCBI:25 631 check_entity AN4580-1 ABL1 D276G mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19779040 This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 8 patients with D276G mutations, 3, 4, and 7 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D276G sequence variation in gene ABL1/NCBI:25 631 check_entity AN4580-1 ABL1 D276G mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed increased incorporations when harboring fusions with the D276G variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 1105nM vs. 823 nM), indicating resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D276G sequence variation in gene ABL1/NCBI:25 631 check_entity AN4580-1 ABL1 D276G mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The D276G mutation was associated with resistance in 2 μM imatinib (1 clone recovered, ~0.71%). In a review of 20 publications, this mutation was previously described in imatinib resistant patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D276G sequence variation in gene ABL1/NCBI:25 631 check_entity AN4580-1 ABL1 D276G mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4553 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D276G sequence variation in gene ABL1/NCBI:25 631 check_entity AN4581-1 ABL1 D363G mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16775234 Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with the D363G secondary variant in 2/10 bacterial clones generated using peripheral blood RNA. They had complete best hematologic and complete best cytogenetic responses to dasatinib which were improved compared to responses in patients with unmutated BCR-ABL1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D363G sequence variation in gene ABL1/NCBI:25 632 check_entity AN4581-1 ABL1 D363G mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4725 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D363G sequence variation in gene ABL1/NCBI:25 632 check_entity AN4582-1 ABL1 D421G mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with D421G evaluated, 1/1 had a complete hematologic response and 0/1 had a major cytogenetic response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D421G sequence variation in gene ABL1/NCBI:25 633 check_entity AN4582-1 ABL1 D421G mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4727 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D421G sequence variation in gene ABL1/NCBI:25 633 check_entity AN4583-1 ABL1 Double Ph ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:12623848 In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. A chronic-phase patient had a partial hematologic response with the Q252H and M351T variants present. The patient progressed to myeloid blast crisis (MBC) and was then negative for secondary variants. However, they had cytogenetic evidence of double Ph-chromosomes and later died. Another CP patient achieved a complete hematologic response (CHR). The Q252H variant was later detected but was absent when the patient progressed to myeloid blast crisis (MBC) at which time cytogenetic evidence of double Ph-chromosomes were present. The patient later died. An accelerated-phase patient had a complete hematologic response with the F359V and M351T variants present. The patient progressed to myeloid blast crisis at which point there were no secondary variants but cytogenetic evidence of double Ph-chromosomes. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ABL1 Double Ph [biomarker_term_in_review] 634 not_mapped AN4583-1 ABL1 Double Ph ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:2878 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ABL1 Double Ph [biomarker_term_in_review] 634 not_mapped AN4584-1 ABL1 E255K mutation ABL1 NCBI:25 gene acute lymphoblastic leukemia DOID:9952 risk 55135-8 PubMed:16775234 Prior to dasatinib treatment, one imatinib-resistant patient with acute lymphoblastic leukemia had the BCR-ABL1 fusion with the E255K secondary variant in 3/12 bacterial clones generated using peripheral blood RNA. They had no best hematologic and no best cytogenetic responses to dasatinib which were worse compared to responses in patient with unmutated BCR-ABL1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255K sequence variation in gene ABL1/NCBI:25 635 check_entity AN4584-1 ABL1 E255K mutation ABL1 NCBI:25 gene acute lymphoblastic leukemia DOID:9952 risk 55135-8 CIViC:4431 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255K sequence variation in gene ABL1/NCBI:25 635 check_entity AN4584-2 ABL1 E255K mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:15194504 COS7 cell lines transfected with BCR-ABL constructs harboring E255K mutations were shown to be resistant to imatinib and exhibited increased kinase activity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255K sequence variation in gene ABL1/NCBI:25 636 check_entity AN4584-2 ABL1 E255K mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19075254 A panel of 18 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The E255K mutation was resistant to imatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255K sequence variation in gene ABL1/NCBI:25 636 check_entity AN4584-2 ABL1 E255K mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:12623848 In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. A late-chronic phase patient had a complete hematologic response but progressed to partial hematologic response just before the detection of E255K variants. The patient died from disease progression. Three accelerated phase (AP) patients had complete hematologic responses but became resistant concurrently or just prior to detection of the E255K variant. They died from disease progression. A fourth AP patient had the M351T variant and required dose escalation. After the addition of chemotherapy, E255K and F359V variants arose. The patient returned to AP at which point E255K variants were the most prevalent. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255K sequence variation in gene ABL1/NCBI:25 636 check_entity AN4584-2 ABL1 E255K mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:15930265 A panel of 16 mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and evaluated for anti-proliferative activity and substrate or auto-phosphorylation assays. The E255K mutation was resistant to imatinib (20-fold IC50 increase for the proliferation assay). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255K sequence variation in gene ABL1/NCBI:25 636 check_entity AN4584-2 ABL1 E255K mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:22371878 This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with E255K, 0/1 had a CHR and 0/1 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255K sequence variation in gene ABL1/NCBI:25 636 check_entity AN4584-2 ABL1 E255K mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with E255K evaluated, 2/2 had complete hematologic responses and 1/2 had a major cytogenetic response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255K sequence variation in gene ABL1/NCBI:25 636 check_entity AN4584-2 ABL1 E255K mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19779040 This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 16 patients with E255K mutations, 6, 9, and 14 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255K sequence variation in gene ABL1/NCBI:25 636 check_entity AN4584-2 ABL1 E255K mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:17264298 In this phase II multinational study, patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. Response rate among 60 imatinib-resistant patients with BCR-ABL mutations did not differ from the rate of the total population of 100 imatinib-resistant or -intolerant patients. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with E255K, 4/6 had MaHRs which was comparable to response rates among wild type patients, and 0/6 had MCyRs which was lower than response rates among wild type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255K sequence variation in gene ABL1/NCBI:25 636 check_entity AN4584-2 ABL1 E255K mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16775234 Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with the E255K secondary variant in 12/12 bacterial clones generated using peripheral blood RNA. They had complete best hematologic and minimal best cytogenetic responses to dasatinib which were comparable to responses in patients with unmutated BCR-ABL1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255K sequence variation in gene ABL1/NCBI:25 636 check_entity AN4584-2 ABL1 E255K mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed increased incorporation when harboring fusions with the E255K variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 1282nM vs. 823 nM), indicating resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255K sequence variation in gene ABL1/NCBI:25 636 check_entity AN4584-2 ABL1 E255K mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:15705718 In an in vitro study, stochastic mutations in the ABL1 region of the p210 BCR-ABL fusion were generated and stably expressed in Ba/F3 cell lines from mutagenized libraries. Combination therapy with 10 μM imatinib and 50 nM Dasatinib resulted in 11 clones, 5 of which had the E255K variant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255K sequence variation in gene ABL1/NCBI:25 636 check_entity AN4584-2 ABL1 E255K mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The E255K mutation was associated with resistance in 16 μM imatinib ( 1 clone recovered, ~3%) and all lower concentrations as well as in 50 nM nilotinib (5 clones, ~11%) and 5 nM dasatinib (2 clones, ~6%), the lowest concentrations tested for these two drugs. In a review of 20 publications, this mutation was described in imatinib resistant patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255K sequence variation in gene ABL1/NCBI:25 636 check_entity AN4584-2 ABL1 E255K mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19652056 In this open-label, phase II registration trial, patients that were imatinib resistant or intolerant underwent nilotinib monotherapy. Within 12 months of nilotinib therapy, there was no significant difference in response to nilotinib treatment between patients with mutations in the Abl1 kinase domain versus without. However, the authors identify Y253H, E255K/V, and F359C/V variants as resistant as they had an IC50 greater than 150 nM. In patients with E255K and/or E255V mutations prior to nilotinib treatment, complete hematological responses were achieved in 5 of 7 patients, major cytogenetic responses in 3 of 7 patients, complete cytogenetic responses in 0 of 7 patients, and a major molecular response in 1 of 7 patients. After a median follow-up of 15.5 months, 6 of 7 patients with this mutation progressed or died. The E255K mutation was present in 6 patients at baseline and newly emerged in 4 patients at progression. The E255V mutation was present in 0 patients at baseline and newly emerged in 3 patients at progression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255K sequence variation in gene ABL1/NCBI:25 636 check_entity AN4584-2 ABL1 E255K mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4431 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255K sequence variation in gene ABL1/NCBI:25 636 check_entity AN4584-2 ABL1 E255K mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4729 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255K sequence variation in gene ABL1/NCBI:25 636 check_entity AN4585-1 ABL1 E255V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:12623848 In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. An AP patient had a complete hematologic response. After 9 months of therapy, the patient progressed returning to chronic phase. Concurrently, the Y253F and E255V variants were found in ~50% and ~50% of BCR-ABL1 transcripts, respectively. Imatinib was withdrawn at 10 months and the patient died 14 months after treatment initiation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255V sequence variation in gene ABL1/NCBI:25 637 check_entity AN4585-1 ABL1 E255V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19075254 In an in vitro study, a Ba/F3 cell line stably expressing the E255V mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance to nilotinib treatment (IC50: 10.31-fold), as compared to Ba/F3 cells expressing BCR-ABL1 fusion protein. Sensitivity was determined by assessing cell proliferation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255V sequence variation in gene ABL1/NCBI:25 637 check_entity AN4585-1 ABL1 E255V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, a Ba/F3-p210BCR-ABL1 cell line was ENU-mutated and exposed to graded concentrations of imatinib, nilotinib or dasatinib to identify resistance mutations. The E255V mutation in the ABL1 portion of the BCR-ABL1 fusion protein was identified and associated with resistance to imatinib (1 clone, 0.43% of viable clones in this treatment, recovered in 4 μM but none at 2, 8, or 16 μM) and nilotinib (1 clone, 1.25%, recovered at 500nM but none at 50, 2000 or 5000nM). In a review of 20 publications, this mutation was described in imatinib resistant patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255V sequence variation in gene ABL1/NCBI:25 637 check_entity AN4585-1 ABL1 E255V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed increased incorporation when harboring fusions with the E255V variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 1350nM vs. 823 nM), indicating resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255V sequence variation in gene ABL1/NCBI:25 637 check_entity AN4585-1 ABL1 E255V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with E255V evaluated, 1/1 had a complete hematologic response and 1/1 had a major cytogenetic response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255V sequence variation in gene ABL1/NCBI:25 637 check_entity AN4585-1 ABL1 E255V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:22371878 This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with E255V, 1/1 had a CHR and 0/1 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255V sequence variation in gene ABL1/NCBI:25 637 check_entity AN4585-1 ABL1 E255V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19779040 This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 11 patients with E255V mutations, 4, 4, and 9 achieved a CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255V sequence variation in gene ABL1/NCBI:25 637 check_entity AN4585-1 ABL1 E255V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16775234 Three chronic myeloid leukemia patients had the BCR-ABL1 fusion with the E255V secondary variant in one or more bacterial clones generated using peripheral blood RNA. They had no best cytogenetic responses but had complete (n = 2) or minor best hematologic responses to dasatinib which were comparable to responses in patients with unmutated BCR-ABL1. The first patient, in chronic phase, had E255V, E255V/Q447R, E255V/T345A, and E255V/T345A/H396R variants in 6/10, 2/10, 1/10, and 1/10 clones, respectively. The second patient, in chronic phase, had E255V and E255K variants in 10/11 and 1/11 clones, respectively. The third patient, in myeloid blast crisis, had E255V and E292V variants in 10/12 and 2/12 clones, respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255V sequence variation in gene ABL1/NCBI:25 637 check_entity AN4585-1 ABL1 E255V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19652056 In this open-label, phase II registration trial, patients that were imatinib resistant or intolerant underwent nilotinib monotherapy. Within 12 months of nilotinib therapy, there was no significant difference in response to nilotinib treatment between patients with mutations in the Abl1 kinase domain versus without. However, the authors identify Y253H, E255K/V, and F359C/V variants as resistant as they had an IC50 greater than 150 nM. In patients with E255K and/or E255V mutations prior to nilotinib treatment, complete hematological responses were achieved in 5 of 7 patients, major cytogenetic responses in 3 of 7 patients, complete cytogenetic responses in 0 of 7 patients, and a major molecular response in 1 of 7 patients. After a median follow-up of 15.5 months, 6 of 7 patients with this mutation progressed or died. The E255K mutation was present in 6 patients at baseline and newly emerged in 4 patients at progression. The E255V mutation was present in 0 patients at baseline and newly emerged in 3 patients at progression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255V sequence variation in gene ABL1/NCBI:25 637 check_entity AN4585-1 ABL1 E255V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4673 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E255V sequence variation in gene ABL1/NCBI:25 637 check_entity AN4586-1 ABL1 E279K mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19779040 This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 8 patients with E279K mutations, 5, 5, and 8 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E279K sequence variation in gene ABL1/NCBI:25 638 check_entity AN4586-1 ABL1 E279K mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed similar incorporation when harboring fusions with the E279K variant of ABL1 compared to those with wildtype ABL1 (IC50 of 778nM vs. 823 nM), indicating that the E279K variant does not induce resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E279K sequence variation in gene ABL1/NCBI:25 638 check_entity AN4586-1 ABL1 E279K mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4743 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E279K sequence variation in gene ABL1/NCBI:25 638 check_entity AN4587-1 ABL1 E292L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed similar incorporation when harboring fusions with the E292L variant of ABL1 compared to those with wildtype ABL1 (IC50 of 863nM vs. 823 nM), indicating that the E292L variant does not induce resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E292L sequence variation in gene ABL1/NCBI:25 639 check_entity AN4587-1 ABL1 E292L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4744 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E292L sequence variation in gene ABL1/NCBI:25 639 check_entity AN4588-1 ABL1 E292V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, a Ba/F3-p210BCR-ABL1 cell line was ENU-mutated and exposed to graded concentrations of imatinib, nilotinib or dasatinib. The E292V mutation in the ABL1 portion of the BCR-ABL1 fusion protein was identified and associated with resistance to nilotinib treatment (1 clone recovered at 50nM). In a review of 20 publications, this mutation was not previously described in imatinib resistant patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E292V sequence variation in gene ABL1/NCBI:25 640 check_entity AN4588-1 ABL1 E292V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4745 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E292V sequence variation in gene ABL1/NCBI:25 640 check_entity AN4589-1 ABL1 E355G mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:12623848 In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. A CP patient had complete cytogenetic response until progressing to accelerated phase with concurrent detection of the E355G variant. After dose escalation, this patient achieved a major cytogenetic response with continued presence of E355G. Another CP patient had a major cytogenetic response to imatinib which was maintained after the detection of the E355G variant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E355G sequence variation in gene ABL1/NCBI:25 641 check_entity AN4589-1 ABL1 E355G mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with E355G evaluated, 2/2 had complete hematologic responses and 1/2 had major cytogenetic responses. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E355G sequence variation in gene ABL1/NCBI:25 641 check_entity AN4589-1 ABL1 E355G mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:17264298 In this phase II multinational study, patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. Response rate among 60 imatinib-resistant patients with BCR-ABL mutations did not differ from the rate of the total population of 100 imatinib-resistant or -intolerant patients. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with E355G, 2/4 had MaHRs and 2/4 had MCyRs which were comparable to response rates among wild type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E355G sequence variation in gene ABL1/NCBI:25 641 check_entity AN4589-1 ABL1 E355G mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19779040 This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 19 patients with E355G mutations, 4, 9, and 17 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E355G sequence variation in gene ABL1/NCBI:25 641 check_entity AN4589-1 ABL1 E355G mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16775234 Prior to dasatinib treatment, three imatinib-resistant patients with chronic myeloid leukemia had the BCR-ABL1 fusion with the E355G secondary variant in one or more bacterial clones. Clones were generated using peripheral blood RNA. The first two, in chronic and accelerated phases, had minimal or no best cytogenetic responses but had complete or no evidence of leukemia best hematologic responses, respectively. Of these, the first had E355G and E355G/Q252R variants in 8/10 and 1/10 clones, respectively, and the second had E355G, E355G/L324Q, and L324Q variants in 6/10, 1/10, and 3/10 clones, respectively. The third patient, in lymphoid blast crisis with the E355G variant in 10/10 clones, had complete best hematologic and partial best cytogenetic responses to dasatinib. All responses were comparable to responses in patients with unmutated BCR-ABL1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E355G sequence variation in gene ABL1/NCBI:25 641 check_entity AN4589-1 ABL1 E355G mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The E355G mutation was associated with resistance in 2 μM imatinib (1 clone recovered, ~0.71%). In a review of 20 publications, this mutation was previously described in imatinib resistant patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E355G sequence variation in gene ABL1/NCBI:25 641 check_entity AN4589-1 ABL1 E355G mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4678 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E355G sequence variation in gene ABL1/NCBI:25 641 check_entity AN4590-1 ABL1 E450Q mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16775234 Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with E450Q/M351T and E450Q variants in 1/10 and 9/10 clones, respectively. Clones were generated using peripheral blood RNA. The patient had complete best cytogenetic and complete best hematologic responses to dasatinib which were improved compared to responses in patients with unmutated BCR-ABL1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E450Q sequence variation in gene ABL1/NCBI:25 642 check_entity AN4590-1 ABL1 E450Q mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4746 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E450Q sequence variation in gene ABL1/NCBI:25 642 check_entity AN4591-1 ABL1 E450V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with E450V evaluated, 1/1 had a complete hematologic response and 1/1 had a major cytogenetic response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E450V sequence variation in gene ABL1/NCBI:25 643 check_entity AN4591-1 ABL1 E450V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4828 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E450V sequence variation in gene ABL1/NCBI:25 643 check_entity AN4592-1 ABL1 E453A mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:22371878 This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with E453A, 1/1 had a CHR and 0/0 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E453A sequence variation in gene ABL1/NCBI:25 644 check_entity AN4592-1 ABL1 E453A mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4829 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E453A sequence variation in gene ABL1/NCBI:25 644 check_entity AN4593-1 ABL1 E453K mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with E453K evaluated, 1/1 had a major cytogenetic response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E453K sequence variation in gene ABL1/NCBI:25 645 check_entity AN4593-1 ABL1 E453K mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4830 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E453K sequence variation in gene ABL1/NCBI:25 645 check_entity AN4594-1 ABL1 E453Q mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with E453Q evaluated, 1/1 had a complete hematologic response and 1/1 had a major cytogenetic response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E453Q sequence variation in gene ABL1/NCBI:25 646 check_entity AN4594-1 ABL1 E453Q mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4832 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E453Q sequence variation in gene ABL1/NCBI:25 646 check_entity AN4595-1 ABL1 E459K mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19779040 This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 12 patients with the E459K mutations, 4, 6, and 11 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E459K sequence variation in gene ABL1/NCBI:25 647 check_entity AN4595-1 ABL1 E459K mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:17264298 In this phase II multinational study, patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. Response rate among 60 imatinib-resistant patients with BCR-ABL mutations did not differ from the rate of the total population of 100 imatinib-resistant or -intolerant patients. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with E459K, 1/3 had MaHRs which was lower than response rates among wild type patients, and 3/3 had MCyRs which was higher than response rates among wild type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E459K sequence variation in gene ABL1/NCBI:25 647 check_entity AN4595-1 ABL1 E459K mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:12623848 In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. A late-chronic phase (CP) patient had a complete hematologic response but acquired resistance 7 months after treatment initiation. At month 11, the L248V, G250E, S417Y, and E459K variants were present in approximately 25, 25, 25, and 50% of transcripts, respectively. The patient died in accelerated phase at month 14. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E459K sequence variation in gene ABL1/NCBI:25 647 check_entity AN4595-1 ABL1 E459K mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4833 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E459K sequence variation in gene ABL1/NCBI:25 647 check_entity AN4596-1 ABL1 E98G mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16775234 Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with the E98G secondary variant in 11/11 bacterial clones generated using peripheral blood RNA. They had complete best hematologic and complete best cytogenetic responses to dasatinib which were improved compared to responses in patients with unmutated BCR-ABL1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E98G sequence variation in gene ABL1/NCBI:25 648 check_entity AN4596-1 ABL1 E98G mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4834 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E98G sequence variation in gene ABL1/NCBI:25 648 check_entity AN4597-1 ABL1 ETV6::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk 55135-8 PubMed:25207766 An adult patient (82 yo) who presented with B-ALL (initial WBC of 183,000) with ETV6-ABL1 fusion was treated with dasatinib as a single agent after his chemotherapy had to be stopped due to toxicity. This resulted in morphological and cytogenetic remission after 2 weeks of treatment. Patient continued dasatinib daily plus 2 cycles of prednisolone (50 mg orally daily) for 4 weeks each. He remained in cytogenetic remission after 8 months of maintenance dasatinib. (See Supplementary Appendix 2, Page 11). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::ABL1 sequence variation in gene ABL1/NCBI:25 649 check_entity AN4597-1 ABL1 ETV6::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk 55135-8 PubMed:30028819 A 4-year-old female presented with relapsed B-cell precursor ALL and no MLL or BCR-ABL1 rearrangement per cytogenetic studies. During multiple periods of short remission and relapse she was treated with high risk induction chemotherapy, craniospinal irradiation and matched unrelated donor bone marrow transplant. Finally, WES and RNA-seq were performed on the tumor and normal samples, which identified a cryptic ETV6-ABL1 fusion as well as a biallelic CDKN2A deletion. She was administered imatinib and achieved a morphologic, cytogenetic, and molecular remission, which were maintained for 18 months. After a fourth relapse, clinical sequencing was repeated and ultimately identified the persisting ETV6-ABL1 fusion (with no mutation identified in the kinase domain of ABL1) as well as a previously undetected MLL2-ADCY9 fusion resulting in truncation of MLL2 (also known as KMT2D). Treatments of Dasatinib, Ponatinib, and Panobinostat were unsuccessful and the patient ultimately succumbed to her disease 7 year after her initial diagnosis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::ABL1 sequence variation in gene ABL1/NCBI:25 649 check_entity AN4597-1 ABL1 ETV6::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk 55135-8 CIViC:2448 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::ABL1 sequence variation in gene ABL1/NCBI:25 649 check_entity AN4597-2 ABL1 ETV6::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 55135-8 PubMed:27229714 This study determined the incidence, clinical characteristics and associated genetic abnormalities in hematologic malignancies with the ETV6-ABL1 fusion. The total of 44 new and previously published ETV6-ABL1 positive cases were detected and characterized using conventional cytogenetics, FISH, RT-PCR, SNP/copy number arrays, expression arrays and a custom Taqman 'low-density array' (LDA card). Among the 44 cases, there were 22 cases of B-ALL (13 children, 9 adults), and 22 myeloid malignancies (18 myeloproliferative neoplasms, and 4 acute myeloid leukemias). The 9 ETV6-ABL1 positive ALL cases (7 diagnosis and 2 relapse samples) that underwent whole genome expression profiling displayed similar expression profiles to the BCR-ABL1 positive leukemia cohort. Also, 9/10 ETV6-ABL1 BCP-ALL cases were classified by custom Taqman assay (designed to detect BCR-ABL1-like expression signature) as BCR-ABL1-like. The study thus shows that in B-ALL, the presence of the ETV6-ABL1 fusion correlates with the BCR-ABL1 like (Ph-like) subtype of the disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::ABL1 sequence variation in gene ABL1/NCBI:25 650 check_entity AN4597-2 ABL1 ETV6::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 55135-8 CIViC:2448 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::ABL1 sequence variation in gene ABL1/NCBI:25 650 check_entity AN4598-1 ABL1 F311I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with F311I evaluated, 1/1 had a complete hematologic response and 1/1 had a major cytogenetic response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F311I sequence variation in gene ABL1/NCBI:25 651 check_entity AN4598-1 ABL1 F311I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4374 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F311I sequence variation in gene ABL1/NCBI:25 651 check_entity AN4599-1 ABL1 F311L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with F311L evaluated, 1/1 had a complete hematologic response and 1/1 had a major cytogenetic response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F311L sequence variation in gene ABL1/NCBI:25 652 check_entity AN4599-1 ABL1 F311L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. 61 clones grew in a combination of 400 nM imatinib and 50 nM nilotinib. Of these, 19 were sequenced and 1 (~5%) was found to have an F311L mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F311L sequence variation in gene ABL1/NCBI:25 652 check_entity AN4599-1 ABL1 F311L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4835 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F311L sequence variation in gene ABL1/NCBI:25 652 check_entity AN4600-1 ABL1 F317C mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The F317C mutation was associated with resistance in 5 nM dasatinib (1 clone recovered, ~ 3%) and 10 nM dasatinib (6 clones, ~11%). In a review of 20 publications, this mutation was previously described in imatinib resistant patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317C sequence variation in gene ABL1/NCBI:25 653 check_entity AN4600-1 ABL1 F317C mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4836 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317C sequence variation in gene ABL1/NCBI:25 653 check_entity AN4601-1 ABL1 F317I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:15705718 In an in vitro study, stochastic mutations in the ABL1 region of a stably expressed p210 BCR-ABL fusion were generated in Ba/F3 cell lines from five independently derived, mutagenized libraries. Dasatinib resistant subclones were identified using 50 nM dasatinib in liquid culture. 201 individual clones were identified representing 10 different mutations at 6 different residues. 1 of these clones had an F317I mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317I sequence variation in gene ABL1/NCBI:25 654 check_entity AN4601-1 ABL1 F317I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The F317I mutation was associated with resistance in 5 nM dasatinib (2 clone recovered, ~ 6%) and 10 nM dasatinib (10 clones, ~18%). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317I sequence variation in gene ABL1/NCBI:25 654 check_entity AN4601-1 ABL1 F317I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4837 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317I sequence variation in gene ABL1/NCBI:25 654 check_entity AN4602-1 ABL1 F317L mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 PubMed:18191450 In an in vitro study, a Ba/F3 cell line stably expressing the F317L mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with similar sensitivity to nilotinib and bafetinib treatment (IC50: 929.8 nM and 293.5 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 642.3 nM and 152.9 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317L sequence variation in gene ABL1/NCBI:25 655 check_entity AN4602-1 ABL1 F317L mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 CIViC:4376 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317L sequence variation in gene ABL1/NCBI:25 655 check_entity AN4602-2 ABL1 F317L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:18818391 BCR-ABL F317L has been shown to confer resistance to dasatinib in patients with CML. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317L sequence variation in gene ABL1/NCBI:25 656 check_entity AN4602-2 ABL1 F317L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:24236021 Molecular dynamics simulations and calculated solvated interaction energies indicate BCR-ABL F317L mutations are Ponatinib sensitive. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317L sequence variation in gene ABL1/NCBI:25 656 check_entity AN4602-2 ABL1 F317L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19075254 A panel of 18 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The F317L mutation was moderately resistant to imatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317L sequence variation in gene ABL1/NCBI:25 656 check_entity AN4602-2 ABL1 F317L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:12623848 In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. A chronic phase (CP) patient had complete hematologic response. The F317L variant was present in ~100% of transcripts at 4 months and the patient progressed to myeloid blast crisis 3 months later. Imatinib was discontinued 9 months after initiation, and the patient went into remission after chemotherapy at month 19. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317L sequence variation in gene ABL1/NCBI:25 656 check_entity AN4602-2 ABL1 F317L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:15930265 In two cell-based studies, a panel of either 18 or 16 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The F317L mutation was moderately resistant to imatinib . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317L sequence variation in gene ABL1/NCBI:25 656 check_entity AN4602-2 ABL1 F317L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with F317L evaluated, 3/3 had major cytogenetic responses. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317L sequence variation in gene ABL1/NCBI:25 656 check_entity AN4602-2 ABL1 F317L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:22371878 This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with F317L, 4/8 had a CHR and 1/7 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317L sequence variation in gene ABL1/NCBI:25 656 check_entity AN4602-2 ABL1 F317L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed increased incorporation when harboring fusions with the F317L variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 1220nM vs. 823 nM), indicating resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317L sequence variation in gene ABL1/NCBI:25 656 check_entity AN4602-2 ABL1 F317L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:15705718 In an in vitro study, stochastic mutations in the ABL1 region of a stably expressed p210 BCR-ABL fusion were generated in Ba/F3 cell lines from five independently derived, mutagenized libraries. Dasatinib resistant subclones were identified using 50 nM dasatinib in liquid culture. 201 individual clones were identified representing 10 different mutations at 6 different residues. 10 of these clones had F317L mutations. To validate resistance to dasatinib, a Ba/F3 cell line stably expressing the F317L mutation in the ABL1 region of the BCR-ABL fusion was generated and associated with higher dasatinib IC50 of 18 nM vs 1.34 nM in wildtype as determined by dose response curves. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317L sequence variation in gene ABL1/NCBI:25 656 check_entity AN4602-2 ABL1 F317L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The F317L mutation was associated with resistance in 2 μM imatinib (2 clones recovered, ~1%), 5 nM dasatinib (6 clones, ~ 17%), and 10 nM dasatinib (4 clones, ~7%). In a review of 20 publications, this mutation was previously described in imatinib resistant patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317L sequence variation in gene ABL1/NCBI:25 656 check_entity AN4602-2 ABL1 F317L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19779040 This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase) patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 14 patients with F317L mutations, 1, 2, and 13 achieved CCyR, MCyR, and CHR to dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. Despite high CHR in patients with the F317L variant, of the 63 variants considered, the authors associate T315I, F317L, and V299L with resistance or lower levels of response to dasatinib due to clinical resistance and low in vitro sensitivity. They suggest considering alternative treatment options for patients with these three variants. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317L sequence variation in gene ABL1/NCBI:25 656 check_entity AN4602-2 ABL1 F317L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:17264298 In this phase II multinational study, patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. Response rate among 60 imatinib-resistant patients with BCR-ABL mutations did not differ from the rate of the total population of 100 imatinib-resistant or -intolerant patients. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with F317L, 4/4 had MaHRs which was higher than response rates among wild type patients, and 0/4 had MCyRs which was lower than response rates among wild type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317L sequence variation in gene ABL1/NCBI:25 656 check_entity AN4602-2 ABL1 F317L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4376 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317L sequence variation in gene ABL1/NCBI:25 656 check_entity AN4603-1 ABL1 F317R mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed higher incorporation when harboring fusions with the F317R variant of ABL1 compared to those with wildtype ABL1 (IC50 of 1286nM vs. 823 nM), indicating resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317R sequence variation in gene ABL1/NCBI:25 657 check_entity AN4603-1 ABL1 F317R mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4838 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317R sequence variation in gene ABL1/NCBI:25 657 check_entity AN4604-1 ABL1 F317S mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:15705718 In an in vitro study, stochastic mutations in the ABL1 region of a stably expressed p210 BCR-ABL fusion were generated in Ba/F3 cell lines from five independently derived, mutagenized libraries. Dasatinib resistant subclones were identified using 50 nM dasatinib in liquid culture. 201 individual clones were identified representing 10 different mutations at 6 different residues. 1 of these clones had an F317S mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317S sequence variation in gene ABL1/NCBI:25 658 check_entity AN4604-1 ABL1 F317S mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4839 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317S sequence variation in gene ABL1/NCBI:25 658 check_entity AN4605-1 ABL1 F317V mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 PubMed:18191450 In an in vitro study, a Ba/F3 cell line stably expressing the dasatinib-resistance variant F317V in the ABL1 portion of the BCR-ABL1 fusion protein was associated with similar sensitivity to imatinib, nilotinib and bafetinib (INNO-406) treatment (IC50: 1053.7, 286.9 nM, 284 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 1712 nM, 642.3 nM, and 152.9 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317V sequence variation in gene ABL1/NCBI:25 659 check_entity AN4605-1 ABL1 F317V mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 CIViC:4381 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317V sequence variation in gene ABL1/NCBI:25 659 check_entity AN4605-2 ABL1 F317V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed increased incorporation when harboring fusions with the F317V variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 1320nM vs. 823 nM), indicating resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317V sequence variation in gene ABL1/NCBI:25 660 check_entity AN4605-2 ABL1 F317V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:15705718 In an in vitro study, stochastic mutations in the ABL1 region of a stably expressed p210 BCR-ABL fusion were generated in Ba/F3 cell lines from five independently derived, mutagenized libraries. Dasatinib resistant subclones were identified using 50 nM dasatinib in liquid culture. 201 individual clones were identified representing 10 different mutations at 6 different residues. 83 of these clones had F317V mutations. To validate resistance to dasatinib, a Ba/F3 cell line stably expressing the F317V mutation in the ABL1 region of the BCR-ABL fusion was generated and associated with higher dasatinib IC50 of 53 nM vs 1.34 nM in wildtype as determined by dose response curves. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317V sequence variation in gene ABL1/NCBI:25 660 check_entity AN4605-2 ABL1 F317V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The F317V mutation was associated with resistance in 5 nM dasatinib (1 clone recovered, ~ 3%) and 25 nM dasatinib (1 clone, ~3%). No clones were recovered at 10 nM dasatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317V sequence variation in gene ABL1/NCBI:25 660 check_entity AN4605-2 ABL1 F317V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4381 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F317V sequence variation in gene ABL1/NCBI:25 660 check_entity AN4606-1 ABL1 F359C mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, a Ba/F3-p210BCR-ABL1 cell line was ENU-mutated and exposed to graded concentrations of imatinib, nilotinib or dasatinib to identify resistance mutations. The F359C mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance to 50nM nilotinib (6 clones recovered, ~13% of viable clones in this treatment) and 2 μM imatinib (6 clones, ~4%). In a review of 20 publications, this mutation was described in imatinib resistant patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359C sequence variation in gene ABL1/NCBI:25 661 check_entity AN4606-1 ABL1 F359C mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:22371878 This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with F359C, 2/2 had a CHR and 1/2 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359C sequence variation in gene ABL1/NCBI:25 661 check_entity AN4606-1 ABL1 F359C mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:17264298 In this phase II multinational study, patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. Response rate among 60 imatinib-resistant patients with BCR-ABL mutations did not differ from the rate of the total population of 100 imatinib-resistant or -intolerant patients. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with F359C, 2/2 had MaHRs and 2/2 had MCyRs which were comparable to response rates among wild type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359C sequence variation in gene ABL1/NCBI:25 661 check_entity AN4606-1 ABL1 F359C mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19779040 This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 5 patients with F359C mutations, 3, 3, and 4 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359C sequence variation in gene ABL1/NCBI:25 661 check_entity AN4606-1 ABL1 F359C mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16775234 Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with G250E and F359C variants in 3/10 and 5/10 clones, respectively. Clones were generated using peripheral blood RNA. The patient had complete best cytogenetic and complete best hematologic responses to dasatinib which were improved compared to responses in patients with unmutated BCR-ABL1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359C sequence variation in gene ABL1/NCBI:25 661 check_entity AN4606-1 ABL1 F359C mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19652056 In this open-label, phase II registration trial, patients that were imatinib resistant or intolerant underwent nilotinib monotherapy. Within 12 months of nilotinib therapy, there was no significant difference in response to nilotinib treatment between patients with mutations in the Abl1 kinase domain versus without. However, the authors identify Y253H, E255K/V, and F359C/V variants as resistant as they had an IC50 of >150nM. In patients with F359C and/or F359V mutations prior to nilotinib treatment, complete hematological responses were achieved in 3 of 10 patients, a major cytogenetic response in 1 of 11 patients, a complete cytogenetic response in 0 of 11 patients, and major molecular response in 0 of 10 patients. After a median follow-up of 15.5 months, 9 of 11 patients with this mutation progressed or died. The F359C mutation was present in 1 patient at baseline and newly emerged in 1 patient at progression. The F359V mutation was present in 4 patients at baseline and newly emerged in 1 patient at progression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359C sequence variation in gene ABL1/NCBI:25 661 check_entity AN4606-1 ABL1 F359C mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4680 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359C sequence variation in gene ABL1/NCBI:25 661 check_entity AN4607-1 ABL1 F359I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed similar incorporation when harboring fusions with the F359I variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 975nM vs. 823 nM), indicating that the variant does not induce resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359I sequence variation in gene ABL1/NCBI:25 662 check_entity AN4607-1 ABL1 F359I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with F359I evaluated, 1/1 had a complete hematologic response and 1/1 had a major cytogenetic response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359I sequence variation in gene ABL1/NCBI:25 662 check_entity AN4607-1 ABL1 F359I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:22371878 This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with F359I evaluated, 2/2 had CHR and 2/2 had MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were occurring. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359I sequence variation in gene ABL1/NCBI:25 662 check_entity AN4607-1 ABL1 F359I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19779040 This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 12 patients with F359I mutations, 7, 10, and 12 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359I sequence variation in gene ABL1/NCBI:25 662 check_entity AN4607-1 ABL1 F359I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16775234 Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with the F359I secondary variant in 9/9 bacterial clones generated using peripheral blood RNA. They had complete best hematologic and no cytogenetic responses to dasatinib which were comparable to responses in patients with unmutated BCR-ABL1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359I sequence variation in gene ABL1/NCBI:25 662 check_entity AN4607-1 ABL1 F359I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4675 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359I sequence variation in gene ABL1/NCBI:25 662 check_entity AN4607-1 ABL1 F359I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4876 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359I sequence variation in gene ABL1/NCBI:25 662 check_entity AN4608-1 ABL1 F359V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19075254 A panel of 18 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The F359V mutation was moderately resistant to imatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359V sequence variation in gene ABL1/NCBI:25 663 check_entity AN4608-1 ABL1 F359V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:12623848 In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. An accelerated-phase (AP) patient improved to chronic phase. M351T, E255K, and F359V variants were each present in ~25% of transcripts beginning at 6, 11, and 14 months, respectively. At 20 months, the patient returned to accelerated phase with an increase in the proportion of E255K variants to ~75% of transcripts. Another AP patient had a complete hematologic response with the M351T variant present in ~25 to ~75% of transcripts and the F359V variant present in ~25% to ~50% of transcripts between 8 and 16 months after therapy initiation but prior to resistance. At 17 months, the patient progressed to myeloid blast crisis and there was cytogenetic evidence of a double Ph-chromosome. At that time, no secondary variants could be detected. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359V sequence variation in gene ABL1/NCBI:25 663 check_entity AN4608-1 ABL1 F359V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:15930265 In two cell-based studies, a panel of either 18 or 16 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The F359V mutation was moderately resistant to imatinib . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359V sequence variation in gene ABL1/NCBI:25 663 check_entity AN4608-1 ABL1 F359V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with F359V evaluated, 6/6 had complete hematologic responses and 4/7 had major cytogenetic responses. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359V sequence variation in gene ABL1/NCBI:25 663 check_entity AN4608-1 ABL1 F359V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:22371878 This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with F359V, 0/2 had a CHR and 1/2 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359V sequence variation in gene ABL1/NCBI:25 663 check_entity AN4608-1 ABL1 F359V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:17264298 In this phase II multinational study, patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. Response rate among 60 imatinib-resistant patients with BCR-ABL mutations did not differ from the rate of the total population of 100 imatinib-resistant or -intolerant patients. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with F359V, 5/7 had MaHRs which was comparable to response rates among wild type patients, and 1/7 had MCyRs which which was lower than response rates among wild type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359V sequence variation in gene ABL1/NCBI:25 663 check_entity AN4608-1 ABL1 F359V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19779040 This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase) patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Of the 27 with F359V mutations, 14, 17, and 25 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359V sequence variation in gene ABL1/NCBI:25 663 check_entity AN4608-1 ABL1 F359V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16775234 Prior to dasatinib treatment, two imatinib-resistant patients with chronic myeloid leukemia (CML) in chronic phase had the BCR-ABL1 fusion, one with the T315I, F359V, M244V, and G250E variants in 2/10, 6/10, 1/10, and 1/10 clones, respectively, and the other with F359V, F359V/F486S, F359V/L273M, and L273M variants in 6/10, 1/10, 2/10, and 1/10 clones, respectively. Clones were generated using peripheral blood RNA. The patients had no best cytogenetic responses and no or complete best hematologic responses to dasatinib. Two additional patients with CML, in myeloid blast crisis, had F359V in 1/10 and 9/10 clones. They had no hematologic and no cytogenetic responses. Overall, responses were poor compared to responses in patients with unmutated BCR-ABL1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359V sequence variation in gene ABL1/NCBI:25 663 check_entity AN4608-1 ABL1 F359V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed similar incorporation when harboring fusions with the F359V variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 933nM vs. 823 nM), indicating that the variant does not induce resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359V sequence variation in gene ABL1/NCBI:25 663 check_entity AN4608-1 ABL1 F359V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The F359V mutation was associated with resistance in 2 μM imatinib (3 clones recovered, ~2%). In a review of 20 publications, this mutation was previously described in imatinib resistant patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359V sequence variation in gene ABL1/NCBI:25 663 check_entity AN4608-1 ABL1 F359V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19652056 In this open-label, phase II registration trial, patients that were imatinib-resistant or intolerant underwent nilotinib monotherapy. Within 12 months of nilotinib therapy, there was no significant difference in response to nilotinib treatment between patients with mutations in the Abl1 kinase domain versus without. However, the authors identify Y253H, E255K/V, and F359C/V variants as resistant as they had an IC50 of >150nM. In patients with F359C and/or F359V mutations prior to nilotinib treatment, complete hematological responses were achieved in 3 of 10 patients, a major cytogenetic response in 1 of 11 patients, a complete cytogenetic response in 0 of 11 patients, and major molecular response in 0 of 10 patients. After a median follow-up of 15.5 months, 9 of 11 patients with this mutation progressed or died. The F359C mutation was present in 1 patient at baseline and newly emerged in 1 patient at progression. The F359V mutation was present in 4 patients at baseline and newly emerged in 1 patient at progression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359V sequence variation in gene ABL1/NCBI:25 663 check_entity AN4608-1 ABL1 F359V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4664 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F359V sequence variation in gene ABL1/NCBI:25 663 check_entity AN4609-1 ABL1 F486S mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19075254 In an in vitro study, a Ba/F3 cell line stably expressing the F486S mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with sensitivity to nilotinib treatment (IC50: 1.85-fold), comparable to Ba/F3 cells expressing BCR-ABL fusion protein. Sensitivity was determined by assessing cell proliferation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F486S sequence variation in gene ABL1/NCBI:25 664 check_entity AN4609-1 ABL1 F486S mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed similar incorporation when harboring fusions with the F486S variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 897nM vs. 823 nM), indicating baseline sensitivity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F486S sequence variation in gene ABL1/NCBI:25 664 check_entity AN4609-1 ABL1 F486S mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:22371878 This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with F486S, 0/1 had a CHR and 0/1 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F486S sequence variation in gene ABL1/NCBI:25 664 check_entity AN4609-1 ABL1 F486S mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19779040 This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 13 patients with F486S mutations, 5, 6, and 12 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F486S sequence variation in gene ABL1/NCBI:25 664 check_entity AN4609-1 ABL1 F486S mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:12623848 In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. An accelerate-phase patient had a complete cytogenetic response until progressing to major cytogenetic response (MCyR) at month 17 and then losing MCyR at month 24 despite dose escalation. At month 9, the F486S variant was found in ~25% of transcripts increasing to ~50% at month 16 and then remaining at a stable proportion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F486S sequence variation in gene ABL1/NCBI:25 664 check_entity AN4609-1 ABL1 F486S mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4721 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F486S sequence variation in gene ABL1/NCBI:25 664 check_entity AN4610-1 ABL1 FOXP1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk 55135-8 PubMed:21391972 In a 16-year old Caucasian female with pre B-cell ALL, the t(3;9)(p12;q34) was identified by FISH. 5'RACE PCR detected the in-frame FOXP1-ABL1 (exon 19 - exon 4) fusion was confirmed by RT-PCR (only detected in tumor cells; absent in normal control cells) and long PCR, cloning and Sanger sequencing. The patient was enrolled on the standard arm (based on positive MRD) for high-risk patients (on account of her age and white blood cell count) of the COALL-97 protocol. The patient was then consolidated with a haplo-identical transplant from her father and remained in complete remission. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FOXP1::ABL1 sequence variation in gene ABL1/NCBI:25 665 check_entity AN4610-1 ABL1 FOXP1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk 55135-8 PubMed:30938769 A 16-year-old Caucasian boy was diagnosed with B-ALL. Karyotype showed an abnormal clone characterized by the t(3;9)(p13;q34.1). This translocation has been shown previously to result in an abnormal fusion between the FOXP1 gene in 3p13 and the ABL1 in 9q34.1 (the fusion was not confirmed in this report by molecular methods). The FOXP1-ABL1 fusion is known to be associated with Ph-like B-ALL subtype of B-ALL, although Ph-like expression profile was not demonstrated in this case report. The patient was treated with Berlin-Frankfurt-Münster (BFM) high-risk 4-drug induction chemotherapy with prednisone, daunorubicin, vincristine, and pegasparaginase and had 0.013% MRD at the end of indusciton. Tyrosine kinase inhibitor dasatinib was added to the consolidation chemotherapy with cyclophosphamide, cytarabine, peg-asparaginase, mercaptopurine, and vincristine. End-of-consolidation bone marrow tested negative for MRD. The patient was continued on standard high-risk BFM therapy, plus dasatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FOXP1::ABL1 sequence variation in gene ABL1/NCBI:25 665 check_entity AN4610-1 ABL1 FOXP1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk 55135-8 CIViC:2551 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FOXP1::ABL1 sequence variation in gene ABL1/NCBI:25 665 check_entity AN4610-2 ABL1 FOXP1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 prognostic 55135-8 PubMed:27894077 The FOXP1-ABL1 fusion was identified in a male patient in a Dutch/German cohort of 77 BCR-ABL1-like cases. The FOXP1-ABL1 fusion was confirmed by PCR and targeted ligation amplification, and was found to fuse exon 27 of FOXP1 to exon 4 of ABL1. The case was shown previously to have BCR-ABL1-like signature by hierarchical clustering of gene expression data (PMID: 23974192). The patient was treated with the ALL9-high risk protocol, did not respond to therapy, and passed away. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FOXP1::ABL1 sequence variation in gene ABL1/NCBI:25 666 check_entity AN4610-2 ABL1 FOXP1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 prognostic 55135-8 CIViC:2551 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FOXP1::ABL1 sequence variation in gene ABL1/NCBI:25 666 check_entity AN4611-1 ABL1 G250E mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 PubMed:18191450 In an in vitro study, a Ba/F3 cell line stably expressing the G250E mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with similar sensitivity to nilotinib treatment (IC50: 866 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 642.3 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G250E sequence variation in gene ABL1/NCBI:25 667 check_entity AN4611-1 ABL1 G250E mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 CIViC:4555 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G250E sequence variation in gene ABL1/NCBI:25 667 check_entity AN4611-2 ABL1 G250E mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19075254 A panel of 18 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The G250E mutation was resistant to imatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G250E sequence variation in gene ABL1/NCBI:25 668 check_entity AN4611-2 ABL1 G250E mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:12623848 In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. A late-chronic phase (CP) patient had a complete hematologic response (CHR) but acquired resistance 7 months after therapy initiation. At month 11, the L248V, G250E, S417Y, E459K variants were present in approximately 25, 25, 25, and 50% of transcripts, respectively. The patient died in accelerated phase at month 14. An accelerated-phase patient had a CHR but progressed to partial hematologic response concurrent with the appearance of the G250E variant in ~25% of transcripts and the M351T variant in ~50% of transcripts. The patient died at 12 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G250E sequence variation in gene ABL1/NCBI:25 668 check_entity AN4611-2 ABL1 G250E mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:15930265 In two cell-based studies, a panel of either 18 or 16 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The G250E mutation was resistant to imatinib . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G250E sequence variation in gene ABL1/NCBI:25 668 check_entity AN4611-2 ABL1 G250E mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with G250E evaluated, 1/1 had a complete hematologic response and 2/2 had major cytogenetic responses. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G250E sequence variation in gene ABL1/NCBI:25 668 check_entity AN4611-2 ABL1 G250E mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:22371878 This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with G250E, 3/6 had a CHR and 0/5 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G250E sequence variation in gene ABL1/NCBI:25 668 check_entity AN4611-2 ABL1 G250E mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19779040 This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Of 60 patients with G250E mutations, 20, 29, and 56 achieved a CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G250E sequence variation in gene ABL1/NCBI:25 668 check_entity AN4611-2 ABL1 G250E mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:17264298 In this phase II multinational study, patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. Response rate among 60 imatinib-resistant patients with BCR-ABL mutations did not differ from the rate of the total population of 100 imatinib-resistant or -intolerant patients. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with G250E, 6/9 had MaHRs which was comparable to response rates among wild type patients, and 1/9 had MCyRs which was lower than response rates among wild type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G250E sequence variation in gene ABL1/NCBI:25 668 check_entity AN4611-2 ABL1 G250E mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed higher incorporation when harboring fusions with the G250E variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 1295nM vs. 823 nM), indicating resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G250E sequence variation in gene ABL1/NCBI:25 668 check_entity AN4611-2 ABL1 G250E mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The G250E mutation was associated with resistance in 2 μM imatinib (3 clone recovered, ~2%), 4 μM imatinib (1 clone recovered, ~0.74%), and 50 nM nilotinib (5 clone, ~11%). In a review of 20 publications, this mutation was previously described in imatinib resistant patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G250E sequence variation in gene ABL1/NCBI:25 668 check_entity AN4611-2 ABL1 G250E mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4555 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G250E sequence variation in gene ABL1/NCBI:25 668 check_entity AN4612-1 ABL1 G340L mutation ABL1 NCBI:25 gene lung non-small cell carcinoma DOID:3908 risk 55135-8 PubMed:26758680 In this in vitro study, the H2110 non-small cell lung cancer cell line (heterozygous for a G340L mutation) was shown to be susceptible to imatinib and dasatinib monotherapies. This line showed a significant reduction in colony formation (P = 0.0001) and MTT assay, which tests for NADH activity (P < 0.001), with imatinib vs vehicle treatment. A significant reduction in colony formation (P < 0.001) with dasatinib treatment vs vehicle was also observed. There was no significant difference in a lung cancer cell line without a known driver (H2126) nor in an immortalized bronchial epithelial line (Beas-2B) with either drug treatment in colony forming and MTT assays. Moreover, a significant increase in cytotoxicity was noted with siRNA facilitated depletion of ABL1 (P < 0.001) with no significant change in H2126 or Beas-2B lines supporting ABL1 as the primary drug target. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G340L sequence variation in gene ABL1/NCBI:25 669 check_entity AN4612-1 ABL1 G340L mutation ABL1 NCBI:25 gene lung non-small cell carcinoma DOID:3908 risk 55135-8 CIViC:1565 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G340L sequence variation in gene ABL1/NCBI:25 669 check_entity AN4613-1 ABL1 G398R mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19075254 In an in vitro study, a Ba/F3 cell line stably expressing the G398R mutation in the ABL1 portion of the BCR-ABL1 gene fusion was associated with sensitivity to nilotinib treatment (IC50: 0.49-fold), comparable to Ba/F3 cells expressing BCR-ABL1 fusion protein (reported to be sensitizing to nilotinib). Sensitivity was determined by assessing cell proliferation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G398R sequence variation in gene ABL1/NCBI:25 670 check_entity AN4613-1 ABL1 G398R mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4872 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G398R sequence variation in gene ABL1/NCBI:25 670 check_entity AN4614-1 ABL1 H396P mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 PubMed:18191450 In an in vitro study, a Ba/F3 cell line stably expressing H396P in the ABL1 portion of the BCR-ABL1 fusion protein was associated with similar sensitivity to nilotinib and bafetinib (INNO-406) treatment (IC50: 986.9 nM and 280.1 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 642.3 nM and 152.9 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H396P sequence variation in gene ABL1/NCBI:25 671 check_entity AN4614-1 ABL1 H396P mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 CIViC:4873 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H396P sequence variation in gene ABL1/NCBI:25 671 check_entity AN4614-2 ABL1 H396P mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with H396P evaluated, 1/1 had a complete hematologic response and 2/2 had major cytogenetic responses. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H396P sequence variation in gene ABL1/NCBI:25 672 check_entity AN4614-2 ABL1 H396P mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. 61 clones grew in a combination of 400 nM imatinib and 50 nM nilotinib. Of these, 19 were sequenced and 1 (~5%) was found to have an H396P mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H396P sequence variation in gene ABL1/NCBI:25 672 check_entity AN4614-2 ABL1 H396P mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed lower incorporation when harboring fusions with the H396P variant of ABL1 compared to those with wildtype ABL1 (IC50 of 683nM vs. 823 nM), indicating the H396P variant induces sensitivity compared to BCR-ABL1 without secondary variants. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H396P sequence variation in gene ABL1/NCBI:25 672 check_entity AN4614-2 ABL1 H396P mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4873 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H396P sequence variation in gene ABL1/NCBI:25 672 check_entity AN4615-1 ABL1 H396R mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19075254 A panel of 18 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The H396R mutation was resistant to imatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H396R sequence variation in gene ABL1/NCBI:25 673 check_entity AN4615-1 ABL1 H396R mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:12623848 In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. An accelerated-phase patient had a return to chronic phase but progressed to myeloid blast crisis after 5 months of therapy. At that time, the M351T and H396R variants were detected in ~50% and ~25% of transcripts, respectively. At 10 months, the patient died. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H396R sequence variation in gene ABL1/NCBI:25 673 check_entity AN4615-1 ABL1 H396R mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:15930265 In two cell-based studies, a panel of either 18 or 16 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The H396R mutation was resistant to imatinib . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H396R sequence variation in gene ABL1/NCBI:25 673 check_entity AN4615-1 ABL1 H396R mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:22371878 This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with H396R, 0/1 had a CHR and 0/1 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H396R sequence variation in gene ABL1/NCBI:25 673 check_entity AN4615-1 ABL1 H396R mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with H396R evaluated, 1/1 had a complete hematologic response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H396R sequence variation in gene ABL1/NCBI:25 673 check_entity AN4615-1 ABL1 H396R mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19779040 This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 33 patients with H396R mutations, 13, 17, and 30 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H396R sequence variation in gene ABL1/NCBI:25 673 check_entity AN4615-1 ABL1 H396R mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed increased incorporation when harboring fusions with the H396R variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 1247nM vs. 823 nM), indicating resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H396R sequence variation in gene ABL1/NCBI:25 673 check_entity AN4615-1 ABL1 H396R mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The H396R mutation was associated with resistance in 2 μM imatinib (1 clone recovered, ~0.71%) and 4 μM imatinib (1 clone, ~0.74%). In a review of 20 publications, this mutation was previously described in imatinib resistant patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H396R sequence variation in gene ABL1/NCBI:25 673 check_entity AN4615-1 ABL1 H396R mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16775234 Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with H396R and E355G variants in 9/11 and 1/11 clones, respectively. Clones were generated using peripheral blood RNA. The patient had no best cytogenetic and complete best hematologic responses to dasatinib which were comparable to responses in patients with unmutated BCR-ABL1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H396R sequence variation in gene ABL1/NCBI:25 673 check_entity AN4615-1 ABL1 H396R mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4683 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H396R sequence variation in gene ABL1/NCBI:25 673 check_entity AN4616-1 ABL1 L248R mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:15705718 In an in vitro study, stochastic mutations in the ABL1 region of a stably expressed p210 BCR-ABL fusion were generated in Ba/F3 cell lines from five independently derived, mutagenized libraries. Dasatinib resistant subclones were identified using 50 nM dasatinib in liquid culture. 201 individual clones were identified representing 10 different mutations at 6 different residues. 1 of these clones had an L248R mutation. To validate resistance to dasatinib, a Ba/F3 cell line stably expressing the L248R mutation in the ABL1 region of the BCR-ABL fusion was generated. The L248R variants was associated with higher dasatinib IC50 of 16 nM vs 1.34 nM in wildtype and higher imatinib IC50 of >10,000 nM vs 323 nM in wildtype as determined by dose response curves. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L248R sequence variation in gene ABL1/NCBI:25 674 check_entity AN4616-1 ABL1 L248R mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The L248R mutation was associated with resistance in 2 μM imatinib (1 clone recovered, ~1%) and 8 μM imatinib (1 clone, ~2%). In a review of 20 publications, this mutation had not been described in imatinib resistant patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L248R sequence variation in gene ABL1/NCBI:25 674 check_entity AN4616-1 ABL1 L248R mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed similar sensitivity to axitinib in fusions with the L248R and F359I variants of ABL1 compared to those with wildtype ABL1 (IC50 of 1385nM vs. 823 nM), indicating resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L248R sequence variation in gene ABL1/NCBI:25 674 check_entity AN4616-1 ABL1 L248R mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4875 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L248R sequence variation in gene ABL1/NCBI:25 674 check_entity AN4616-1 ABL1 L248R mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4876 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L248R sequence variation in gene ABL1/NCBI:25 674 check_entity AN4617-1 ABL1 L248V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19075254 A panel of 18 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The L248V mutation was moderately resistant to imatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L248V sequence variation in gene ABL1/NCBI:25 675 check_entity AN4617-1 ABL1 L248V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:12623848 In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. A late-chronic phase (CP) patient had a complete hematologic response but acquired resistance after 7 months of therapy and discontinued imatinib 3 months later. At month 11, the L248V, G250E, S417Y, E459K variants were present in approximately 25, 25, 25, and 50% of transcripts, respectively. The patient died in myeloid blast crisis at month 14 after a bone marrow transplant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L248V sequence variation in gene ABL1/NCBI:25 675 check_entity AN4617-1 ABL1 L248V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, a Ba/F3-p210BCR-ABL1 cell line was ENU-mutated and exposed to graded concentrations of imatinib, nilotinib or dasatinib to identify resistance mutations. The L248V mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance to 2 μM imatinib (3 clones recovered, ~2% of viable clones in this treatment), 50nM nilotinib (1 clone, ~2%), and 5nM dasatinib (3 clones, ~9%). In a review of 20 publications, this mutation was described in imatinib resistant patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L248V sequence variation in gene ABL1/NCBI:25 675 check_entity AN4617-1 ABL1 L248V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with L248V evaluated, 3/3 had complete hematologic responses and 2/3 had major cytogenetic responses. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L248V sequence variation in gene ABL1/NCBI:25 675 check_entity AN4617-1 ABL1 L248V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed decreased incorporation when harboring fusions with the L248V variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 1393nM vs. 823 nM), indicating resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L248V sequence variation in gene ABL1/NCBI:25 675 check_entity AN4617-1 ABL1 L248V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19779040 This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 15 patients with L248V mutations, 6, 10, and 15 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L248V sequence variation in gene ABL1/NCBI:25 675 check_entity AN4617-1 ABL1 L248V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:17264298 In this phase II multinational study, 60 imatinib-resistantpatients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with L248V, 3/3 had MaHRs and 1/3 had MCyRs which were comparable to response rates among wild type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L248V sequence variation in gene ABL1/NCBI:25 675 check_entity AN4617-1 ABL1 L248V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4714 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L248V sequence variation in gene ABL1/NCBI:25 675 check_entity AN4618-1 ABL1 L298V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with L298V evaluated, 1/1 had a complete hematologic response and 0/1 had a major cytogenetic response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L298V sequence variation in gene ABL1/NCBI:25 676 check_entity AN4618-1 ABL1 L298V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:1414 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L298V sequence variation in gene ABL1/NCBI:25 676 check_entity AN4619-1 ABL1 L364I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16775234 Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with the L364I secondary variant in 9/12 bacterial clones generated using peripheral blood RNA. They had complete best hematologic and no cytogenetic responses to dasatinib which were comparable to responses in patients with unmutated BCR-ABL1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L364I sequence variation in gene ABL1/NCBI:25 677 check_entity AN4619-1 ABL1 L364I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4877 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L364I sequence variation in gene ABL1/NCBI:25 677 check_entity AN4619-1 ABL1 L364I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4888 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L364I sequence variation in gene ABL1/NCBI:25 677 check_entity AN4620-1 ABL1 L364P mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with L364P evaluated, 1/1 had a major cytogenetic response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L364P sequence variation in gene ABL1/NCBI:25 678 check_entity AN4620-1 ABL1 L364P mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4884 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L364P sequence variation in gene ABL1/NCBI:25 678 check_entity AN4621-1 ABL1 L384M mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, a Ba/F3-p210BCR-ABL1 cell line was ENU-mutated and exposed to graded concentrations of imatinib, nilotinib or dasatinib to identify resistance mutations. The L384M mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance in 50nM nilotinib (1 clone recovered, ~2% of viable clones in this treatment) and 2 μM imatinib (1 clone, ~0.7%). L384M was one of 3 novel mutations that were not identified in imatinib resistant patients from a review of 20 publications. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L384M sequence variation in gene ABL1/NCBI:25 679 check_entity AN4621-1 ABL1 L384M mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed similar incorporation when harboring fusions with the L384M variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 916nM vs. 823 nM), indicating baseline sensitivity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L384M sequence variation in gene ABL1/NCBI:25 679 check_entity AN4621-1 ABL1 L384M mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19779040 This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, a majority of patients with and without ABL1 mutation had comparable complete hematologic response, major cytogenetic response, complete cytogenetic response (CCyR), and major molecular response. However, out of 2 patients with the L384M mutation, 0 achieved CCyR with dasatinib monotherapy. Analyses by variant included patients with multiple kinase domain mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L384M sequence variation in gene ABL1/NCBI:25 679 check_entity AN4621-1 ABL1 L384M mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4885 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L384M sequence variation in gene ABL1/NCBI:25 679 check_entity AN4622-1 ABL1 L387F mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, a Ba/F3-p210BCR-ABL1 cell line was ENU-mutated and exposed to graded concentrations of imatinib, nilotinib or dasatinib. The L387F mutation in the ABL1 portion of the BCR-ABL1 fusion protein was identified and associated with resistance to nilotinib treatment (1 clone recovered at 50nM). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L387F sequence variation in gene ABL1/NCBI:25 680 check_entity AN4622-1 ABL1 L387F mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:22371878 This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with L387F, 1/1 had a CHR and 0/1 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L387F sequence variation in gene ABL1/NCBI:25 680 check_entity AN4622-1 ABL1 L387F mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4886 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L387F sequence variation in gene ABL1/NCBI:25 680 check_entity AN4623-1 ABL1 L387M mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19779040 This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 5 patients with L387M mutations, 4, 4, and 5 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L387M sequence variation in gene ABL1/NCBI:25 681 check_entity AN4623-1 ABL1 L387M mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16775234 Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with L387M, L387M/F192L, and E450G variants in 7/10, 2/10, and 1/10 clones, respectively. Clones were generated using peripheral blood RNA. The patient had minimal best cytogenetic and complete best hematologic responses to dasatinib which were comparable to responses in patients with unmutated BCR-ABL1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L387M sequence variation in gene ABL1/NCBI:25 681 check_entity AN4623-1 ABL1 L387M mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4887 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L387M sequence variation in gene ABL1/NCBI:25 681 check_entity AN4624-1 ABL1 LSM14A::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic;prognostic 55135-8 PubMed:28408464 This retrospective study included 1389 cases of high-risk pediatric B-ALL, of which 284 were identified by TaqMan Low Density Array to have a BCR-ABL1-like (Ph-like) gene expression signature. RT-PCR or RNAseq performed on Ph-like, CRLF2 negative patients revealed 17 cases with ABL1 fusions with 8 different partner genes. There was one case of the LSM14A-ABL1 fusion. Considering the previously confirmed Ph-like expression signature in the tested cases, the results suggest that the presence of the LSM14A-ABL1 fusion in B-ALL indicates the BCR-ABL1-like (Ph-like) subtype of the disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::LSM14A::ABL1 sequence variation in gene ABL1/NCBI:25 682 check_entity AN4624-1 ABL1 LSM14A::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic;prognostic 55135-8 PubMed:31434701 This retrospective study reported the outcome of 24 patients with Ph-like acute lymphoblastic leukemia (Ph-like ALL) harboring ABL-class fusions who were treated with a combination of tyrosine kinase inhibitors (TKIs) and chemotherapy. Of the 24 patients reported, 12 had fusions involving ABL1 including 1 case with LSM14A-ABL1. The patient with LSM14A-ABL1 was a 36 year old male who also had a IKZF1 intragenic deletion. He had a poor prednisone response and did not reach complete remission after vincristine-dexamethasone-rituximab or a combination of dasatinib and chemotherapy, although some of the patients in this case series appeared to benefit from the introduction of TKIs. The patient died early of sepsis in a context of uncontrolled disease (survival 2 months). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::LSM14A::ABL1 sequence variation in gene ABL1/NCBI:25 682 check_entity AN4624-1 ABL1 LSM14A::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic;prognostic 55135-8 CIViC:3141 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::LSM14A::ABL1 sequence variation in gene ABL1/NCBI:25 682 check_entity AN4625-1 ABL1 M244V mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 PubMed:15930265 A panel of 16 mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and evaluated for antiproliferative activity and substrate or auto-phosphorylation assays. The authors considered the M244V mutation sensitive to imatinib (IC50: 2000 vs. 260 nmol/L, 8x fold change, in a proliferative assay compared to Ba/F3 cells with unmutated BCR-ABL fusions). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M244V sequence variation in gene ABL1/NCBI:25 683 check_entity AN4625-1 ABL1 M244V mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 PubMed:18191450 In an in vitro study, a Ba/F3 cell line stably expressing the M244V mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with similar sensitivity to dasatinib and nilotinib treatment (IC50: 93.1 nM and 891.4 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 87.6 nM and 642.3 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M244V sequence variation in gene ABL1/NCBI:25 683 check_entity AN4625-1 ABL1 M244V mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 CIViC:4662 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M244V sequence variation in gene ABL1/NCBI:25 683 check_entity AN4625-2 ABL1 M244V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:12623848 In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. A late-chronic phase patient had only a partial hematologic response which improved to a major cytogenetic response after dose escalation 18 months after therapy initiation. At months 7 and 8, the M244V was present in 100% of transcripts. No further testing for secondary variants was performed. At 18 months, 25% of cells were Ph-positive, but this did not meet the authors' threshold for loss of MCR which is >65% Ph-positive cells or an increase of 30%. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M244V sequence variation in gene ABL1/NCBI:25 684 check_entity AN4625-2 ABL1 M244V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19779040 This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 46 patients with M244V mutations, 20, 27, and 45 achieved a CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M244V sequence variation in gene ABL1/NCBI:25 684 check_entity AN4625-2 ABL1 M244V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:17264298 In this phase II multinational study, 60 imatinib-resistant patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with M244V, 4/5 had MaHRs which was higher than response rates among wild type patients, and 2/5 had MCyRs which was comparable to response rates among wild type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M244V sequence variation in gene ABL1/NCBI:25 684 check_entity AN4625-2 ABL1 M244V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16775234 Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with the M244V secondary variant in 12/12 bacterial clones generated using peripheral blood RNA. They had complete best hematologic and no cytogenetic responses to dasatinib which were comparable to responses in patients with unmutated BCR-ABL1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M244V sequence variation in gene ABL1/NCBI:25 684 check_entity AN4625-2 ABL1 M244V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with M244V evaluated, 2/2 had complete hematologic responses and 2/3 had major cytogenetic responses. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M244V sequence variation in gene ABL1/NCBI:25 684 check_entity AN4625-2 ABL1 M244V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:22371878 This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with M244V evaluated, 3/3 had CHR and 2/3 had MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M244V sequence variation in gene ABL1/NCBI:25 684 check_entity AN4625-2 ABL1 M244V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The M244V mutation was associated with resistance in 2 μM imatinib (1 clone recovered, 0.71%). In a review of 20 publications, this mutation was described in imatinib resistant patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M244V sequence variation in gene ABL1/NCBI:25 684 check_entity AN4625-2 ABL1 M244V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed similar incorporation when harboring fusions with the M244V variant of ABL1 compared to those with wildtype ABL1 (IC50 of 690nM vs. 823 nM), indicating that the M244V variant does not induce resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M244V sequence variation in gene ABL1/NCBI:25 684 check_entity AN4625-2 ABL1 M244V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4662 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M244V sequence variation in gene ABL1/NCBI:25 684 check_entity AN4625-2 ABL1 M244V mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4888 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M244V sequence variation in gene ABL1/NCBI:25 684 check_entity AN4626-1 ABL1 M343T mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed increased incorporation when harboring fusions with the M343T variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 1175nM vs. 823 nM), indicating resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M343T sequence variation in gene ABL1/NCBI:25 685 check_entity AN4626-1 ABL1 M343T mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4889 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M343T sequence variation in gene ABL1/NCBI:25 685 check_entity AN4627-1 ABL1 M351T mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 PubMed:18191450 In an in vitro study, a Ba/F3 cell line stably expressing the M351T mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with similar sensitivity to nilotinib, dasatinib, and bafetinib treatment (IC50: 580.4 nM, 88 nM, 582.9 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 642.3 nM, 87.6 nM, 152.9 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M351T sequence variation in gene ABL1/NCBI:25 686 check_entity AN4627-1 ABL1 M351T mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 CIViC:4556 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M351T sequence variation in gene ABL1/NCBI:25 686 check_entity AN4627-2 ABL1 M351T mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19075254 A panel of 18 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The M351T mutation was sensitive to imatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M351T sequence variation in gene ABL1/NCBI:25 687 check_entity AN4627-2 ABL1 M351T mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:12623848 In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. Three CP patients, with the M351T variants detected prior to resistance, had hematologic responses prior to progression. One patient became resistant after the appearance of the M351T variant but responded to dose escalation. The last patient, who also had the Q252H variant, progressed to myeloid blast crisis (MBC) after which there was cytogenetic evidence of a double Ph-chromosome and no detectable secondary variants. Three accelerated-phase (AP) patients returned to CP and had M351T variants. One of these patients also had E255K and F359V variants and progressed to AP. The remaining two, one of whom also had H396R variant, progressed to MBC and died. Two additional AP patients also had M351T variants but initially had CHRs. One who also had the G250E variant died from disease progression. The other also had the F359V variant progressed to MBC with cytogenetic evidence of the double Ph-chromosome and no detectable secondary variants at progression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M351T sequence variation in gene ABL1/NCBI:25 687 check_entity AN4627-2 ABL1 M351T mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:15930265 In two cell-based studies, a panel of either 18 or 16 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The M351T mutation was sensitive to imatinib . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M351T sequence variation in gene ABL1/NCBI:25 687 check_entity AN4627-2 ABL1 M351T mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:22371878 This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with M351T, 1/1 had a CHR and 0/1 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M351T sequence variation in gene ABL1/NCBI:25 687 check_entity AN4627-2 ABL1 M351T mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19779040 This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 54 patients with M351T mutations, 25, 28, and 51 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M351T sequence variation in gene ABL1/NCBI:25 687 check_entity AN4627-2 ABL1 M351T mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:17264298 In this phase II multinational study, patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. Response rate among 60 imatinib-resistant patients with BCR-ABL mutations did not differ from the rate of the total population of 100 imatinib-resistant or -intolerant patients. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with M351T, 3/6 had MaHRs which was comparable to response rates among wild type patients, and 1/6 had MCyRs which was lower than response rates among wild type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M351T sequence variation in gene ABL1/NCBI:25 687 check_entity AN4627-2 ABL1 M351T mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16775234 Prior to dasatinib treatment, four imatinib-resistant patients with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with the M351T and M351S; M351T; M351T; and M351T secondary variants in 8/9 and 1/9; 4/10; 10/10; and 11/11 bacterial clones, respectively. Clones were generated using peripheral blood RNA. They had complete response as best hematologic response and complete (n = 3) or partial (n = 1) responses as best cytogenetic response to dasatinib. An additional patient, in myeloid blast crisis, had the M351T variant in 10/10 clones with complete response as best hematologic response and complete response as best cytogenetic response to dasatinib. An additional patient in accelerated phase had the M351T and M351A variants in 6/10 and 1/10 clones, respectively, with complete response as best hematologic response and none as best cytogenetic response to dasatinib. Overall, responses among these patients were comparable to those among patients with unmutated BCR-ABL1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M351T sequence variation in gene ABL1/NCBI:25 687 check_entity AN4627-2 ABL1 M351T mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The M351T mutation was associated with resistance in 2 μM imatinib (1 clone recovered, ~0.71%). In a review of 20 publications, this mutation was previously described in imatinib resistant patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M351T sequence variation in gene ABL1/NCBI:25 687 check_entity AN4627-2 ABL1 M351T mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed decreased incorporation when harboring fusions with the M351T variant of ABL1 compared to those with wildtype ABL1 (IC50 of 553nM vs. 823 nM), indicating the M351T variant induces sensitivity compared to BCR-ABL1 without secondary variants. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M351T sequence variation in gene ABL1/NCBI:25 687 check_entity AN4627-2 ABL1 M351T mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4556 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M351T sequence variation in gene ABL1/NCBI:25 687 check_entity AN4628-1 ABL1 M388L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16775234 Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with Y253H, M388L, and M388L/M244V variants in 4/10, 5/10, and 1/10 clones, respectively. Clones were generated using peripheral blood RNA. The patient had no response as best cytogenetic response and complete response as best hematologic response to dasatinib which were comparable to responses in patients with unmutated BCR-ABL1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M388L sequence variation in gene ABL1/NCBI:25 688 check_entity AN4628-1 ABL1 M388L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4890 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M388L sequence variation in gene ABL1/NCBI:25 688 check_entity AN4629-1 ABL1 N146S mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16775234 Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in accelerated phase had the BCR-ABL1 fusion with G250E/E138G/I242T/K271R/V338M, G250E/E138G/I242T/K271R, G250E/I242T/K271R/V338M/N146S, and N146S variants in 3/12, 1/12, 1/12, and 7/12 clones, respectively. Clones were generated using peripheral blood RNA. The patient had no response as best cytogenetic response and complete response as best hematologic response to dasatinib which were comparable to responses in patients with unmutated BCR-ABL1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N146S sequence variation in gene ABL1/NCBI:25 689 check_entity AN4629-1 ABL1 N146S mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4891 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N146S sequence variation in gene ABL1/NCBI:25 689 check_entity AN4630-1 ABL1 NUP153::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 55135-8 PubMed:28408464 This study included 1389 cases of high-risk pediatric B-ALL, of which 284 were identified by TaqMan Low Density Array to have a BCR-ABL1-like (Ph-like) gene expression signature. RT-PCR or RNAseq performed on Ph-like, CRLF2 negative patients revealed 17 cases with ABL1 fusions with 8 different partner genes. There was one case of the NUP153-ABL1 fusion. Considering the previously confirmed Ph-like expression signature in the tested cases, the results suggest that the presence of the NUP153-ABL1 fusion in B-ALL indicates the BCR-ABL1-like (Ph-like) subtype of the disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::NUP153::ABL1 sequence variation in gene ABL1/NCBI:25 690 check_entity AN4630-1 ABL1 NUP153::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 55135-8 CIViC:3140 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::NUP153::ABL1 sequence variation in gene ABL1/NCBI:25 690 check_entity AN4631-1 ABL1 NUP214::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk 55135-8 PubMed:23175662 A 22-year-old male with B-cell acute lymphoblastic leukemia was treated with induction therapy. FISH using a BCR-ABL1 probe demonstrated 50-80 extrachromosomal copies of ABL1; FISH using probes to the 3' regions of ABL1 and NUP214 confirmed NUP214-ABL1 amplification in ~99% of cells. The NUP214-ABL1 amplification was also confirmed by MLPA and SNP6.0 analysis. Additionally, this patient harbored a focal deletion of IKZF1 (exons 2-7) and CDKN2A/B (exons 1-2). Day 29 marrow showed complete morphological remission; however PCR-based IgVH MRD rearrangement studies revealed clonal IgVH rearrangement (1 in 10^4 cells). Patient underwent sibling donor allogenic stem cell transplant, and at 4 months is in complete remission. NUP214-ABL1 positive patient primary cells were cultured with various tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib, and ponatinib). After 72-hour culture there was no significant reduction in viable cell numbers or increase in apoptosis, when compared to the no drug control. The in vitro sensitivity to TKIs may be attributed to variable NUP214-ABL1 copy number and/or focal deletions of IKZF1 and CDKN2A/B. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::NUP214::ABL1 sequence variation in gene ABL1/NCBI:25 691 check_entity AN4631-1 ABL1 NUP214::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk 55135-8 CIViC:2529 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::NUP214::ABL1 sequence variation in gene ABL1/NCBI:25 691 check_entity AN4631-2 ABL1 NUP214::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic;prognostic;risk 55135-8 PubMed:26681761 A 15-year-old girl with B-cell precursor ALL was placed into the very high risk group after showing corticoid resistance on treatment day 8, and induction failure on day 35 (MRD >0.01). The patient received a successful bone marrow transplant and at day 100 showed a complete remission (CR). The patient relapsed 6 months later, and second line therapy was unsuccessful. During this relapse, SNP microarray was performed on the diagnostic sample and identified amplification of 9q34 flanked by the NUP214 and ABL1 genes. Follow-up molecular studies confirmed a NUP214-ABL1 fusion gene. The patient was then started on dasatinib in combination with vincristine and dexamethasone. The patient achieved a second CR, and continued on dasatinib until her disease relapsed 2 months later. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::NUP214::ABL1 sequence variation in gene ABL1/NCBI:25 692 check_entity AN4631-2 ABL1 NUP214::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic;prognostic;risk 55135-8 PubMed:22897847 Transcriptome and whole genome sequencing were performed on 15 cases of B-lymphoblastic leukemia/lymphoma (B-ALL) that were previously shown to have a BCR-ABL1-like (Ph-like) expression signature. Two cases were positive for the NUP214-ABL1 fusion, identified by RNA-seq analysis. In both cases the fusion was generated by a small copy number gain (duplication) in 9q34, with the breakpoints in the two partner genes. Considering the previously shown Ph-like expression signature in the studied cases, the results suggest association of the NUP214-ABL1 fusion in B-ALL with the Ph-like genetic subtype of the disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::NUP214::ABL1 sequence variation in gene ABL1/NCBI:25 692 check_entity AN4631-2 ABL1 NUP214::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic;prognostic;risk 55135-8 PubMed:33357483 A multicenter, retrospective, cohort study that included 122 pediatric patients (aged 1-18 years) with newly diagnosed ABL-class fusion B-cell acute lymphocytic leukemia who had not received tyrosine-kinase inhibitor treatment as a first-line therapy. ABL-class genes included ABL1, ABL2, CSF1R and PDGFRB. There were 33% of patients (40/122) that harbored an ABL1 fusion, including 7 with a NUP214-ABL1 fusion. For patients that were ABL1 fusion positive the 5-year event-free survival was 68.6% (54.5-86.3), the 5-year overall survival was 82.9% (71.2-96.4) and the 5-year cumulative incidence of relapse was 29.6% (15.0-45.9). Additionally ABL1 fusion positive patients had the lowest levels of MRD at the end of induction therapy (20/29 evaluable patients had less than 10^-2). Of patients with NUP214-ABL1, 4/7 had MRD <10^-2 at the end of induction. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::NUP214::ABL1 sequence variation in gene ABL1/NCBI:25 692 check_entity AN4631-2 ABL1 NUP214::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic;prognostic;risk 55135-8 CIViC:2529 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::NUP214::ABL1 sequence variation in gene ABL1/NCBI:25 692 check_entity AN4632-1 ABL1 Non-P-Loop Mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Among 115 patients with mutational analysis at baseline, subsets were evaluated for complete hematologic response (CHR) and major cytogenetic response (MCyR). Both were comparable for patients with non-P-loop mutations versus patient without Abl1 mutations [ CHR = 22/23 (96%) vs. 27/27; MCyR = 26/39 (67%) vs. 19/35 (54%)]. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::non-p-loop:mutation sequence variation in gene ABL1/NCBI:25 693 check_entity AN4632-1 ABL1 Non-P-Loop Mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:22371878 This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Among 39 patients with mutational analysis at baseline, subsets were evaluated for complete hematologic response (CHR) and major cytogenetic response (MCyR). Both were comparable for patients with non-P-loop mutations versus patient without Abl1 mutations [ CHR = 18/29 (62%) vs. 34/44 (77%); MCyR = 9/26 (35%) vs. 15/43 (35%)]. The authors observe responses with bosutanib monotherapy across many BCR-ABL mutations with the notable exception of T315I. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::non-p-loop:mutation sequence variation in gene ABL1/NCBI:25 693 check_entity AN4632-1 ABL1 Non-P-Loop Mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:2249 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::non-p-loop:mutation sequence variation in gene ABL1/NCBI:25 693 check_entity AN4633-1 ABL1 P-Loop Mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Among 115 patients with mutational analysis at baseline, subsets were evaluated for complete hematologic response (CHR) and major cytogenetic response (MCyR). Both were comparable for patients with P-loop mutations versus patients without Abl1 mutations [ CHR = 9/9 vs. 27/27; MCyR = 7/10 vs. 19/35 (54%)]. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::p-loop:mutation sequence variation in gene ABL1/NCBI:25 694 check_entity AN4633-1 ABL1 P-Loop Mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:22371878 This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Among 39 patients with mutational analysis at baseline, subsets were evaluated for complete hematologic response (CHR) and major cytogenetic response (MCyR). Both were comparable for patients with P-loop mutations versus patients without Abl1 mutations [ CHR = 9/14 (64%) vs. 34/44 (77%); MCyR = 4/13 (31%) vs. 15/43 (35%)]. The authors observe responses with bosutanib monotherapy across many BCR-ABL mutations with the notable exception of T315I. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::p-loop:mutation sequence variation in gene ABL1/NCBI:25 694 check_entity AN4633-1 ABL1 P-Loop Mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:12623848 In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. Of 14 patients who started the study in late chronic phase and had p-loop or non-p-loop mutations, 6/6 with p-loop mutations died compared to no deaths during the course of the study for those with non-p-loop mutations (P=0.0013). 14 patients who started the study in accelerated phase and had p-loop or non-p-loop mutations, 6/7 with p-loop mutations died and 3/6 with non-p-loop mutations died (P=0.14). Overall, this data suggests p-loop mutations that arise during late-chronic phase support resistance to imatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::p-loop:mutation sequence variation in gene ABL1/NCBI:25 694 check_entity AN4633-1 ABL1 P-Loop Mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:2248 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::p-loop:mutation sequence variation in gene ABL1/NCBI:25 694 check_entity AN4634-1 ABL1 Q252H mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 PubMed:18191450 In an in vitro study, a Ba/F3 cell line stably expressing the Q252H mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with similar sensitivity to dasatinib and nilotinib treatment (IC50: 62.3 nM and 895.5 nM) as compared to wild-type expressing Ba/F3 cells (IC50: 87.6 nM and 642.3 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q252H sequence variation in gene ABL1/NCBI:25 695 check_entity AN4634-1 ABL1 Q252H mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 CIViC:4719 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q252H sequence variation in gene ABL1/NCBI:25 695 check_entity AN4634-2 ABL1 Q252H mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19075254 A panel of 18 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The Q252H mutation was sensitive to imatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q252H sequence variation in gene ABL1/NCBI:25 696 check_entity AN4634-2 ABL1 Q252H mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:12623848 In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. A chronic-phase (CP) patient achieved a complete hematologic response (CHR). The Q252H variant was detected but was absent when the patient progressed to myeloid blast crisis (MBC) with a double Philadelphia chromosome and died. A second CP patient had a partial hematologic response (PHR) with the Q252H and M351T variants. They progressed to MBC and the double Ph-chromosome was later detected without any secondary variants prior to death. The third CP patient had a PHR but became resistant. The Q252H variant was later detected and the patient died in MBC. An accelerated-phase (AP) patient had a CHR but progressed to MBC with the appearance of the Q252H variant. The patient died in MBC after a bone marrow transplant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q252H sequence variation in gene ABL1/NCBI:25 696 check_entity AN4634-2 ABL1 Q252H mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed increased incorporation when harboring fusions with the Q252H variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 1155nM vs. 823 nM), indicating resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q252H sequence variation in gene ABL1/NCBI:25 696 check_entity AN4634-2 ABL1 Q252H mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19779040 This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Of 6 patients with Q252H mutations, 1, 1, and 3 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. The authors identify Q252H as one of 4 variants with a low CCyR but advise caution when interpreting these results due to low sample size. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q252H sequence variation in gene ABL1/NCBI:25 696 check_entity AN4634-2 ABL1 Q252H mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:15705718 In an in vitro study, stochastic mutations in the ABL1 region of a stably expressed p210 BCR-ABL fusion were generated in Ba/F3 cell lines from five independently derived, mutagenized libraries. Dasatinib resistant subclones were identified using 50 nM dasatinib in liquid culture. 201 individual clones were identified representing 10 different mutations at 6 different residues. 1 of these clones had an Q252H mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q252H sequence variation in gene ABL1/NCBI:25 696 check_entity AN4634-2 ABL1 Q252H mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The Q252H mutation was associated with resistance to 4 μM and 16 μM imatinib (4 clones [~3%] and 1 clone [~3%] recovered, respectively) as well as 10 nM dasatinib (1 clone [~2%]). No clones recovered at 2 μM/8 μM imatinib or 5 nM dasatinib. In a review of 20 publications, this mutation was previously described in imatinib resistant patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q252H sequence variation in gene ABL1/NCBI:25 696 check_entity AN4634-2 ABL1 Q252H mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4719 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q252H sequence variation in gene ABL1/NCBI:25 696 check_entity AN4635-1 ABL1 R351W mutation ABL1 NCBI:25 gene lung non-small cell carcinoma DOID:3908 risk 55135-8 PubMed:26758680 In this in vitro study, the H1915 non-small cell lung cancer cell line (homozygous for a R351W mutation) was shown to be susceptible to dasatinib. This line showed a significant reduction in colony formation (P < 0.001) and MTT assay, which tests for NADH activity (P = 1.09 x 10^5), with dasatinib vs vehicle treatment. There was no significant difference in a lung cancer cell line without a known driver (H2126) nor in an immortalized bronchial epithelial line (Beas-2B) with either drug treatment in colony forming and MTT assays. Additionally, reduction in cell viability upon kinase inhibitor treatment could be rescued with tetracycline-induced overexpression of resistant ABL1-T315I (P < 0.001) confirming the genetic dependency of this cell line on ABL1. Moreover, a significant increased in cytotoxicity was noted with siRNA facilitated depletion of ABL1 (P < 0.005) with no significant change in H2126 or Beas-2B lines supporting ABL1 as the primary drug target. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R351W sequence variation in gene ABL1/NCBI:25 697 check_entity AN4635-1 ABL1 R351W mutation ABL1 NCBI:25 gene lung non-small cell carcinoma DOID:3908 risk 55135-8 CIViC:1564 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R351W sequence variation in gene ABL1/NCBI:25 697 check_entity AN4636-1 ABL1 RANBP2::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic;risk 55135-8 PubMed:28408464 This study included 1389 cases of high-risk pediatric B-ALL, of which 284 were identified by TaqMan Low Density Array to have a Ph-like gene expression signature. RT-PCR or RNAseq performed on Ph-like, CRLF2 negative patients revealed 17 cases with ABL1 fusions with 8 different partner genes. There were three cases with the RANBP2-ABL1 fusion. Considering the previously confirmed Ph-like expression signature in the tested cases, the results suggest that the presence of the RANBP2-ABL1 fusion in B-ALL indicates the BCR-ABL1-like (Ph-like) subtype of the disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RANBP2::ABL1 sequence variation in gene ABL1/NCBI:25 698 check_entity AN4636-1 ABL1 RANBP2::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic;risk 55135-8 PubMed:31434701 This retrospective study reported the outcome of 24 patients with Ph-like acute lymphoblastic leukemia (Ph-like ALL) harboring ABL-class fusions, who were treated with a combination of tyrosine kinase inhibitors (TKIs) and chemotherapy. Of the 24 patients reported, 12 had fusions involving ABL1; in 7/12 patients the ABL1 fusion was detected at diagnosis, and in 5/12 it was identified at relapse. One relapse patient was found to have a RANBP2-ABL1 fusion. This patient was a 20 year old female. An IKZF1 intragenic deletion was detected in her leukemia in addition to the RANBP2-ABL1 fusion. She had good initial prednisone response and reached complete remission (CR) after treatment on the GRAALL2005R trial. However, she relapsed with refractory disease. The RANBP2-ABL1 fusion was detected at relapse, and dasatinib (140 mg daily) was added to chemotherapy; this resulted in a brief response even though her leukemia was previously refractory to several lines of salvage treatment (best MRD level 8x10-3). However, the patient experienced another relapse and died of progressive disease. The case illustrates partial response to TKIs in combination with chemotherapy in a relapsed Ph-like B-ALL with RANBP2-ABL1 fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RANBP2::ABL1 sequence variation in gene ABL1/NCBI:25 698 check_entity AN4636-1 ABL1 RANBP2::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic;risk 55135-8 CIViC:3137 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RANBP2::ABL1 sequence variation in gene ABL1/NCBI:25 698 check_entity AN4637-1 ABL1 RCSD1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 diagnostic;risk 55135-8 PubMed:27125982 This case report describes a 15 year old patient with relapsed B-ALL positive for the RCSD1-ABL1 fusion, who was successfully treated with chemotherapy with addition of imatinib; the patient remained disease free for 36 months. This case supports sensitivity of B-ALL with RCSD1-ABL1 fusions to ABL-type tyrosine kinase inhibitors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RCSD1::ABL1 sequence variation in gene ABL1/NCBI:25 699 check_entity AN4637-1 ABL1 RCSD1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 diagnostic;risk 55135-8 PubMed:17541395 De Braekeleer et al. reported a 11-yr-old boy with pre-B ALL associated with a t(1;9)(q24;q34) translocation. FISH analysis using bacterial artificial chromosome (BAC) clones showed colocalization of BACs containing the ABL1 and RCSD1 genes, probably indicating the presence of a RCSD1-ABL1 fusion gene. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RCSD1::ABL1 sequence variation in gene ABL1/NCBI:25 699 check_entity AN4637-1 ABL1 RCSD1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 diagnostic;risk 55135-8 PubMed:19794096 Authors reported a 40-yr-old male patient with pre-B ALL and t(1;9)(q24;q34) translocation. Two different RCSD1-ABL1 fusion transcripts, presumably resulting from alternative splicing, were identified, one consisting of the first three exons of RCSD1 fused to ABL1 starting from exon 4, the second of the first two exons of RCSD1 fused to exon 4 of ABL1. The patient received a modified CVAD induction therapy. After 2 induction courses, the BM had residual disease with 50% of leukemic blasts. At day 10 from the start of the 3rd induction regimen, dasatinib was introduced at a dose of 140 mg once daily. Two weeks later morphological remission was confirmed, and only minimal residual disease (1.5% of leukemic cells) was detectable by FISH. The first consolidation therapy consisted of dasatinib 140 mg once daily and high-dose methotrexate. BM at four weeks post consolidation showed complete morphological and cytogenetic remission (CCyR). Dasatinib was continued until an allogeneic hematopoietic stem cell transplantation (HSCT) was performed four months after diagnosis. After transplantation, no TKI therapy was used. At 12 months from HSCT, the patient experienced a cytogenetic relapse and a month later a hematologic relapse. Immunosuppressive drugs were discontinued, and the patient received a re-induction therapy with dasatinib 70 mg twice daily combined with one cycle of high-dose chemotherapy. The patient successfully reentered in CCyR, which has been maintained with dasatinib monotherapy for more than nine months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RCSD1::ABL1 sequence variation in gene ABL1/NCBI:25 699 check_entity AN4637-1 ABL1 RCSD1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 diagnostic;risk 55135-8 PubMed:26600955 Authors reported a 15-year-old female patient with B-ALL diagnosed in June 2014. Conventional cytogenetics and FISH identified t(1;9)(q23;q34) and RCSD1ABL1 fusion. Microarray identified an approximately 70 kb deletion at 7p12.2 disrupting the IKZF1 gene. The patient was enrolled on AALL-1131 and received a 4-drug induction therapy with Vincristine/Daunorubicin/Pegaspargase/Prednisone. Her day 8 peripheral blood minimal residual disease (MRD) testing showed 18–25% blasts and her day 29 bone marrow evaluation revealed induction failure. She continued chemotherapy per the very high-risk control arm of AALL-1131 with the addition of dasatinib due to the RCSD1-ABL1 fusion. Her consolidation course was complicated due to presumed fungal infection and C. difficile colitis, but she was able to complete the consolidation treatment. The last bone marrow done on November 2014 showed no evidence of persistent/recurrent leukemia. The patient had a bone marrow transplant from a sibling in November 2014, but a few weeks after transplant she developed severe sepsis as well as capillary leak syndrome. She remained admitted to the intensive care unit where she unfortunately died on March 12, 2015. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RCSD1::ABL1 sequence variation in gene ABL1/NCBI:25 699 check_entity AN4637-1 ABL1 RCSD1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 diagnostic;risk 55135-8 PubMed:21863287 Author reported a 31-year-old male patient diagnosed with B-ALL. RT-PCR and sequence analyses detected transcription of a single RCSD1-ABL1 fusion gene variant, which had breakpoints in exon 3 of RCSD1 and exon 4 of ABL1. The patient was treated with hyper-CVAD combination without achieving complete remission (CR). Therefore, the patient was treated with combination chemotherapy comprising 800 mg of imatinib for 7 days and 40 mg of dexamethasone for 4 days followed by 140 mg of dasatinib daily. On day 74, lymphoblasts disappeared from the peripheral blood, but 15% remained in the bone marrow. A second course of hyper-CVAD with 140 mg of dasatinib daily was administered. Twenty days after therapy using 1.5 g of methotrexate and cytarabine (total dose; 18 g), lymphoblasts suddenly increased by 82%. Administration of 40 mg of dexamethasone for 4 days was highly effective in reducing lymphoblast count. Administration of triplicated dexamethasone and dasatinib achieved stable disease with partial remission in the bone marrow. However, during the seventh administration of dexamethasone, the disease recurred and there was no further response to treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RCSD1::ABL1 sequence variation in gene ABL1/NCBI:25 699 check_entity AN4637-1 ABL1 RCSD1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 diagnostic;risk 55135-8 PubMed:23168614 Authors studied five patients with B-ALL and potential RCSD1-ABL1 fusion. Patients’ age ranged from 11 to 40 years. Patient 1 was previously reported in PMID 17541395. Sequencing showed that the first three exons of RCSD1 were fused to exons 4– 11 of ABL1 in all five patients. Gene expression signature of patient 1 and 3 was distinct from that of ALL patients with BCR–ABL1 gene. Several genes overexpressed in the RCSD1–ABL1 group compared with the BCR–ABL1 group code transcription factors such as AFF1 and PBX4. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RCSD1::ABL1 sequence variation in gene ABL1/NCBI:25 699 check_entity AN4637-1 ABL1 RCSD1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 diagnostic;risk 55135-8 PubMed:28057740 Authors reported a 61-year old female diagnosed with B-ALL in August 2012. The RCSD1-ABL1 t(1;9)(q22;q34) fusion between exon 3 of RCSD1 and exon 4 of ABL1 was identified by RT-PCR. The patient was enrolled on GMALL elderly (01/2003) and treated accordingly with an induction failure. She therefore continued chemotherapy with high-dose methotrexate and asparaginase. Her disease achieved first complete remission in January 2013, and high-dose cytarabine was administered. The patient experienced a BM relapse in April 2013. Re-induction chemotherapy with one cycle of FLAG-Ida comprising fludarabine, cytarabine, GCSF and idarubicin was administered, but BM revealed residual disease with 70% of leukemic blasts in May 2013. The patient was included in the BEZ235 study and treated with an oral PI3K/mTOR inhibitor, but no remission could be achieved. Salvage therapy with single agent dasatinib was initiated at a dose of 100 mg once daily, in July 2013. A stable disease with partial remission in the BM was achieved. Moreover, inhibition of RCSD1-ABL1 activity by dasatinib was shown by Western analysis of phosphorylated ABL1 and its downstream target CRKL. Treatment with dasatinib was complemented with two cycles of chemotherapy, including clofarabine and cyclophosphamide. CR 2 was achieved in October 2013, whereas minimal residual disease (MRD) levels still remained positive. In this regard, treatment with blinatumomab was started within the MT103-203 study in January 2014, and MRD levels became negative. In March 2014, allo-SCT was performed successfully. Since then, there is an ongoing remission that, to date, has lasted 30 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RCSD1::ABL1 sequence variation in gene ABL1/NCBI:25 699 check_entity AN4637-1 ABL1 RCSD1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 diagnostic;risk 55135-8 PubMed:25768406 Authors reported a 26 year-old female patient with B-ALL and RCSD1-ABL1 fusion identified by FISH and PCR. Sequencing showed that RCSD1 exon 3 was fused to ABL1 exon 4. This patient was treated with chemotherapy and HSC transplant and relapsed. Ex vivo drug response profiling (DRP) of the patient leukemic blasts was performed at first relapse. Resistance and/or low response were observed for dasatinib and nilotinib, and measurable responses were noted to ponatinib. This differential response to ponatinib as compared with dasatinib was confirmed in a secondary dose-response study and in mice inoculated with leukemia cells. Then the patient was started on ponatinib monotherapy (45 mg/day) based on her RCSD1-ABL1 fusion and achieved a remission. She received a second HSC transplant but relapsed at day 77 post transplantation. Ponatinib was restarted at this time that resulted in response but didn’t reach remission. The patient died of a septic shock 2 weeks later. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RCSD1::ABL1 sequence variation in gene ABL1/NCBI:25 699 check_entity AN4637-1 ABL1 RCSD1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 diagnostic;risk 55135-8 CIViC:2550 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RCSD1::ABL1 sequence variation in gene ABL1/NCBI:25 699 check_entity AN4637-2 ABL1 RCSD1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic;risk 55135-8 PubMed:25207766 The RCSD1-ABL1 fusion was identified in a 6 yo boy with Ph-like B-ALL (expression signature verified by low density gene expression array) and hyperleukocytosis. Following standard induction therapy the patient had an MRD of 16.4% in bone marrow, indicating a poor response. Addition of imatinib decreased MRD to 2% at day 29. In addition, this study reports that expression of the RCSD1-ABL1 fusion protein in murine Ba/F3 cells promotes cytokine-independent proliferation and that viable cells were reduced following exposure to dasatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RCSD1::ABL1 sequence variation in gene ABL1/NCBI:25 700 check_entity AN4637-2 ABL1 RCSD1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic;risk 55135-8 PubMed:28408464 This study included 1389 cases of high-risk pediatric B-ALL, of which 284 were identified by TaqMan Low Density Array to have a Ph-like gene expression signature. RT-PCR or RNAseq performed on Ph-like, CRLF2 negative patients revealed 17 cases with ABL1 fusions with 8 different partner genes. There was one case with the RCSD1-ABL1 fusion. Considering the previously confirmed Ph-like signature in the tested cases, the results suggest that the presence of the RCSD1-ABL1 fusion in B-ALL correlates with the BCR-ABL1-like (Ph-like) subtype of the disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RCSD1::ABL1 sequence variation in gene ABL1/NCBI:25 700 check_entity AN4637-2 ABL1 RCSD1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic;risk 55135-8 PubMed:22897847 The study evaluated 15 B-ALL cases which were previously identified as Ph-like using prediction analysis of microarrays (PAM). Paired-end messenger RNA sequencing (RNA-seq) was performed to identify underlying genetic drivers. The RCSD1-ABL1 fusion was identified in a 15 yo boy with confirmed Ph-like B-ALL signature from Children’s Oncology Group (COG) AALL0232 study. WBC was 47.8x109L. Outcome data was not provided. This observation suggests that the presence of the RCSD1-ABL1 fusion in B-ALL is associated with the Ph-like molecular subtype of the disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RCSD1::ABL1 sequence variation in gene ABL1/NCBI:25 700 check_entity AN4637-2 ABL1 RCSD1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic;risk 55135-8 PubMed:27855558 Authors reported a 15-year-old female diagnosed with B-ALL with the t(1;9)(q24;q34.1). RNAseq data were consistent with a fusion between the exon 3 of RCSD1 and exon 4 of ABL1, resulting in the formation of an in-frame RCSD1-ABL1 fusion transcript. The patient achieved complete remission upon addition of TKIs to the post-induction chemotherapy regimen, but developed fatal complications after HSCT. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RCSD1::ABL1 sequence variation in gene ABL1/NCBI:25 700 check_entity AN4637-2 ABL1 RCSD1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic;risk 55135-8 CIViC:2550 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RCSD1::ABL1 sequence variation in gene ABL1/NCBI:25 700 check_entity AN4638-1 ABL1 SFPQ::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk 55135-8 PubMed:21388681 The authors describe two cases of B-lymphoblastic leukemia (B-ALL) with the t(1;9)(p34;q34) rearrangement, resulting in a fusion between the pre-mRNA processing protein gene SFPQ and the ABL1 kinase gene. Patient 1 was a 19-year old female patient with common B-cell ALL expressing 2 myeloid markers. Due to the presence of the 2 myeloid markers, she was treated with a classic acutemyeloid leukemia (AML) induction regimen (cytarabine and idarubicin), along with imatinib due to the involvement of the ABL1 locus. Patient achieved complete remission, followed by a consolidation regimen with cytarabine and mitoxantrone, a non-familial allogeneic hematopoietic stem cell transplantation with a dose-reduced conditioning, and a maintenance treatment with dasatinib. Complete remission was maintained 32 months after the allograft. Patient 2 was a 28 year old female, diagnosed with common B-ALL (EGIL B-II), and was included in the GRAALL 2005 protocol with intensified cyclophosphamide administration, and was corticosensitive but chemoresistant (60% blasts at day 8). She achieved complete remission after the induction regimen, and this was followed by consolidation regimen with cytarabine, high-dose methotrexate and cyclophosphamide. After this, familial allograft with her brother as donor was performed, and she remained in complete remission 18 months after allograft. FISH and sequencing have confirmed the fusion between SFPQ-ex9 and ABL-ex4 in both patients. The authors conclude that the t(1;9)(p34;q34), fusing SFPQ in 1p34 with ABL1 in 9q34, represents a recurrent abnormality in B-ALL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SFPQ::ABL1 sequence variation in gene ABL1/NCBI:25 701 check_entity AN4638-1 ABL1 SFPQ::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk 55135-8 PubMed:32306475 Using fluorescence in situ hybridization (FISH) analysis with break-apart probes, the authors screened retrospectively 55 pediatric and 50 adult B-lymphoblastic leukemia (B-ALL) cases negative for common drivers (B-other) for rearrangements involving ABL1, ABL2 and PDGFRB tyrosine kinase genes. Three (6%) of the adult but none of the childhood B-other cases were positive for ABL-class aberrations. One of these adult patients was a 29-year old male with a t(1;9)(p34;q34). RT-PCR and sequencing confirmed that the translocation resulted in a rare SFPQ-ABL1 fusion. The patient was treated with allogenic stem-cell transplant with addition of dasatinib and imatinib, and was in remission at the time of publication (28 months after the diagnosis). A review of 6 previously published cases with SFPQ-ABL1 fusion indicated that exon 9 of SFPQ and exon 4 of ABL1 were consistently involved. The fusion was typically found in adolescents/younger adults without hyperleukocytosis, and IKZF1 deletions were recurrently found. In the cases reported, patients who were not treated with tyrosine kinase inhibitors (TKIs) and/or allogeneic stem cell transplantation had relapsed, and the authors therefore suggest that TKIs should be added to the therapy of SFPQ-ABL1-positive B-ALL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SFPQ::ABL1 sequence variation in gene ABL1/NCBI:25 701 check_entity AN4638-1 ABL1 SFPQ::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk 55135-8 PubMed:18205209 A 22-year-old male presenting with B-lymphoblastic leukemia (B-ALL) characterized by a t(1;9)(p34;q34) was found to carry an SFPQ-ABL1 fusion. The fusion was confirmed by amplification of the genomic breakpoints and RT-PCR; it was shown to be in-frame and to encode the N-terminal domain of the SFPQ-encoded protein and the entire tyrosine kinase domain and C-terminal sequences of the ABL1 kinase. The SFPQ (Splicing Factor Proline And Glutamine Rich) gene, encoding a protein that specifically binds to intronic polypyrimidine tracts in pre-mRNA and regulates signal-induced alternative splicing, was thus described as a new 5’ partner of the ABL1 gene in B-ALL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SFPQ::ABL1 sequence variation in gene ABL1/NCBI:25 701 check_entity AN4638-1 ABL1 SFPQ::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk 55135-8 PubMed:29507076 219 newly diagnosed NCI high-risk, Ph-negative, B-ALL patients between ages 1 to 18 were enrolled on DFCI ALL Consortium protocol 05-001 (NCT00400946) between 2005 and 2011. This study sought to determine the frequency of kinase-activating fusions in this patient cohort. Testing of 105 patients by validated multiplex reverse transcriptase polymerase chain reaction (RT-PCR) assays identified one male patient (age>10) with the SFPQ-ABL1 fusion. This patient was also positive for the IKZF1 gene deletion. Although no other information is available for the patient with the SFPQ-ABL1 fusion, in univariate analysis, fusion-positivity and IKZF1 deletion were each associated with inferior event-free survival and IKZF1 deletion also retained statistical significance in multivariable analysis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SFPQ::ABL1 sequence variation in gene ABL1/NCBI:25 701 check_entity AN4638-1 ABL1 SFPQ::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk 55135-8 CIViC:3156 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SFPQ::ABL1 sequence variation in gene ABL1/NCBI:25 701 check_entity AN4638-2 ABL1 SFPQ::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 55135-8 PubMed:27894117 A 34-year-old woman was hospitalized because of weakness and mild fever. Physical examination revealed multiple and superficial lymph nodes. Peripheral blood counting showed a 47% blasts. Bone marrow aspirates showed marked hypercellularity and 72.5% blasts, but no Auer body. Karyotype analysis showed a t(1;9)(p34;q34), resulting in a SFPQ-ABL1 fusion. After two courses of VDP induction chemotherapy containing vindesine, daunorubicin, and prednisone, the patient achieved CR with 1.5% blasts in bone marrow. Unfortunately, the patient relapsed with 55% blasts in bone marrow in February 2014. Eventually, the patient died from disease progression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SFPQ::ABL1 sequence variation in gene ABL1/NCBI:25 702 check_entity AN4638-2 ABL1 SFPQ::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 55135-8 CIViC:3156 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SFPQ::ABL1 sequence variation in gene ABL1/NCBI:25 702 check_entity AN4639-1 ABL1 SNX2::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 prognostic;risk 55135-8 PubMed:24215620 A 7-yr-old boy with B-cell precursor acute lymphoblastic leukemia was found to harbor the SNX2-ABL1 fusion gene. Gene expression analysis showed enrichment for BCR-ABL1+ ALL using GSEA. After first relapse (15 months after diagnosis) the patient was given imatinib at a dose of 240 mg/m2/d once daily and his disease stabilized for 2 months. The patient received dasatinib (80 mg/m2/d once daily) after an umbilical cord blood transplant and did not respond to treatment. Patient was put back on imatinib at a dose of 600 mg/m2/d once daily which rapidly decreased the number of blast cells. However, 6 months after transplant he had bone marrow relapse and did not again achieve remission by the time of reporting. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SNX2::ABL1 sequence variation in gene ABL1/NCBI:25 703 check_entity AN4639-1 ABL1 SNX2::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 prognostic;risk 55135-8 PubMed:21391972 In a 29-year-old man with pre B-cell ALL, the t(5;9)(q23;q34) [SNX2-ABL1] was identified. The SNX2-ABL1 fusion, which joins the N-terminal domain of SNX2 without the PX domain to ABL1 exon 4, was detected by RACE PCR and confirmed by RT-PCR and Sanger sequencing. The patient responded to initial chemotherapy, but relapsed early. He then demonstrated a response to hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-C-VAD), but relapsed again. The patient next received imatinib and supportive measures, including hydroxycarbamide, but unfortunately succumbed to his disease approximately one year after diagnosis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SNX2::ABL1 sequence variation in gene ABL1/NCBI:25 703 check_entity AN4639-1 ABL1 SNX2::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 prognostic;risk 55135-8 PubMed:24367893 SNX2-ABL1 protein (SNX2 exon 3 to ABL1 exon 4) was transfected in murine Ba/F3 cells and proliferation rates in the presence of IL-3, and tyrosine kinase inhibitors, imatinib and dasatinib was compared to BCR-ABL1 p190 and p210 transfected Ba/F3 cells. Cell proliferation assays showed that SNX2-ABL1 transfected cells had over 20% and 50% of cell survival after 24-hr incubation with imatinib (2µM) and dasatinib (10nM). SNX2-ABL1 transfected cells continued to proliferate again 48 hr after treatment with dasatinib (10nM). This data was further supported by apoptosis (annexin V-propidium iodide) studies. In addition, newer tyrosine kinase inhibitors including nilotinib (500nM), bafetinib (500nM), rebastinib (500nM), and ponatinib (100nM), were examined and SNX2-ABL1 cells showed a better response, but still some resistance to these compounds. Further examination of downstream phosphorylation of SNX2-ABL1 cells showed only partial inhibition with imatinib and dasatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SNX2::ABL1 sequence variation in gene ABL1/NCBI:25 703 check_entity AN4639-1 ABL1 SNX2::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 prognostic;risk 55135-8 PubMed:28278724 A 16 yr-old male with precursor B-ALL was found to have the t(5;9)(q23;q34) in his peripheral blasts. Fluorescence in situ hybridization (FISH), RT-PCR, and sequencing of the product confirmed a SNX2-ABL1 fusion gene (SNX2 exon 3 fused in frame to ABL1 exon 4) was present. The patient also was found to carry an IKZF1 deletion (exons 2-8) and amplification of PAX5. The patient was treated with vindesine, idarubicin, and dexamethasone (VDP) and VDCP (plus cyclophosphamide) regimens. He received two bone marrow transplants, but eventually died of disease. The patient did not receive tyrosine-kinase inhibitors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SNX2::ABL1 sequence variation in gene ABL1/NCBI:25 703 check_entity AN4639-1 ABL1 SNX2::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 prognostic;risk 55135-8 CIViC:2547 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SNX2::ABL1 sequence variation in gene ABL1/NCBI:25 703 check_entity AN4639-2 ABL1 SNX2::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 55135-8 PubMed:27176795 This retrospective study intended to clarify clinical characteristics of patients with B-lymphoblastic leukemia/lymphoma (B-ALL) and kinase fusions that are not well described (excluding ETV6-RUNX1, E2A-PBX1, MLL rearrangements and BCR-ABL). The SNX2-ABL1 fusion is rare; in this study investigating 373 high risk pediatric B-ALL patients of which 29 demonstrated uncommon kinase gene fusions, only one case with SNX2-ABL1 (exon 3-exon 4) was observed. Gene expression profiles were compared to Ph-positive B-ALL and reportedly all fusion-containing samples (except P2RY8-CRLF2) were similar to BCR-ABL1-positive patients. This patient did not respond to tyrosine kinase inhibitors administered in combination with chemotherapy at the first or second relapses. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SNX2::ABL1 sequence variation in gene ABL1/NCBI:25 704 check_entity AN4639-2 ABL1 SNX2::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 55135-8 PubMed:25207766 In the study involving 1725 B-ALL patients, 264 were identified by microarray-based algorithm to have a Ph-like expression signature. Next generation sequencing (RNAseq, WGS, and/or WES) performed on 154 Ph-like patients revealed 91% possessed genomic alterations activating kinase signaling with 96 (62%) involving rearrangements. In one adolescent male, an in-frame SNX2-ABL1 fusion (exon 3 and exon 4) with the ABL1 tyrosine kinase domain intact was identified and confirmed by RT-PCR and Sanger. This patient, evaluated by WES and RNA-seq, also harbored IKZF1, EBF1, and VPREB deletions, and was designated Ph-like non CRLF2. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SNX2::ABL1 sequence variation in gene ABL1/NCBI:25 704 check_entity AN4639-2 ABL1 SNX2::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 55135-8 CIViC:2547 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SNX2::ABL1 sequence variation in gene ABL1/NCBI:25 704 check_entity AN4640-1 ABL1 T315A mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 PubMed:18191450 In an in vitro study, a Ba/F3 cell line stably expressing the dasatinib-resistance variant T315A in the ABL1 portion of the BCR-ABL1 fusion protein was associated with similar sensitivity to nilotinib and bafetinib (INNO-406) treatment (IC50: 949.2 nM, 422.5 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 642.3 nM and 152.9 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315A sequence variation in gene ABL1/NCBI:25 705 check_entity AN4640-1 ABL1 T315A mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 CIViC:4742 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315A sequence variation in gene ABL1/NCBI:25 705 check_entity AN4640-2 ABL1 T315A mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:15705718 In an in vitro study, stochastic mutations in the ABL1 region of a stably expressed p210 BCR-ABL fusion were generated in Ba/F3 cell lines from five independently derived, mutagenized libraries. Dasatinib resistant subclones were identified using 50 nM dasatinib in liquid culture. 201 individual clones were identified representing 10 different mutations at 6 different residues. 60 of these clones had T315A mutations. To validate resistance to dasatinib, Ba/F3 cell lines stably expressing a T315A mutation in the ABL1 region of the BCR-ABL fusion were generated. T315A was associated with higher dasatinib IC50 of 125 nM vs 1.34 nM in wildtype as determined by dose response curves. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315A sequence variation in gene ABL1/NCBI:25 706 check_entity AN4640-2 ABL1 T315A mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed decreased incorporation when harboring fusions with the T315A variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 389nM vs. 823 nM), indicating T315A induces sensitivity compared to BCR-ABL1 without secondary variants. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315A sequence variation in gene ABL1/NCBI:25 706 check_entity AN4640-2 ABL1 T315A mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4742 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315A sequence variation in gene ABL1/NCBI:25 706 check_entity AN4641-1 ABL1 T315I mutation ABL1 NCBI:25 gene acute lymphoblastic leukemia DOID:9952 risk 55135-8 PubMed:17264298 In this phase II multinational study, patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. Response rate among 60 imatinib-resistant patients with BCR-ABL mutations did not differ from the rate of the total population of 100 imatinib-resistant or -intolerant patients. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with T315I, 0/5 had MaHRs and 0/5 had MCyRs which were lower than response rates among wild type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315I sequence variation in gene ABL1/NCBI:25 707 check_entity AN4641-1 ABL1 T315I mutation ABL1 NCBI:25 gene acute lymphoblastic leukemia DOID:9952 risk 55135-8 PubMed:25686603 Bone marrow mononuclear cells (BM MNCs) were isolated from three acute lymphoblastic leukemia patients with the BCR-ABL1 T315I variant who were pretreated with various chemotherapeutics and dasatinib. 2/3 patient's BM MNCs were considered sensitive to ponatinib and axitinib using drug sensitivity scoring of proliferation assays. Additionally, BCR-ABL T315I showed sensitivity to ponitinib and axitinib in Ba/F3 cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315I sequence variation in gene ABL1/NCBI:25 707 check_entity AN4641-1 ABL1 T315I mutation ABL1 NCBI:25 gene acute lymphoblastic leukemia DOID:9952 risk 55135-8 CIViC:4373 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315I sequence variation in gene ABL1/NCBI:25 707 check_entity AN4641-2 ABL1 T315I mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 PubMed:18191450 In an in vitro study, a Ba/F3 cell line stably expressing the T315I mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance to nilotinib, imatinib, dasatinib, and bafetinib (INNO-406) treatment (IC50: > 2000.0 nM) as compared to wild-type BCR-ABL1 expressing Ba/F3 cells (IC50: 642.3 nM, 1712 nM, 87.6 nM and 152.9 nM). Sensitivity was determined by assessing cell proliferation using the MTT assay. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315I sequence variation in gene ABL1/NCBI:25 708 check_entity AN4641-2 ABL1 T315I mutation ABL1 NCBI:25 gene cancer DOID:162 risk 55135-8 CIViC:4373 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315I sequence variation in gene ABL1/NCBI:25 708 check_entity AN4641-3 ABL1 T315I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:20537386 In chronic myeloid leukemia patients with the ABL T315I mutation, tumors have shown to be resistant to imatinib treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315I sequence variation in gene ABL1/NCBI:25 709 check_entity AN4641-3 ABL1 T315I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:15194504 COS7 cell lines transfected with BCR-ABL constructs harboring T315I mutations were shown to be resistant to imatinib and exhibited increased kinase activity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315I sequence variation in gene ABL1/NCBI:25 709 check_entity AN4641-3 ABL1 T315I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25349473 Ponatinib has shown to be effective in patients with BCR-ABL kinase domain mutations including T315I. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315I sequence variation in gene ABL1/NCBI:25 709 check_entity AN4641-3 ABL1 T315I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:23190221 Study describes a phase 1 clinical trial of ponatinib in treatment of 81 refractory Philadelphia chromosome-positive leukemias. 43 of these patients were considered to have chronic-phase CML. All 12 chronic-phase CML patients with a T315I mutation showed a complete hematologic response. Furthermore, 91% of these patients were estimated to remain in response at 1 year (95% CI, Kaplan-Meier analysis). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315I sequence variation in gene ABL1/NCBI:25 709 check_entity AN4641-3 ABL1 T315I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19075254 A panel of 18 mutations representing 85% of known mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and were grouped according to their anti-proliferative activity. Mutant cell lines that exhibited a greater than 4-fold increase in IC50 value were considered resistant to drug, 2-4 fold increase in IC50 were moderately resistant and less than 2-fold change in IC50 was sensitive to drug treatment. The T315I mutation was resistant to imatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315I sequence variation in gene ABL1/NCBI:25 709 check_entity AN4641-3 ABL1 T315I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:12623848 In this study, patients on imatinib monotherapy were monitored for ABL1 kinase domain variants in BCR-ABL1 fusions amplified from peripheral blood RNA. A late-chronic phase (CP) patient had major cytogenetic response until 11 months after therapy initiation when they acquired resistance. The T315I variant was present in ~25%, ~75%, and ~100% of transcripts at month 9, 11, and 16 months, respectively. An accelerated-phase patient had a complete cytogenetic response but progressed to leukemic blast crisis 9 months after therapy initiation when the T315I variant was present in 100% of transcripts. The patient died at 9.5 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315I sequence variation in gene ABL1/NCBI:25 709 check_entity AN4641-3 ABL1 T315I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:15930265 A panel of 16 mutations seen in imatinib CML patents were used to evaluate the effectiveness of drug binding. All mutations were compared with non-mutated BCR-ABL protein and evaluated for anti-proliferative activity and substrate or auto-phosphorylation assays. The T315I mutation was resistant to imatinib (>25-fold IC50 increase for the proliferation assay). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315I sequence variation in gene ABL1/NCBI:25 709 check_entity AN4641-3 ABL1 T315I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:22371878 This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with T315I, 2/7 had a CHR and 0/6 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315I sequence variation in gene ABL1/NCBI:25 709 check_entity AN4641-3 ABL1 T315I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with T315I evaluated, 1/2 had a complete hematologic response and 0/3 had major cytogenetic responses. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315I sequence variation in gene ABL1/NCBI:25 709 check_entity AN4641-3 ABL1 T315I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19779040 This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 21 patients with T315I mutations, 0, 2, and 6 achieved CCyR, MCyR, and CHR to dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. Of the 63 variants considered, the authors associate T315I, F317L, and V299L with resistance to dasatinib or lower levels of response due to clinical resistance and low in vitro sensitivity. They suggest considering alternative treatment options for patients with these variants. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315I sequence variation in gene ABL1/NCBI:25 709 check_entity AN4641-3 ABL1 T315I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In this study, enzymatic profiling, crystal structures, and proliferation assays using Ba/F3 with the BCR-ABL1 variant showed higher sensitivity to axitinib in fusions with the T315I variant of ABL1 compared to wildtype ABL1 (IC50 of 21nM vs. 217 nM in resazurin assay; IC50 of 98 nM vs. 823 nM in tritiated thymidine assay). Bone marrow mononuclear cells (BM MNCs) were isolated from a chronic myeloid leukemia patients with the BCR-ABL1 T315I variant who was pretreated with imatinib, dasatinib, and chemotherapy. This patient's cells were sensitive to Ponatinib and Axitinib and insensitive to Nilotinib, Imatinib, and Dasatinib according to drug sensitivity scoring in proliferation assays. The patient was given axitinib monotherapy resulting in a significant decrease in T315I transcript levels in bone marrow (P<0.05). The authors note this as an example of a drug specifically targeting the secondary mutant resistant form of a protein. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315I sequence variation in gene ABL1/NCBI:25 709 check_entity AN4641-3 ABL1 T315I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16775234 Prior to dasatinib treatment, two imatinib-resistant patients with chronic myeloid leukemia in accelerated phase had the BCR-ABL1 fusion with the T315I secondary variant in 8/10 and 10/10 bacterial clones generated using peripheral blood RNA. They had none as best hematologic response and none as best cytogenetic response to dasatinib which were worse compared to responses in patients with unmutated BCR-ABL1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315I sequence variation in gene ABL1/NCBI:25 709 check_entity AN4641-3 ABL1 T315I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:15705718 In an in vitro study, stochastic mutations in the ABL1 region of the p210 BCR-ABL fusion were generated and stably expressed in Ba/F3 cell lines from mutagenized libraries. Combination therapy with 10 μM imatinib and 50 nM dasatinib resulted in a single clone with the T315I variant. Combination therapy with 25 nM dasatinib resulted in 11 clones, 6 of which had the T315I variant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315I sequence variation in gene ABL1/NCBI:25 709 check_entity AN4641-3 ABL1 T315I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. The T315I mutation was associated with resistance in 400 nM imatinib + 50 nM nilotinib (3 clones, ~16%), 2 μM imatinib + 1 μM nilotinib (8 clones, 100%), and 4 μM imatinib + 2 μM nilotinib (2 clones, 100%) combination treatments. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315I sequence variation in gene ABL1/NCBI:25 709 check_entity AN4641-3 ABL1 T315I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:17264298 In a phase II study of 60 imatinib-resistant patients with BCR-ABL mutations, 5 had T315I mutations assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315I sequence variation in gene ABL1/NCBI:25 709 check_entity AN4641-3 ABL1 T315I mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4373 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T315I sequence variation in gene ABL1/NCBI:25 709 check_entity AN4642-1 ABL1 TKD MUTATION ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19779040 This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, imatinib-resistant patients with and without ABL1 mutation had comparable complete hematologic response [CHR= 90% (345/384) vs. 93% (390/421)], major cytogenetic response [MCyR= 56% (211/384) vs. 58% (243/421)], complete cytogenetic response [CCyR= 43% (164/384) vs. 47% (196/421)], and major molecular response [MMR= 31% (115/367) vs. 36% (145/404)]. Of the 63 imatinib-resistant variants observed (see comment), the authors associate T315I, F317L, and V299L with resistance to dasatinib or lower levels of response due to clinical resistance and low in vitro sensitivity. However, F317L does have a high CHR. They suggest considering alternative treatment options for patients with these three variants. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::tkd:mutation sequence variation in gene ABL1/NCBI:25 710 check_entity AN4642-1 ABL1 TKD MUTATION ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Among 115 patients with mutational analysis at baseline, subsets were evaluated for complete hematologic response (CHR) and major cytogenetic response (MCyR). Both were comparable for patients with Abl1 mutation versus without [CHR = 33/34 vs. 27/27; MCyR = 41/59 (69%) vs. 19/35 (54%)]. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::tkd:mutation sequence variation in gene ABL1/NCBI:25 710 check_entity AN4642-1 ABL1 TKD MUTATION ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19652056 In this open-label, phase II registration trial, patients that were imatinib resistant (n = 192) or intolerant (n = 89) underwent nilotinib monotherapy. Prior to nilotinib treatment, 105 and 9 patients with baseline BCR-ABL mutations were imatinib resistant and intolerant, respectively. Within 12 months of therapy, among patients with baseline mutations, complete hematologic response was achieved in 57 (71%) of 80 [vs. 35 (80%) of 80 Abl1 wildtype patients, P = .393], major cytogenetic response in 49 of 100 [vs. 52 (60%) of 87, P = .145], complete cytogenetic response in 32 of 100 [vs. 35 (40%) of 87, P = .285], and major molecular response in 19 (22%) of 87 [vs. 22 (29%) of 76, P = .366]. These data shows no significant difference in nilotinib efficacy between patients with baseline mutations in the Abl1 kinase domain versus without. The authors observe clinical efficacy of nilotinib for many of the 29 variants found and identify only Y253H, E255K/V, and F359C/V as resistance conferring variants with IC50 greater than 150 nM. Individuals with T315I variants (3% of total population) were excluded. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::tkd:mutation sequence variation in gene ABL1/NCBI:25 710 check_entity AN4642-1 ABL1 TKD MUTATION ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:22371878 This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Among 39 patients with mutational analysis at baseline, subsets were evaluated for complete hematologic response (CHR) and major cytogenetic response (MCyR). Both were comparable for patients with Abl1 mutation versus without [CHR = 26/39 (67%) vs. 34/44 (77%); MCyR = 11/35 (31%) vs. 15/43 (35%)]. The authors observe responses with bosutanib monotherapy across many BCR-ABL mutations with the notable exception of T315I. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::tkd:mutation sequence variation in gene ABL1/NCBI:25 710 check_entity AN4642-1 ABL1 TKD MUTATION ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:2244 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::tkd:mutation sequence variation in gene ABL1/NCBI:25 710 check_entity AN4643-1 ABL1 V299L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19075254 In an in vitro study, a Ba/F3 cell line stably expressing the V299L mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with sensitivity to nilotinib treatment (IC50: 1.34-fold), comparable to Ba/F3 cells expressing BCR-ABL1 fusion protein. Sensitivity was determined by assessing cell proliferation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V299L sequence variation in gene ABL1/NCBI:25 711 check_entity AN4643-1 ABL1 V299L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:22371878 This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with V299L, 1/2 had a CHR and 0/2 had a MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V299L sequence variation in gene ABL1/NCBI:25 711 check_entity AN4643-1 ABL1 V299L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19779040 This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response, major cytogenetic response, complete cytogenetic response (CCyR), and major molecular response. There was 1 patient with a V299L mutation who did not achieved CCyR with dasatinib monotherapy. Analyses by variant included patients with multiple kinase domain mutations. Of the 63 variants considered, the authors associate T315I, F317L, and V299L with resistance to dasatinib or lower levels of response due to clinical resistance and low in vitro sensitivity. They suggest considering alternative treatment options for patients with these variants. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V299L sequence variation in gene ABL1/NCBI:25 711 check_entity AN4643-1 ABL1 V299L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:15705718 In an in vitro study, stochastic mutations in the ABL1 region of a stably expressed p210 BCR-ABL fusion were generated in Ba/F3 cell lines from five independently derived, mutagenized libraries. Dasatinib resistant subclones were identified using 50 nM dasatinib in liquid culture. 201 individual clones were identified representing 10 different mutations at 6 different residues. 1 of these clones had an V299L mutation. To validate resistance to dasatinib, a Ba/F3 cell line stably expressing the V299L mutation in the ABL1 region of the BCR-ABL fusion was generated and associated with higher dasatinib IC50 of 18 nM vs 1.34 nM in wildtype as determined by dose response curves. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V299L sequence variation in gene ABL1/NCBI:25 711 check_entity AN4643-1 ABL1 V299L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, stochastic mutations were introduced into the ABL1 region of a stably expressed p210 BCR-ABL fusion in Ba/F3 cells using N-ethyl-N-nitrosourea mutagenesis. Resulting clones were grown in a range of tyrosine kinase inhibitor concentrations to identify resistance mutations. Of the 11 clones that grew in a combination of 400 nM imatinib and 10 nM dasatinib, 1 (9%) was found to have a V299L mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V299L sequence variation in gene ABL1/NCBI:25 711 check_entity AN4643-1 ABL1 V299L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed decreased incorporation when harboring fusions with the V299L variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 188nM vs. 823 nM), indicating V299L induces sensitivity compared to BCR-ABL1 without secondary variants. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V299L sequence variation in gene ABL1/NCBI:25 711 check_entity AN4643-1 ABL1 V299L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4730 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V299L sequence variation in gene ABL1/NCBI:25 711 check_entity AN4643-1 ABL1 V299L mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4729 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V299L sequence variation in gene ABL1/NCBI:25 711 check_entity AN4644-1 ABL1 Y253H mutation ABL1 NCBI:25 gene acute lymphoblastic leukemia DOID:9952 risk 55135-8 PubMed:16775234 Prior to dasatinib treatment, one imatinib-resistant patient with acute lymphoblastic leukemia had the BCR-ABL1 fusion with Y253H and Y253H/Q252R variants in 9/10 and 1/10 clones, respectively. Clones were generated using peripheral blood RNA. The patient had complete response as best cytogenetic response and complete response as best hematologic response to dasatinib which were improved compared to responses in a patient with unmutated BCR-ABL1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y253H sequence variation in gene ABL1/NCBI:25 712 check_entity AN4644-1 ABL1 Y253H mutation ABL1 NCBI:25 gene acute lymphoblastic leukemia DOID:9952 risk 55135-8 CIViC:4550 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y253H sequence variation in gene ABL1/NCBI:25 712 check_entity AN4644-2 ABL1 Y253H mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16772610 In an in vitro study, a Ba/F3-p210BCR-ABL1 cell line was ENU-mutated and exposed to graded concentrations of imatinib, nilotinib or dasatinib to identify resistance mutations. The Y253H mutation in the ABL1 portion of the BCR-ABL1 fusion protein was associated with resistance to 50nM nilotinib (14 clones recovered, ~30% of viable clones in this treatment), 500nM nilotinib (50 clones, ~63%), and 16 nM imatinib (16 clones; ~48%). Resistant clones were also found at 2, 4, and 8 μM imatinib. In a review of 20 publications, this mutation was described in imatinib resistant patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y253H sequence variation in gene ABL1/NCBI:25 713 check_entity AN4644-2 ABL1 Y253H mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:25686603 In a proliferation assay measuring tritiated thymidine incorporation in the presence of axitinib, Ba/F3 cells carrying the BCR-ABL1 variant showed similar incorporation when harboring fusions with the Y253H variant of ABL1 compared to fusions with wildtype ABL1 (IC50 of 867nM vs. 823 nM), indicating that the variant does not induce resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y253H sequence variation in gene ABL1/NCBI:25 713 check_entity AN4644-2 ABL1 Y253H mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:21865346 In this retrospective study, imatinib-resistant or -intolerant patients, with chronic phase CML and BCR-ABL fusions, were treated with bosutanib monotherapy. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. The authors conclude that bosutanib is effective across all BCR-ABL mutations observed except T315I. Of patients with Y253H evaluated, 1/1 had a complete hematologic response and 1/1 had a major cytogenetic response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y253H sequence variation in gene ABL1/NCBI:25 713 check_entity AN4644-2 ABL1 Y253H mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:22371878 This was a retrospective study of dasatinib and/or nilotinib-resistant or -intolerant patients pretreated with imatinib aimed at evaluating the efficacy of bosutanib monotherapy. All patients had chronic phase CML and BCR-ABL fusions. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were comparable for patients with Abl1 mutation versus without. Of patients with Y253H evaluated, 5/6 had CHR and 4/6 had MCyR. Nine patients in this study had multiple kinase domain mutations, but it was not indicated when mutations were co-occuring. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y253H sequence variation in gene ABL1/NCBI:25 713 check_entity AN4644-2 ABL1 Y253H mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:17264298 In this phase II multinational study, 60 imatinib-resistant patients with accelerated phase CML and BCR-ABL fusions were treated with dasatinib monotherapy. 44 (73%) of 60 BCR-ABL mutant patients achieved major hematologic responses (MaHRs) and 18 (30%) of 60 achieved major cytogenetic responses (MCyRs). Of patients with Y253H, 5/6 had MaHRs which was higher than response rates among wild type patients and 2/6 had MCyRs which was comparable to response rates among wild type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y253H sequence variation in gene ABL1/NCBI:25 713 check_entity AN4644-2 ABL1 Y253H mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19779040 This is a retrospective study of imatinib-resistant (n = 805) or -intolerant (n = 238), chronic myeloid leukemia (chronic-phase), patients with mutations in the BCR-ABL gene fusion kinase domain from the START-C, START-R, and CA180-034 trials. With dasatinib monotherapy, patients with and without ABL1 mutation had comparable complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR). Out of 23 patients with the Y253H mutation, 14, 15, and 20 achieved CCyR, MCyR, and CHR with dasatinib monotherapy, respectively. Analyses by variant included patients with multiple kinase domain mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y253H sequence variation in gene ABL1/NCBI:25 713 check_entity AN4644-2 ABL1 Y253H mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:16775234 Prior to dasatinib treatment, one imatinib-resistant patient with chronic myeloid leukemia in chronic phase had the BCR-ABL1 fusion with the Y253H secondary variant in 11/11 bacterial clones generated using peripheral blood RNA. They had complete response as best hematologic response and complete response as best cytogenetic response to dasatinib which were improved compared to responses in patients with unmutated BCR-ABL1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y253H sequence variation in gene ABL1/NCBI:25 713 check_entity AN4644-2 ABL1 Y253H mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 PubMed:19652056 In this open-label, phase II registration trial, patients that were imatinib resistant or intolerant underwent nilotinib monotherapy. Within 12 months of nilotinib therapy, there was no significant difference in response to nilotinib treatment between patients with mutations in the Abl1 kinase domain versus without. However, the authors identify Y253H, E255K/V, and F359C/V variants as resistant as they had an IC50 of >150 nM. In patients with Y253H mutations prior to nilotinib treatment, complete hematologic response was achieved in 0 of 6 patients, major cytogenetic response in 1 of 8 patients, complete cytogenetic response in 0 of 8 patients, and major molecular response in 0 of 7 patients. After median follow-up of 15.5 months, 3 of 8 patients with this mutation progressed or died. The Y253H mutation was present in two patients at baseline and newly emerged in two patients at progression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y253H sequence variation in gene ABL1/NCBI:25 713 check_entity AN4644-2 ABL1 Y253H mutation ABL1 NCBI:25 gene chronic myeloid leukemia DOID:8552 risk 55135-8 CIViC:4550 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y253H sequence variation in gene ABL1/NCBI:25 713 check_entity AN4645-1 ABL1 ZMIZ1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk 55135-8 PubMed:18007576 A 18-month-old female with B-cell acute lymphoblastic leukemia. Chromosome and FISH analysis using a BCR-ABL1 probe confirmed the involvement of ABL1 in a t(9;10)(q34;q22.3) translocation. Follow-up molecular analysis using RT-PCR confirmed the presence of a ZMIZ1-ABL1 fusion transcript (ZMIZ1 exon 14 and ABL1 exon 2). Patient was treated according to standard risk protocol without kinase inhibitors and is in first complete remission. Authors note that The ZMIZ1-ABL1 fusion transcript predicts the the synthesis of ZMIZ1-ABL fusion protein, which contains one of the proline-rich domains of ZMIZ1 and ABL tyrosine kinase domain. Similar to other oncogenic fusion proteins, the proline-rich domain of ZMIZ1 is involved in protein-protein interactions, and therefore the fusion may encode a constitutively activated tyrosine kinase that promotes cellular transformation. The authors further note that patients with t(9;10) would be eligible for imatinib treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ZMIZ1::ABL1 sequence variation in gene ABL1/NCBI:25 714 check_entity AN4645-1 ABL1 ZMIZ1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk 55135-8 CIViC:3138 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ZMIZ1::ABL1 sequence variation in gene ABL1/NCBI:25 714 check_entity AN4645-2 ABL1 ZMIZ1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic;prognostic 55135-8 PubMed:28408464 This study included 1389 cases of high-risk pediatric B-ALL, of which 284 were identified by TaqMan Low Density Array to have a BCR-ABL1-like (Ph-like) gene expression signature. RT-PCR or RNAseq performed on Ph-like, CRLF2 negative patients revealed 17 cases with ABL1 fusions with 8 different partner genes. There were three cases with the ZMIZ1-ABL1 fusion. Considering the previously confirmed Ph-like expression signature in the tested cases, the results suggest that the presence of the ZMIZ1-ABL1 fusion in B-ALL indicates the BCR-ABL1-like (Ph-like) subtype of the disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ZMIZ1::ABL1 sequence variation in gene ABL1/NCBI:25 715 check_entity AN4645-2 ABL1 ZMIZ1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic;prognostic 55135-8 PubMed:33357483 A multicenter, retrospective, cohort study that included 122 paediatric patients (aged 1-18 years) with newly diagnosed ABL-class fusion B-cell acute lymphocytic leukemia who had not received tyrosine-kinase inhibitor treatment as a first-line therapy. ABL-class genes included ABL1, ABL2, CSF1R and PDGFRB. There were 33% of patients (40/122) that harbored an ABL1 fusion, including 16 with a ZMIZ1-ABL1 fusion. For patients that were ABL1 fusion positive the 5-year event-free survival was 68.6% (54.5-86.3), the 5-year overall survival was 82.9% (71.2-96.4) and the 5-year cumulative incidence of relapse was 29.6% (15.0-45.9). Additionally ABL1 fusion positive patients had the lowest levels of MRD at the end of induction therapy. Patients with ZMIZ1-ABL1 had a median MRD between 10^-3 and <10^4 at the end of induction, but between fusion parters, MRD did not differ significantly. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ZMIZ1::ABL1 sequence variation in gene ABL1/NCBI:25 715 check_entity AN4645-2 ABL1 ZMIZ1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic;prognostic 55135-8 PubMed:27894077 Study comprised 574 children with newly diagnosed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and focused on B-other/BCR-ABL-like which were identified by hierarchical clustering of gene expression data. RT-PCR followed by Sanger sequencing for detection of tyrosine kinase fusions was performed for 153 cases. There were 14 fusions found among the BCR-ABL-like cases (14/77=18%), which included one case with a ZMIZ1-ABL1 (exon 18 and exon 2). ZMIZ1-AML1 fusion was among a group of nine fusions found, and characterized by the authors as predictive for activated ABL signaling. The 8-year cumulative incidence of relapse for the fusion-positive BCR-ABL1-like group (35%) was comparable to the fusion-negative BCR-ABL1-like group (35%), and worse than non-BCR-ABL1-like B-other group (17%, p=0.07). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ZMIZ1::ABL1 sequence variation in gene ABL1/NCBI:25 715 check_entity AN4645-2 ABL1 ZMIZ1::ABL1 mutation ABL1 NCBI:25 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic;prognostic 55135-8 CIViC:3138 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ZMIZ1::ABL1 sequence variation in gene ABL1/NCBI:25 715 check_entity AN4646-1 ABL2 Fusion ABL2 NCBI:27 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 risk PubMed:25207766 The ABL2-RCSD1 fusion was identified in a 5 yo boy with Ph-like B-ALL and Klinefelter syndrome. Following standard induction therapy the patient had an MRD of 1.2% in bone marrow, and continued to be MRD positive at 6 months off therapy (0.029%). He received imatinib and a bone marrow performed 2 months later showed no MRD. He maintained remission at one year post-diagnosis, on chemotherapy and imatinib. In addition, this study reports that expression of the ABL2-RCSD1 fusion protein in murine Ba/F3 cells promotes cytokine-independent proliferation and viable cells were reduced following exposure to dasatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ABL2/NCBI:27 716 check_entity AN4646-1 ABL2 Fusion ABL2 NCBI:27 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 risk CIViC:2444 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ABL2/NCBI:27 716 check_entity AN4647-1 ACTA1 EXPRESSION ACTA1 NCBI:58 gene lung adenocarcinoma DOID:3910 prognostic 44700-3 PubMed:26950277 ActA level was measured in serum and plasma samples of 64/87 lung adenocarcinoma patients and 46/66 age- and gender-matched controls (ELISA). ActA Levels were higher in patients than in controls and were significantly correlated with disease stage and metastasis. Patients were stratified as having high or low ActA levels using the median expression level. LADC patients with high serum or plasma ActA levels had significantly shorter OS than those with low circulating ActA concentrations (p < 0.0001 in both) and were identified as an independent prognostic factor (p=0.004 and p=0.002, respectively). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene ACTA1/NCBI:58 717 AN4647-1 ACTA1 EXPRESSION ACTA1 NCBI:58 gene lung adenocarcinoma DOID:3910 prognostic 44700-3 CIViC:542 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene ACTA1/NCBI:58 717 AN4648-1 ACVR1 G328E mutation ACVR1 NCBI:90 gene diffuse midline glioma, H3 K27M-mutant DOID:0080684 diagnostic PubMed:24705252 Sequencing (whole genome or exome) was performed on a series of 26 pediatric patients (1.7 to 13.6 years old), 7 had missense mutations in ACVR1. Two patients with G328E mutation were identified. This mutation had not been previously reported in other cancer types, indicating it was supportive of a diagnosis of high grade pontine glioma. PEDIATRIC assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G328E sequence variation in gene ACVR1/NCBI:90 718 check_entity AN4648-1 ACVR1 G328E mutation ACVR1 NCBI:90 gene diffuse midline glioma, H3 K27M-mutant DOID:0080684 diagnostic CIViC:2159 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G328E sequence variation in gene ACVR1/NCBI:90 718 check_entity AN4649-1 ACVR1 G328V mutation ACVR1 NCBI:90 gene diffuse midline glioma, H3 K27M-mutant DOID:0080684 diagnostic PubMed:24705250 Sequencing of 39 pediatric midline high-grade astrocytomas identified 5 patients with ACVR1 mutations. The authors identified an increase in endogenous phospho-SMAD1/5/8 signal in diffuse intrinsic pontine glioma (DIPG) cells harboring ACVR1 G328V, with corresponding increase in phospho-SMAD1/5/8 staining as well. By PCR, the authors show strong increase in fold change of mRNA expression in downstream proteins of the ACVR1/BMP pathway, ID, ID2, ID3 and SNAI1 in ACVR1-mutant DIPG cell line compared to glioblastoma cells (KNS42 cells). These activating ACVR1 mutations were exclusively in midline high grade astrocytomas (P = 0.0040, Fisher's exact test). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G328V sequence variation in gene ACVR1/NCBI:90 719 check_entity AN4649-1 ACVR1 G328V mutation ACVR1 NCBI:90 gene diffuse midline glioma, H3 K27M-mutant DOID:0080684 diagnostic PubMed:24705254 In a study sequencing 61 patients (median age 6.3) with diffuse intrinsic pontine glioma (DIPG), 12 variants affecting ACVR1 were observed. Five patients had G328V within the kinase domain. The ACVR1 G328V mutation was expressed using the pCDH511b vector in immortalized normal human astrocytes (iNHAs) where it activated downstream BMP signaling and enhanced cell growth. Activating ACVR1 mutations are recurrent and support diagnosis of high grade glioma. PEDIATRIC assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G328V sequence variation in gene ACVR1/NCBI:90 719 check_entity AN4649-1 ACVR1 G328V mutation ACVR1 NCBI:90 gene diffuse midline glioma, H3 K27M-mutant DOID:0080684 diagnostic PubMed:24705252 It has been reported that recurrent activating somatic mutations (R206H, R258G, G328E/V/W, G356D) in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase, are in 21% (11/52) of DIPG samples. The mutations were highly specific to DIPG, with an overall frequency of 0.3% in other tumors present in the Catalogue of Somatic Mutations in Cancer database. Data was collected from whole genome sequencing on 20 pre-treated biopsy samples of DIPG as well as whole exome sequencing from 1 biopsy sample and five samples obtained at autopsy. An additional 26 DIPG biopsy samples were screened via Sanger sequencing and identified the variant (G328W). DIPG cases with somatic mutations of ACVR1 (R206H, R258G, G328E/V/W, G356D) had longer overall survival (n=11 versus 41; median of 14.9 versus 10.9 months; p=0.05, log-rank test). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G328V sequence variation in gene ACVR1/NCBI:90 719 check_entity AN4649-1 ACVR1 G328V mutation ACVR1 NCBI:90 gene diffuse midline glioma, H3 K27M-mutant DOID:0080684 diagnostic CIViC:1594 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G328V sequence variation in gene ACVR1/NCBI:90 719 check_entity AN4650-1 ACVR1 G328W mutation ACVR1 NCBI:90 gene diffuse midline glioma, H3 K27M-mutant DOID:0080684 diagnostic PubMed:24705252 It has been reported that recurrent activating somatic mutations (R206H, R258G, G328E/V/W, G356D) in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase, are in 21% (11/52) of DIPG samples. The mutations were highly specific to DIPG, with an overall frequency of 0.3% in other tumors present in the Catalogue of Somatic Mutations in Cancer database. Data was collected from whole genome sequencing on 20 pre-treated biopsy samples of DIPG as well as whole exome sequencing from 1 biopsy sample and five samples obtained at autopsy. An additional 26 DIPG biopsy samples were screened via Sanger sequencing and identified the variant (G328W). DIPG cases with somatic mutations of ACVR1 (R206H, R258G, G328E/V/W, G356D) had longer overall survival (n=11 versus 41; median of 14.9 versus 10.9 months; p=0.05, log-rank test). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G328W sequence variation in gene ACVR1/NCBI:90 720 check_entity AN4650-1 ACVR1 G328W mutation ACVR1 NCBI:90 gene diffuse midline glioma, H3 K27M-mutant DOID:0080684 diagnostic CIViC:2156 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G328W sequence variation in gene ACVR1/NCBI:90 720 check_entity AN4651-1 ACVR1 G356D mutation ACVR1 NCBI:90 gene diffuse midline glioma, H3 K27M-mutant DOID:0080684 diagnostic PubMed:24705252 It has been reported that recurrent activating somatic mutations (R206H, R258G, G328E/V/W, G356D) in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase, are in 21% (11/52) of DIPG samples. The mutations were highly specific to DIPG, with an overall frequency of 0.3% in other tumors present in the Catalogue of Somatic Mutations in Cancer database. Data was collected from whole genome sequencing on 20 pre-treated biopsy samples of DIPG as well as whole exome sequencing from 1 biopsy sample and five samples obtained at autopsy. An additional 26 DIPG biopsy samples were screened via Sanger sequencing and identified the variant (G328W). DIPG cases with somatic mutations of ACVR1 (R206H, R258G, G328E/V/W, G356D) had longer overall survival (n=11 versus 41; median of 14.9 versus 10.9 months; p=0.05, log-rank test). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G356D sequence variation in gene ACVR1/NCBI:90 721 check_entity AN4651-1 ACVR1 G356D mutation ACVR1 NCBI:90 gene diffuse midline glioma, H3 K27M-mutant DOID:0080684 diagnostic CIViC:3530 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G356D sequence variation in gene ACVR1/NCBI:90 721 check_entity AN4652-1 ACVR1 Gain-of-Function ACVR1 NCBI:90 gene malignant astrocytoma DOID:3069 diagnostic PubMed:24705250 The authors used whole exome sequencing on 39 midline pediatric high-grade astrocytomas (pHGAs) and identified 5 with mutations in ACVR1, with 2 occurring at G328 (G328V and G328E). The authors state that somatic mutations are specific to tumor location -- gain-of-function mutations in ACVR1 (such as G328V) occur in tumors of the pons in conjunction with H3.1 K27M (as compared to thalamic tumors with FGFR1 mutations). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ACVR1 Gain-of-Function [biomarker_term_in_review] 722 not_mapped AN4652-1 ACVR1 Gain-of-Function ACVR1 NCBI:90 gene malignant astrocytoma DOID:3069 diagnostic CIViC:1937 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ACVR1 Gain-of-Function [biomarker_term_in_review] 722 not_mapped AN4653-1 ACVR1 Mutation ACVR1 NCBI:90 gene diffuse midline glioma, H3 K27M-mutant DOID:0080684 diagnostic PubMed:24705252 It has been reported that recurrent activating somatic mutations (R206H, R258G, G328E/V/W, G356D) in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase, are in 21% (11/52) of DIPG samples. The mutations were highly specific to DIPG, with an overall frequency of 0.3% in other tumors present in the Catalogue of Somatic Mutations in Cancer database. Data was collected from whole genome sequencing on 20 pre-treated biopsy samples of DIPG as well as whole exome sequencing from 1 biopsy sample and five samples obtained at autopsy. An additional 26 DIPG biopsy samples were screened via Sanger sequencing and identified the variant (G328W). DIPG cases with somatic mutations of ACVR1 (R206H, R258G, G328E/V/W, G356D) had longer overall survival (n=11 versus 41; median of 14.9 versus 10.9 months; p=0.05, log-rank test). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ACVR1/NCBI:90 723 check_entity AN4653-1 ACVR1 Mutation ACVR1 NCBI:90 gene diffuse midline glioma, H3 K27M-mutant DOID:0080684 diagnostic CIViC:2852 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ACVR1/NCBI:90 723 check_entity AN4654-1 ACVR1 R206H mutation ACVR1 NCBI:90 gene diffuse midline glioma, H3 K27M-mutant DOID:0080684 diagnostic PubMed:24705252 It has been reported that recurrent activating somatic mutations (R206H, R258G, G328E/V/W, G356D) in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase, are in 21% (11/52) of DIPG samples. The mutations were highly specific to DIPG, with an overall frequency of 0.3% in other tumors present in the Catalogue of Somatic Mutations in Cancer database. Data was collected from whole genome sequencing on 20 pre-treated biopsy samples of DIPG as well as whole exome sequencing from 1 biopsy sample and five samples obtained at autopsy. An additional 26 DIPG biopsy samples were screened via Sanger sequencing and identified the variant (G328W). DIPG cases with somatic mutations of ACVR1 (R206H, R258G, G328E/V/W, G356D) had longer overall survival (n=11 versus 41; median of 14.9 versus 10.9 months; p=0.05, log-rank test). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R206H sequence variation in gene ACVR1/NCBI:90 724 check_entity AN4654-1 ACVR1 R206H mutation ACVR1 NCBI:90 gene diffuse midline glioma, H3 K27M-mutant DOID:0080684 diagnostic CIViC:3529 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R206H sequence variation in gene ACVR1/NCBI:90 724 check_entity AN4655-1 AGR2 EXPRESSION AGR2 NCBI:10551 gene breast cancer DOID:1612 risk PubMed:24167368 mRNA expression of AGR2 in 61 patients with tamoxifen treated postmenopausal breast cancer was determined by qRT-PCR and was inversely associated with treatment response and progression free survival (p= 0.0011, p = 0.0366 respectively). AGR2 protein expression as assessed by IHC was not significantly associated with treatment outcome. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene AGR2/NCBI:10551 725 AN4655-1 AGR2 EXPRESSION AGR2 NCBI:10551 gene breast cancer DOID:1612 risk CIViC:369 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene AGR2/NCBI:10551 725 AN4656-1 AKT1 E17K mutation AKT1 NCBI:207 gene breast cancer DOID:1612 risk 42777-3 PubMed:23888070 Breast cancer cell lines with the AKT1 E17K mutation did not show sensitivity to AKT inhibitor MK-2206, unlike cell lines with PIK3CA mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E17K sequence variation in gene AKT1/NCBI:207 726 check_entity AN4656-1 AKT1 E17K mutation AKT1 NCBI:207 gene breast cancer DOID:1612 risk 42777-3 PubMed:26351323 In a phase-I study of AZD5363, partial response was observed in 2 patients with breast and ovarian carcinoma, respectively, and AKT1 E17K mutations. While full study results have not yet been published, this paper highlights in vitro results that further confirm the role of AKT E17K mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E17K sequence variation in gene AKT1/NCBI:207 726 check_entity AN4656-1 AKT1 E17K mutation AKT1 NCBI:207 gene breast cancer DOID:1612 risk 42777-3 CIViC:4 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E17K sequence variation in gene AKT1/NCBI:207 726 check_entity AN4656-2 AKT1 E17K mutation AKT1 NCBI:207 gene cancer DOID:162 risk 42777-3 PubMed:28489509 AKT1 E17K mutations are oncogenic and occur in many cancers at a low prevalence. We performed a multihistology basket study of AZD5363. 58 patients with advanced solid tumors were treated. In patients with AKT1 E17K-mutant tumors (n = 52) and a median of 5 lines of prior therapy, the median PFS was 5.5 months , 6.6 months and 4.2 months in patients with ER+ breast, gynecologic, and other solid tumors, respectively. In an exploratory biomarker analysis, imbalance of the AKT1 E17K-mutant allele, most frequently caused by copy-neutral loss-of-heterozygosity targeting the wild-type allele, was associated with longer PFS as was the presence of coincident PI3K pathway hotspot mutations. Persistent declines in AKT1 E17K in cfDNA were associated with improved PFS and response. Responses were not restricted to patients with detectable AKT1 E17K in pretreatment cfDNA. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E17K sequence variation in gene AKT1/NCBI:207 727 check_entity AN4656-2 AKT1 E17K mutation AKT1 NCBI:207 gene cancer DOID:162 risk 42777-3 CIViC:4 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E17K sequence variation in gene AKT1/NCBI:207 727 check_entity AN4656-3 AKT1 E17K mutation AKT1 NCBI:207 gene melanoma DOID:1909 risk 42777-3 PubMed:24735930 A cell line with AKT E17K mutation was found to be sensitive to AKT inhibition with GSK2141795B in this study. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E17K sequence variation in gene AKT1/NCBI:207 728 check_entity AN4656-3 AKT1 E17K mutation AKT1 NCBI:207 gene melanoma DOID:1909 risk 42777-3 PubMed:24265155 In an in vitro study, a M229 cell line endogenously expressing BRAF V600E mutation (a known vemurafenib sensitizing mutation) and overexpressing AKT1 E17K mutation was associated with resistance to vemurafenib treatment, as compared to cells expressing BRAF V600E mutation and wildtype AKT1. Resistance was determined by assessing cell survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E17K sequence variation in gene AKT1/NCBI:207 728 check_entity AN4656-3 AKT1 E17K mutation AKT1 NCBI:207 gene melanoma DOID:1909 risk 42777-3 CIViC:4 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E17K sequence variation in gene AKT1/NCBI:207 728 check_entity AN4657-1 AKT1 Overexpression AKT1 NCBI:207 gene melanoma DOID:1909 risk 42777-3 PubMed:24265155 An in vitro study of M229 (a human melanoma cell line) endogenously expressing wild-type AKT1 and BRAF V600E (a known BRAF inhibitor sensitizing mutation) found that cells induced to stably over-express AKT1 (via viral transduction with additional copies of AKT1) were not significantly more resistant to vemurafenib (a BRAFi) than cells transduced with empty vectors, which served as the negative controls. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene AKT1/NCBI:207 729 AN4657-1 AKT1 Overexpression AKT1 NCBI:207 gene melanoma DOID:1909 risk 42777-3 CIViC:2233 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene AKT1/NCBI:207 729 AN4658-1 AKT1 Q79K mutation AKT1 NCBI:207 gene melanoma DOID:1909 risk 42777-3 PubMed:24265152 The AKT1 Q79K mutation has been shown to confer resistance to BRAF inhibitors (vemurafenib) in melanoma cell line M229. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q79K sequence variation in gene AKT1/NCBI:207 730 check_entity AN4658-1 AKT1 Q79K mutation AKT1 NCBI:207 gene melanoma DOID:1909 risk 42777-3 PubMed:24265155 In an in vitro study, a M229 cell line endogenously expressing BRAF V600E mutation (a known vemurafenib sensitizing mutation) and overexpressing AKT1 Q79K mutation was associated with resistance to vemurafenib treatment, as compared to cells expressing BRAF V600E mutation and wildtype AKT1. Resistance was determined by assessing cell survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q79K sequence variation in gene AKT1/NCBI:207 730 check_entity AN4658-1 AKT1 Q79K mutation AKT1 NCBI:207 gene melanoma DOID:1909 risk 42777-3 CIViC:169 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q79K sequence variation in gene AKT1/NCBI:207 730 check_entity AN4659-1 AKT1 S473 Phosphorylation AKT1 NCBI:207 gene colorectal cancer DOID:9256 prognostic 42777-3 PubMed:17590872 This retrospective study examines outcomes of 158 primary sporadic colorectal cancer patients who had undergone surgical resection and were treated with 5-fluorouracil based chemotherapy. Cytoplasmic overexpression of phosphorylated AKT (as assessed by IHC), was not associated with differences in disease specific survival compared to lower levels of p-AKT expression (n = 89 high, n = 69 low; p = 0.8737) or in relapse free survival (n=54 high, n = 42 low; p = 0.1974). Authors note some tumors harbored KRAS or PIK3CA mutations, but that the presence of mutations in either gene didn't correlate with levels of p-AKT expression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition AKT1 S473 Phosphorylation [biomarker_term_in_review] 731 not_mapped AN4659-1 AKT1 S473 Phosphorylation AKT1 NCBI:207 gene colorectal cancer DOID:9256 prognostic 42777-3 CIViC:3126 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition AKT1 S473 Phosphorylation [biomarker_term_in_review] 731 not_mapped AN4660-1 AKT2 Amplification AKT2 NCBI:208 gene lung adenocarcinoma DOID:3910 risk PubMed:25982012 Case report of a 74-year old woman with EGFR- and ALK-negative lung adenocarcinoma. FISH identified a deletion of 5'RET (FISH, indicating RET-gene rearrangement) and genomic testing confirmed a fusion of KIF5B and RET, as well as an AKT2 gene amplification. The patient was enrolled in a clinical trial with vandetanib and everolimus (NCT01582191) with everolimus used to enhance brain accumulation of vandetanib. After two cycles of therapy a repeat MRI brain showed a decrease in the intracranial disease burden and PET/CT showed systemic response as well. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene AKT2/NCBI:208 732 AN4660-1 AKT2 Amplification AKT2 NCBI:208 gene lung adenocarcinoma DOID:3910 risk CIViC:631 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene AKT2/NCBI:208 732 AN4661-1 AKT2 EXPRESSION AKT2 NCBI:208 gene breast cancer DOID:1612 risk PubMed:22842582 In HER2+ metastatic breast cancer treated with trastuzumab (n = 74 patients), the expression of AKT2 and pAkt-Thr308 and/or pAkt-Ser473 localized in nucleus+cytoplasm was associated with an improved time to progression (TTP) and overall survival (OS) compared to AKT2 negative tumors as measured by immunohistochemistry. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene AKT2/NCBI:208 733 AN4661-1 AKT2 EXPRESSION AKT2 NCBI:208 gene breast cancer DOID:1612 risk CIViC:274 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene AKT2/NCBI:208 733 AN4662-1 AKT3 E17K mutation AKT3 NCBI:10000 gene melanoma DOID:1909 risk PubMed:24265155 An in vitro study of M229 (a human melanoma cell line) endogenously expressing wildtype AKT3 and BRAF V600E (a known BRAF inhibitor sensitizing mutation) found that cells virally induced to stably over-express AKT3 E17K were significantly more resistant to BRAF inhibition via vemurafenib than cells transduced with empty vectors (40% vs 20% survival, p = .0033). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E17K sequence variation in gene AKT3/NCBI:10000 734 check_entity AN4662-1 AKT3 E17K mutation AKT3 NCBI:10000 gene melanoma DOID:1909 risk CIViC:1201 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E17K sequence variation in gene AKT3/NCBI:10000 734 check_entity AN4663-1 AKT3 Overexpression AKT3 NCBI:10000 gene breast cancer DOID:1612 risk PubMed:27297869 Upregulation of AKT3 due to epigenetic reprogramming may confer acquired resistance to AKT inhibitor (MK2206) in breast cancer preclinical model. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene AKT3/NCBI:10000 735 AN4663-1 AKT3 Overexpression AKT3 NCBI:10000 gene breast cancer DOID:1612 risk CIViC:1275 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene AKT3/NCBI:10000 735 AN4663-2 AKT3 Overexpression AKT3 NCBI:10000 gene melanoma DOID:1909 risk PubMed:24265155 An in vitro study of M229 (a human melanoma cell line) endogenously expressing wildtype AKT3 and BRAF V600E (a known BRAF inhibitor sensitizing mutation) found that cells induced to stably over-express AKT3 (via viral transduction of additional copies of wild type AKT3) were significantly more resistant to BRAF inhibition by vemurafenib than cells transduced with empty vectors (30% vs 20% survival, p = .0064). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene AKT3/NCBI:10000 736 AN4663-2 AKT3 Overexpression AKT3 NCBI:10000 gene melanoma DOID:1909 risk CIViC:1275 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene AKT3/NCBI:10000 736 AN4663-3 AKT3 Overexpression AKT3 NCBI:10000 gene triple-receptor negative breast cancer DOID:0060081 risk PubMed:24335962 AKT3 was found to be preferentially required for the proliferation and tumor growth of TNBC. It was found to be upregulated in a set of TNBC cell lines compared to other breast cancer types. Depletion of AKT3 in TNBC sensitizes cells to the pan-Akt inhibitor GSK690693. It was found that depletion of Akt3 potentially inhibits the growth of TNBC cell lines in three-dimensional (3D) spheroid cultures and in mouse xenograft models, which imply that therapeutic targeting of AKT3 may provide a new treatment option for TNBCs. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene AKT3/NCBI:10000 737 AN4663-3 AKT3 Overexpression AKT3 NCBI:10000 gene triple-receptor negative breast cancer DOID:0060081 risk CIViC:1275 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene AKT3/NCBI:10000 737 AN4664-1 ALCAM EXPRESSION ALCAM NCBI:214 gene colorectal cancer DOID:9256 risk PubMed:24708484 112 patients with rectal cancer who received 5-FU based chemotherapy and surgery were retrospectively analyzed for expression of Ki67, TS, BAX, EpCAM, p53, p21, EGFR, CD44, CD133, CD166, HIF1α and ALDH1. Pretreatment CD166 (ALCAM) expression level was associated with poor disease free survival (p = 0.003; HR 5.61; 95% CI 1.81, 17.35). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene ALCAM/NCBI:214 738 AN4664-1 ALCAM EXPRESSION ALCAM NCBI:214 gene colorectal cancer DOID:9256 risk CIViC:352 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene ALCAM/NCBI:214 738 AN4665-1 ALDH1A2 Overexpression ALDH1A2 NCBI:8854 gene head and neck squamous cell carcinoma DOID:5520 prognostic PubMed:26634247 IHC for expression of ALDH1A2 and CRABP2 was performed in 89 patients with squamous cell carcinoma of the head and neck. High expression of both, ALDH1A2 and CRABP2 (in comparison to ALDH1A2 low or ALDH1A2 high and CRABP2 low) was significantly associated with OS and PFS in multivariate Cox analysis (OS, HR: 0.303, 95%CI 0.14–0.63, p-value 0.002 PFS, HR: 0.395, 95%CI 0.20–0.77, p-value 0.007). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ALDH1A2/NCBI:8854 739 AN4665-1 ALDH1A2 Overexpression ALDH1A2 NCBI:8854 gene head and neck squamous cell carcinoma DOID:5520 prognostic PubMed:23635773 ALDH1A2 protein levels were determined (IHC) in 115 patients with oropharyngeal squamous cell carcinoma with known HPV status (n = 89 non–HPV-driven; n = 26 HPV-driven). Low to moderate ALDH1A2 protein levels (combined as ALDH1A2low) were identified in keratinocytes of healthy mucosa as well as 73 (63.5%) primary tumors, and high ALDH1A2 protein levels in 42 (36.5%) primary tumors. Significantly higher ALDH1A2 protein levels were identified in HPV-driven than non-HPV-driven tumors. Moreover, PFS and OS strongly correlated with the ALDH1A2 protein expression level (OS, P < 0.001; PFS, P = 0.001; log-rank/Mantel-Cox test. Previous analyses in the same study identify hypermethylation of ALDH1A2 as the underlying mechanism of differential protein expression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ALDH1A2/NCBI:8854 739 AN4665-1 ALDH1A2 Overexpression ALDH1A2 NCBI:8854 gene head and neck squamous cell carcinoma DOID:5520 prognostic CIViC:468 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ALDH1A2/NCBI:8854 739 AN4666-1 ALDH1A2 Underexpression ALDH1A2 NCBI:8854 gene head and neck squamous cell carcinoma DOID:5520 risk PubMed:26634247 FaDu (a high ALDH1A2 expression cell line) and Cal27 (a low expression cell line) were treated with all-trans retinoic acid (ATRA), Adapalene or Fenretinide. This led to concentration dependent decrease in the survival fraction in both cell lines with higher efficacy in Cal27 (ED50 ≈ 1 μM) as compared to FaDu cells (ED ≈ 44 μM). Treatment with 3 μM ATRA sensitized Cal27 cells to irradiation at a dose of 2 Gy, but had no or only a minor effect on ALDH1A2-postitive cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ALDH1A2/NCBI:8854 740 AN4666-1 ALDH1A2 Underexpression ALDH1A2 NCBI:8854 gene head and neck squamous cell carcinoma DOID:5520 risk CIViC:469 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ALDH1A2/NCBI:8854 740 AN4667-1 ALK Alternative Transcript (ATI) ALK NCBI:238 gene mucosal melanoma DOID:0050929 risk 100019-9 PubMed:29054983 ALK expression was analyzed in 45 melanoma patient-derived xenografts (PDXs), with 11/45 showing ALK expression. Four PDX tumours had only wild-type ALK expression, four had only ALK alternative transcript (ATI) expression, two had wild-type and ATI expression, and one had ALK ATI and multiple EML4-ALK fusion variants. In vitro and in vivo experiments showed that an EML4-ALK fusion expressing sample responded to ALK inhibitors while wild-type ALK and ALK ATI expressing samples did not. Decreased activity in downstream signaling targets with ALK inhibitor treatment was noted for samples expressing fusion ALK but not those expressing only ALK ATI. Further, a patient with metastatic mucosal melanoma expressing ALK ATI was treated with the ALK/ROS1/TRK inhibitor entrectinib but experienced rapid clinical and radiologic progression resulting in treatment discontinuation after two weeks. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ALK Alternative Transcript (ATI) [biomarker_term_in_review] 741 not_mapped AN4667-1 ALK Alternative Transcript (ATI) ALK NCBI:238 gene mucosal melanoma DOID:0050929 risk 100019-9 CIViC:813 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ALK Alternative Transcript (ATI) [biomarker_term_in_review] 741 not_mapped AN4667-2 ALK Alternative Transcript (ATI) ALK NCBI:238 gene skin melanoma DOID:8923 risk 100019-9 PubMed:26444240 Expression of an alternative ALK transcript (ATI), encompassing exons 20–29 preceded by ~400 base pairs (bp) of intron 19, but not exons 1–19 was identified in three samples of thyroid cancer and melanoma. In TCGA samples, ALK ATI was expressed in approx. 11% of melanoma samples. Functional activity of ALK ATI was shown in-vitro. In vivo studies confirmed oncogenic activity of ALK ATI similar to other ALK mutations or fusions and sensitivity to crizotinib. A patient with metastatic melanoma and ALK ATI expression but no MET or ALK aberrations identified with FISH and a 341-gene panel sequencing was treated with crizotinib and had symptomatic improvement and tumor shrinkage within 6 weeks of therapy assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ALK Alternative Transcript (ATI) [biomarker_term_in_review] 742 not_mapped AN4667-2 ALK Alternative Transcript (ATI) ALK NCBI:238 gene skin melanoma DOID:8923 risk 100019-9 CIViC:813 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ALK Alternative Transcript (ATI) [biomarker_term_in_review] 742 not_mapped AN4668-1 ALK Amplification ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:22277784 Amplification of wild-type EML4-ALK in the non-small cell lung carcinoma cell line, H3122, caused resistance to crizotinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ALK/NCBI:238 743 AN4668-1 ALK Amplification ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:22235099 This study analyzed patients with non small cell lung cancer (NSCLC) who were positive for EML4-ALK fusions (ALK+) and progressed on crizotinib monotherapy. One out of 11 patients with acquired crizotinib resistance showed >4-fold increase in rearranged ALK copy number between pre- and post- crizotinib biopsies as measured by FISH. This patient's tumor did not harbor ALK point mutations, and was wt for KRAS and EGFR. This patient was a 51 year old non-smoking male with adenocarcinoma, whose best response was partial response (454 days on crizotinib, 2 prior lines of therapy). The authors suggest that ALK copy number gain alone may induce crizotinib resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ALK/NCBI:238 743 AN4668-1 ALK Amplification ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:23344087 One patient with ALK-rearranged non-small cell lung cancer and an acquired resistance to crizotinib showed new ALK amplification (4.1 fold increase compared to pre-crizotinib specimen as measured by FISH) and harbored an EGFR L858R mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ALK/NCBI:238 743 AN4668-1 ALK Amplification ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4172 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ALK/NCBI:238 743 AN4669-1 ALK C1156Y mutation ALK NCBI:238 gene lung adenocarcinoma DOID:3910 risk 100019-9 PubMed:20979473 A 28 year-old patient with T4N3M1 stage lung adenocarcinoma harboring an EML4-ALK variant 1 fusion was treated with crizotinib after failing conventional therapy. The patient achieved a partial response, but progressed after 5 months of treatment. Molecular analysis at relapse identified C1156Y in the ALK kinase domain of the fusion at an allele frequency of 41.8%. This variant was undetected by Sanger sequencing in the tumor collected before crizotinib treatment. Cytotoxicity assays revealed Ba/F3 cells expressing EML4-ALK C1156Y were more resistant to crizontinib than those expressing EML4-ALK wildtype. Immunoblot demonstrated crizontinib reduced tyrosine phosphorylation of the wildtype fusion, but not the EML4-ALK C1156Y fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C1156Y sequence variation in gene ALK/NCBI:238 744 check_entity AN4669-1 ALK C1156Y mutation ALK NCBI:238 gene lung adenocarcinoma DOID:3910 risk 100019-9 CIViC:4225 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C1156Y sequence variation in gene ALK/NCBI:238 744 check_entity AN4669-2 ALK C1156Y mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:26698910 In this case report, a patient with metastatic, ALK-rearranged NSCLC with C1156Y mutation had tumor progression under sequential treatment with first crizotinib, then ceritinib and finally AUY922. Subsequent chemotherapy (carboplatin–pemetrexed) was administered and the patient had a response for 6 months before progression. Exome sequencing revealed the C1156Y mutation was present in <7% of the pretreatment tumor and in ~50% of the crizotinib tumor prior to ceritinib therapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C1156Y sequence variation in gene ALK/NCBI:238 745 check_entity AN4669-2 ALK C1156Y mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:24675041 EML4-ALK variant 3 containing NSCLC cell line H2228 xenografts in SCID beige mice were treated with increasing doses of crizotinib up to 100 mg/kg per day by oral gavage. At approximately 40 days tumors progressed. 80 progressed tumors were tested for ALK mutations, and 6 mutant ALK variants were found. Two of the mutations were at ALK C1156Y. In Ba/F3 cells, EML4-ALK variant 3 with C1156Y was introduced and tested for crizotinib sensitivity. Survival IC50 value of 177 nM was reported, which is 9.3 times the IC50 reported for crizotinib in EML4-ALK wild-type Ba/F3 cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C1156Y sequence variation in gene ALK/NCBI:238 745 check_entity AN4669-2 ALK C1156Y mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4225 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C1156Y sequence variation in gene ALK/NCBI:238 745 check_entity AN4669-2 ALK C1156Y mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4253 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C1156Y sequence variation in gene ALK/NCBI:238 745 check_entity AN4670-1 ALK CAD::ALK mutation ALK NCBI:238 gene colorectal cancer DOID:9256 risk 100019-9 PubMed:26633560 A patient with colorectal cancer harboring a CAD-ALK fusion gene was treated with the ALK inhibitor entrectinib, resulting in durable objective tumor response. A CT scan four weeks after treatment initiation showed a 38% reduction in target lesions, and response was ongoing after 4 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CAD::ALK sequence variation in gene ALK/NCBI:238 746 check_entity AN4670-1 ALK CAD::ALK mutation ALK NCBI:238 gene colorectal cancer DOID:9256 risk 100019-9 CIViC:2638 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CAD::ALK sequence variation in gene ALK/NCBI:238 746 check_entity AN4671-1 ALK CLTC::ALK mutation ALK NCBI:238 gene diffuse large B-cell lymphoma DOID:0050745 prognostic;risk 100019-9 PubMed:21494621 A cell line called LM1 was established from the bone marrow of a 13 year old female patient with relapsed CLTC-ALK positive diffuse large B-cell lymphoma (DLBCL). The patient had been heavily treated with chemotherapy before establishment of the cell line. The cell line maintained the tumor immunophenotype. SNP analysis of patient bone marrow mononuclear cells and LM1 showed chromosomal changes associated with the cell line but 94.7% of SNPs were identically called. ALK kinase inhibitor TAE684 induced cell death in LM1 cells at low nanomolar concentrations, while it did not significantly effect the ALK-rearrangement negative DLBCL cell line Karpas422. LM1 cells formed tumors in 3/10 SCID and 9/10 NOD-SCID mice. CD30 and CD138 immmunostaining were maintained between original tumor and LM1 xenografts. In mice, LM1 but not Karpas422 xenografts regressed with TAE684 administration, and complete remission for 13 weeks was observed before experiment was terminated. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CLTC::ALK sequence variation in gene ALK/NCBI:238 747 check_entity AN4671-1 ALK CLTC::ALK mutation ALK NCBI:238 gene diffuse large B-cell lymphoma DOID:0050745 prognostic;risk 100019-9 PubMed:19636007 CLTC-ALK is one of the most common ALK fusions found in diffuse large B cell lymphoma (DLBCL). In a retrospective study of 38 patients with ALK-rearranged DLBCL, 3 were CD20 positive. Only one showed cytoplasmic, nuclear and nucleolar staining associated with NPM-ALK, while the others showed granular cytoplasmic ALK stain characteristic for CLTC-ALK. Seven molecularly characterized cases were positive for CLTC-ALK. 6/7 patients were treated with CHOP chemotherapy with survival of 5, 10, 26 and 27 months, and two alive at end of study, and one CD20 positive patient was treated with CHOP chemotherapy supplemented with CD20-targeted rituximab, with survival of 8 months, resulting in median survival of 26 months for this group. Although these numbers are not sufficient for statistical comparison, they compare unfavorably to 3.1 year overall survival and 45% 5 year survival of CHOP treated DLBCL patients, and even less favorably to R-CHOP standard of care for CD20 positive DLBCL, suggesting poor prognosis for CLTC-ALK DLBCL and need for updated treatment in this cohort. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CLTC::ALK sequence variation in gene ALK/NCBI:238 747 check_entity AN4671-1 ALK CLTC::ALK mutation ALK NCBI:238 gene diffuse large B-cell lymphoma DOID:0050745 prognostic;risk 100019-9 PubMed:26221234 A 21 year old male presented with lymphadenopathy and a low density mass in pancreas. Histopathological analysis showed diffuse tumor cell infiltrate (CD20/EMA negative) with cytoplasmic ALK. RT-PCR indicated CLTC-ALK fusion. The patient was diagnosed with splenic ALK + diffuse large B cell lymphoma (DLBCL), Stage III, Group A with an IPI of 3. CHOP-21 chemotherapy regimen was administered with improvement in abdominal lymph nodes but worsening in retroperitoneal lymph nodes assessed via standardized uptake values. Subsequent ICE chemotherapy regiment relieved some symptoms prompting the patient to refuse further treatment despite other indications of disease progression. Therapy was reinstated after worsening of disease. GEMOX chemotherapy was administered with dexamethasone and 250mg crizotinib twice daily resulting in symptom relief, decreased lymphadenopathy and LDH decline. The disease then progressed and the patient died 2 months after crizotinib initiation. The authors conclude that partial response to crizotinib was observed and that in future trials ALK rearranged DLBCL patients might see increased benefit with earlier application of targeted therapy during the treatment course. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CLTC::ALK sequence variation in gene ALK/NCBI:238 747 check_entity AN4671-1 ALK CLTC::ALK mutation ALK NCBI:238 gene diffuse large B-cell lymphoma DOID:0050745 prognostic;risk 100019-9 CIViC:516 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CLTC::ALK sequence variation in gene ALK/NCBI:238 747 check_entity AN4672-1 ALK EML4::ALK e2-e20 ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:18927303 Multiplex RT-PCR to detect in-frame fusions of EML4 to ALK was performed on total RNA from 253 lung adenocarcinomas, and 9 samples were found to contain such fusions, one of which was a novel fusion containing EML4 exon 2 and exon 20 of ALK. This was called variant 5. Two versions of this variant were seen: 5a consisted of EML4 exon 2 fused to ALK exon 20 while 5b contained a 117bp intronic ALK region between the two exons. Genomic PCR showed that EML4-ALK variant 5 tumor cells contained a single EML4-ALK fusion, suggesting 5a and 5b arise from alternate splicing. 5a and 5b showed in-vitro kinase activity and transformed 3T3 cells in cell culture. 5a and 5b transformed 3T3 cells formed tumors when injected in 8/8 nude mice, but 3T3 transformed with ALK alone did not. These results suggest that EML4-ALK variant 5 is a driver mutation in lung adenocarcinoma targetable by ALK inhibitors like crizotinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ALK EML4::ALK e2-e20 [biomarker_term_in_review] 748 not_mapped AN4672-1 ALK EML4::ALK e2-e20 ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:497 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ALK EML4::ALK e2-e20 [biomarker_term_in_review] 748 not_mapped AN4672-2 ALK EML4::ALK e2-e20 ALK NCBI:238 gene renal cell carcinoma DOID:4450 risk 100019-9 PubMed:22252991 Adenocarcinoma cells were detected via urinary cytology in a 53 year old woman. Cancer morphology suggested papillary renal cell carcinoma (RCC), type 2A. EML4-ALK variant 5 was discovered in tumor tissue using PCR with EML4 and ALK specific primers. The authors conclude that their findings confirm the potential for ALK targeting therapy in select cases of RCC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ALK EML4::ALK e2-e20 [biomarker_term_in_review] 749 not_mapped AN4672-2 ALK EML4::ALK e2-e20 ALK NCBI:238 gene renal cell carcinoma DOID:4450 risk 100019-9 CIViC:497 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ALK EML4::ALK e2-e20 [biomarker_term_in_review] 749 not_mapped AN4673-1 ALK EML4::ALK e20-e20 ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:20979469 In the PROFILE 1001 study, from 31 NSCLC tumors positive for ALK fusions with sufficient material for RT-PCR aided exon breakpoint identification, 1 case of EML4-ALK variant 2 (EML4 exon 20 fused to ALK exon 20) was found. This patient had adenocarcinoma and a 9 pack year smoking history. Crizotinib treatment duration was over 16 weeks. The patient had multiple lines of prior treatment and showed a partial response to first-time crizotinib treatment. Overall, in the 82 ALK positive patients treated in the study, 46 had partial responses (including this patient) and 1 had a complete response for an overall response rate of 57%. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ALK EML4::ALK e20-e20 [biomarker_term_in_review] 750 not_mapped AN4673-1 ALK EML4::ALK e20-e20 ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:22912387 EML4-ALK variants v1 (E13;A20), v2 (E20;A20), v3a (E6;A20) and v3b (E6ins33;A20) were expressed in Ba/F3 cells using retrovirus. While all constructs rendered Ba/F3 cells IL3-independant, marked differences in sensitivity to ALK inhibitors TAE684 and crizotinib were observed, where v2 was most sensitized to growth inhibition and v3a the least, with v1 and v3b intermediate. While phospho-ALK western blots indicated that the ALK inhibitors acted similarly on both v2 and v3a EML4-ALK variants, blots of cyclohexamide-treated cells showed that v2 had a shorter half-life than 3a in the transduced cells, potentially explaining increased v2 sensitivity. Assays with a panel of mutated EML4-ALK variants of varied length suggested that longer EML4-ALK variants are less stable in cells, although this tendency was not observed across other types of ALK fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ALK EML4::ALK e20-e20 [biomarker_term_in_review] 750 not_mapped AN4673-1 ALK EML4::ALK e20-e20 ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:496 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ALK EML4::ALK e20-e20 [biomarker_term_in_review] 750 not_mapped AN4674-1 ALK EML4::ALK e6-e20 ALK NCBI:238 gene cancer DOID:162 risk 100019-9 PubMed:25408655 This case study presented a 53-year-old never-smoker with a poorly differentiated malignant neoplasm. Morphology and immunohistochemistry were unable to establish the primary tumor site. Right upper extremity (RUE), scalp, and multiple lung lesions were apparent. A lung lesion sample with sufficient material for molecular profiling was not attainable but sufficient material was present from the RUE for hybrid capture genomic profiling (FoundationOne kit was used). EML4-ALK variant 3 was found, and the patient was started on crizotinib. Rapid symptom improvement was seen. After 1 month, a CT scan showed significant size reduction in lung tumors, and after 5 months the patient was asymptomatic with an entirely negative examination. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ALK EML4::ALK e6-e20 [biomarker_term_in_review] 751 not_mapped AN4674-1 ALK EML4::ALK e6-e20 ALK NCBI:238 gene cancer DOID:162 risk 100019-9 CIViC:499 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ALK EML4::ALK e6-e20 [biomarker_term_in_review] 751 not_mapped AN4674-2 ALK EML4::ALK e6-e20 ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:18593892 In a cohort of 75 NSCLC patients that had tested positive for 3 EML4-ALK rearrangements, two individuals were identified via RT-PCR with a novel EML4-ALK translocation involving the first 6 exons of EML4 fused to the kinase domain of ALK. Genomic PCR resolved a single breakpoint, but 2 variants of the fusion were observed in cells. Variant 3a consisted of fusion at EML4 exon 6 and ALK exon 20, while variant 3b fused a 33 bp intronic EML4 region between EML4 exon 6 and ALK exon 20. 3a and 3b showed strong in-vitro kinase activity, transformed mouse 3T3 cells, and 3b-transformed 3T3 cells formed tumors in 8/8 nude mice. The ALK inhibitor 2,4-pyrimidinediamine inhibited growth of the 3a/b containing NCI-H2228 NSCLC cell line. The results indicate that 3a/b is a targetable driver-mutation as other EML4-ALK variants. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ALK EML4::ALK e6-e20 [biomarker_term_in_review] 752 not_mapped AN4674-2 ALK EML4::ALK e6-e20 ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:20979469 In a set of 31 patients with NSCLC, RT-PCR was performed to test for known EML4-ALK variants. Five patients tested positive for the 3a/3b EML4-ALK variant. Of these, 4 had partial response (PR), and one had disease progression (DP), and this was the only DP in the group of 31. In contrast, of the 13 testing positive for EML4-ALK variant 1, 12 showed PR, and 1 showed stable disease. These results potentially mirror findings in the H2228 3a/3b containing NSCLC cell line where some literature indicates it does respond as strongly to ALK inhibition as other EML4-ALK NSCLC cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ALK EML4::ALK e6-e20 [biomarker_term_in_review] 752 not_mapped AN4674-2 ALK EML4::ALK e6-e20 ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:18451166 In a panel of 602 cancer cell lines, 3/134 NSCLC cell lines showed <0.5% cell viability following treatment with the ALK inhibitor TAE684. Of these, NCI-H2228 harbored EML4-ALK variant 3a/b (EML4 exon 6 and ALK exon 20). TAE684 inhibited Akt and Erk1/2 phosphorylation in H2228 cells and appeared to induce a cytostatic response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ALK EML4::ALK e6-e20 [biomarker_term_in_review] 752 not_mapped AN4674-2 ALK EML4::ALK e6-e20 ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:18594010 Exon-array and RT-PCR was used to screen a panel of 83 NSCLC cell lines for EML4-ALK variants. The cell lines NCI-H3122 (containing EML4-ALK variant 1) and NCI-H2228 (containing the EML4 exon 6 and ALK exon 20 fusion-variant 3a/3b) were identified. TAE684 (0.1uM) appreciably inhibited growth as well as Akt and Erk1/2 phosphorylation in variant 1 containing H3122 cells. However, incomplete inhibition in 3a/3b containing H2228 cells was observed. H2228 growth inhibition by TAE684 was more similar to NSCLC cell lines harboring KRAS and EGFR mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ALK EML4::ALK e6-e20 [biomarker_term_in_review] 752 not_mapped AN4674-2 ALK EML4::ALK e6-e20 ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:22912387 Ba/F3 cells transduced with EML4-ALK variants v1 (E13;A20), v2 (E20;A20), v3a (E6;A20) and v3b (E6ins33;A20) showed differential sensitivity to both crizotinib and TAE684, with variant 3a (E6;A20) being the least sensitive. The authors suggest that the type/structure of ALK fusion may have some impact on patient outcome in targeted therapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ALK EML4::ALK e6-e20 [biomarker_term_in_review] 752 not_mapped AN4674-2 ALK EML4::ALK e6-e20 ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:24675041 Ceritinib was 28x more potent (GI50 3.8nM) than crizotinib (GI50 107nM) at inhibiting growth of H2228, an NSCLC cell line which harbors the EML4-ALK variant 3a/3b. SCID mice xenografted with H2228 were treated for 14 days with crizotinib (100 mg/kg) or ceritinib (25 or 50 mg/kg). All treatments caused tumor regression, but tumors recurred within 11 days after crizotinib treatment withdrawal. 4/8 mice treated with 25 mg/kg ceritinib showed regrowth after 1 month treatment withdrawal. The remaining 4/8 mice treated at 25 mg/kg ceritinib, and all mice treated at 50 mg/kg ceritinib maintained complete remission for four months. While 100 mg/kg crizotinib in mice approximates levels 3-5 times the maximal tolerated dose in humans, the authors state 25 to 50 mg/kg ceritinib in mice is predicted to approximate tolerable doses in humans. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ALK EML4::ALK e6-e20 [biomarker_term_in_review] 752 not_mapped AN4674-2 ALK EML4::ALK e6-e20 ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:499 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ALK EML4::ALK e6-e20 [biomarker_term_in_review] 752 not_mapped AN4675-1 ALK EML4::ALK mutation ALK NCBI:238 gene cancer DOID:162 risk 100019-9 PubMed:22034911 A Ba/F3 cell line expressing EML4-ALK variant 1 was created, and then exposed to the DNA modifying agent ENU. Cells were subsequently cultured in 96 well plates at increasing concentrations of crizotinib (250, 500, 720, 1000, 1440 and 2000 nM). Cell growth occurred in all wells at 250 nM, and was absent at 2000 nM. From 500 through 1440 nM there were progressively fewer resistant clones present. 422 mutations representing 16 different sites were identified. EML4-ALK F1245C was found at 500 nM crizotinib, and was among the 10 most frequently observed mutations. Ba/F3 cells with unaltered EML4-ALK had crizotinib IC50 values for viability of 132 +/- 45 nM. EML4-ALK F1245C clones from the selection assay had IC50 viability value of 425 +/- 100 nM, while Ba/F3 cells expressing reintroduced EML4-ALK F1245C had IC50 value of 269 +/- 194 nM. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 753 check_entity AN4675-1 ALK EML4::ALK mutation ALK NCBI:238 gene cancer DOID:162 risk 100019-9 PubMed:24675041 Ba/F3 cells expressing the EML4-ALK S1206Y variant were treated with ceritinib, and survival GI50 value of 1.5 nM was obtained, which compares favorably with GI50 of 1.7 for the highly ceritinib sensitive EML4-ALK wild-type variant obtained in parallel experiments, as well as the GI50 value of 16 nM obtained for crizotinib treatment of EML4-ALK wild-type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 753 check_entity AN4675-1 ALK EML4::ALK mutation ALK NCBI:238 gene cancer DOID:162 risk 100019-9 PubMed:25727400 Ba/F3 cell line expressing EML4-ALK variant 3 with G1202R ALK mutation was assessed for alectinib sensitivity and IC50 for survival of 868 nM was reported, which was 64.4x higher than the IC50 reported for alectinib on Ba/F3 with EML4-ALK wild-type. Similar experiments using NPM-ALK instead of EML4-ALK yielded survival IC50 of 549 nM of NPM-ALK G1202R to alectinib, which was 27.9 times higher than IC50 for NPM-ALK wild-type. Western blots of Ba/F3 with NPM-ALK wild-type showed ablation of pALK levels above 100 nM alectinib, while pALK levels were essentially unchanged up to 1000 nM in NPM-ALK G1202R Ba/F3 cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 753 check_entity AN4675-1 ALK EML4::ALK mutation ALK NCBI:238 gene cancer DOID:162 risk 100019-9 CIViC:4221 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 753 check_entity AN4675-1 ALK EML4::ALK mutation ALK NCBI:238 gene cancer DOID:162 risk 100019-9 CIViC:4309 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 753 check_entity AN4675-1 ALK EML4::ALK mutation ALK NCBI:238 gene cancer DOID:162 risk 100019-9 CIViC:4237 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 753 check_entity AN4675-2 ALK EML4::ALK mutation ALK NCBI:238 gene lung acinar adenocarcinoma DOID:6482 risk 100019-9 PubMed:23181703 A 39-year-old man presented was observed to have lung acinar adenocarcinoma. Treatment with chemotherapy produced no remarkable response. A EGFR L858R point mutation was observed; the patient was therefore treated with erlotinib, but the disease progressed after 30 days. A second biopsy identified a EML4-ALK fusion, which may explain the therapeutic resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 754 check_entity AN4675-2 ALK EML4::ALK mutation ALK NCBI:238 gene lung acinar adenocarcinoma DOID:6482 risk 100019-9 CIViC:5 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 754 check_entity AN4675-3 ALK EML4::ALK mutation ALK NCBI:238 gene lung adenocarcinoma DOID:3910 risk 100019-9 PubMed:20979473 A 28 year-old patient with non-small cell lung cancer that failed conventional therapy was found to harbor the EML4-ALK (E13;A20) fusion using reverse transcription PCR. Treatment with 250mg crizotinib twice daily resulted in rapid improvement of symptoms and disease control for 5 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 755 check_entity AN4675-3 ALK EML4::ALK mutation ALK NCBI:238 gene lung adenocarcinoma DOID:3910 risk 100019-9 CIViC:5 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 755 check_entity AN4675-3 ALK EML4::ALK mutation ALK NCBI:238 gene lung adenocarcinoma DOID:3910 risk 100019-9 CIViC:4225 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 755 check_entity AN4675-3 ALK EML4::ALK mutation ALK NCBI:238 gene lung adenocarcinoma DOID:3910 risk 100019-9 CIViC:4230 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 755 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:17625570 A retroviral cDNA expression library was constructed using a lung adenocarcinoma specimen from a 67 year old NSCLC patient, and transfected into mouse 3T3 fibroblasts which were assessed for transformed foci. Analysis of clones from one transformed focus yielded a novel fusion. This fusion generated a protein with N-terminal consisting of EML4 exons 1-13 and C-terminal consisting of ALK exons 20-29, which comprise the intracellular kinase domain of ALK. In subsequent experiments using EML4-ALK or altered versions, the transforming potential of EML4-ALK was found to be dependent on a functional ALK kinase activity as well as the EML4 basic domain, which was shown to have an important role in EML4-ALK dimer formation. BA/F3 cells expressing EML4-ALK were able to grow independently of IL3 addition, but addition of ALK inhibitor WHI-P154 induced cell death and inhibited tyrosine phosphorylation of EML4-ALK. These results indicated that EML4-ALK may be a driver mutation in NSCLC, and a target for ALK inhibitor treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:21258415 In preclinical work using H3122 NSCLC cells which contain the EML4-ALK variant 1, administration of the Hsp90 inhibitor IPI-504 caused marked decrease of EML4-ALK protein levels at concentrations lower than those used to knock down protein levels of drivers such as HER2 or EGFR in other cell lines, making it the most sensitive Hsp90 client protein the authors had encountered. IPI-504 treatment caused regression of H3122 tumors in nude mice, whereas Hsp90 inhibitors usually only cause growth inhibition in these models. Combined treatment of these mice with IPI-504 and crizotinib caused an even stronger tumor regression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:22912387 Transduction of Ba/F3 cells with EML4-ALK variant 1 causes IL3 independent growth. Incubation of EML4-ALK variant 1 transduced Ba/F3 cells with Hsp90 inhibitor 17-DMAG caused cell death that was reversible with IL3 addition, suggesting that 17-DMAG was effecting the EML4-ALK driver of IL3-independant proliferation, and that EML4-ALK variant 1 is a client protein of Hsp90. The degree of Hsp90 dependence, and targetability of EML4-ALK for Hsp90 inhibition, may vary among ALK fusion variants. Addition of crizotinib to 17-DMAG caused synergistic death effects, suggesting potential clinical benefit for this inhibitor combination in targeting EML4-ALK variant 1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:20979469 In the PROFILE 1001 study of crizotinib in 82 patients with ALK-rearranged NSCLC, 31 patients with sufficient tumor material were tested using RT-PCR for the presence of certain EML4-ALK variants. 13/31 tested patients had the EML4-ALK variant 1. Of these, 12/13 had a partial response, and 1 had stable disease. This response rate of 92% is in contrast to the 57% response rate in the overall patient population, but the numbers of patients with specific EML4-ALK breakpoints were insufficient to correlate with patient response rate. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:26554404 EML4-ALK variant 1 containing H-3122 NSCLC cells were treated with second generation ALK inhibitor PF-06463922. PF-06463922 was 125x more potent at reducing cell viability than crizotinib. Control neuroblastoma cell lines with wild-type ALK did not show inhibition below 3800 nM with either drug. At values of 10 and 100 nM, PF-06463922 showed increased ability to inhibit ALK 1278 tyrosine phosphorylation in H3122 cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:21575866 CH5424802 treatment resulted in significant tumor regression in xenograft models produced from Ba/F3 cells expressing EML4-ALK or EML4-ALK with the L1196M mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:22277784 Amplification of wild-type EML4-ALK in the non-small cell lung carcinoma cell line, H3122, caused resistance to crizotinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:21791641 Case-report of a patient with an acquired EML4::ALK L1152R mutation and resistance to crizotinib treatment. The L1152R variant was not present in the pre-crizotinib sample. A cell line model also showed resistance against ALK inhibition. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:22235099 This study analyzed patients with non small cell lung cancer (NSCLC) who were positive for EML4-ALK fusions (ALK+) and progressed on crizotinib monotherapy. One ALK+ patient harbored the common E6;A20 fusion with ALK G1269A co-mutation in post-crizotinib progression biopsies. The presence of ALK G1269A pre-crizotinib could not be evaluated. This patient was a 21 year old non-smoking male with adenocarcinoma, wt for KRAS and EGFR, negative for ALK copy number gain, who experienced crizotinib as a 2nd line therapy. The patient's best response on crizotinib was stable disease (377 days on treatment). In vitro, Ba/F3 cell line expressing EML4-ALK fusion (E6a;A20, a known sensitizing alteration) and ALK G1269A co-mutation demonstrated resistance to crizotinib treatment (341 nmol/L vs. 22 nmol/L) compared to Ba/F3 cells expressing EML4-ALK fusion. Resistance was determined by assessing cell viability and colony formation. Levels of phosphorylation of ALK, ERK, STAT3, and AKT were higher in ALK+ G1269A mutant cells than ALK+ controls, by western blot. The authors note that ALK G1269A likely induces resistance by preventing crizotinib from accessing its binding pocket in the ALK kinase domain. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:23344087 2 out of 7 patients with an acquired resistance to crizotinib had a G1269A mutation. One of these patients also harbored a L1196M mutation. In vitro follow-up showed reduced crizotinib-induced ALK dephosphorylation (293T) and apoptosis (Ba/F3) when EML4-ALK G1269A overexpression was compared to EML4-ALK overexpression in these cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:26698910 In this case report, a patient with metastatic, ALK-rearranged NSCLC with C1156Y mutation had tumor progression under sequential treatment with first crizotinib, then ceritinib and finally AUY922. Subsequent chemotherapy (carboplatin–pemetrexed) was administered and the patient had a response for 6 months before progression. Exome sequencing revealed the C1156Y mutation was present in <7% of the pretreatment tumor and in ~50% of the crizotinib tumor prior to ceritinib therapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:25228534 The EML4 ALK variant 1 containing NSCLC cell line H3122 is highly sensitive to alectinib, and an alectinib resistant derivative cell line H3122 CHR-A1 was generated by incubation of H3122 in increasing levels of alectinib culminating in 1 micro-molar, over a course of 7 months. The ALK kinase domain mutation V1180L was found in these cells, and Ba/F3 cells expressing EML4 ALK V1180L were highly resistant to alectinib. Simulations indicated that the V1180L mutation interfered with alectinib binding. The V1180L mutation was found to be more resistant to alectinib than the I1171T mutation found in an ALK-positive NSCLC patient who developed alectinib resistance on lower dose alectinib (300mg twice daily). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:26775591 A 52 year old male never smoker was diagnosed with stage IV NSCLC adenocarcinoma and was treated with chemotherapy with eventual disease progression. He tested positive for ALK rearrangement via break apart FISH assay, and started crizotinib with near complete response for 27 months. Progression then occurred and biopsy of a pleural nodule was performed with hybrid-capture NGS. EML4-ALK variant 3 with F1245C mutation was found with allele frequency of 2% and tumor purity 13%. Due to slow progression and low tumor burden crizotinib was maintained for additional 8 months, and then he was transitioned onto ceritinib at 750 mg daily. After 3 months ceritinib, complete radiographic response was seen and the patient was without evidence of disease at 6 months. Dose was reduced to 600 mg ceritinib daily due to gastrointestinal side effects. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:24675041 The crizotinib-resistant MGH045 cell line with EML4-ALK L1196M was treated with crizotinib or ceritinib. In nude mice with MGH045 xenografts, tumor response to crizotinib did not differ appreciably from vehicle, while ceritinib controlled tumor growth. Ceritinib inhibited Ba/F3 cells expressing EML4-ALK L1196M slightly stronger than ALK wild-type, but approximately double the potency as crizotinib, indicating ceritinib sensitivity in Ba/F3 EML4-ALK L1196M cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:25393796 Case study describes a caucasian male (age 38) never smoker presenting with stage IV non-small cell lung cancer with an ALK rearrangement. Patient was given crizotinib and exhibited a partial response after 5 months with brain metastasis occurring at 21 months. Patient then received alectinib and exhibited partial response however liver metastasis presented after 12 months on alectinib. Sequencing of this liver metastasis revealed an EML4-ALK fusion with an I1171S variant at a variant frequency of 36% (tumor purity estimated as 70%). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:5 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4230 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4172 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4237 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4309 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4308 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4255 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4312 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4225 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4253 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4351 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4221 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-4 ALK EML4::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4357 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 756 check_entity AN4675-5 ALK EML4::ALK mutation ALK NCBI:238 gene malignant pleural mesothelioma DOID:7474 risk 100019-9 PubMed:32600123 A 33 year old M non-smoker with no cancer family history and no known exposure to asbestos showed weakness, chest pain, and plural effusion (PE) accumulation. Mass in right lung was seen under enhanced CT. Patient was diagnosed with stage IIIB (cT4N2M0) malignant pleural mesothelioma (MPM) using National Comprehensive Cancer Network (NCCN) guidelines on MPM staging (v.1.2018). Patient was given palliative chemotherapy for two cycles, which reduced the PE and improved physical mobility. Targeted NGS panel with 520 genes of PE showed EML4::ALK variant 3 (allelic fraction 24.21%). After 1 month symptoms were alleviated and NGS showed reduced EML4::ALK abundance (allelic fraction 8.22%). After 2 months CT showed tumor shrinkage. This was evaluated as partial response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 757 check_entity AN4675-5 ALK EML4::ALK mutation ALK NCBI:238 gene malignant pleural mesothelioma DOID:7474 risk 100019-9 CIViC:5 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 757 check_entity AN4675-5 ALK EML4::ALK mutation ALK NCBI:238 gene malignant pleural mesothelioma DOID:7474 risk 100019-9 CIViC:4328 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 757 check_entity AN4675-5 ALK EML4::ALK mutation ALK NCBI:238 gene malignant pleural mesothelioma DOID:7474 risk 100019-9 CIViC:4329 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::ALK sequence variation in gene ALK/NCBI:238 757 check_entity AN4676-1 ALK Exon 4-11 Deletion ALK NCBI:238 gene neuroblastoma DOID:769 risk 100019-9 PubMed:27049722 The MYCN amplification positive relapsed neuroblastoma-derived cell line CLB-BAR contains the driver ALK DEL 11-14 mutation, which removes extracellular domain exons 4 through 11. Brigatinib treatment of CLB-BAR cells reduced MYCN protein levels and ALK phosphorylation (Y1604) similar to crizotnib. Brigatinib reduced CLB-BAR cellular proliferation more effectively than crizotinib (IC50 75.2 vs 186.4nM). CLB-BAR xenografts in BalbC/NUDE mice responded to brigatinib with reduced tumor volume and weight (N=8/group) as well as reduced ALK phosphorylation and MYCN levels compared to untreated controls. Release of brigatinib administration at day 15 resulted in tumor growth (N=2). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:4-11:deletion sequence variation in gene ALK/NCBI:238 758 check_entity AN4676-1 ALK Exon 4-11 Deletion ALK NCBI:238 gene neuroblastoma DOID:769 risk 100019-9 CIViC:546 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:4-11:deletion sequence variation in gene ALK/NCBI:238 758 check_entity AN4677-1 ALK F1174L mutation ALK NCBI:238 gene inflammatory myofibroblastic tumor DOID:0050905 risk 100019-9 PubMed:21030459 Ba/F3 cells expressing the RANBP2-ALK fusion containing an F1174L mutation were more resistant to crizotinib treatment than Ba/F3 cells expressing RANBP2-ALK without this mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F1174L sequence variation in gene ALK/NCBI:238 759 check_entity AN4677-1 ALK F1174L mutation ALK NCBI:238 gene inflammatory myofibroblastic tumor DOID:0050905 risk 100019-9 CIViC:8 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F1174L sequence variation in gene ALK/NCBI:238 759 check_entity AN4677-2 ALK F1174L mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:21030459 Ba/F3 cells expressing the EML4-ALK fusion containing an F1174L mutation were more resistant to crizotinib treatment than Ba/F3 cells expressing EML4-ALK without this mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F1174L sequence variation in gene ALK/NCBI:238 760 check_entity AN4677-2 ALK F1174L mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:8 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F1174L sequence variation in gene ALK/NCBI:238 760 check_entity AN4677-3 ALK F1174L mutation ALK NCBI:238 gene neuroblastoma DOID:769 risk 100019-9 PubMed:21575866 CH5424802 (Alectinib) is effective in inhibiting the activity of the F1174L ALK mutant in a kinase activity assay and proliferation assay using neuroblastoma KELLY cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F1174L sequence variation in gene ALK/NCBI:238 761 check_entity AN4677-3 ALK F1174L mutation ALK NCBI:238 gene neuroblastoma DOID:769 risk 100019-9 PubMed:21948233 High levels of crizotinib can overcome drug resistance of Ba/F3 cells expressing the EML4-ALK fusion containing the F1174L mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F1174L sequence variation in gene ALK/NCBI:238 761 check_entity AN4677-3 ALK F1174L mutation ALK NCBI:238 gene neuroblastoma DOID:769 risk 100019-9 PubMed:22072639 Cells lines expressing ALK harboring the F1174L mutation are less sensitive to growth inhibition by crizotinib than cells expressing the R1275Q mutation. The authors conclude that this effect should be surmountable with higher doses of crizotinib and/or with higher-affinity inhibitors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F1174L sequence variation in gene ALK/NCBI:238 761 check_entity AN4677-3 ALK F1174L mutation ALK NCBI:238 gene neuroblastoma DOID:769 risk 100019-9 PubMed:18923525 SH-SY5Y and Kelly cells with mutant ALK (F1174L) and Ba/F3 cells overexpressing ALK harboring the F1174L mutation are sensitive to TAE684-mediated growth inhibition. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F1174L sequence variation in gene ALK/NCBI:238 761 check_entity AN4677-3 ALK F1174L mutation ALK NCBI:238 gene neuroblastoma DOID:769 risk 100019-9 PubMed:23598171 In a Phase I trial (NCT00939770) of the drug crizotinib in pediatric patients, a subset of 11 neuroblastoma patients were characterized for mutations in ALK. Of these 11 patients, 4 had the F1174L mutation. Among these 4 patients, stable disease (SD) was observed in one, and progressive disease (PD) was observed in 3 others after administration of crizotinib. In contrast, in the remaining 7 patients with mutations different than F1174L, 4 had PD, 2 had SD and one had complete response as best response after initiation of crizotinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F1174L sequence variation in gene ALK/NCBI:238 761 check_entity AN4677-3 ALK F1174L mutation ALK NCBI:238 gene neuroblastoma DOID:769 risk 100019-9 PubMed:26786851 The SH-SY5Y neuroblastoma cell line containing the F1174L ALK mutation was found to undergo cell death when treated with the ALK/IGF1R inhibitor AZD3463. These cells were more sensitive than other neuroblastoma cell lines containing wild-type ALK. Marked inhibition of soft agar colony formation of SH-SY5Y cells was also observed with drug treatment. AZD3463 inhibited Akt signaling in these cells within two hours of treatment, and activated apoptosis and autophagy pathways. Treatment of SH-SY5Y cells implanted into left kidneys of nude mice resulted in almost complete tumor regression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F1174L sequence variation in gene ALK/NCBI:238 761 check_entity AN4677-3 ALK F1174L mutation ALK NCBI:238 gene neuroblastoma DOID:769 risk 100019-9 PubMed:26554404 Efficacy of the second generation ALK inhibitor PF-06463922 was tested on ALK mutation F1174L containing neuroblastoma-derived cells. COG-N-453x and SH-SY5Y xenografts showed some inhibition when treated with crizotinib, but showed complete growth inhibition with PF-06463922 treatment. This corresponded to 0% event free survival (EFS) in these mice by 6 weeks with crizotinib treatment, but 100% EFS with PF-06463922 treatment. Comparison of crizotinib and PF-06463922 growth inhibition in F1174L cells SH-SY5Y, NBSD 415-IMDM and KELLY showed increased sensitivity to PF-06463922, as compared to crizotinib. Inhibition effects were not seen on neuroblastoma cells with wild type ALK (NB-EBc1, SK-N-BE(2)C). Decreased phosphorylation on ALK tyrosine 1278 was seen with PF-06463922 over crizotinib at 10 and 100 nM concentrations in SH-SY5Y cells. PF-06463922 was well tolerated in the in-vivo models. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F1174L sequence variation in gene ALK/NCBI:238 761 check_entity AN4677-3 ALK F1174L mutation ALK NCBI:238 gene neuroblastoma DOID:769 risk 100019-9 CIViC:8 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F1174L sequence variation in gene ALK/NCBI:238 761 check_entity AN4678-1 ALK F1245C mutation ALK NCBI:238 gene cancer DOID:162 risk 100019-9 PubMed:22034911 A Ba/F3 cell line expressing EML4-ALK variant 1 was created, and then exposed to the DNA modifying agent ENU. Cells were subsequently cultured in 96 well plates at increasing concentrations of crizotinib (250, 500, 720, 1000, 1440 and 2000 nM). Cell growth occurred in all wells at 250 nM, and was absent at 2000 nM. From 500 through 1440 nM there were progressively fewer resistant clones present. 422 mutations representing 16 different sites were identified. EML4-ALK F1245C was found at 500 nM crizotinib, and was among the 10 most frequently observed mutations. Ba/F3 cells with unaltered EML4-ALK had crizotinib IC50 values for viability of 132 +/- 45 nM. EML4-ALK F1245C clones from the selection assay had IC50 viability value of 425 +/- 100 nM, while Ba/F3 cells expressing reintroduced EML4-ALK F1245C had IC50 value of 269 +/- 194 nM. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F1245C sequence variation in gene ALK/NCBI:238 762 check_entity AN4678-1 ALK F1245C mutation ALK NCBI:238 gene cancer DOID:162 risk 100019-9 CIViC:4221 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F1245C sequence variation in gene ALK/NCBI:238 762 check_entity AN4678-2 ALK F1245C mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:26775591 A 52 year old male never smoker was diagnosed with stage IV NSCLC adenocarcinoma and was treated with chemotherapy with eventual disease progression. He tested positive for ALK rearrangement via break apart FISH assay, and started crizotinib with near complete response for 27 months. Progression then occurred and biopsy of a pleural nodule was performed with hybrid-capture NGS. EML4-ALK variant 3 with F1245C mutation was found with allele frequency of 2% and tumor purity 13%. Due to slow progression and low tumor burden crizotinib was maintained for additional 8 months, and then he was transitioned onto ceritinib at 750 mg daily. After 3 months ceritinib, complete radiographic response was seen and the patient was without evidence of disease at 6 months. Dose was reduced to 600 mg ceritinib daily due to gastrointestinal side effects. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F1245C sequence variation in gene ALK/NCBI:238 763 check_entity AN4678-2 ALK F1245C mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4221 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F1245C sequence variation in gene ALK/NCBI:238 763 check_entity AN4678-3 ALK F1245C mutation ALK NCBI:238 gene neuroblastoma DOID:769 risk 100019-9 PubMed:26554404 Patient derived xenografts of neuroblastoma Felix cells with F1245C ALK mutation in CB17 SCID mice showed growth inhibition with crizotinib treatment over control, and mice had improved duration of event-free survival (EFS) with crizotinib treatment over vehicle, but EFS with crizotinib went down to 0% by six weeks. In contrast, PF-06463922 treatment induced complete tumor regression and EFS rate of 100% at six weeks. PF-06463922 inhibited viability in Felix cells at 37x efficacy over crizotinib, with IC50 values of 21.8 +/- 0.4 and 814.0 +/- 119 respectively. PF-06463922 was well tolerated in the animal models. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F1245C sequence variation in gene ALK/NCBI:238 764 check_entity AN4678-3 ALK F1245C mutation ALK NCBI:238 gene neuroblastoma DOID:769 risk 100019-9 PubMed:23598171 A participant in Children's Oncology Group (COG) study AVDL0912 with measurable neuroblastoma mutated at ALK F1245C was administered crizotinib at 100mg twice daily. The patient showed progressive disease as best response after two 28-day cycles on crizotinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F1245C sequence variation in gene ALK/NCBI:238 764 check_entity AN4678-3 ALK F1245C mutation ALK NCBI:238 gene neuroblastoma DOID:769 risk 100019-9 CIViC:545 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F1245C sequence variation in gene ALK/NCBI:238 764 check_entity AN4679-1 ALK F1245V mutation ALK NCBI:238 gene neuroblastoma DOID:769 risk 100019-9 PubMed:28183697 Clinical trial of entrectinib in patients with ALK/ROS/TRK altered tumors. One patient with an ALK F1245V-mutant neuroblastoma achieved a durable, confirmed partial response (PR) lasting 8.3 months. The patient remained on study treatment for more than 3.5 years because of clinical benefit. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F1245V sequence variation in gene ALK/NCBI:238 765 check_entity AN4679-1 ALK F1245V mutation ALK NCBI:238 gene neuroblastoma DOID:769 risk 100019-9 CIViC:1269 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F1245V sequence variation in gene ALK/NCBI:238 765 check_entity AN4680-1 ALK Fusion ALK NCBI:238 gene anaplastic large cell lymphoma DOID:0050744 risk 100019-9 PubMed:21345110 Crizotinib at 250mg daily was given to two patients with relapsed ALK-rearranged anaplastic large cell lymphoma (ALCL). Patient one, 26 yrs old, had been treated with the CHOP-15 chemotherapy regimen, then salvage chemotherapy to prepare for autologous bone marrow transplant but ultimately relapsed. After initiation of crizotinib, PET, CT and bone marrow aspirates showed complete remission of previous lesions at 28 days. At time of publication the patient continued to show persistent response at 6 months. A 20 year old patient relapsed after one month of CHOP, and was treated with further chemotherapy and autologous bone marrow transplantation resulting in partial response of 1 month. Crizotinib was initialized, and after 12 days PET scan showed complete regression of all lesions. On day 60 bone marrow aspirates were ALK-negative (pretreatment evaluation showed 8% ALK-positive). The authors conclude these two cases indicate sensitivity to crizotinib of relapsed ALK-rearranged ALCL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 766 check_entity AN4680-1 ALK Fusion ALK NCBI:238 gene anaplastic large cell lymphoma DOID:0050744 risk 100019-9 PubMed:28787259 In this phase I/II study, 26 patients with relapsed/refractory ALK-positive ALCL were administered crizotinib orally twice daily in 28-day cycles as a single agent for an indefinite duration. Patients with relapsed ALCL achieved an objective response rate of 90%. The overall response rates for patients with ALCL treated at doses of 165 and 280 mg/m2 were 83% and 90%, respectively. Rates of complete response were 83% and 80% for 165 and 280 mg/m2 dose groups, respectively. The most common grade 3 or 4 adverse event was decreased neutrophil count. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 766 check_entity AN4680-1 ALK Fusion ALK NCBI:238 gene anaplastic large cell lymphoma DOID:0050744 risk 100019-9 CIViC:495 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 766 check_entity AN4680-2 ALK Fusion ALK NCBI:238 gene breast cancer DOID:1612 risk 100019-9 PubMed:19737969 84 breast cancer samples acquired from commercial sources were assayed on Affymetrix human exon 1.0 arrays. A computational method was used to find potential gene fusions which assessed differential exon expression between the 3' and 5' ends of each gene. Two potential fusions were found and assessed using RNA ligase mediated rapid amplifiation of cDNA ends and RT-PCR. The fusions were EML4-ALK variants 1 and 2. Genomic PCR identified fusion breakpoints, and these differed from breakpoints for these EML4-ALK variants reported in NSCLC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 767 check_entity AN4680-2 ALK Fusion ALK NCBI:238 gene breast cancer DOID:1612 risk 100019-9 CIViC:495 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 767 check_entity AN4680-3 ALK Fusion ALK NCBI:238 gene cancer DOID:162 risk 100019-9 PubMed:28183697 Two phase I studies in patients with advanced or metastatic solid tumors, including patients with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 768 check_entity AN4680-3 ALK Fusion ALK NCBI:238 gene cancer DOID:162 risk 100019-9 PubMed:25727400 EML4-ALK with ALK G1269A has been seen in crizotinib resistant NSCLC, and this mutation was tested for Brigatinib sensitivity via ectopic expression in Ba/F3 cells, where half maximal inhibitory concentration of 9 nM was seen, which was 1.5 times the IC50 of EML4-ALK wild-type to brigatinib. NPM-ALK G1269A was also tested for brigatinib sensitivity, and IC50 values of 11 nM were reported for both NPM-ALK G1269A and NPM-ALK wild-type. In western blotting, brigatinib at and above 100 nM ablated pALK signal (Y 1604), indicating sensitivity of this variant to brigatinib together with the other results. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 768 check_entity AN4680-3 ALK Fusion ALK NCBI:238 gene cancer DOID:162 risk 100019-9 PubMed:35233056 This clinical study was conducted on patients harboring either ROS1 or ALK rearrangements, and were treated with Crizotinib. The two sub-protocols F(ALK rearrangements) and G(ROS1 rearrangements) had 4 evaluable patients each. Sub-protocols F and G had the response rates of 50% (90% CI; 9.8%-90.2%), and 25% (90% CI; 1.3-75.1) respectively. The PFS for sub-protocol F was 3.8 months and that for sub-protocol G was 4.3 months. Median overall survival for the sub-protocols F and G were 4.8 months and 6.2 months respectively. The study suggested modest antitumor activity for both the sub-protocols. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 768 check_entity AN4680-3 ALK Fusion ALK NCBI:238 gene cancer DOID:162 risk 100019-9 CIViC:495 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 768 check_entity AN4680-3 ALK Fusion ALK NCBI:238 gene cancer DOID:162 risk 100019-9 CIViC:4311 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 768 check_entity AN4680-3 ALK Fusion ALK NCBI:238 gene cancer DOID:162 risk 100019-9 CIViC:4708 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 768 check_entity AN4680-4 ALK Fusion ALK NCBI:238 gene colorectal adenocarcinoma DOID:0050861 risk 100019-9 PubMed:19737969 26 colorectal adenocarcinoma samples were run on Affymetrix human Exon 1.0 arrays and a computational method that assessed differential 5' and 3' gene expression for each gene was used to find potential rearrangements. One sample showed potential rearrangement and RT-PCR demonstrated an EML4-ALK fusion where EML4 exon 21 was fused to ALK exon 13. This EML4-ALK variant is different from those commonly found in NSCLC. Genomic PCR verified the existence of the fusion breakpoint in intronic space, indicating that some colorectal adenocarcinoma may have targetable ALK-fusion driver mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 769 check_entity AN4680-4 ALK Fusion ALK NCBI:238 gene colorectal adenocarcinoma DOID:0050861 risk 100019-9 CIViC:495 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 769 check_entity AN4680-5 ALK Fusion ALK NCBI:238 gene diffuse large B-cell lymphoma DOID:0050745 risk 100019-9 PubMed:24330038 A 27 year old female patient with advanced-stage IV, CD20 negative diffuse large B cell lymphoma (DLBCL). ALK rearrangement was determined by FISH, but the ALK fusion partner was not determined due to limited tissue. The patient underwent treatment with CHOP chemotherapy regimen and radiation but did not respond. The patient progressed following salvage chemotherapy and autologous stem cell transplant. Crizotinib was then administered at 250 mg twice daily, and LDH levels rapidly dropped along with disappearance of palpable lymphadenopathy, but progression ensued after 21 days and the patient died soon after. The authors attribute the short response to crizotinib to the possibility of this tumor having an ALK fusion variant less responsive to ALK inhibition and to a high Ki-67 index in the patient, and deem that despite the brief response, crizotinib shows promise in ALK rearranged DLBCL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 770 check_entity AN4680-5 ALK Fusion ALK NCBI:238 gene diffuse large B-cell lymphoma DOID:0050745 risk 100019-9 CIViC:495 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 770 check_entity AN4680-6 ALK Fusion ALK NCBI:238 gene epithelioid inflammatory myofibroblastic sarcoma DOID:0080372 risk 100019-9 PubMed:25028698 This is a case report of a 22-year-old Japanese man with a pelvic mesenchymal neoplasm. Tumor analysis include IHC and RT-PCR led to diagnosis of epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK fusion. Despite two surgical excision procedures, local recurrence rapidly occurred, and the tumor developed resistance to conventional chemotherapy with doxorubicin. Subsequent administration of crizotinib resulted in relief of severe pain and durable tumor shrinkage at least 10 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 771 check_entity AN4680-6 ALK Fusion ALK NCBI:238 gene epithelioid inflammatory myofibroblastic sarcoma DOID:0080372 risk 100019-9 CIViC:495 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 771 check_entity AN4680-7 ALK Fusion ALK NCBI:238 gene inflammatory myofibroblastic tumor DOID:0050905 diagnostic;risk 100019-9 PubMed:23598171 As part of a phase 1 dose-escalation trial (NCT00939770), seven patients between ages 12 months and 22 years with relapsed or refractory inflammatory myofibroblastic tumors with ALK-rearrangement were given crizotinib. In six patients with measurable disease, responses included 3 with partial response and 3 with stable disease. One patient with evaluable disease had stable disease with treatment ongoing at the time of publication. Crizotinib was well tolerated in this group of pediatric patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 772 check_entity AN4680-7 ALK Fusion ALK NCBI:238 gene inflammatory myofibroblastic tumor DOID:0050905 diagnostic;risk 100019-9 PubMed:10383129 Fluorescence in situ hybridization with a probe flanking the ALK gene at 2p23 and immunohistochemistry revealed ALK expression, suggesting ALK fusions in three cases of IMT. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 772 check_entity AN4680-7 ALK Fusion ALK NCBI:238 gene inflammatory myofibroblastic tumor DOID:0050905 diagnostic;risk 100019-9 PubMed:28787259 In this phase I/II study, 14 patients with metastatic or inoperable ALK-positive IMT were administered crizotinib orally twice daily in 28-day cycles as a single agent for an indefinite duration. The overall response rate for patients with IMT (treated at 100, 165, and 280 mg/m2/dose) was 86%. Complete responses were seen in 36% of patients, partial response in 50%, and stable disease in the remaining 14%. Median time to first CR/PR was 28.5 days, and median duration of treatment was 1.63 years. The most common adverse event was decreased neutrophil count. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 772 check_entity AN4680-7 ALK Fusion ALK NCBI:238 gene inflammatory myofibroblastic tumor DOID:0050905 diagnostic;risk 100019-9 PubMed:29352732 9 patients with ALK-positive inflammatory myofibroblastic tumour (IMT) enrolled in the PROFILE 1013 (NCT01121588) phase 1b single-arm, open-label, multi-centre study received crizotinib. ORR was 67% for IMT (95% CI, 30–93), with 1 CR, 5 PRs, and 3 SDs. PFS at 2 years was 66.7% (95% CI, 28.2–87.8). Note that ALK positive included ALK mutations, but the mutation vs. fusion status for the patients in the IMT group was not specified. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 772 check_entity AN4680-7 ALK Fusion ALK NCBI:238 gene inflammatory myofibroblastic tumor DOID:0050905 diagnostic;risk 100019-9 CIViC:495 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 772 check_entity AN4680-8 ALK Fusion ALK NCBI:238 gene lung adenocarcinoma DOID:3910 risk 100019-9 PubMed:25922291 In an evaluation of a patient with crizotinib-sensitive lung adenocarcinoma, an EML4-ALK-E13;A20 rearrangement was identified using CGP. The patient attained a reduction in the target lesions by 14.2%, however, the patient relapsed 17 months later. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 773 check_entity AN4680-8 ALK Fusion ALK NCBI:238 gene lung adenocarcinoma DOID:3910 risk 100019-9 PubMed:22277784 A patient with ALK-rearranged lung adenocarcinoma responded to crizotinib treatment and then had relapse. Biopsy was taken within half a month and total DNA was extracted from the sample. Exons 20-28, which correspond to the tyrosine kinase domain of ALK, were sequenced, and ALK G1202A was found. CKIT focal amplification by FISH was also observed. Tumor sample before crizotinib treatment was not available in this case. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 773 check_entity AN4680-8 ALK Fusion ALK NCBI:238 gene lung adenocarcinoma DOID:3910 risk 100019-9 CIViC:495 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 773 check_entity AN4680-8 ALK Fusion ALK NCBI:238 gene lung adenocarcinoma DOID:3910 risk 100019-9 CIViC:4236 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 773 check_entity AN4680-9 ALK Fusion ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:21642865 Among 95 patients with NSCLC in this study, 15 had an ALK translocation. ORR of these patients compared to EGFR mutated or wild-type tumors was superior (46.7 versus 4.7 versus 16.2%, p = 0.001). TYMS expression was lower in ALK-positive cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 774 check_entity AN4680-9 ALK Fusion ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:26973324 Updated results from ASCEND-1 trial assessing safety and activity of ceritinib in ALK rearranged locally advanced or metastatic NSCLC. 255 patients were enrolled and received at least one dose of ceritinib 750 mg/day, of whom 246 had ALK-rearranged NSCLC (Median follow-up: 11.1 months). Overall response rate was 72% [95% CI 61-82] of 83 ALK inhibitor-naive patients and 56% [49-64] of 163 ALK inhibitor-pretreated patients. Median duration of response was 17·0 months (95% CI 11.3-non-estimable [NE]) in ALK inhibitor-naive patients and 8.3 months (6.8-9.7) in ALK inhibitor-pretreated patients. Median progression-free survival was 18.4 months (95% CI 11.1-NE) in ALK inhibitor-naive patients and 6.9 months (5.6-8.7) in ALK inhibitor-pretreated patients. Brain metastases control was reported in 79% [95% CI 54-94] of 19 ALK inhibitor-naive patients and in 65% [54-76] of 75 ALK inhibitor-pretreated patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 774 check_entity AN4680-9 ALK Fusion ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:20979469 In the Phase I study PROFILE 1001 (NCT00585195), a recommended crizotinib dose of 250 mg twice daily for 28 day cycles was established. Among 1,500 advanced NSCLC patients who were screened for ALK-rearrangement using a break-apart FISH assay, 82 patients were eligible for crizotinib treatment. Overall response rate was 57%, with 46 partial responses and one complete response. Since crizotinib inhibits MET, 33 patients with available tissue were screened for MET amplification and were found negative, further indicating that patient response was due to ALK inhibition. 31 patients were tested via RT-PCR for known EML4-ALK fusions, and 13 were shown to have EML4-ALK variant 1, four cases had variant 3, and one instance of variants 2, 3b and 5 were seen. 9 were unidentified, suggesting other fusion partners in these instances. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 774 check_entity AN4680-9 ALK Fusion ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:23724913 This two arm Phase III study named PROFILE 1007 (NCT00932893) was performed to assess crizotinib vs. established chemotherapy in non-small cell lung cancer patients positive for ALK rearrangement (assessed by break-apart FISH) with locally advanced or metastatic disease. 347 patients with disease progression after one round of platinum-based chemotherapy were randomized to receive crizotinib (N=173) or chemotherapy (N=174) consisting of pemetrexed in pemetrexed-naive patients and docetaxel for patients previously treated with pemetrexed. The primary endpoint - progression free survival (PFS) - was found to be significantly better for patients treated with crizotinib (median 7.7 months) than with chemotherapy (median 3.0 months) (hazard ratio for disease progression or death with crizotinib, 0.49; 95% CI, 0.37 to 0.64; P<0.001). Response rates were 65% for crizotinib treatment and 20% for chemotherapy (P<0.001). Improvements in quality of life were also reported. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 774 check_entity AN4680-9 ALK Fusion ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:25470694 This phase 3 trial named PROFILE 1014 (NCT01154140) compared crizotinib to established chemotherapy in first-line treatment for this disease. The study consisted of 343 patients with advanced or metastatic NSCLC that tested positive for ALK rearrangement via break-apart FISH assay, and had no prior systemic treatment. Patients were assigned in a 1:1 ratio to crizotinib (N=172) or pemetrexed with cisplatin or carboplatin (N=171). Progression free survival was significantly longer with crizotinib treatment than chemotherapy (10.9 vs. 7.0 months; hazard ratio for progression or death with crizotinib, 0.45; 95% CI, 0.35 to 0.60;P<0.001), and objective response rate was higher with crizotinib treatment than chemotherapy (75% vs. 45%, P<0.001). Improvement in quality of life was also reported. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 774 check_entity AN4680-9 ALK Fusion ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:24478318 This retrospective study of patients from the PROFILE 1001 and 1005 studies of crizotinib in advanced ALK-rearranged NSCLC assessed the potential benefit of crizotinib beyond progressive disease (CBPD), defined as continuation of crizotinib for 3 or more weeks after disease progression on crizotinib. 194 patients who had developed PD by data cutoff were studied, where 120 received crizotinib for a median duration of 19.4 weeks and 74 discontinued crizotinib after PD. No gross imbalances in clinicopathologic features of the two groups were evident. Significantly longer overall survival was observed in the crizotinib continuing group from time of PD (16.4 vs. 3.9 months; hazard ratio 0.27, 95% CI: 0.17–0.42; P < 0.0001), and from the time of initial crizotinib (29.6 vs. 10.8 months; HR 0.30, 95% CI: 0.19–0.46; P < 0.0001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 774 check_entity AN4680-9 ALK Fusion ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:27022118 This prospective Phase III study named Profile 1014 on NSCLC ALK-rearranged patients assessed intracranial disease control rate (IC-DCR) in the subset of patients entering the study with preexisting treated brain metastasis (tBM). IC-DCR was significantly improved in the tBM group given crizotinib (N=39) over chemotherapy (pemetrexed + cisplatin or carboplatin; N=40) at 12 weeks (85% vs. 45%, P<0.001), and at 24 weeks (56% vs. 25%, P=0.006). Progression free survival was also significantly improved with crizotinib over chemotherapy in the tBM subgroup (9.0 vs. 4.0 months; HR 0.40; P<0.001), where in the intent to treat population it was 10.9 vs. 7.0 months (HR 0.45; P<0.001), indicating that the difficult to treat BM population obtained benefit from crizotinib at both the brain and systemic level. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 774 check_entity AN4680-9 ALK Fusion ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:20940188 In this study, heavily pretreated advanced NSCLC patients with various molecular tumor makeup were treated with Hsp90 inhibitor IPI-504 to assess overall response rate. The study did not reach the targeted endpoint of 20% ORR. However, of 3/12 patients found to be ALK-rearranged via break apart FISH assay, 2 showed a partial response and the third stable disease, which was durable for 7.2 months. The authors note that the break apart FISH assay used to determine ALK-rearrangement status does not determine the identity of the ALK fusion partner and the promising results shown here may be dependent on the nature of the ALK fusion partner. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 774 check_entity AN4680-9 ALK Fusion ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:23639470 In this initial report of a single-arm Phase I and II study (JapicCTI-101264) of alectinib (CH5424802), 46 patients with advanced or metastatic ALK-rearranged non small cell lung cancer (NSCLC) were assessed for objective response during phase II. ALK positivity was assessed via IHC and verified with FISH or RT-PCR. Patients had received one or more rounds of previous chemotherapy, but no prior targeted therapy towards ALK. From the 46 patients, 41 showed partial response, and 2 showed complete response. CNS metastases in three patients which had not received prior brain irradiation showed response to alectinib. Alectinib was generally well tolerated, and the authors conclude that alectinib compared favorably to crizotinib and could be an effective and safe option in ALK-rearranged NSCLC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 774 check_entity AN4680-9 ALK Fusion ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:26938871 In this case study of a critically ill 29 year old male nonsmoker with advanced metastatic ALK-positive NSCLC, alectinib (CH5424802), was administered as first line treatment. Where most clinical trials only admit patients with Eastern Cooperative Oncology Performance status (PS) of 0 or 1, this patient had PS 4 due to respiratory failure, multiple bone metastases and complications from disseminated intravascular coagulation (DIC). Administration of alectinib at 300 mg twice daily was followed by marked improvement seen in tests associated with DIC, pulmonary metastasis and change in PS from 4 to 0. Further improvements after a couple of months suggested a rapid complete response. Alectinib was well tolerated in this first line treatment of a critically ill ALK-positive NSCLC patient. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 774 check_entity AN4680-9 ALK Fusion ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:25153538 In this Phase I trial (NCT01588028) in 47 patients, alectinib was assessed for its effectiveness in treating locally advanced or metastatic ALK-positive NSCLC that had progressed or been resistant to crizotinib treatment. ALK rearrangement was assessed via approved break apart FISH kit, and patients with asymptomatic CNS metastases were also included. Patients were divided into different cohorts receiving different doses of alectinib. In the 600 mg cohort (N=13), ten were assessable, and there were 4 confirmed partial responses, 3 unconfirmed partial responses and 3 instances of stable disease. Also, five of nine patients throughout the cohorts with measurable baseline CNS lesions showed partial response to alectinib. Cerebrospinal fluid levels of alectinib increased linearly with blood alectinib levels, indicating it effectively crossed the blood-brain barrier. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 774 check_entity AN4680-9 ALK Fusion ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:26708155 In this Phase II trial of 87 patients (NCT01871805), alectinib was assayed for safety and efficacy in ALK positive NSCLC that had progressed on crizotinib. Of 69 patients with measurable disease, 35 achieved objective response, with median duration of response 13.5 months. Of 16 patients with measurable CNS disease, four achieved CNS complete response and 8 showed CNS partial response. median duration of CNS response was 11.1 months. 2 deaths were observed, and 1 was judged related to study treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 774 check_entity AN4680-9 ALK Fusion ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:21933749 In a retrospective study comparing survival outcomes in a subgroup of 82 ALK-positive crizotinib-treated patients enrolled in a phase 1 clinical trial (NCT00585195), crizotinib therapy was associated with improved survival. For the crizotinib-treated, ALK-positive patient group, 1 year survival was 74% and 2 year overall survival was 54%, compared with 72% and 36% for the control group (ALK-positive crizotinib naive patients). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 774 check_entity AN4680-9 ALK Fusion ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:26466010 A phase-3 clinical trial evaluated 347 patients with ALK-positive lung cancer. The study compared crizotinib treatment (n=173) with chemotherapy treatment of either pemetrexed or docetaxel (n=174). In the crizotinib arm, the response rate was significantly higher (65% vs 20%; P<0.001), the progression-free survival was increased (7.7 months vs. 3.0 months; HR=0.49, 95%CI:14 months-26 months; p<0.001), however, there was no significant improvement in overall survival (HR=1.02; 95%CI:0.68-1.54; P=0.54). Of the patients on crizotinib treatment, global quality of life was improved relative to baseline when compared to chemotherapy patients (+5 mean change, -5 mean change; P<0.001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 774 check_entity AN4680-9 ALK Fusion ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:28475456 In a phase II randomized trial we evaluated two regimens of Brigatinib in Crizotinib-refractory ALK-pos. NSCLC. They were randomly assigned (1:1) to oral Brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg. Of 222 patients enrolled (arm A: n = 112, arm B: n = 110), 154 (69%) had baseline brain metastases and 164 of 222 (74%) had received prior chemotherapy. ORR was 45 (arm A) and 54% (B). Investigator-assessed median PFS was 9.2 months (A) and 12.9 months (B). Independent review committee-assessed intracranial ORR in patients with measurable brain metastases at baseline was 42% (11/26, A) and 67% (12/18, B). Brigatinib yielded substantial whole-body and intracranial responses as well as robust PFS; 180 mg (with lead-in) showed consistently better efficacy than 90 mg, with acceptable safety. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 774 check_entity AN4680-9 ALK Fusion ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:28586279 In a randomized, open-label phase 3 trial 303 patients with ALK-positive, previously untreated NSCLC (including asympt. CNS disease) were randomized to reiceive either Alectinib or Crizotinib. During a median follow-up of 17.6 months (crizotinib) and 18.6 months (alectinib), an event of disease progression/death occurred in 41% (62/152 pt) in the alectinib group and 68% (102/151 patients) in the crizotinib group. 12-month event-free survival rate 68.4% with alectinib vs. 48.7% with crizotinib. A total of 18 patients (12%) in the alectinib group had an event of CNS progression, compared to 68 patients (45%) in the crizotinib group. Response rates were 82.9% (Alectinib) and 75.5% (crizotinib). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 774 check_entity AN4680-9 ALK Fusion ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:28602779 In a phase 3 trial, patients with previously treatmented NSCLC with ALK fusion were randomly assigned to ceritinib or chemotherapy. Ceritinib showed a significant improvement in median PFS compared with chemotherapy (5·4 months [95% CI 4·1-6·9] for ceritinib vs 1·6 months [1·4-2·8] for chemotherapy; hazard ratio 0·49 [0·36-0·67]; p<0·0001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 774 check_entity AN4680-9 ALK Fusion ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:30413378 In a phase 2 trial, patients with NSCLC with ALK fusion received lorlatinib. In treatment-naive patients, ORR was 90.0% In patients with at least one previous ALK tyrosine kinase inhibitor, ORR were achieved in 47.0%.In patients who had only received crizotinib ORR was achieved in 69.5%. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 774 check_entity AN4680-9 ALK Fusion ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:28501140 A randomized phase 3 trial (J-ALEX) of 207 Japanese ALK-positive NSCLC patients compared the efficacy and safety of alectinib (300mg twice daily) and crizotinib (250mg twice daily) in the first-line setting. When used as a first line treatment the median progression-free survival of the alectinib group was unreached (95% CI 17.5–not estimated) versus 10.2 months (95% CI 8.3–13.9) in the crizotinib group (HR 0.31; 95% CI 0.17–0·57). In the overall intent to treat population, Alectinib showed improved median PFS (HR 0.34; 99.7% CI 0.17-0.71; stratified log-rank p<0·0001) with an unreached PFS (95% CI 20.3-not estimated) compared to 10.2 months (95% CI 8.2-12.0) for crizotinib. The safety profile of alectinib was favorable relative to crizotinib with fewer dose interruptions (29% vs 74%) and fewer grade 3-4 adverse events (26% vs 52%). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 774 check_entity AN4680-9 ALK Fusion ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:32780660 The phase III ALTA-1L open-label randomized trial examined 275 NSCLC patients given brigatinib (137 patients) vs crizotinib (138 patients). Patients were ALK fusion positive by an FDA-approved diagnostic test and had not previously received ALK inhibitors. Brigatinib showed superior PFS compared to crizotinib (HR 0.49 [95% CI, 0.35 to 0.68]; log-rank P < .0001; median, 24.0 v 11.0 months). Initial results from this trial were previously reported in 2018 (PMID: 30280657). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 774 check_entity AN4680-9 ALK Fusion ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:24675041 The NSCLC cell line MGH021-4, harboring SQSTM1-ALK G1269A, was 6 times more sensitive to ceritinib (80nM GI50) than crizotinib (500 nM) in proliferation assays and caused notable reductions in phospho-ALK and phospho-AKT (detected by Western blot) at concentrations 10 fold lower than crizotinib. GI50 values were similar in Ba/F3 cells expressing either EML4-ALK wild-type or EML4-ALK G1269A (1.6nM and 2.2nM, respectively). In contrast, crizotinib treatment of Ba/F3 with EML4-ALK G1269A had survival GI50 of 130nM. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 774 check_entity AN4680-9 ALK Fusion ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:495 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 774 check_entity AN4680-9 ALK Fusion ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4311 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 774 check_entity AN4680-10 ALK Fusion ALK NCBI:238 gene thyroid gland anaplastic carcinoma DOID:0080522 risk 100019-9 PubMed:24687827 A patient with anaplastic thyroid carcinoma harboring ALK rearrangement received crizotinib after chemotherapy for pulmonary recurrence. Crizotinib showed confirmed response of more than 90% by tumor volume, and her response has been stable on follow-up. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 775 check_entity AN4680-10 ALK Fusion ALK NCBI:238 gene thyroid gland anaplastic carcinoma DOID:0080522 risk 100019-9 CIViC:495 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 775 check_entity AN4680-11 ALK Fusion ALK NCBI:238 gene vagina sarcoma DOID:1901 risk 100019-9 PubMed:26942346 Patient was 34-year-old woman with vaginal sarcoma, which was excised with positive surgical margins. Fluorescence in situ hybridization testing of her tumor revealed anaplastic lymphoma kinase gene rearrangements. A 3-cm mass recurred 1 month later. Treatment with crizotinib resulted in complete regression of all visible or palpable tumor within 3 weeks. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 776 check_entity AN4680-11 ALK Fusion ALK NCBI:238 gene vagina sarcoma DOID:1901 risk 100019-9 CIViC:495 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ALK/NCBI:238 776 check_entity AN4681-1 ALK G1202R mutation ALK NCBI:238 gene cancer DOID:162 risk 100019-9 PubMed:25727400 Ba/F3 cell line expressing EML4-ALK variant 3 with G1202R ALK mutation was assessed for alectinib sensitivity and IC50 for survival of 868 nM was reported, which was 64.4x higher than the IC50 reported for alectinib on Ba/F3 with EML4-ALK wild-type. Similar experiments using NPM-ALK instead of EML4-ALK yielded survival IC50 of 549 nM of NPM-ALK G1202R to alectinib, which was 27.9 times higher than IC50 for NPM-ALK wild-type. Western blots of Ba/F3 with NPM-ALK wild-type showed ablation of pALK levels above 100 nM alectinib, while pALK levels were essentially unchanged up to 1000 nM in NPM-ALK G1202R Ba/F3 cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G1202R sequence variation in gene ALK/NCBI:238 777 check_entity AN4681-1 ALK G1202R mutation ALK NCBI:238 gene cancer DOID:162 risk 100019-9 CIViC:4237 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G1202R sequence variation in gene ALK/NCBI:238 777 check_entity AN4681-2 ALK G1202R mutation ALK NCBI:238 gene lung adenocarcinoma DOID:3910 risk 100019-9 PubMed:22277784 A patient with ALK-rearranged lung adenocarcinoma responded to crizotinib treatment and then had relapse. Biopsy was taken within half a month and total DNA was extracted from the sample. Exons 20-28, which correspond to the tyrosine kinase domain of ALK, were sequenced, and ALK G1202A was found. CKIT focal amplification by FISH was also observed. Tumor sample before crizotinib treatment was not available in this case. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G1202R sequence variation in gene ALK/NCBI:238 778 check_entity AN4681-2 ALK G1202R mutation ALK NCBI:238 gene lung adenocarcinoma DOID:3910 risk 100019-9 CIViC:4236 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G1202R sequence variation in gene ALK/NCBI:238 778 check_entity AN4681-3 ALK G1202R mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:22277784 The G1202R mutation in the EML4-ALK fusion was found to confer resistance to crizotinib in Ba/F3 cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G1202R sequence variation in gene ALK/NCBI:238 779 check_entity AN4681-3 ALK G1202R mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:24675041 Ba/F3 cells expressing EML4-ALK variant 1 with ALK G1202R mutation were assessed for ceritinib sensitivity. Crizotinib was shown to confer significantly more potency than ceritinib (43-fold decrease in IC50). EML4-ALK variant 3 NSCLC cell line H2228 was used in SCID mouse xenografts which were exposed to increasing crizotinib up to 100 mg/kg. Within 40 days tumors progressed, and progressed tumors were assayed for ALK mutation. Of 80 tumors, 6 had ALK mutation and 3 of these were G1202R. Treatment of crizotinib progressed tumors with ceritinib resulted in tumor growth which did not differ appreciably from crizotinib or vehicle treatment of these tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G1202R sequence variation in gene ALK/NCBI:238 779 check_entity AN4681-3 ALK G1202R mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4237 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G1202R sequence variation in gene ALK/NCBI:238 779 check_entity AN4681-4 ALK G1202R mutation ALK NCBI:238 gene malignant pleural mesothelioma DOID:7474 risk 100019-9 PubMed:32600123 This case report describes a 33 year-old non-smoker with no known exposure to asbestos who was diagnosed with stage IIIB malignant pleural mesothelioma. Panel next generation sequencing (NGS) of 520 genes revealed an EML4::ALK fusion and the patient was subsequently treated with alectinib. After 1 month of therapy the patient showed clinical improvement, and plasma NGS revealed a decrease in EML4::ALK allele fraction (AF) from 24.21% to 8.22%. Progressive disease was confirmed after 4.5 months of alectinib therapy at which time plasma NGS revealed the emergence of two acquired resistance mutations, I1171N (AF=4.24%) and L1196M (AF=0.33). He then received lorlatinib and achieved a PR within one month with 34% tumour shrinkage. He began showing signs of progression after 3.6 months of lorlatinib treatment. Plasma NGS at that time identified a third concurrent acquired resistance mutation G1202R (AF=3.07%) in cis with L1196M, suggesting the combination of concurrent I1171N, L1196M, and G1202R were responsible for acquired resistance to lorlatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G1202R sequence variation in gene ALK/NCBI:238 780 check_entity AN4681-4 ALK G1202R mutation ALK NCBI:238 gene malignant pleural mesothelioma DOID:7474 risk 100019-9 CIViC:4329 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G1202R sequence variation in gene ALK/NCBI:238 780 check_entity AN4682-1 ALK G1269A mutation ALK NCBI:238 gene cancer DOID:162 risk 100019-9 PubMed:25727400 EML4-ALK with ALK G1269A has been seen in crizotinib resistant NSCLC, and this mutation was tested for Brigatinib sensitivity via ectopic expression in Ba/F3 cells, where half maximal inhibitory concentration of 9 nM was seen, which was 1.5 times the IC50 of EML4-ALK wild-type to brigatinib. NPM-ALK G1269A was also tested for brigatinib sensitivity, and IC50 values of 11 nM were reported for both NPM-ALK G1269A and NPM-ALK wild-type. In western blotting, brigatinib at and above 100 nM ablated pALK signal (Y 1604), indicating sensitivity of this variant to brigatinib together with the other results. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G1269A sequence variation in gene ALK/NCBI:238 781 check_entity AN4682-1 ALK G1269A mutation ALK NCBI:238 gene cancer DOID:162 risk 100019-9 CIViC:4311 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G1269A sequence variation in gene ALK/NCBI:238 781 check_entity AN4682-2 ALK G1269A mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:24675041 The NSCLC cell line MGH021-4, harboring SQSTM1-ALK G1269A, was 6 times more sensitive to ceritinib (80nM GI50) than crizotinib (500 nM) in proliferation assays and caused notable reductions in phospho-ALK and phospho-AKT (detected by Western blot) at concentrations 10 fold lower than crizotinib. GI50 values were similar in Ba/F3 cells expressing either EML4-ALK wild-type or EML4-ALK G1269A (1.6nM and 2.2nM, respectively). In contrast, crizotinib treatment of Ba/F3 with EML4-ALK G1269A had survival GI50 of 130nM. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G1269A sequence variation in gene ALK/NCBI:238 782 check_entity AN4682-2 ALK G1269A mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:22235099 This study analyzed patients with non small cell lung cancer (NSCLC) who were positive for EML4-ALK fusions (ALK+) and progressed on crizotinib monotherapy. One ALK+ patient harbored the common E6;A20 fusion with ALK G1269A co-mutation in post-crizotinib progression biopsies. The presence of ALK G1269A pre-crizotinib could not be evaluated. This patient was a 21 year old non-smoking male with adenocarcinoma, wt for KRAS and EGFR, negative for ALK copy number gain, who experienced crizotinib as a 2nd line therapy. The patient's best response on crizotinib was stable disease (377 days on treatment). In vitro, Ba/F3 cell line expressing EML4-ALK fusion (E6a;A20, a known sensitizing alteration) and ALK G1269A co-mutation demonstrated resistance to crizotinib treatment (341 nmol/L vs. 22 nmol/L) compared to Ba/F3 cells expressing EML4-ALK fusion. Resistance was determined by assessing cell viability and colony formation. Levels of phosphorylation of ALK, ERK, STAT3, and AKT were higher in ALK+ G1269A mutant cells than ALK+ controls, by western blot. The authors note that ALK G1269A likely induces resistance by preventing crizotinib from accessing its binding pocket in the ALK kinase domain. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G1269A sequence variation in gene ALK/NCBI:238 782 check_entity AN4682-2 ALK G1269A mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:23344087 2 out of 7 patients with an acquired resistance to crizotinib had a G1269A mutation. One of these patients also harbored a L1196M mutation. In vitro follow-up showed reduced crizotinib-induced ALK dephosphorylation (293T) and apoptosis (Ba/F3) when EML4-ALK G1269A overexpression was compared to EML4-ALK overexpression in these cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G1269A sequence variation in gene ALK/NCBI:238 782 check_entity AN4682-2 ALK G1269A mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4311 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G1269A sequence variation in gene ALK/NCBI:238 782 check_entity AN4682-2 ALK G1269A mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4312 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G1269A sequence variation in gene ALK/NCBI:238 782 check_entity AN4683-1 ALK HIP1::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:25393796 Case study describes a female (age 58) never-smoker presenting with stage IV NSCLC with an ALK rearrangement (confirmed by fish). Patient was treated with crizotinib (partial response) and alectinib (complete response). Liver metastasis was noted after 12 months with sequencing revealing a HIP1-ALK fusion with a I1171N variant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::HIP1::ALK sequence variation in gene ALK/NCBI:238 783 check_entity AN4683-1 ALK HIP1::ALK mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4332 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::HIP1::ALK sequence variation in gene ALK/NCBI:238 783 check_entity AN4684-1 ALK I1171 mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:25228534 The I1171T mutation in ALK fusions was found in a NSCLC patient shown positive for ALK rearrangement via break apart FISH assay, who progressed after 8 months of crizotinib, and then progressed again after 4 months of alectinib. The MGH056-1 cell line was derived from this patient, and this cell line was resistant to alectinib. Sequencing of MGH056-1 cells revealed the I1171T mutation in ALK. In cell culture studies Ba/F3 cells with EML4-ALK I1171T required more that 10x the concentration of alectinib to significantly reduce viability that was required for EML4-ALK wild-type expressing cells. Computer simulation studies indicated that the I1171T mutation interfered with alectinib binding at the ALK active site. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I1171 sequence variation in gene ALK/NCBI:238 784 check_entity AN4684-1 ALK I1171 mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:24675041 Ba/F3 cells expressing EML4-ALK variant 3 with ALK I1171T mutation were treated with ceritinib, and survival IC50 of 2.6 nM was observed, which compares favorably with highly ceritinib sensitive EML4-ALK wild-type variant 1 survival IC50 of 1.7 nM reported from parallel experiments. Tumors from mice with EML4-ALK variant 3 H2228 NSCLC cell xenografts which had progressed after approximately 40 days of crizotinib treatment were sequenced for ALK mutations. I1171T was found as one of 6 ALK resistance mutations from 80 sequenced tumors. Treatment of these mouse xenograft models with ceritinib reduced tumor volume to zero, while in contrast tumor size increased with crizotinib treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I1171 sequence variation in gene ALK/NCBI:238 784 check_entity AN4684-1 ALK I1171 mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:25736571 A 51 year old female never-smoker was diagnosed with stage IV NSCLC with liver metastases. ALK rearrangement was verified via FISH. She was treated with crizotinib at 250 mg twice daily but discontinued due to adverse response. She then started alectinib at 600 mg twice daily with partial response, but new liver metastases then formed at 5 months. Liver tumor biopsy was performed and was estimated to be 15% tumor tissue. Next-generation sequencing discovered an ALK I1171N mutation. The tumor was not sequenced prior to alectinib resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I1171 sequence variation in gene ALK/NCBI:238 784 check_entity AN4684-1 ALK I1171 mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:523 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I1171 sequence variation in gene ALK/NCBI:238 784 check_entity AN4685-1 ALK I1171N mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:25393796 Case study describes a female (age 58) never-smoker presenting with stage IV NSCLC with an ALK rearrangement (confirmed by fish). Patient was treated with crizotinib (partial response) and alectinib (complete response). Liver metastasis was noted after 12 months with sequencing revealing a HIP1-ALK fusion with a I1171N variant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I1171N sequence variation in gene ALK/NCBI:238 785 check_entity AN4685-1 ALK I1171N mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4332 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I1171N sequence variation in gene ALK/NCBI:238 785 check_entity AN4685-2 ALK I1171N mutation ALK NCBI:238 gene malignant pleural mesothelioma DOID:7474 risk 100019-9 PubMed:32600123 This case report describes a 33 year-old non-smoker with no known exposure to asbestos who was diagnosed with stage IIIB malignant pleural mesothelioma. Panel next generation sequencing (NGS) of 520 genes revealed an EML4::ALK fusion and the patient was subsequently treated with alectinib. After 1 month of therapy the patient showed clinical improvement, and plasma NGS revealed a decrease in EML4::ALK allele fraction (AF) from 24.21% to 8.22%. Progressive disease was confirmed after 4.5 months of alectinib therapy at which time plasma NGS revealed the emergence of two acquired resistance mutations, I1171N (AF=4.24%) and L1196M (AF=0.33). He then received lorlatinib and achieved a PR within one month with 34% tumour shrinkage, suggesting lorlatinib sensitivity despite compound I1171N and L1196M acquired mutations. He began showing signs of progression after 3.6 months of lorlatinib treatment and plasma NGS at that time identified a third concurrent acquired resistance mutation G1202R (AF=3.07%) in cis with L1196M. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I1171N sequence variation in gene ALK/NCBI:238 786 check_entity AN4685-2 ALK I1171N mutation ALK NCBI:238 gene malignant pleural mesothelioma DOID:7474 risk 100019-9 CIViC:4328 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I1171N sequence variation in gene ALK/NCBI:238 786 check_entity AN4685-2 ALK I1171N mutation ALK NCBI:238 gene malignant pleural mesothelioma DOID:7474 risk 100019-9 CIViC:4329 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I1171N sequence variation in gene ALK/NCBI:238 786 check_entity AN4686-1 ALK I1171S mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:25393796 Case study describes a caucasian male (age 38) never smoker presenting with stage IV non-small cell lung cancer with an ALK rearrangement. Patient was given crizotinib and exhibited a partial response after 5 months with brain metastasis occurring at 21 months. Patient then received alectinib and exhibited partial response however liver metastasis presented after 12 months on alectinib. Sequencing of this liver metastasis revealed an EML4-ALK fusion with an I1171S variant at a variant frequency of 36% (tumor purity estimated as 70%). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I1171S sequence variation in gene ALK/NCBI:238 787 check_entity AN4686-1 ALK I1171S mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4357 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I1171S sequence variation in gene ALK/NCBI:238 787 check_entity AN4687-1 ALK I1171T mutation ALK NCBI:238 gene neuroblastoma DOID:769 risk 100019-9 PubMed:29907598 This case reports a 16-mo-old boy with metastatic neuroblastoma (stage M). Genomic analysis of a diagnostic biopsy of the tumor and matched normal identified two germline mutations in FANCA and somatic ALK-I1171T mutation. Functional investigation of this mutation including PC12 cell neurite outgrowth, NIH3T3 transformation and phosophoproteomics showing increased ALK signaling all suggested that it was a gain function. The patient was treated with Ceritinib as a monotherapy for 7.5 months. The residual primary decreased in size (44% volume reduction at 6 months of treatment) and was surgically removed. At 21 months of followup a complete remission was observed (including all metastatic sites). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I1171T sequence variation in gene ALK/NCBI:238 788 check_entity AN4687-1 ALK I1171T mutation ALK NCBI:238 gene neuroblastoma DOID:769 risk 100019-9 CIViC:3239 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I1171T sequence variation in gene ALK/NCBI:238 788 check_entity AN4688-1 ALK KANK4::ALK mutation ALK NCBI:238 gene pancreatic acinar cell adenocarcinoma DOID:5742 risk 100019-9 PubMed:35005993 Case report of a 62-year old male patient diagnosed with pancreatic acinar cell carcinoma. Liver metastases were diagnosed and treatment was started with gemcitabine plus nab-paclitaxel regimen. After disease progression, patient received chemotherapy with fluorouracil, leucovorin, and irinotecan for 6 months followed by disease progression and third-line fluorouracil, leucovorin, and oxaliplatin again followed by disease-progression. Sequencing using the FoundationOne CDxF1CDx assay revealed ASXL1 R596fs*107 and BCORL1 V937fs*10 mutations as well as a KANK4-ALK gene fusion, which was confirmed by FISH. Treatment with alectinib was started and partial response was ongoing 4 months from the start of therapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KANK4::ALK sequence variation in gene ALK/NCBI:238 789 check_entity AN4688-1 ALK KANK4::ALK mutation ALK NCBI:238 gene pancreatic acinar cell adenocarcinoma DOID:5742 risk 100019-9 CIViC:3869 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KANK4::ALK sequence variation in gene ALK/NCBI:238 789 check_entity AN4689-1 ALK L1152R mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:21791641 Case-report of a patient with an acquired EML4::ALK L1152R mutation and resistance to crizotinib treatment. The L1152R variant was not present in the pre-crizotinib sample. A cell line model also showed resistance against ALK inhibition. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L1152R sequence variation in gene ALK/NCBI:238 790 check_entity AN4689-1 ALK L1152R mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4255 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L1152R sequence variation in gene ALK/NCBI:238 790 check_entity AN4690-1 ALK L1196M mutation ALK NCBI:238 gene lung adenocarcinoma DOID:3910 risk 100019-9 PubMed:20979473 A 28 year-old patient with non-small cell lung cancer was found to harbor the EML4-ALK (E13;A20) fusion using reverse transcription PCR. Treatment with 250mg crizotinib twice daily resulted in rapid improvement of symptoms and disease control for 5 months, followed by rapid disease progression. Analysis of pleural effusion samples obtained after relapse found L1196M at an allele frequency of 14%. This variant was undetected by Sanger sequencing in the tumor collected before crizotinib treatment. Cytotoxicity assays revealed Ba/F3 cells expressing EML4-ALK L1196M were more resistant to crizontinib than those expressing EML4-ALK wildtype. Immunoblot demonstrated crizontinib reduced tyrosine phosphorylation of the wildtype fusion, but not the EML4-ALK L1196M fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L1196M sequence variation in gene ALK/NCBI:238 791 check_entity AN4690-1 ALK L1196M mutation ALK NCBI:238 gene lung adenocarcinoma DOID:3910 risk 100019-9 CIViC:4230 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L1196M sequence variation in gene ALK/NCBI:238 791 check_entity AN4690-2 ALK L1196M mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:21575866 CH5424802 treatment resulted in significant tumor regression in xenograft models produced from Ba/F3 cells expressing EML4-ALK or EML4-ALK with the L1196M mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L1196M sequence variation in gene ALK/NCBI:238 792 check_entity AN4690-2 ALK L1196M mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:22277784 The L1196M mutation in the EML4-ALK fusion was found to confer resistance to crizotinib in Ba/F3 cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L1196M sequence variation in gene ALK/NCBI:238 792 check_entity AN4690-2 ALK L1196M mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:24675041 The crizotinib-resistant MGH045 cell line with EML4-ALK L1196M was treated with crizotinib or ceritinib. In nude mice with MGH045 xenografts, tumor response to crizotinib did not differ appreciably from vehicle, while ceritinib controlled tumor growth. Ceritinib inhibited Ba/F3 cells expressing EML4-ALK L1196M slightly stronger than ALK wild-type, but approximately double the potency as crizotinib, indicating ceritinib sensitivity in Ba/F3 EML4-ALK L1196M cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L1196M sequence variation in gene ALK/NCBI:238 792 check_entity AN4690-2 ALK L1196M mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4230 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L1196M sequence variation in gene ALK/NCBI:238 792 check_entity AN4690-3 ALK L1196M mutation ALK NCBI:238 gene malignant pleural mesothelioma DOID:7474 risk 100019-9 PubMed:32600123 This case report describes a 33 year-old non-smoker with no known exposure to asbestos who was diagnosed with stage IIIB malignant pleural mesothelioma. Panel next generation sequencing (NGS) of 520 genes revealed an EML4::ALK fusion and the patient was subsequently treated with alectinib. After 1 month of therapy the patient showed clinical improvement, and plasma NGS revealed a decrease in EML4::ALK allele fraction (AF) from 24.21% to 8.22%. Progressive disease was confirmed after 4.5 months of alectinib therapy at which time plasma NGS revealed the emergence of two acquired resistance mutations, I1171N (AF=4.24%) and L1196M (AF=0.33). He then received lorlatinib and achieved a PR within one month with 34% tumour shrinkage, suggesting lorlatinib sensitivity despite compound I1171N and L1196M acquired mutations. He began showing signs of progression after 3.6 months of lorlatinib treatment and plasma NGS at that time identified a third concurrent acquired resistance mutation G1202R (AF=3.07%) in cis with L1196M. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L1196M sequence variation in gene ALK/NCBI:238 793 check_entity AN4690-3 ALK L1196M mutation ALK NCBI:238 gene malignant pleural mesothelioma DOID:7474 risk 100019-9 CIViC:4328 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L1196M sequence variation in gene ALK/NCBI:238 793 check_entity AN4690-3 ALK L1196M mutation ALK NCBI:238 gene malignant pleural mesothelioma DOID:7474 risk 100019-9 CIViC:4329 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L1196M sequence variation in gene ALK/NCBI:238 793 check_entity AN4691-1 ALK L1198F mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:26698910 Case report of a patient with metastatic ALK-rearranged NSCLC. After developing resistance to first and second line ALK inhibitors mediated by a C1156Y mutation, the patient had a partial response with the third generation ALK-inhibitor lorlatinib. The patient progressed on lorlatinib after 8 months, at which point whole exome sequencing revealed an EML4-ALK C1156Y–L1198F double mutation. In vitro, the double mutation was resistant to lorlatinib but sensitive to crizotinib. The patient was started on crizotinib again and had a clinical response that lasted for 6 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L1198F sequence variation in gene ALK/NCBI:238 794 check_entity AN4691-1 ALK L1198F mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4253 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L1198F sequence variation in gene ALK/NCBI:238 794 check_entity AN4692-1 ALK Mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:24670165 In a phase 1 clinical trial (NCT01283516) 130 patients with advanced cancers all harboring ALK alterations were treated with ceritinib. Of 114 NSCLC patients treated with at least 400 mg/daily ceritinib, 1 had a complete response, 65 had a partial response, 25 had stable disease, 12 had progressive disease, and 11 withdrew from the study early. Ceritinib dosed at 400 mg or higher had similar results in patients who had or had not received prior crizotinib treatment. Overall response rate for patients with prior crizotinib treatment (83 out of 122) was 56% with median progression free survival of 6.9 months. For patients who had no prior crizotinib treatment, median progression free survival was 10.4 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ALK/NCBI:238 795 check_entity AN4692-1 ALK Mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:508 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ALK/NCBI:238 795 check_entity AN4693-1 ALK NPM::ALK mutation ALK NCBI:238 gene anaplastic large cell lymphoma DOID:0050744 risk 100019-9 PubMed:18089725 NPM-ALK in anaplastic large cell lymphoma (ALCL) was the first ALK-fusion to be discovered and characterized. In this study, targeted activity against NPM-ALK by the ALK and MET inhibitor crizotinib was assessed in cell lines and tumor xenograft models. Treatment of NPM-ALK positive ALCL cell lines Karpas299 and SU-DHL-1 potently inhibited growth, and this was seen to occur at concentrations which also inhibited NPM-ALK phosphorylation in these cells. Administration of 100mg/kg/d crizotinib resulted in complete regression of all tumors, indicating that NPM-ALK could be an effective target for crizotinib in ALCL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::NPM::ALK sequence variation in gene ALK/NCBI:238 796 check_entity AN4693-1 ALK NPM::ALK mutation ALK NCBI:238 gene anaplastic large cell lymphoma DOID:0050744 risk 100019-9 PubMed:23598171 In the second part of this Phase I study NCT00939770, nine patients between the ages of 12 months and 22 years with anaplastic large cell lymphoma (ALCL), who were refractory to treatment and for whom no further known treatments were available, were treated with crizotinib. Six patients with detectable NPM-ALK transcript levels responded with partial response, 1 with complete response, and 1 with stable disease. Crizotinib was well tolerated in these children. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::NPM::ALK sequence variation in gene ALK/NCBI:238 796 check_entity AN4693-1 ALK NPM::ALK mutation ALK NCBI:238 gene anaplastic large cell lymphoma DOID:0050744 risk 100019-9 CIViC:509 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::NPM::ALK sequence variation in gene ALK/NCBI:238 796 check_entity AN4693-2 ALK NPM::ALK mutation ALK NCBI:238 gene cancer DOID:162 risk 100019-9 PubMed:25727400 In Ba/F3 cells, crizotinib sensitivty of the NPM-ALK variant was compared to crizotinib sensitivity of EML4-ALK variant 3. 50% of maximal inhibitory concentration for NPM-ALK was 42 nM, which was approximately 4x greater than IC50 of 11 nM obtained for EML4-ALK. The IC50 for parental Ba/F3 supplemented with IL3 was 2299 nM, resulting in a fold difference of 209.2 for EML4-ALK and 55.1 for NPM-ALK, indicating some reduced sensitivity for NPM-ALK in direct comparison to EML4-ALK, but substantial sensitization to crizotinib for NPM-ALK in Ba/F3 cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::NPM::ALK sequence variation in gene ALK/NCBI:238 797 check_entity AN4693-2 ALK NPM::ALK mutation ALK NCBI:238 gene cancer DOID:162 risk 100019-9 CIViC:509 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::NPM::ALK sequence variation in gene ALK/NCBI:238 797 check_entity AN4694-1 ALK R1275Q mutation ALK NCBI:238 gene neuroblastoma DOID:769 risk 100019-9 PubMed:18923525 TAE684 inhibits growth of Ba/F3 cells expressing ALK mutations; however, cells with the R1275Q mutation were inhibited at a higher IC50 than those expressing F1174L. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R1275Q sequence variation in gene ALK/NCBI:238 798 check_entity AN4694-1 ALK R1275Q mutation ALK NCBI:238 gene neuroblastoma DOID:769 risk 100019-9 PubMed:22072639 Cells lines expressing ALK harboring the F1174L mutation are less sensitive to growth inhibition by crizotinib than cells expressing the R1275Q mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R1275Q sequence variation in gene ALK/NCBI:238 798 check_entity AN4694-1 ALK R1275Q mutation ALK NCBI:238 gene neuroblastoma DOID:769 risk 100019-9 PubMed:23598171 This Phase I study of crizotinib involved a cohort of pediatric neuroblastoma patients between ages 12 months and 22 years. In 11 patients with characterized ALK mutations, 4 had R1275Q mutations, and two of these were germline mutations. Of these 2 germline patients, 1 showed stable disease (SD) and 1 complete response (CR). In contrast, in the 7 characterized patients with ALK mutations that were not R1275Q, 6 showed PD and 1 SD. The authors conclude this finding is promising and merits further study. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R1275Q sequence variation in gene ALK/NCBI:238 798 check_entity AN4694-1 ALK R1275Q mutation ALK NCBI:238 gene neuroblastoma DOID:769 risk 100019-9 PubMed:26554404 In NB-1643 and LAN-5 neuroblastoma cell lines containing R1275Q mutation, PF-06463922 showed 51 and 19 fold greater effect on cell viability over crizotinib treatment respectively. ALK wild-type neuroblastoma cell lines did not show differential sensitivity to the treatments within the sensitivity range of R1275Q cells, and had IC50 values above 3800 nM to the inhibitors. NB-1653 cells induced tumors in CB17 SCID mice and crizotinib treatment inhibited tumor growth over vehicle treatment, but PF-06463922 induced complete tumor regression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R1275Q sequence variation in gene ALK/NCBI:238 798 check_entity AN4694-1 ALK R1275Q mutation ALK NCBI:238 gene neuroblastoma DOID:769 risk 100019-9 CIViC:9 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R1275Q sequence variation in gene ALK/NCBI:238 798 check_entity AN4695-1 ALK RANBP2::ALK mutation ALK NCBI:238 gene inflammatory myofibroblastic tumor DOID:0050905 risk 100019-9 PubMed:20979472 ALK-rearrangements are seen in 50% of inflammatory myofibroblastic tumor (IMT) cases. A 44 year old man was diagnosed with IMT. He was treated with surgery and catheter placement for administration of cisplatin, doxyrubicin and mitomycin C. Break-apart FISH showed ALK rearrangement, and immunohistochemical staining was characteristic of RANBP2 rearrangement. After further chemotherapy along with maintenance imatinib, crizotinib was started at 200mg twice daily, and a maximal partial response was achieved 5 months later, with regrowth occurring 2 months later. After further surgery, crizotinib was restarted at 250mg twice daily and almost 2 years later the patient was in complete radiographic remission. Another patient with non-ALK rearranged IMT was administered crizotinib in this study but did not respond. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RANBP2::ALK sequence variation in gene ALK/NCBI:238 799 check_entity AN4695-1 ALK RANBP2::ALK mutation ALK NCBI:238 gene inflammatory myofibroblastic tumor DOID:0050905 risk 100019-9 CIViC:510 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RANBP2::ALK sequence variation in gene ALK/NCBI:238 799 check_entity AN4696-1 ALK S1206Y mutation ALK NCBI:238 gene cancer DOID:162 risk 100019-9 PubMed:24675041 Ba/F3 cells expressing the EML4-ALK S1206Y variant were treated with ceritinib, and survival GI50 value of 1.5 nM was obtained, which compares favorably with GI50 of 1.7 for the highly ceritinib sensitive EML4-ALK wild-type variant obtained in parallel experiments, as well as the GI50 value of 16 nM obtained for crizotinib treatment of EML4-ALK wild-type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S1206Y sequence variation in gene ALK/NCBI:238 800 check_entity AN4696-1 ALK S1206Y mutation ALK NCBI:238 gene cancer DOID:162 risk 100019-9 CIViC:4309 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S1206Y sequence variation in gene ALK/NCBI:238 800 check_entity AN4696-2 ALK S1206Y mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:22277784 The S1206Y mutation in the EML4-ALK fusion was found to confer resistance to crizotinib in Ba/F3 cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S1206Y sequence variation in gene ALK/NCBI:238 801 check_entity AN4696-2 ALK S1206Y mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4309 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S1206Y sequence variation in gene ALK/NCBI:238 801 check_entity AN4697-1 ALK STRN::ALK mutation ALK NCBI:238 gene colon adenocarcinoma DOID:234 risk 100019-9 PubMed:26933125 Patients with metastatic colorectal cancer with STRN-ALK fusion, sporadic microsatellite instability high (MSI-H) and KRAS R164Q received ALK inhibitor ceritinib. After pts received ceritinib perinumbilica cutaneous metastasis disappeared. Although the size of pelvic tumor by CT scan did not changed, there has been resolution of all contrast enhancing tumor by CT scan. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::STRN::ALK sequence variation in gene ALK/NCBI:238 802 check_entity AN4697-1 ALK STRN::ALK mutation ALK NCBI:238 gene colon adenocarcinoma DOID:234 risk 100019-9 CIViC:2094 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::STRN::ALK sequence variation in gene ALK/NCBI:238 802 check_entity AN4698-1 ALK T1151dup mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:22277784 A lung adenocarcinoma patient responded to crizotinib treatment for 12 months, after which the cancer relapsed and sequencing of the ALK tyrosine kinase domain revealed a 1151insT mutation. This mutation was not found in the pre-crizotinib biopsy. EML4-ALK T1151insT was expressed In Ba/F3 cells and an IC50 of 431.8 nM was obtained, which was 16 times higher than for EML4-ALK wild-type, indicating strong crizotinib resistance. EML4-ALK containing H3122 NSCLC cells were incubated in increasing levels of crizotinib inducing resistance. The resulting cell line H3122 CR2 had IC50 10x greater to crizotinib than parental H3122, and was found to contain 1151 insT mutation. In western blots, pALK levels in H3122 CR2 cells remained apparent under 1000 nM crizotinib, whereas pALK signal was ablated under these conditions in parental H3122 cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::t1151dup:mutation sequence variation in gene ALK/NCBI:238 803 check_entity AN4698-1 ALK T1151dup mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4308 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::t1151dup:mutation sequence variation in gene ALK/NCBI:238 803 check_entity AN4699-1 ALK V1180L mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 PubMed:25228534 The EML4 ALK variant 1 containing NSCLC cell line H3122 is highly sensitive to alectinib, and an alectinib resistant derivative cell line H3122 CHR-A1 was generated by incubation of H3122 in increasing levels of alectinib culminating in 1 micro-molar, over a course of 7 months. The ALK kinase domain mutation V1180L was found in these cells, and Ba/F3 cells expressing EML4 ALK V1180L were highly resistant to alectinib. Simulations indicated that the V1180L mutation interfered with alectinib binding. The V1180L mutation was found to be more resistant to alectinib than the I1171T mutation found in an ALK-positive NSCLC patient who developed alectinib resistance on lower dose alectinib (300mg twice daily). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V1180L sequence variation in gene ALK/NCBI:238 804 check_entity AN4699-1 ALK V1180L mutation ALK NCBI:238 gene lung non-small cell carcinoma DOID:3908 risk 100019-9 CIViC:4351 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V1180L sequence variation in gene ALK/NCBI:238 804 check_entity AN4700-1 APC Mutation APC NCBI:324 gene colon carcinoma DOID:1520 risk 20990-8 PubMed:22440753 Canonical Wnt signaling in colon carcinoma cells with APC mutation was inhibited by JW55 treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene APC/NCBI:324 805 check_entity AN4700-1 APC Mutation APC NCBI:324 gene colon carcinoma DOID:1520 risk 20990-8 CIViC:174 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene APC/NCBI:324 805 check_entity AN4700-2 APC Mutation APC NCBI:324 gene colorectal cancer DOID:9256 risk 20990-8 PubMed:23539443 G007-LK inhibits in vivo tumor growth in a subset of APC-mutant colorectal cancers xenograft models but may be limited by intestinal toxicity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene APC/NCBI:324 806 check_entity AN4700-2 APC Mutation APC NCBI:324 gene colorectal cancer DOID:9256 risk 20990-8 CIViC:174 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene APC/NCBI:324 806 check_entity AN4701-1 AR F877L mutation AR NCBI:367 gene prostate cancer DOID:10283 risk 100019-9 PubMed:23779130 Mutations F876L in the ligand binding domain of the androgen receptor confered resistance to enzalutamide and ARN-509, causing these compounds to function as partial agonists in two prostate cancer cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F877L sequence variation in gene AR/NCBI:367 807 check_entity AN4701-1 AR F877L mutation AR NCBI:367 gene prostate cancer DOID:10283 risk 100019-9 CIViC:175 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F877L sequence variation in gene AR/NCBI:367 807 check_entity AN4702-1 AR Mutation AR NCBI:367 gene prostate cancer DOID:10283 risk 100019-9 PubMed:26000489 In a study of 150 patients with metastatic castration resistant prostate cancer (mCRPC), 71.3% of cases (n=107) harbored androgen receptor (AR) pathway aberrations. Within the AR mutation cohort, 78 patients had AR amplification mutations, 16 patients had AR missense mutations, and 13 patients had mutations in ZBTB16, NCOR1, FOXA1, and SPOP, which are all AR regulators or downstream effectors. All AR mutations were exclusive to mCRPC neoplasms and were not found in primary prostate cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene AR/NCBI:367 808 check_entity AN4702-1 AR Mutation AR NCBI:367 gene prostate cancer DOID:10283 risk 100019-9 CIViC:596 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene AR/NCBI:367 808 check_entity AN4703-1 AR OVEREXPRESSION AR NCBI:367 gene breast cancer DOID:1612 risk 100019-9 PubMed:24356815 In-vitro and xenograft studies of response of breast cancer cell lines to PI3K/mTOR inhibitor NVP-BEZ235 showed that sensitivity correlated with expression of the androgen receptor (AR). Reintroduction of AR expression resensitized nonresponsive AR-negative cells to NVP-BEZ235. A dihydrotestosterone (DHT) and NVP-BEZ235 combination achieved tumor regression and complete response in AR/ER expressing tumors (xenografts). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene AR/NCBI:367 809 AN4703-1 AR OVEREXPRESSION AR NCBI:367 gene breast cancer DOID:1612 risk 100019-9 CIViC:355 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene AR/NCBI:367 809 AN4704-1 AR V7 EXPRESSION AR NCBI:367 gene prostate cancer DOID:10283 risk 100019-9 PubMed:25184630 Detection of AR-V7 in circulating tumor cells of 62 patients treated with either enzalitamide (n=31) or arbiraterone (n=31), was correlated with lower PSA response rates and PSA PFS in men receiving enzalutamide or abiraterone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene AR/NCBI:367 810 AN4704-1 AR V7 EXPRESSION AR NCBI:367 gene prostate cancer DOID:10283 risk 100019-9 CIViC:358 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene AR/NCBI:367 810 AN4705-1 AR W742 mutation AR NCBI:367 gene prostate carcinoma DOID:10286 risk 100019-9 PubMed:12517791 LNCaP-FGC cells with mutations at codon 741 (W741C, W741L) were able to use bicalutamide as an AR agonist, promoting cell growth and increased prostate-specific antigen secretion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::W742 sequence variation in gene AR/NCBI:367 811 check_entity AN4705-1 AR W742 mutation AR NCBI:367 gene prostate carcinoma DOID:10286 risk 100019-9 CIViC:176 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::W742 sequence variation in gene AR/NCBI:367 811 check_entity AN4706-1 ARAF S214C mutation ARAF NCBI:369 gene lung cancer DOID:1324 risk PubMed:27478040 194 somatic mutations seen in primary lung cancers were functionally evaluated using three approaches: (1) differences in pattern or extent of changes in gene expression in A549 cells induced by transduction of lentiviral vectors containing mutant vs. wild-type genes; (2) xenograft assay based on human lung epithelial cells harbouring the variant introduced in mice and subsequent measurement of tumour size; (3) evaluation of resistance to erlotinib, afatinib, lapatinib, sofarenib and trametinib in PC9 isogenic lines expressing mutant alleles. ARAF S214C mutations showed differences in gene expression from wild-type, induced tumour formation, and in the presence of erlotinib rescued cell viability. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S214C sequence variation in gene ARAF/NCBI:369 812 check_entity AN4706-1 ARAF S214C mutation ARAF NCBI:369 gene lung cancer DOID:1324 risk CIViC:10 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S214C sequence variation in gene ARAF/NCBI:369 812 check_entity AN4706-2 ARAF S214C mutation ARAF NCBI:369 gene lung non-small cell carcinoma DOID:3908 risk PubMed:24569458 In one patient with S214C mutation, the use of sorafenib has led to more than 5 years of survival and near remission. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S214C sequence variation in gene ARAF/NCBI:369 813 check_entity AN4706-2 ARAF S214C mutation ARAF NCBI:369 gene lung non-small cell carcinoma DOID:3908 risk CIViC:10 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S214C sequence variation in gene ARAF/NCBI:369 813 check_entity AN4707-1 ARAF S214F mutation ARAF NCBI:369 gene lung cancer DOID:1324 risk PubMed:27478040 194 somatic mutations seen in primary lung cancers were functionally evaluated using three approaches: (1) differences in pattern or extent of changes in gene expression in A549 cells induced by transduction of lentiviral vectors containing mutant vs. wild-type genes; (2) xenograft assay based on human lung epithelial cells harbouring the variant introduced in mice and subsequent measurement of tumour size; (3) evaluation of resistance to erlotinib, afatinib, lapatinib, sofarenib and trametinib in PC9 isogenic lines expressing mutant alleles. ARAF S214F mutations showed differences in gene expression from wild-type, induced tumour formation, and in the presence of erlotinib rescued cell viability. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S214F sequence variation in gene ARAF/NCBI:369 814 check_entity AN4707-1 ARAF S214F mutation ARAF NCBI:369 gene lung cancer DOID:1324 risk CIViC:4338 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S214F sequence variation in gene ARAF/NCBI:369 814 check_entity AN4708-1 ARAF S490T mutation ARAF NCBI:369 gene colorectal cancer DOID:9256 risk PubMed:27729313 Phase 1b study of vemurafenib, cetuximab and irinotecan in 19 BRAF V600E mutant colorectal cancer patients. cfDNA panel sequencing was performed in 10 patients after disease progression. One patient had an acquired ARAF S490T mutation that was not identified before treatment initiation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S490T sequence variation in gene ARAF/NCBI:369 815 check_entity AN4708-1 ARAF S490T mutation ARAF NCBI:369 gene colorectal cancer DOID:9256 risk CIViC:803 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S490T sequence variation in gene ARAF/NCBI:369 815 check_entity AN4709-1 ARAF V145L mutation ARAF NCBI:369 gene lung cancer DOID:1324 risk PubMed:27478040 194 somatic mutations seen in primary lung cancers were functionally evaluated using three approaches: (1) differences in pattern or extent of changes in gene expression in A549 cells induced by transduction of lentiviral vectors containing mutant vs. wild-type genes; (2) xenograft assay based on human lung epithelial cells harbouring the variant introduced in mice and subsequent measurement of tumour size; (3) evaluation of resistance to erlotinib, afatinib, lapatinib, sofarenib and trametinib in PC9 isogenic lines expressing mutant alleles. ARAF V145L did not show evidence of effect in any of these assays. Authors suggest it is a passenger mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V145L sequence variation in gene ARAF/NCBI:369 816 check_entity AN4709-1 ARAF V145L mutation ARAF NCBI:369 gene lung cancer DOID:1324 risk CIViC:4339 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V145L sequence variation in gene ARAF/NCBI:369 816 check_entity AN4710-1 AREG Expression AREG NCBI:374 gene colorectal cancer DOID:9256 risk PubMed:23374602 226 cetuximab-treated patients with colorectal cancer (CRC) were analyzed for mRNA expression (by qPCR) of EGFR and its ligands (EGF, TGFA, AREG and EREG). High AREG mRNA expression in KRAS wild type tumours was a favorable predictor in a multivariate analysis (median survival 33 vs. 15 months, p=0.0005). Cetuximab-treated patients with AREG-low KRAS wild type CRC had poor survival, similar to KRAS mutated CRC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene AREG/NCBI:374 817 AN4710-1 AREG Expression AREG NCBI:374 gene colorectal cancer DOID:9256 risk PubMed:26867820 'Prospectively planned retrospective biomarker study in archived tumor tissue from 323 patients from the PICCOLO trial (panitumumab plus irinotecan in CRC patients with KRAS wt). Tumors were classified as ''high expressor'' (either EREG or AREG mRNA level) or ''low expressor'' (neither EREG nor AREG in top tertile). For RAS wild-type patients with high ligand expression, median PFS was 8.3 [4.0-11.0] months (irinotecan with panitumumab) vs 4.4 [2.8-6.7] months (irinotecan alone); HR, 0.38 [95% CI, 0.24-0.61]; P < .001. In RAS wild-type patients with low ligand expression, median PFS was 3.2 [2.7-8.1] months (irinotecan with panitumumab) vs 4.0 [2.7-7.5] months (irinotecan); HR, 0.93 [95% CI, 0.64-1.37]; P = .73; interaction test results were significant [P = .01]). Results were less clear for response rate (interaction P = .17) and OS (interaction P = .11).' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene AREG/NCBI:374 817 AN4710-1 AREG Expression AREG NCBI:374 gene colorectal cancer DOID:9256 risk CIViC:311 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene AREG/NCBI:374 817 AN4710-2 AREG Expression AREG NCBI:374 gene head and neck squamous cell carcinoma DOID:5520 risk PubMed:21653686 47 HNSCC patients treated with cetuximab/docetaxel were retrospectively analyzed for EGFRvIII, EGFR and AREG expression with IHC. 45% of cases expressed high level of AREG. High AREG expression in tumor cells was associated with reduced overall survival (hazard ratio: 2.2, P = 0.002) and progression free survival (hazard ratio: 2.2, P = 0.016) compared to patients with low AREG expression score. AREG was an independent prognosticator of OS in multivariate Cox analysis. High EGFRvIII and AREG expression levels identified SCCHN (squamous cell carcinoma, head and neck) patients that were less likely to benefit from combination treatment with cetuximab and docetaxel. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene AREG/NCBI:374 818 AN4710-2 AREG Expression AREG NCBI:374 gene head and neck squamous cell carcinoma DOID:5520 risk CIViC:311 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene AREG/NCBI:374 818 AN4710-3 AREG Expression AREG NCBI:374 gene lung non-small cell carcinoma DOID:3908 risk PubMed:21791641 A cell line (DFCI076) with EML1-ALK fusion and resistance mutation L1152R showed no response to ALK inhibition with crizotinib or TAE684. There was co-dependancy on AKT and EGFR-signaling and inhibition of both pathways led to decreased cell-growth. Amphiregulin (AREG) production was identified as a potential mediator of EGFR-activation (no other alterations detectable). The same mechanism could be reproduced in a cell line (H3122) without EML1-ALK mutation and resistance to crizotinib that was acquired in-vitro. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene AREG/NCBI:374 819 AN4710-3 AREG Expression AREG NCBI:374 gene lung non-small cell carcinoma DOID:3908 risk PubMed:23344087 Five patients with acquired resistance to crizotinib showed high concentration of amphiregulin in malignant pleural effusions. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene AREG/NCBI:374 819 AN4710-3 AREG Expression AREG NCBI:374 gene lung non-small cell carcinoma DOID:3908 risk CIViC:311 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene AREG/NCBI:374 819 AN4711-1 ARID1A Loss ARID1A NCBI:8289 gene ovarian clear cell carcinoma DOID:0050934 risk PubMed:27364904 High-throughput drug screens in OCCC tumor cell model identified synthetic lethal (SL) interaction between the kinase inhibitor dasatinib and ARID1A mutation. Imposing ARID1A deficiency upon a variety of human or mouse cells induced dasatinib sensitivity, both in vitro and in vivo. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ARID1A Loss [biomarker_term_in_review] 820 not_mapped AN4711-1 ARID1A Loss ARID1A NCBI:8289 gene ovarian clear cell carcinoma DOID:0050934 risk PubMed:25686104 A screen was performed to identify small molecule inhibitors that inhibit growth of ARID1A inactivated cells using shRNA knockdown in ARID1A wild-type ovarian clear cell carcinoma (OCCC) cell line RMG1. The EZH2 inhibitor GSK126 was the drug with the highest selectivity against ARID1A knockdown cells as measured by decrease in acini size in 3D culture. GSK126 also decreased growth of ARID1A mutant ovarian cancer cell lines (TOV21G, OVISE, OVTOKO and SKOV3) but not wild-type cell lines. OVISE cells were injected into immunocompromised mice to to test GSK126 in vivo and treatment caused significant decreases in orthotopic tumour sizes relative to controls. It was also noted that GSK126 caused reduced OCCC dissemination as measured by the number of tumour nodules following intraperitoneal injection of OVISE cells in immunocompromised mice. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ARID1A Loss [biomarker_term_in_review] 820 not_mapped AN4711-1 ARID1A Loss ARID1A NCBI:8289 gene ovarian clear cell carcinoma DOID:0050934 risk PubMed:37418832 In this phase 2 clinical study, 28 patients with recurrent Clear Cell Carcinoma of the Ovary, Fallopian Tube, Peritoneum, or Endometrium, harboring either wild-type ARID1A or ARID1A loss were recruited, and treated with Dasatinib. Of the 28 patients, 15 patients had retained BAF250a, while 13 had a loss of BAF250a. In this cohort, 53.6% of the patients had disease progression, 28% had stable disease, however, only one patient had a partial response. The median duration of stable disease was 5.67 months (3.55 - 20.73) in the loss of BAF250a group, and it was 4.65 months (1.58 - 17.84) in the retained BAF250a group. Overall, the study reported that Dasatinib was not effective as a single-agent treatment for recurrent Clear Cell Carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ARID1A Loss [biomarker_term_in_review] 820 not_mapped AN4711-1 ARID1A Loss ARID1A NCBI:8289 gene ovarian clear cell carcinoma DOID:0050934 risk CIViC:1267 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ARID1A Loss [biomarker_term_in_review] 820 not_mapped AN4711-1 ARID1A Loss ARID1A NCBI:8289 gene ovarian clear cell carcinoma DOID:0050934 risk CIViC:4882 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ARID1A Loss [biomarker_term_in_review] 820 not_mapped AN4712-1 ARID1A P1175FS*5 mutation ARID1A NCBI:8289 gene ovarian clear cell carcinoma DOID:0050934 risk PubMed:27364904 In an in vitro study, a HCH1 cell line expressing ARID1A P1172fs mutation demonstrated increased sensitivity to dasatinib treatment, compared to ES2, KK and RMG-1 cells expressing wild-type ARID1A. Sensitivity was determined by assessing cell survival. Authors also observed a modest increase in dasatinib-induced G1 arrest in HCH1 compared to ARID1A wt models (p<0.05) assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::p1175fs*5:mutation sequence variation in gene ARID1A/NCBI:8289 821 check_entity AN4712-1 ARID1A P1175FS*5 mutation ARID1A NCBI:8289 gene ovarian clear cell carcinoma DOID:0050934 risk CIViC:1590 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::p1175fs*5:mutation sequence variation in gene ARID1A/NCBI:8289 821 check_entity AN4713-1 ARID1A Q456* mutation ARID1A NCBI:8289 gene colorectal cancer DOID:9256 risk PubMed:27364904 In an in vitro study, human colorectal cancer cell line HCT116 cell line was made to homozygously express ARID1A Q546* via adeno-associated virus-mediated somatic gene targeting. Compared to the parent HCT116 cell line expressing wildtype ARID1A, the cell line expression ARID1A Q546* was significantly more sensitive to dasatinib (p<0.001). Sensitivity was determined by assessing cell survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q456* sequence variation in gene ARID1A/NCBI:8289 822 check_entity AN4713-1 ARID1A Q456* mutation ARID1A NCBI:8289 gene colorectal cancer DOID:9256 risk CIViC:1418 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q456* sequence variation in gene ARID1A/NCBI:8289 822 check_entity AN4714-1 ARID1A Underexpression ARID1A NCBI:8289 gene clear cell renal cell carcinoma DOID:4467 prognostic PubMed:25628030 This study included 290 patients with Clear Cell Renal Cell Carcinoma whose tumor tissues were sampled and then analyzed. These samples were then divided according to ARID1A expression after immunohistochemical staining. Of the 290 patients, 213 had a low ARID1A expression and 77 patients had a high expression. Low ARID1A expression was associated with higher nuclear grade (P<0.001), advanced pTNM stage (P=0.013), shorter cancer-specific survival (p=0.001) and progression-free survival (P<0.001). After a multivariate analysis using Cox proportional hazards, it was found that ARID1A expression levels are an independent predictor of progression-free survival in patients with CCRCC, although no significant correlation was found between the expression levels and cancer-specific survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ARID1A/NCBI:8289 823 AN4714-1 ARID1A Underexpression ARID1A NCBI:8289 gene clear cell renal cell carcinoma DOID:4467 prognostic CIViC:1984 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ARID1A/NCBI:8289 823 AN4714-2 ARID1A Underexpression ARID1A NCBI:8289 gene ovarian clear cell carcinoma DOID:0050934 prognostic PubMed:22101352 In a study of 60 individuals with ovarian clear cell carcinoma, ARID1A expression was analyzed using immunohistochemistry. Of these 60 patients, 9 (15%) patients had a loss of ARID1A expression. Results showed that a low ARID1A expression was significantly related to advanced FIGO stages (P=0.02) and high CA125 levels (P=0.01). Patients with low expression experienced shorter progression free survival than those with no loss of expression (P<0.01). In a multivariate analysis it was found that a loss of ARID1A expression was significant for shorter disease free survival (P=0.03) and shorter overall survival for patients whose ovarian clear cell carcinoma was treated with platinum-based chemotherapy (P=0.015). Lastly, tumors with low expression were significantly more likely to be resistant to primary adjuvant chemotherapy than tumors with a higher expression (P=0.04). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ARID1A/NCBI:8289 824 AN4714-2 ARID1A Underexpression ARID1A NCBI:8289 gene ovarian clear cell carcinoma DOID:0050934 prognostic CIViC:1984 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ARID1A/NCBI:8289 824 AN4714-3 ARID1A Underexpression ARID1A NCBI:8289 gene stomach cancer DOID:10534 prognostic PubMed:22808142 In this study, real-time quantitative RT-PCR assays were used in 66 pairs of cancerous and matched adjacent normal tissues. In 43 of those pairs, the expression level of ARID1A was significantly lower in the cancerous tissue than in the normal tissue (P=0.0029). This was then again tested using Western Blotting. Consistent with the real-time PCR results, there was a lower expression of ARID1A in 13 of the tumor tissue samples compared to the normal tissue samples (P=0.0015). In an immunohistochemical analysis of 224 tissue blocks, 115 of those had a decreased ARID1A expression. The data conveyed that lower ARID1A expression was correlated with depth of tumor infiltration (P=0.001). Lastly, cell proliferation in regards to ARID1A expression was tested in cell lines. The cells with silenced expression of ARID1A had a much greater growth than those with greater expression of the protein. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ARID1A/NCBI:8289 825 AN4714-3 ARID1A Underexpression ARID1A NCBI:8289 gene stomach cancer DOID:10534 prognostic CIViC:1984 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ARID1A/NCBI:8289 825 AN4715-1 ARID1A Wildtype ARID1A NCBI:8289 gene ovarian clear cell carcinoma DOID:0050934 risk PubMed:37418832 In this phase 2 clinical study, 28 patients with recurrent Clear Cell Carcinoma of the Ovary, Fallopian Tube, Peritoneum, or Endometrium, harboring either wild-type ARID1A or ARID1A loss were recruited, and treated with Dasatinib. Of the 28 patients, 15 patients had retained BAF250a, while 13 had a loss of BAF250a. In this cohort, 53.6% of the patients had disease progression, 28% had stable disease, however, only one patient had a partial response. The median duration of stable disease was 5.67 months (3.55 - 20.73) in the loss of BAF250a group, and it was 4.65 months (1.58 - 17.84) in the retained BAF250a group. Overall, the study reported that Dasatinib was not effective as a single-agent treatment for recurrent Clear Cell Carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ARID1A Wildtype [biomarker_term_in_review] 826 not_mapped AN4715-1 ARID1A Wildtype ARID1A NCBI:8289 gene ovarian clear cell carcinoma DOID:0050934 risk CIViC:4882 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ARID1A Wildtype [biomarker_term_in_review] 826 not_mapped AN4716-1 ASNS Amplification ASNS NCBI:440 gene ovarian cancer DOID:2394 risk PubMed:17088436 ASNS amplification and expression was associated with resistance to L-asparaginase in ovarian cancer and leukemia cell lines. ASNS silencing increased sensitivity to l-ASP in 2/3 of ovarian cancer cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ASNS/NCBI:440 827 AN4716-1 ASNS Amplification ASNS NCBI:440 gene ovarian cancer DOID:2394 risk CIViC:405 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ASNS/NCBI:440 827 AN4717-1 ASS1 Loss ASS1 NCBI:445 gene ovarian cancer DOID:2394 risk 81820-3 PubMed:19533750 Preclinical evidence for epigenetic inactivation of ASS1 as a determinant of response to platinum chemotherapy suggesting that silencing of ASS1 contributes to treatment failure and clinical relapse in ovarian cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ASS1 Loss [biomarker_term_in_review] 828 not_mapped AN4717-1 ASS1 Loss ASS1 NCBI:445 gene ovarian cancer DOID:2394 risk 81820-3 CIViC:2106 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ASS1 Loss [biomarker_term_in_review] 828 not_mapped AN4717-2 ASS1 Loss ASS1 NCBI:445 gene sarcoma DOID:1115 risk 81820-3 PubMed:27735949 90% out of 700 sarcoma samples (comprising 45 histologies) demonstrated loss or reduction of argininosuccinate synthetase 1 expression. Arginine auxotrophy confers sensitivity to arginine deprivation. In sarcoma models, arginine deprivation therapy with pegylated arginine deiminase (ADI-PEG20) maintains a prolonged state of arginine starvation without causing cell death. Combination of ADI-PEG20 and chloroquine led to synergistic cell death via necroptosis and apoptosis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ASS1 Loss [biomarker_term_in_review] 829 not_mapped AN4717-2 ASS1 Loss ASS1 NCBI:445 gene sarcoma DOID:1115 risk 81820-3 CIViC:2106 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ASS1 Loss [biomarker_term_in_review] 829 not_mapped AN4718-1 ASXL1 EXON 12 MUTATION ASXL1 NCBI:171023 gene acute myeloid leukemia DOID:9119 prognostic 99965-6 PubMed:23018865 In patients with de novo AML who received intensive chemotherapy, ASXL1 mutations (N=51) were associated with shorter overall (P<0.001) and event free survival (P=0.012) compared to ASXL1 wild-type (N=430). Multivariate analysis identified ASXL1 mutations as an independent factor for adverse overall survival (P=0.032, relative risk: 1.70). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12:mutation sequence variation in gene ASXL1/NCBI:171023 830 check_entity AN4718-1 ASXL1 EXON 12 MUTATION ASXL1 NCBI:171023 gene acute myeloid leukemia DOID:9119 prognostic 99965-6 CIViC:553 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12:mutation sequence variation in gene ASXL1/NCBI:171023 830 check_entity AN4719-1 ASXL1 Mutation ASXL1 NCBI:171023 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic 99965-6 PubMed:25412851 In patients with acute myeloid leukemia, in a univariate analysis those with mutations in ASXL1 had worse overall survival than wild-type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ASXL1/NCBI:171023 831 check_entity AN4719-1 ASXL1 Mutation ASXL1 NCBI:171023 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic 99965-6 PubMed:25308295 In a meta-analysis of six studies totalling 3311 patients with non-M3 acute myeloid leukemia, those with mutations in ASXL1 had worse overall survival than wild-type patients (Hazard ratio 1.86, 95% CI 1.49-2.33). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ASXL1/NCBI:171023 831 check_entity AN4719-1 ASXL1 Mutation ASXL1 NCBI:171023 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic 99965-6 PubMed:22031865 In older patients (>59 years) with cytogenetically normal acute myeloid leukemia classified as ELN favorable, multivariate analysis identified ASXL1 mutations (12/99 patients) were associated with lower complete remission rates (P = 0.03), disease-free survival (P < 0.001), overall survival (P < 0.001), and event-free survival (P < 0.001). This confirmed results from univariate analysis of patients not stratified by ELN category, but cytogenetically normal and older (38/220 patients). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ASXL1/NCBI:171023 831 check_entity AN4719-1 ASXL1 Mutation ASXL1 NCBI:171023 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic 99965-6 PubMed:27276561 Patients with Acute Myeloid Leukemia showed an synergistic mortality rate with ASXL1 and SRSF2 co-mutations such that individual mutations of either ASXL1 or SRSF2 resulted in ~20% probability of survival after 10 years, whereas co-mutations resulted in a 100% mortality rate after 4 years. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ASXL1/NCBI:171023 831 check_entity AN4719-1 ASXL1 Mutation ASXL1 NCBI:171023 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic 99965-6 CIViC:177 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ASXL1/NCBI:171023 831 check_entity AN4719-2 ASXL1 Mutation ASXL1 NCBI:171023 gene myelofibrosis DOID:4971 prognostic 99965-6 PubMed:26124496 An ASXL1 mutation, especially in conjunction with DNMT3A and EZH2 mutations, results in a fourfold increase in resistance to treatment with ruxolitinib and a reduced time to treatment discontinuation (TTD) for patients with myelofibrosis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ASXL1/NCBI:171023 832 check_entity AN4719-2 ASXL1 Mutation ASXL1 NCBI:171023 gene myelofibrosis DOID:4971 prognostic 99965-6 CIViC:177 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ASXL1/NCBI:171023 832 check_entity AN4720-1 ATM A2062V mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 PubMed:23585524 Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the A2062V variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the A2062V variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 87% of cells by FISH. Western blot showed stable ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A2062V sequence variation in gene ATM/NCBI:472 833 check_entity AN4720-1 ATM A2062V mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 CIViC:1143 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A2062V sequence variation in gene ATM/NCBI:472 833 check_entity AN4721-1 ATM C2488Y mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 PubMed:23585524 Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the C2488Y variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the C2488Y variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 90% of cells by FISH. Western blot showed stable ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C2488Y sequence variation in gene ATM/NCBI:472 834 check_entity AN4721-1 ATM C2488Y mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 CIViC:1146 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C2488Y sequence variation in gene ATM/NCBI:472 834 check_entity AN4722-1 ATM D1682H mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 PubMed:23585524 Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the D1682H variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the D1682H variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 93% of cells by FISH. Western blot showed stable ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D1682H sequence variation in gene ATM/NCBI:472 835 check_entity AN4722-1 ATM D1682H mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 CIViC:1142 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D1682H sequence variation in gene ATM/NCBI:472 835 check_entity AN4723-1 ATM D1930V mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 PubMed:23585524 Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the D1930V variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the D1930V variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 88% of cells by FISH. Western blot showed null ATM expression. Treatment with doxorubicin resulted in p21 expression greater than 300% that of untreated wild-type controls. This was considered by the authors to be similar to treated wild-type controls with a median expression level 815% that of untreated controls suggesting this variant does not support resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D1930V sequence variation in gene ATM/NCBI:472 836 check_entity AN4723-1 ATM D1930V mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 CIViC:1134 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D1930V sequence variation in gene ATM/NCBI:472 836 check_entity AN4724-1 ATM E2187* mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 PubMed:23585524 Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the E2187* variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the E2187* variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 96% of cells by FISH. Western blot showed null ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E2187* sequence variation in gene ATM/NCBI:472 837 check_entity AN4724-1 ATM E2187* mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 CIViC:1136 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E2187* sequence variation in gene ATM/NCBI:472 837 check_entity AN4725-1 ATM F1025L mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 PubMed:23585524 Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the F1025L variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the F1025L variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 93% of cells by FISH. Western blot showed stable ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F1025L sequence variation in gene ATM/NCBI:472 838 check_entity AN4725-1 ATM F1025L mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 CIViC:1132 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F1025L sequence variation in gene ATM/NCBI:472 838 check_entity AN4726-1 ATM F2732V mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 PubMed:23585524 Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the F2732V variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the F2732V variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 98% of cells by FISH. Western blot showed stable ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F2732V sequence variation in gene ATM/NCBI:472 839 check_entity AN4726-1 ATM F2732V mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 CIViC:1138 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F2732V sequence variation in gene ATM/NCBI:472 839 check_entity AN4727-1 ATM K293* mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 PubMed:23585524 Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the K293* variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the K293* variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 92% of cells by FISH. Western blot showed null ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K293* sequence variation in gene ATM/NCBI:472 840 check_entity AN4727-1 ATM K293* mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 CIViC:1129 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K293* sequence variation in gene ATM/NCBI:472 840 check_entity AN4728-1 ATM K468FS mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 PubMed:23585524 Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the K468FS variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the K468FS variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 91% of cells by FISH. Western blot showed null ATM expression. Treatment with doxorubicin resulted in p21 expression greater than 300% that of untreated wild-type controls. This was considered by the authors to be similar to treated wild-type controls with a median expression level 815% that of untreated controls suggesting this variant does not support resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::k468fs:mutation sequence variation in gene ATM/NCBI:472 841 check_entity AN4728-1 ATM K468FS mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 CIViC:1140 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::k468fs:mutation sequence variation in gene ATM/NCBI:472 841 check_entity AN4729-1 ATM L2427P mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 PubMed:23585524 Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the L2427P variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the L2427P variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 94% of cells by FISH. Western blot showed stable ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L2427P sequence variation in gene ATM/NCBI:472 842 check_entity AN4729-1 ATM L2427P mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 CIViC:1137 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L2427P sequence variation in gene ATM/NCBI:472 842 check_entity AN4730-1 ATM Mutation ATM NCBI:472 gene castration-resistant prostate carcinoma DOID:0080909 risk 21624-2 PubMed:32343890 This study (PMID 32343890) by de Bono et al, is a randomized, open-label, phase 3 trial evaluating the PARP inhibitor olaparib in 387 men with metastatic castration-resistant prostate cancer (mCRPC) who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone).The study found that in men with mCRPC who had disease progression while receiving enzalutamide or abiraterone and who had somatic or germline deleterious alterations (irrespective of zygosity) in any of the following HRR genes (BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L), olaparib was associated with longer progression-free survival and better measures of response and patient- reported end points than either enzalutamide or abiraterone (PFS HR 0.49 [0.38, 0.63]). For patients with ATM mutations specifically, PFS HR 1.04 [0.61-1.87]. Based on the results of this study, On May 19, 2020, the Food and Drug Administration approved olaparib (LYNPARZA) for adult patients with deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC, who have progressed following prior treatment with enzalutamide or abiraterone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ATM/NCBI:472 843 check_entity AN4730-1 ATM Mutation ATM NCBI:472 gene castration-resistant prostate carcinoma DOID:0080909 risk 21624-2 CIViC:178 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ATM/NCBI:472 843 check_entity AN4730-2 ATM Mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 prognostic;risk 21624-2 PubMed:26837699 In a study of 406 previously untreated CLL cases, a multivariate analysis indicated that aberrations (N=44; mixed pathogenic germline and somatic) in exons 2-63 of ATM were significantly associated with shorter time to first treatment (HR: 1.36; 95% CI: 1.05-1.76; P = 0.021). These mutations were not significantly associated with overall survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ATM/NCBI:472 844 check_entity AN4730-2 ATM Mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 prognostic;risk 21624-2 PubMed:23585524 Primary cells from chronic lymphocytic leukemia patients were treated with doxorubicin to induce double-strand (DSB). In this setting, cells harboring rare ATM variants (n=8) had significantly higher viability, measured by mitochondrial dehydrogenase activity, compared to wildtype cells (n=8, p < 0.001) suggesting resistance. A qPCR functional assay showed that samples with rare ATM variants (n= 20) had significantly less p21 expression after treatment with doxorubicin compared to treated wildtype controls (n=31, p < 0.001). Furthermore, there was significantly decreased expression of BBC3, BAX, and GADD45 genes which are downstream of ATM in the DNA damage response. In the above studies, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for p21 induction to confirm wildtype p53. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ATM/NCBI:472 844 check_entity AN4730-2 ATM Mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 prognostic;risk 21624-2 PubMed:21993670 ATM point mutations were found in 8/57 patients with CLL and were associated with a shorter treatment-free interval, suggesting a more aggressive course. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ATM/NCBI:472 844 check_entity AN4730-2 ATM Mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 prognostic;risk 21624-2 CIViC:178 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ATM/NCBI:472 844 check_entity AN4730-3 ATM Mutation ATM NCBI:472 gene glioblastoma DOID:3068 risk 21624-2 PubMed:23960094 Glioblastoma cell lines were shown to have increased sensitivity to Temozolomide when siRNA-induced ATM knockdown was applied. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ATM/NCBI:472 845 check_entity AN4730-3 ATM Mutation ATM NCBI:472 gene glioblastoma DOID:3068 risk 21624-2 CIViC:178 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ATM/NCBI:472 845 check_entity AN4730-4 ATM Mutation ATM NCBI:472 gene hematologic cancer DOID:2531 risk 21624-2 PubMed:20739657 Olaparib was found to inhibit cancer cell growth in ATM mutant cell lines of several blood cancers including Lymphoblastoid Leukemia, Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia, and in a murine xenograft model of Mantle Cell Lymphoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ATM/NCBI:472 846 check_entity AN4730-4 ATM Mutation ATM NCBI:472 gene hematologic cancer DOID:2531 risk 21624-2 CIViC:178 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ATM/NCBI:472 846 check_entity AN4730-5 ATM Mutation ATM NCBI:472 gene mantle cell lymphoma DOID:0050746 risk 21624-2 PubMed:20124459 Two ATM deficient mantle cell lymphoma (MCL) cell lines were more sensitive to PARP-1 inhibition with olaparib or PJ-34 than 4 other MCL cell lines. shRNA mediated ATM knockdown in a cell line increased sensitivity to olaparib. These results were confirmed in a xenograft model. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ATM/NCBI:472 847 check_entity AN4730-5 ATM Mutation ATM NCBI:472 gene mantle cell lymphoma DOID:0050746 risk 21624-2 CIViC:178 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ATM/NCBI:472 847 check_entity AN4730-6 ATM Mutation ATM NCBI:472 gene melanoma DOID:1909 risk 21624-2 PubMed:23960094 Melanoma cell lines were shown to have increased sensitivity to Temozolomide when siRNA-induced ATM knockdown was applied. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ATM/NCBI:472 848 check_entity AN4730-6 ATM Mutation ATM NCBI:472 gene melanoma DOID:1909 risk 21624-2 CIViC:178 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ATM/NCBI:472 848 check_entity AN4730-7 ATM Mutation ATM NCBI:472 gene prostate cancer DOID:10283 risk 21624-2 PubMed:26510020 Response to olaparib was observed in 4 of 5 with prostate cancer patients with ATM aberrations (2 germline). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ATM/NCBI:472 849 check_entity AN4730-7 ATM Mutation ATM NCBI:472 gene prostate cancer DOID:10283 risk 21624-2 CIViC:178 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ATM/NCBI:472 849 check_entity AN4731-1 ATM N2875H mutation ATM NCBI:472 gene prostate cancer DOID:10283 risk 21624-2 PubMed:26510020 Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. Overall, 4/6 patients (3/5 with no other identified aberrations in DNA repair genes) with several germline and somatic aberrations of ATM had a response. Responders included a single patient with a somatic missense mutation (ATM N2875H) and no other alterations in ATM or other DNA repair genes. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N2875H sequence variation in gene ATM/NCBI:472 850 check_entity AN4731-1 ATM N2875H mutation ATM NCBI:472 gene prostate cancer DOID:10283 risk 21624-2 CIViC:240 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N2875H sequence variation in gene ATM/NCBI:472 850 check_entity AN4732-1 ATM R3008C mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 PubMed:23585524 Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the R3008C variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. In a patient sample with the R3008C variant of ATM in trans with a wild-type allele, confirmed by sanger sequencing, western blot showed stable ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. The authors propose that this variant has a dominant-negative effect. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R3008C sequence variation in gene ATM/NCBI:472 851 check_entity AN4732-1 ATM R3008C mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 CIViC:877 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R3008C sequence variation in gene ATM/NCBI:472 851 check_entity AN4733-1 ATM S2289* mutation ATM NCBI:472 gene prostate cancer DOID:10283 risk 21624-2 PubMed:26510020 Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. Overall, 4/6 patients (3/5 with no other identified aberrations in DNA repair genes) with several germline and somatic aberrations of ATM had a response. Responders included a single patient with a somatic frameshift mutation (ATM V2288fs*1) predicted to result in truncation prior to the PI3K catalytic domain and other domains for p53 recognition and response to DNA damage. No other alterations in ATM were observed; however, this patient also had frameshift mutations in MLH3, MRE11 and NBN. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S2289* sequence variation in gene ATM/NCBI:472 852 check_entity AN4733-1 ATM S2289* mutation ATM NCBI:472 gene prostate cancer DOID:10283 risk 21624-2 CIViC:239 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S2289* sequence variation in gene ATM/NCBI:472 852 check_entity AN4734-1 ATM T2666A mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 PubMed:23585524 Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. Cells were treated with doxorubicin to induce double-strand (DSB) and p21 induction was monitored by qPCR. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the T2666A variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 91% of cells by FISH. Western blot showed null ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T2666A sequence variation in gene ATM/NCBI:472 853 check_entity AN4734-1 ATM T2666A mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 CIViC:875 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T2666A sequence variation in gene ATM/NCBI:472 853 check_entity AN4735-1 ATM Underexpression ATM NCBI:472 gene cancer DOID:162 risk 21624-2 PubMed:23761041 ATM-deficient H1395 and HT144 cancer cell lines showed growth inhibition when treated with DNA PKcs inhibitors KU-0060648 and NU7441. These agents also increased the lifespan of mice transfused with ATM-deficient lymphoma cells when compared with etoposide or control. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ATM/NCBI:472 854 AN4735-1 ATM Underexpression ATM NCBI:472 gene cancer DOID:162 risk 21624-2 CIViC:179 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ATM/NCBI:472 854 AN4735-2 ATM Underexpression ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 prognostic 21624-2 PubMed:9788599 43 B-CLL patients with LoH or reduced protein levels (<50% normal expression, radioimmunoassay, western blot) of ATM were found to have significantly shorter overall survival (35.6 vs. 97.3 months; P=0.003) when compared to 108 patients with normal expression levels. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ATM/NCBI:472 855 AN4735-2 ATM Underexpression ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 prognostic 21624-2 CIViC:179 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ATM/NCBI:472 855 AN4735-3 ATM Underexpression ATM NCBI:472 gene gastric adenocarcinoma DOID:3717 risk 21624-2 PubMed:24841718 Low ATM protein expression led to sensitivity to PARP inhibitors in TP53 -ve gastric cancer cell lines (8 lines were used for various aspects of this study). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ATM/NCBI:472 856 AN4735-3 ATM Underexpression ATM NCBI:472 gene gastric adenocarcinoma DOID:3717 risk 21624-2 CIViC:179 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ATM/NCBI:472 856 AN4735-4 ATM Underexpression ATM NCBI:472 gene pancreatic cancer DOID:1793 prognostic 21624-2 PubMed:25423555 Absent expression of ATM, as assessed by IHC in 133 pancreatic ductal adenocarcinomas, was found to be associated with dismal prognosis (median survival, 9.6 months), whereas expression of ATM was associated with increased survival (17.7 months, P = 0.001). Furthermore loss of expression of nuclear phosphorylated Ser1981-ATM (IHC) was indicative of the worst prognosis (median survival, 10.8 vs 14.3 months [low expression] vs 31.1 months [high expression], P < 0.001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ATM/NCBI:472 857 AN4735-4 ATM Underexpression ATM NCBI:472 gene pancreatic cancer DOID:1793 prognostic 21624-2 CIViC:179 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ATM/NCBI:472 857 AN4735-5 ATM Underexpression ATM NCBI:472 gene stomach cancer DOID:10534 risk 21624-2 PubMed:26282658 A randomized phase 2 trial investigating the efficiency of Olaparib plus Paclitaxel vs. Placebo plus Paclitaxel in recurrent or metastatic gastric cancer patients. 123 patients received treatment. Combination treatment did not significantly improve ORR (26,4% vs 19,1%) or PFS (3,91m vs 3,55 m) but OS (13,8 m vs. 8,3 m) in the overall cohort. A subcohort of ATM low expressing tumours (14%) experienced a greater improvement of OS (not reached vs. 8,2 m) and a trend towards improved PFS (5,29 m vs 3,68 m). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ATM/NCBI:472 858 AN4735-5 ATM Underexpression ATM NCBI:472 gene stomach cancer DOID:10534 risk 21624-2 CIViC:179 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ATM/NCBI:472 858 AN4736-1 ATM c.7089+1del ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 PubMed:23585524 Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the c.7089+1del variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the c.7089+1del variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 98% of cells by FISH. Western blot showed stable ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ATM c.7089+1del [biomarker_term_in_review] 859 not_mapped AN4736-1 ATM c.7089+1del ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 CIViC:2919 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ATM c.7089+1del [biomarker_term_in_review] 859 not_mapped AN4737-1 ATM c.7515+1_2del ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 PubMed:23585524 Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the c.7515+1_2del variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. A patient sample had the c.7515+1_2del variant of ATM, confirmed by sanger sequencing, in trans with a loss of function 11q deletion found in 95% of cells by FISH. Western blot showed null ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ATM c.7515+1_2del [biomarker_term_in_review] 860 not_mapped AN4737-1 ATM c.7515+1_2del ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 CIViC:2920 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ATM c.7515+1_2del [biomarker_term_in_review] 860 not_mapped AN4738-1 ATM c.902-1G>T mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 PubMed:23585524 Primary peripheral blood mononuclear cells were taken from chronic lymphocytic leukemia patients, some of whom had prior therapy. The effect of the c.902-1G>T variant on ATM expression was tested by western blot, and the effect on ATM function was tested by treating with doxorubicin to induce double-strand breaks (DSB) and monitoring p21 induction. To confirm wild type p53, parallel cell cultures were treated with fludarabine generating single-strand breaks, in addition to DSB, and monitored for adequate p21 induction. In a patient sample with the c.902-1G>T variant of ATM, confirmed by sanger sequencing, western blot showed null ATM expression. Treatment with doxorubicin resulted in a p21 expression level of less than 300% that of untreated wild-type controls. This was much lower than the median expression level of treated controls which was 815% that of untreated controls, supporting resistance. The authors note that this patient had uniparental disomy of 11q. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.902-1g>t:mutation sequence variation in gene ATM/NCBI:472 861 check_entity AN4738-1 ATM c.902-1G>T mutation ATM NCBI:472 gene chronic lymphocytic leukemia DOID:1040 risk 21624-2 CIViC:2918 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.902-1g>t:mutation sequence variation in gene ATM/NCBI:472 861 check_entity AN4739-1 ATR I774FS mutation ATR NCBI:545 gene endometrial cancer DOID:1380 prognostic 53841-3 PubMed:19470935 Extension and reduction of the ATR exon 10 A10 repeat (alters codon I774) was associated with poorer overall and disease-free survival in patients with endometrioid endometrial cancer when compared to patients with wildtype ATR and with or without microsatellite instability. These ATR mutations were observed in 12 of 248 patients (4.8%, 3 insertions, 9 deletions). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::i774fs:mutation sequence variation in gene ATR/NCBI:545 862 check_entity AN4739-1 ATR I774FS mutation ATR NCBI:545 gene endometrial cancer DOID:1380 prognostic 53841-3 CIViC:267 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::i774fs:mutation sequence variation in gene ATR/NCBI:545 862 check_entity AN4740-1 ATRX Deletion ATRX NCBI:546 gene cancer DOID:162 risk 53841-3 PubMed:23284920 Transgenic mice were generated with conditional knockouts affecting exon 18 of the mouse ATRX gene, previously shown to be an equivalent of a loss of function. Macrophages derived from the knockout mice were significantly more sensitive to 5-FU (P<0.05) compared to macrophages derived from wild-type mice, as demonstrated by reduced survival by TUNEL assays. Re-introduction of ATRX rescued cells from 5-FU treatment. Similar significant (P<0.05) increases in TUNEL-positive cells were seen for ATRX-deficient neurons treated with 5-FU, as well as myoblasts and embryonic fibroblasts treated with 5-FU or cisplatin. The authors conclude that ATRX loss leads to sensitivity to DNA damaging agents. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene ATRX/NCBI:546 863 check_entity AN4740-1 ATRX Deletion ATRX NCBI:546 gene cancer DOID:162 risk 53841-3 CIViC:3177 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene ATRX/NCBI:546 863 check_entity AN4741-1 ATRX Mutation ATRX NCBI:546 gene malignant astrocytoma DOID:3069 diagnostic 53841-3 PubMed:23104868 Whole exome sequencing of 4 low grade gliomas (LGGs) and targeted sequencing of 28 LGGs revealed ATRX variants are found exclusively in a subset of IDH1-mutant, 1p/19q intact LGGs. Paired blood samples were sequenced in all cases and mutations were confirmed by Sanger. IDH1mutation was found in 28/32 LGGs and of these 12 possessed an ATRX mutation (~43%). In all 12 ATRX mutated cases 1p/19q was intact (correlation p=0.0003), and ATRX variants were not observed in the 12 1p/19q codeleted cases. Additionally, multiplex mRNA profiling of 28 astrocytic tumors with subclasses assigned based on 75 gene signatures demonstrated ATRX mutations were associated (p=.0044) with the early progenitor-like subclass (EPL) (11/13 EPL cases harbored ATRX mutants). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ATRX/NCBI:546 864 check_entity AN4741-1 ATRX Mutation ATRX NCBI:546 gene malignant astrocytoma DOID:3069 diagnostic 53841-3 CIViC:3072 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ATRX/NCBI:546 864 check_entity AN4742-1 ATRX Underexpression ATRX NCBI:546 gene childhood low-grade glioma DOID:0080830 prognostic 53841-3 PubMed:29948154 Loss of ATRX was identified in 12 of 247 patients with PLGGs using immunohistochemistry. Survival analysis showed that ATRX loss was associated with adverse overall survival (p<0.0001) and progression-free survival (p=0.0002) [mt (n=10) vs wt (n=175)]. In a multivariate analysis taking into account age, grade, histology, tumour location, and extent of resection, ATRX was still an independent prognosticator of PFS [HR 3.85 (95% CI 1.27–11.65); p = 0.017], and OS [HR 3.53 (95% CI 1.02–12.24); p = 0.047]. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ATRX/NCBI:546 865 AN4742-1 ATRX Underexpression ATRX NCBI:546 gene childhood low-grade glioma DOID:0080830 prognostic 53841-3 CIViC:644 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ATRX/NCBI:546 865 AN4742-2 ATRX Underexpression ATRX NCBI:546 gene glioblastoma DOID:3068 prognostic 53841-3 PubMed:26936505 In a glioblastoma mouse model induced by NRAS and p53 knockdown, ATRX loss was associated with a decreased median survival (69 days vs. 84 days; P = .0032). Also, the tumors grew to a larger size at earlier time points. ATRX loss was also associated with greater microsatellite instability. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ATRX/NCBI:546 866 AN4742-2 ATRX Underexpression ATRX NCBI:546 gene glioblastoma DOID:3068 prognostic 53841-3 CIViC:644 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ATRX/NCBI:546 866 AN4742-3 ATRX Underexpression ATRX NCBI:546 gene malignant astrocytoma DOID:3069 risk 53841-3 PubMed:23904111 A retrospective tumor sample study found that the loss of ATRX expression (less than 10% of nuclei) in IDH-mutant astrocytomas treated with temozolomide or a combination of procarbazine, lomustine and vincristine (PCV) was associated with better outcomes. Patients with IDH-mutant tumors and ATRX expression loss (n=40) experienced greater time to treatment failure (55.6 months vs. 31.8 months; P = 0.0168) and a greater progression-free survival (37.1 months vs. 18.1 months; P = 0.038) compared to patients with IDH-mutant tumors with ATRX expression (n=9). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ATRX/NCBI:546 867 AN4742-3 ATRX Underexpression ATRX NCBI:546 gene malignant astrocytoma DOID:3069 risk 53841-3 CIViC:644 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ATRX/NCBI:546 867 AN4743-1 AURKA Amplification AURKA NCBI:6790 gene esophagus adenocarcinoma DOID:4914 risk PubMed:22302096 Antitumour effect of alisertib treatment in esophageal adenocarcinomas can be intensified in combination with cisplatin. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene AURKA/NCBI:6790 868 AN4743-1 AURKA Amplification AURKA NCBI:6790 gene esophagus adenocarcinoma DOID:4914 risk CIViC:180 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene AURKA/NCBI:6790 868 AN4744-1 AURKA EXPRESSION AURKA NCBI:6790 gene esophagus squamous cell carcinoma DOID:3748 risk PubMed:25924824 A retrospective study examining the expression of AURKA in tumor samples of 78 esophageal squamous cell carcinoma patients found that positive expression of AURKA (>10% of cells by IHC) was correlated with increased clinical response to chemoradiation therapy consisting of cisplatin, 5-fluorouracil, and 40 gy radiation (P = 0.0003). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene AURKA/NCBI:6790 869 AN4744-1 AURKA EXPRESSION AURKA NCBI:6790 gene esophagus squamous cell carcinoma DOID:3748 risk CIViC:158 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene AURKA/NCBI:6790 869 AN4744-2 AURKA EXPRESSION AURKA NCBI:6790 gene ovarian carcinoma DOID:4001 prognostic PubMed:19157502 In patients with ovarian carcinomas, those with Aurora kinase A expression (as measured by immunohistochemistry) had increased progression-free and overall survival compared to those without expression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene AURKA/NCBI:6790 870 AN4744-2 AURKA EXPRESSION AURKA NCBI:6790 gene ovarian carcinoma DOID:4001 prognostic CIViC:158 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene AURKA/NCBI:6790 870 AN4745-1 AURKA Overexpression AURKA NCBI:6790 gene cervical adenocarcinoma DOID:3702 risk PubMed:12559175 In the cervial andenocarcinoma cell line HeLa, when AURK-A was overexpressed, the cells were resistant to the apoptotic effects of Taxol. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene AURKA/NCBI:6790 871 AN4745-1 AURKA Overexpression AURKA NCBI:6790 gene cervical adenocarcinoma DOID:3702 risk CIViC:181 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene AURKA/NCBI:6790 871 AN4745-2 AURKA Overexpression AURKA NCBI:6790 gene lung non-small cell carcinoma DOID:3908 risk PubMed:25082261 High levels of Aurora-A expression (retrospectively assessed by IHC in 102 NSCLC patients) predicted poorer overall survival and progression free survival in a population treated with surgery and cisplatin-based chemotherapy. In-vitro data confirmed these results and overexpression or knockdown of AURKA decreased or increased in-vitro sensitivity to cisplatin. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene AURKA/NCBI:6790 872 AN4745-2 AURKA Overexpression AURKA NCBI:6790 gene lung non-small cell carcinoma DOID:3908 risk CIViC:181 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene AURKA/NCBI:6790 872 AN4745-3 AURKA Overexpression AURKA NCBI:6790 gene ovarian serous carcinoma DOID:0050933 risk PubMed:27209210 A study of 41 patients with high-grade ovarian serous carcinoma found that high expression levels of AURKA correlated with poorer overall survival (P = 0.001; HR 0.14) and platinum therapy resistance (P < 0.001). Expression of AURKA was measured using immunohistochemical techniques on tumor samples. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene AURKA/NCBI:6790 873 AN4745-3 AURKA Overexpression AURKA NCBI:6790 gene ovarian serous carcinoma DOID:0050933 risk CIViC:181 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene AURKA/NCBI:6790 873 AN4746-1 AXL EXPRESSION AXL NCBI:558 gene esophagus squamous cell carcinoma DOID:3748 prognostic PubMed:27172793 Immunohistochemical analysis of tumors from 116 esophageal squamous cell carcinoma found that expression of AXL was associated with increased progression of the tumor (P < 0.0001), increased risk of death (HR = 2.09 ; P = 0.028), and increased risk of distant metastasis (OR = 3.96 ; P = 0.029). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene AXL/NCBI:558 874 AN4746-1 AXL EXPRESSION AXL NCBI:558 gene esophagus squamous cell carcinoma DOID:3748 prognostic CIViC:647 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene AXL/NCBI:558 874 AN4747-1 B2M S14FS mutation B2M NCBI:567 gene skin melanoma DOID:8923 risk PubMed:27433843 Paired tumor samples were analyzed from four patients with metastatic melanoma and initial response with a subsequent relapse under pembrolizumab (PD-1 checkpoint inhibitor) therapy. Baseline biopsies were obtained before therapy initiation with pembrolizumab. A B2M frame-shift deletion in exon 1 was identified as the only new homozygous mutation among 24 new relapse-specific mutations. Immunohistochemistry revealed loss of MHC1 outer-membrane localization. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::B2M sequence variation in gene B2M/NCBI:567 875 check_entity AN4747-1 B2M S14FS mutation B2M NCBI:567 gene skin melanoma DOID:8923 risk CIViC:612 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::B2M sequence variation in gene B2M/NCBI:567 875 check_entity AN4748-1 B4GALT1 Overexpression B4GALT1 NCBI:2683 gene renal cell carcinoma DOID:4450 prognostic PubMed:27092876 438 patients with non-metastatic clear-cell renal carcinoma were were retrospectively analysed for B4GALT1 expression via IHC. High B4GALT1 expression was associated with poor overall survival (P<0.001 and P<0.001 in training and validation cohort) and identified as an independent adverse prognostic factor for survival (P=0.007 and P=0.002). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene B4GALT1/NCBI:2683 876 AN4748-1 B4GALT1 Overexpression B4GALT1 NCBI:2683 gene renal cell carcinoma DOID:4450 prognostic CIViC:521 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene B4GALT1/NCBI:2683 876 AN4749-1 BAP1 ALTERNATIVE TRANSCRIPT (ATI) BAP1 NCBI:8314 gene malignant mesothelioma DOID:1790 risk PubMed:28389374 A novel alternative splice isoform of BAP1 (BAP1Δ) that misses part of the catalytic domain showed reduced deubiquitinating activity compared with full-length BAP1. 4 MPM cell lines expressing more than 20% of BAP1Δ were more sensitive to olaparib (a PARP1 inhibitor) than 4 cell lines with less BAP1Δ expression, and this sensitivity was enhanced when olaparib treatment was combined with GDC0980 (a dual PI3K-mTOR inhibitor). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BAP1 ALTERNATIVE TRANSCRIPT (ATI) [biomarker_term_in_review] 877 not_mapped AN4749-1 BAP1 ALTERNATIVE TRANSCRIPT (ATI) BAP1 NCBI:8314 gene malignant mesothelioma DOID:1790 risk CIViC:2087 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BAP1 ALTERNATIVE TRANSCRIPT (ATI) [biomarker_term_in_review] 877 not_mapped AN4750-1 BAP1 EXPRESSION BAP1 NCBI:8314 gene uveal melanoma DOID:6039 prognostic PubMed:25147369 In patients with uveal melanoma, those with BAP1 expression (determined by immunohistochemical staining) had better survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene BAP1/NCBI:8314 878 AN4750-1 BAP1 EXPRESSION BAP1 NCBI:8314 gene uveal melanoma DOID:6039 prognostic CIViC:182 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene BAP1/NCBI:8314 878 AN4751-1 BAP1 Mutation BAP1 NCBI:8314 gene clear cell renal cell carcinoma DOID:4467 prognostic PubMed:23797736 In patients with clear cell renal cell carcinoma, in a multivariate analysis those with mutations in BAP1 had worse overall survival than wild-type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BAP1/NCBI:8314 879 check_entity AN4751-1 BAP1 Mutation BAP1 NCBI:8314 gene clear cell renal cell carcinoma DOID:4467 prognostic PubMed:23792563 In patients with clear cell renal cell carcinoma, those with nonsilent mutations of BAP1 had worse overall survival than wild-type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BAP1/NCBI:8314 879 check_entity AN4751-1 BAP1 Mutation BAP1 NCBI:8314 gene clear cell renal cell carcinoma DOID:4467 prognostic CIViC:183 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BAP1/NCBI:8314 879 check_entity AN4751-2 BAP1 Mutation BAP1 NCBI:8314 gene malignant mesothelioma DOID:1790 risk PubMed:25970771 A siRNA screen identified BAP1 associated with HDAC1 and HDAC2 expression. HDAC2 or BAP1 depletion sensitized a mesothelioma cell line (MSTO-211H) to HDAC inhibitors MC1568, vorinostat or mocetinostat. The paper indicates however, that temporary BAP knockdown might not adequately reflect long-term BAP1 mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BAP1/NCBI:8314 880 check_entity AN4751-2 BAP1 Mutation BAP1 NCBI:8314 gene malignant mesothelioma DOID:1790 risk CIViC:183 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BAP1/NCBI:8314 880 check_entity AN4751-3 BAP1 Mutation BAP1 NCBI:8314 gene renal cell carcinoma DOID:4450 prognostic;risk PubMed:23797736 In patients with clear cell renal cell carcinoma, in a multivariate analysis those with mutations in BAP1 had worse overall survival than wild-type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BAP1/NCBI:8314 881 check_entity AN4751-3 BAP1 Mutation BAP1 NCBI:8314 gene renal cell carcinoma DOID:4450 prognostic;risk PubMed:27751729 This study evaluated the effects of everolimus and sunitinib on patients with metastatic renal cell carcinoma. A total of 220 patients with RCC were evaluated for 341 genes at 540x coverage. Of all 220 patients, 19% of had BAP1 mutations. Patients with BAP1 mutations treated with first line everolimus followed by sunitinib (N=87 wildtype, 22 mutant) were associated with shorter progression free survival (median [95% CI] 4.9 [2.9 - 8.1] vs 10.5 [7.3 - 12.9] mo; HR 1.84 [1.1-3.2]; P=0.02). For patients treated with sunitinib followed by everolimus (N=91 wildtype, 20 mutant) were associated with a trend towards shorter progression free survival (median [95% CI] 8.1 [3.1-11.3] vs 11.0 [8.3-13.8] mo; HR 1.69 [0.9-3.2]; P=0.06). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BAP1/NCBI:8314 881 check_entity AN4751-3 BAP1 Mutation BAP1 NCBI:8314 gene renal cell carcinoma DOID:4450 prognostic;risk CIViC:183 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BAP1/NCBI:8314 881 check_entity AN4751-4 BAP1 Mutation BAP1 NCBI:8314 gene uveal melanoma DOID:6039 risk PubMed:22038994 Somatic and germline BAP1 mutations are associated with uveal melanoma. In this preclinical study, gene set enrichment analysis revealed HDAC inhibitors as potential drugs in BAP1 mutant uveal melanomas. HDAC inhibitors VPA, TSA, LBH-589, and SAHA (vorinostat) were tested in-vitro and led to decreased proliferation (all inhibitors) decreased viability and cytotoxicity (TSA, SAHA, LBH-589) in-vitro and in-vivo (VPA). RNAi mediated BAP1 knockdown increased sensitivity to HDAC inhibition (VPA). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BAP1/NCBI:8314 882 check_entity AN4751-4 BAP1 Mutation BAP1 NCBI:8314 gene uveal melanoma DOID:6039 risk CIViC:183 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BAP1/NCBI:8314 882 check_entity AN4752-1 BARD1 Loss-of-function BARD1 NCBI:580 gene colorectal cancer DOID:9256 risk PubMed:27197561 Loss of BARD1 function through the expression of a BARD1 splice variant, BARD1β, results in a more malignant phenotype with decreased RAD51 foci formation, reduced BRCA1 E3 ubiquitin ligase activity, and decreased nuclear BRCA1 protein localization. BARD1β sensitizes colon cancer cells to poly ADP ribose polymerase 1 (PARP-1) inhibition even in a BRCA1 WT background. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BARD1 Loss-of-function [biomarker_term_in_review] 883 not_mapped AN4752-1 BARD1 Loss-of-function BARD1 NCBI:580 gene colorectal cancer DOID:9256 risk CIViC:2095 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BARD1 Loss-of-function [biomarker_term_in_review] 883 not_mapped AN4753-1 BARD1 Mutation BARD1 NCBI:580 gene castration-resistant prostate carcinoma DOID:0080909 risk PubMed:32343890 This randomized, open-label, phase 3 trial evaluated the PARP inhibitor olaparib in 387 men with metastatic castration-resistant prostate cancer (mCRPC) who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). The study found that in men with mCRPC who had somatic or germline deleterious alterations (irrespective of zygosity) in any of the following HRR genes (BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L), olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone (PFS HR 0.49 [0.38, 0.63]). A total of 4 patients had BARD1 mutations, 3 olaparib arm and 1 control arm. Based on the results of this study, on May 19, 2020, the Food and Drug Administration approved olaparib (LYNPARZA) for adult patients with deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC, who have progressed following prior treatment with enzalutamide or abiraterone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BARD1/NCBI:580 884 check_entity AN4754-1 BARD1 Mutation LOC581485 NCBI:581485 gene castration-resistant prostate carcinoma DOID:0080909 risk CIViC:4390 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::bard1:mutation sequence variation in gene LOC581485/NCBI: 885 check_entity AN4755-1 BCL2 F104I mutation BCL2 NCBI:596 gene follicular lymphoma DOID:0050873 risk PubMed:31234236 This study identified BCL2 F104I mutation in one Follicular Lymphoma patient who developed resistance to venetoclax. Codon 104 is located at the venetoclax binding site of BCL2. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F104I sequence variation in gene BCL2/NCBI:596 886 check_entity AN4755-1 BCL2 F104I mutation BCL2 NCBI:596 gene follicular lymphoma DOID:0050873 risk CIViC:2951 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F104I sequence variation in gene BCL2/NCBI:596 886 check_entity AN4756-1 BCL2 G101V mutation BCL2 NCBI:596 gene chronic lymphocytic leukemia DOID:1040 risk PubMed:31160589 This study described the similar crystal structures of BCL-2 wild-type and G101V when bound to venetoclax. Steady state competition surface plasmon resonance experiments demonstrated a ~177 fold decrease in venetoclax affinity for G101V (Ki=3.2nM) versus WT (Ki=.018nM). Resistance is acquired by a knock-on effect in the P2 pocket of V101 on an adjacent residue, E152 as affinity for venetoclax was restored in BCL2 G101V through the introduction of an E152A mutation (Ki =.002nM). Additionally, BCL2 G101V maintains similar affinity for apoptotic BH3 peptides, which assists in the prevention of apoptosis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G101V sequence variation in gene BCL2/NCBI:596 887 check_entity AN4756-1 BCL2 G101V mutation BCL2 NCBI:596 gene chronic lymphocytic leukemia DOID:1040 risk CIViC:2829 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G101V sequence variation in gene BCL2/NCBI:596 887 check_entity AN4756-2 BCL2 G101V mutation BCL2 NCBI:596 gene chronic lymphocytic leukemia/small lymphocytic lymphoma DOID:6354 risk PubMed:32232486 The effective cohort in this study was 11 CLL patients who were first treated with ibrutinib and then on progression treated with venetoclax until progression. Patient samples were sequenced before and after progression on venetoclax. The previously described BCL2 G101V mutation was observed in 1 patient at progression assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G101V sequence variation in gene BCL2/NCBI:596 888 check_entity AN4756-2 BCL2 G101V mutation BCL2 NCBI:596 gene chronic lymphocytic leukemia/small lymphocytic lymphoma DOID:6354 risk CIViC:2829 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G101V sequence variation in gene BCL2/NCBI:596 888 check_entity AN4757-1 BCL2 IGH::BCL2 mutation BCL2 NCBI:596 gene diffuse large B-cell lymphoma DOID:0050745 diagnostic PubMed:12075054 The t(14;18) transloaction of BCL2 is shown to be associated with germinal-center B-cell–like diffuse large-B-cell lymphomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::IGH::BCL2 sequence variation in gene BCL2/NCBI:596 889 check_entity AN4757-1 BCL2 IGH::BCL2 mutation BCL2 NCBI:596 gene diffuse large B-cell lymphoma DOID:0050745 diagnostic CIViC:151 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::IGH::BCL2 sequence variation in gene BCL2/NCBI:596 889 check_entity AN4758-1 BCL2 Mutation BCL2 NCBI:596 gene follicular lymphoma DOID:0050873 prognostic PubMed:25452615 In a multivariate analysis, BCL2 mutations and high FL international prognostic index were independent risk factors for transformation and death due to lymphoma. Some mutant Bcl-2 proteins exhibited enhanced antiapoptotic capacity in vitro. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BCL2/NCBI:596 890 check_entity AN4758-1 BCL2 Mutation BCL2 NCBI:596 gene follicular lymphoma DOID:0050873 prognostic CIViC:2109 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BCL2/NCBI:596 890 check_entity AN4759-1 BCL2 Overexpression BCL2 NCBI:596 gene diffuse large B-cell lymphoma DOID:0050745 prognostic PubMed:9207459 In patients with Diffuse Large B-Cell Lymphoma, those with increased levels of BCL2 were shown to have decreased overall, disease-free, and relapse-free survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene BCL2/NCBI:596 891 AN4759-1 BCL2 Overexpression BCL2 NCBI:596 gene diffuse large B-cell lymphoma DOID:0050745 prognostic CIViC:152 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene BCL2/NCBI:596 891 AN4760-1 BCL2L11 Deletion Polymorphism BCL2L11 NCBI:10018 gene chronic myeloid leukemia DOID:8552 risk PubMed:22426421 DNA sequencing was performed in five Ph+ CML samples with sensitivity or resistance to imatinib. A structural variation in BIM2 (BCL2L11) with an identical 2,903-bp genomic deletion was identified in all three resistant samples. 2,597 healthy individuals were screened and the deletion polymorphism was identified in 12.3% of East Asian Population but 0% in African or European Population. In-vitro, imatinib-induced apoptosis was reduced in cells harboring the BIM deletion polymorphism. Two East Asian CML cohorts (n=203) treated with imatinib were analzed for the polymorphism. Overall odds ratio for resistant disease among subjects with the deletion polymorphism compared to those without it was 2.94 (P = 0.02, 95% CI 1.17–7.43). Patients with the polymorphism, compared to those without, were more likely to be resistant without BCR-ABL mutations than resistant with BCR-ABL mutation or sensitive (odds ratio = 1.90, 95% CI 1.08–4.35). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion:polymorphism sequence variation in gene BCL2L11/NCBI:10018 892 check_entity AN4760-1 BCL2L11 Deletion Polymorphism BCL2L11 NCBI:10018 gene chronic myeloid leukemia DOID:8552 risk CIViC:522 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion:polymorphism sequence variation in gene BCL2L11/NCBI:10018 892 check_entity AN4760-2 BCL2L11 Deletion Polymorphism BCL2L11 NCBI:10018 gene lung non-small cell carcinoma DOID:3908 risk PubMed:22426421 The BIM (BCL2L11) deletion polymorphism was identified in an EGFR Mutant NSCLC cell line with resistance to EGFR-TKI (HCC2779). Introduction of this polymorphism in a previously EGFR-inhibitor sensitive cell line led to TKI-resistance. In 141 NSCLC patients with EGFR mutations, the presence of the polymorphism (N=26) was predictive of a significantly shorter PFS under treatment with EGFR-TKI (6.6 months vs. 11.9 months, p = 0.0027). Patients received either gefitinib only (N=136) or erlotinib only (N=5). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion:polymorphism sequence variation in gene BCL2L11/NCBI:10018 893 check_entity AN4760-2 BCL2L11 Deletion Polymorphism BCL2L11 NCBI:10018 gene lung non-small cell carcinoma DOID:3908 risk CIViC:522 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion:polymorphism sequence variation in gene BCL2L11/NCBI:10018 893 check_entity AN4761-1 BCOR ITD mutation BCOR NCBI:54880 gene central nervous system tumor with BCOR internal tandem duplication DOID:0081315 diagnostic;risk PubMed:26919435 The authors generated genome-wide DNA methylation profiles of 323 tumors with an institutional diagnosis of ‘primitive neuroectodermal tumors of the central nervous system (CNS-PNETs)’, which are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Four novel methylation profiles were identified. One of those profiles was exhibited by 10/323 (3 %) cases, and all these tumors were found to have a duplicated region in exon 15 of BCOR [BCOR internal tandem duplication (ITD)] by DNA/RNA sequencing, identical to that of the BCOR ITD in other tumor types including clear cell sarcomas of the kidney, undifferentiated round cell sarcomas in infants, and primitive myxoid mesenchymal tumour of infancy. The authors compared DNA methylation pattern of the BCOR-ITD positive cases with an in-house collection of > 10,000 methylation profiles from a broad variety of pediatric and adult CNS tumors. Additional tumors with variety of histologies showed the same methylation profile as BCOR-ITD positive cases, and were also found to have BCOR-ITD. The authors proposed that BCOR-ITD defines a specific molecular subtype of CNS tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd::mutation sequence variation in gene BCOR/NCBI:54880 894 check_entity AN4761-1 BCOR ITD mutation BCOR NCBI:54880 gene central nervous system tumor with BCOR internal tandem duplication DOID:0081315 diagnostic;risk PubMed:31104347 10 cases of high-grade neuroepithelial tumor (HGNET) with BCOR exon 15 ITD were studied. In addition, 25 previously reported and published patients were included in survival analyses. These tumors are newly proposed to belong to a separate entity with a distinct methylation profile and a characteristic genetic alteration. The authors further describe their clinical, pathologic, radiographic, and genetic features. Shared histologic characteristics included predominantly solid growth, glioma‐like fibrillarity, perivascular pseudorosettes, and palisading necrosis, but absence of microvascular proliferation. Immunohistochemistry testing showed absent GFAP expression, no synaptophysin expression, variable OLIG2 and NeuN positivity, and diffuse strong BCOR nuclear positivity. In 6 of 10 cases, BCOR ex15 ITD was the only pathogenic alteration seen, while other cases showed additional genetic abnormalities including CDKN2A/B homozygous deletion, TERT amplification or promoter hotspot mutation, and damaging mutations in TP53, BCORL1, EP300, SMARCA2 and STAG2. The authors conclude that their findings further support inclusion of HG NET with BCOR ex15 ITD as a distinct CNS tumor entity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd::mutation sequence variation in gene BCOR/NCBI:54880 894 check_entity AN4761-1 BCOR ITD mutation BCOR NCBI:54880 gene central nervous system tumor with BCOR internal tandem duplication DOID:0081315 diagnostic;risk PubMed:29226988 Six cases of CNS high-grade neuroepithelial tumor (HGNET) with BCOR exon 15 internal tandem duplication (ITD) were studied. The authors analyzed their clinical, pathologic and molecular characteristic and compared them with Clear Cell Sarcoma of Kidney (CCSK) and soft tissue sarcoma with the same genetic abnormality (BCOR ex15 ITD). Cases of CNS HGNET with BCOR ex15 ITD were histologically characterized by glial cell morphology, ependymoma-like perivascular pseudorosettes and palisading necrosis. Immunohistochemically, they showed diffuse staining of Olig2, and focal staining of GFAP, S-100 protein and synaptophysin. Clinically, histologically and immunohistochemically CNS HG NETs with BCOR ex15 ITD were distinct from CCSK and soft tissue sarcomas with BCOR ex15 ITD, supporting that these should be considered a unique type of CNS tumor. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd::mutation sequence variation in gene BCOR/NCBI:54880 894 check_entity AN4761-1 BCOR ITD mutation BCOR NCBI:54880 gene central nervous system tumor with BCOR internal tandem duplication DOID:0081315 diagnostic;risk CIViC:4547 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd::mutation sequence variation in gene BCOR/NCBI:54880 894 check_entity AN4761-2 BCOR ITD mutation BCOR NCBI:54880 gene kidney clear cell sarcoma DOID:4880 diagnostic;risk PubMed:26573325 BCOR internal tandem duplications (ITDs) were found frequently in cases of clear cell sarcoma of kidney (CCSK), a rare pediatric renal cancer. The study initially evaluated 3 CCSK samples by whole exome sequencing and whole transcriptome sequencing. All 3 samples demonstrated BCOR ITD by RNA sequencing. This was further validated by targeted DNA sequencing of a validation institutional cohort of 11 primary and 2 matched metastatic CCSK cases, and an additional external cohort of 13 CCSK samples. Overall, BCOR ITDs were found in 85% (23/27 cases). No BCOR ITDs were found in neither matched normal kidney/blood, nor other childhood renal cancers. Upregulation of mutant BCOR transcripts and protein expression by immunoblotting and immunohistochemistry was shown. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd::mutation sequence variation in gene BCOR/NCBI:54880 895 check_entity AN4761-2 BCOR ITD mutation BCOR NCBI:54880 gene kidney clear cell sarcoma DOID:4880 diagnostic;risk PubMed:26098867 High BCOR expression which was associated with an internal tandem duplication (ITD) of 89 to 144 bp in exon 16 of the BCOR gene was identified in 20 of 20 (100%) of cases of clear cell sarcoma of the kidney, but not in any of the other 193 pediatric renal tumors tested. This suggested that BCOR ITD may be useful in the diagnosis of clear cell sarcoma of the kidney. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd::mutation sequence variation in gene BCOR/NCBI:54880 895 check_entity AN4761-2 BCOR ITD mutation BCOR NCBI:54880 gene kidney clear cell sarcoma DOID:4880 diagnostic;risk PubMed:26516930 Whole transcriptome sequencing on tumors from 8 patients with clear cell sarcoma of the kidney identified BCOR ITD and overexpression of BCOR in all samples. The BCOR ITD was confirmed on tumor DNA. All samples showed numerous deleterious SNVs and InDels, but none were common among all samples. BCOR ITD was the only common, recurrent alteration. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd::mutation sequence variation in gene BCOR/NCBI:54880 895 check_entity AN4761-2 BCOR ITD mutation BCOR NCBI:54880 gene kidney clear cell sarcoma DOID:4880 diagnostic;risk CIViC:4547 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd::mutation sequence variation in gene BCOR/NCBI:54880 895 check_entity AN4761-3 BCOR ITD mutation BCOR NCBI:54880 gene sarcoma DOID:1115 diagnostic PubMed:27428733 BCOR expression was evaluated in a cohort of 25 small blue round cell tumors (SBRCTs) with BCOR fusions (BCOR::MAML3, BCOR::CCNB3), BCOR exon 15 ITDs, or YWHAE-NUTM2B fusion (which is known to upregulate BCOR) using anti-BCOR monoclonal antibody clone C-10 (sc-514576) as an immunohistochemical marker. A control group consisted of 20 small blue round cell tumors (SBRCTs) with various non-BCOR genetic abnormalities, 10 fusion-negative SBRCTs, 74 synovial sarcomas, 29 rhabdomyosarcomas, and other sarcoma types. All SBRCTs with BCOR-fusions and most tumors with BCOR ITD (93%), showed strong and diffuse nuclear BCOR immunoreactivity; these tumors were also positive for SATB2 expression. Sarcomas with BCOR fusions and BCOR-ITDs share molecular features (including high BCOR expression and the presence of SATB2 expression), and BCOR immunohistochemical stain is a highly sensitive marker for SBRCTs with BCOR abnormalities. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd::mutation sequence variation in gene BCOR/NCBI:54880 896 check_entity AN4761-3 BCOR ITD mutation BCOR NCBI:54880 gene sarcoma DOID:1115 diagnostic CIViC:4547 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd::mutation sequence variation in gene BCOR/NCBI:54880 896 check_entity AN4762-1 BCOR Mutation BCOR NCBI:54880 gene stomach cancer DOID:10534 prognostic PubMed:27313181 46 patients with poorly cohesive, signet-cell ring, gastric carcinoma were evaluated for genetic mutations. Overall survival rate of BCOR positive cases were significantly better than BCOR negative cases cases (p=0.038). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BCOR/NCBI:54880 897 check_entity AN4762-1 BCOR Mutation BCOR NCBI:54880 gene stomach cancer DOID:10534 prognostic CIViC:659 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BCOR/NCBI:54880 897 check_entity AN4763-1 BEND2 CHD7::BEND2 mutation BEND2 NCBI:139105 gene pancreatic endocrine carcinoma DOID:1798 risk PubMed:31160355 A 35 year-old patient presented with a grade 3 pancreatic neuroendocrine tumor and liver metastasis. Whole genome sequencing and RNAseq revealed a previously undescribed somatic translocation between Chromosome 8 and X (t(8;X)(q12.2;p22.13)), which produces an in-frame CHD7::BEND2 fusion (exon 2 and exon 5). RNA-seq results showed increased expression of BEND2 downstream from the fusion breakpoints, indicating its enhanced expression. The authors hypothesize that activation of BEND2, either by fusion or increased expression, may promote oncogenic activity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CHD7::BEND2 sequence variation in gene BEND2/NCBI:139105 898 check_entity AN4763-1 BEND2 CHD7::BEND2 mutation BEND2 NCBI:139105 gene pancreatic endocrine carcinoma DOID:1798 risk CIViC:4244 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CHD7::BEND2 sequence variation in gene BEND2/NCBI:139105 898 check_entity AN4764-1 BIRC3 TRUNCATING MUTATION BIRC3 NCBI:330 gene chronic lymphocytic leukemia DOID:1040 prognostic 99127-3 PubMed:24943832 BIRC3 mutations were identified in 23 of 919 screened CLLs. They are strongly linked to non-mutated IGHV genes (18/23, P = 0.0001), a widely recognized prognostic signature for poor outcome. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::truncating:mutation sequence variation in gene BIRC3/NCBI:330 899 check_entity AN4764-1 BIRC3 TRUNCATING MUTATION BIRC3 NCBI:330 gene chronic lymphocytic leukemia DOID:1040 prognostic 99127-3 CIViC:586 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::truncating:mutation sequence variation in gene BIRC3/NCBI:330 899 check_entity AN4765-1 BIRC5 NUCLEAR EXPRESSION BIRC5 NCBI:332 gene lung non-small cell carcinoma DOID:3908 risk PubMed:24961465 Patients with nuclear survivin (BIRC5) expression had significantly better responses to taxane-platinum chemotherapy than those with low tumor N-survivin expression (P < 0.001) in a retrospective analysis of 48 patients with non-small cell lung cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene BIRC5/NCBI:332 900 AN4765-1 BIRC5 NUCLEAR EXPRESSION BIRC5 NCBI:332 gene lung non-small cell carcinoma DOID:3908 risk CIViC:364 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene BIRC5/NCBI:332 900 AN4766-1 BIRC5 Overexpression BIRC5 NCBI:332 gene Her2-receptor positive breast cancer DOID:0060079 risk PubMed:23204226 13 HER2 breast cancer patients were treated with trastuzumab and then trastuzumab + docetaxel prior to surgery. Pretreatment biopsies and post-treatment surgical samples were obtained, and microarray performed. 5 of 13 patients responded to treatment, and pretreatment biopsies from non-responders showed significantly higher survivin (BIRC5) mRNA (p=0.026) levels than responders. In HER2 positive, trastuzumab-sensitive BT474 cells, overexpression of survivin blunted sensitivity to trastuzumab. In HER2 positive trastuzumab-resistant breast cancer cell lines, knockdown of survivin with RNAi or with YM155 induced growth inhibition and apoptosis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene BIRC5/NCBI:332 901 AN4766-1 BIRC5 Overexpression BIRC5 NCBI:332 gene Her2-receptor positive breast cancer DOID:0060079 risk CIViC:574 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene BIRC5/NCBI:332 901 AN4767-1 BIRC7 Amplification BIRC7 NCBI:79444 gene colon cancer DOID:219 risk PubMed:23188704 Livin (BIRC7) overexpression in two colon cancer cell lines (RKO and SW620) increased resistance of these cells to cisplatin. siRNA knockdown of Livin rendered the cells more sensitive to cisplatin. The study also further showed that cytoplasmic Livin levels increased in four colon cancer cell lines (RKO, SW620, HCT116, and KM12C) after cisplatin treatment in a dose-dependent manner. This study highlighted Livin as a potential player in colon cancer therapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene BIRC7/NCBI:79444 902 AN4767-1 BIRC7 Amplification BIRC7 NCBI:79444 gene colon cancer DOID:219 risk CIViC:247 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene BIRC7/NCBI:79444 902 AN4768-1 BRAF A598V mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:31580757 In a retrospective study from 20 institutes in 4 countries, the efficacy of BRAF inhibitor and/or MEK inhibitor in patients with melanoma harboring BRAF nonV600E/K mutations were evaluated. Treated with BRAF inhibitor monotherapy, response rate were 27%(4/15) for V600R, 100%(2/2) for V600D, 0% (0/2) for V600_K601>E, 0% (0/1) for V600G, 0% (0/1) for V600L, 0% (0/1) for V600_S602>DT, 0% (0/5) for L597, 0% (0/6) for K601E, 0% (0/2) for G469, 0% (0/1) for G593D,and 0% (0/1) for T599_V600insT Treated with MEK inhibitor monotherapy, response rate were 100% (1/1) for L597, and 0% (0/1) for K601E. Treated with BRAF inhibitor and MEK inhibitor combination thearpy, response rate were 55% (16/29) for V600R, 67% (2/3) for V600D, 50% (1/2) for V600_K601>E, 50% (1/2) for V600M, 22% (2/9) for L597,25% (1/4) for K601E, 67% (2/3) for G469, and 0% (0/1) for A598V. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A598V sequence variation in gene BRAF/NCBI:673 903 check_entity AN4768-1 BRAF A598V mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 CIViC:2695 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A598V sequence variation in gene BRAF/NCBI:673 903 check_entity AN4769-1 BRAF AGK::BRAF mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:23890088 BRAF fusion AGK-BRAF was associated with decreased sensitivity to vemurafenib and increased sensitivity to sorafenib in-vitro. A single patient with this fusion showed durable response to sorafenib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::AGK::BRAF sequence variation in gene BRAF/NCBI:673 904 check_entity AN4769-1 BRAF AGK::BRAF mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 CIViC:281 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::AGK::BRAF sequence variation in gene BRAF/NCBI:673 904 check_entity AN4770-1 BRAF AKAP9::BRAF mutation BRAF NCBI:673 gene thyroid gland papillary carcinoma DOID:3969 diagnostic 53844-7 PubMed:15630448 The AKAP9-BRAF fusion gene was found in 3/28 tumor samples of radiation-associated papillary thyroid carcinoma, and no samples of non-radiation associated papillary thyroid carcinoma. This fusion was associated with elevated BRAF kinase activity, similar to the V600E variant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::AKAP9::BRAF sequence variation in gene BRAF/NCBI:673 905 check_entity AN4770-1 BRAF AKAP9::BRAF mutation BRAF NCBI:673 gene thyroid gland papillary carcinoma DOID:3969 diagnostic 53844-7 CIViC:184 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::AKAP9::BRAF sequence variation in gene BRAF/NCBI:673 905 check_entity AN4771-1 BRAF Amplification BRAF NCBI:673 gene colorectal cancer DOID:9256 risk 53844-7 PubMed:25673644 Paired pre-treatment and post-progression tumor biopsies from BRAF-mutant CRC patients treated with RAF inhibitor combinations were analyzed. Alterations in MAPK pathway genes were found in resistant tumors not present in matched pre-treatment tumors, including KRAS amplification, BRAF amplification, and a MEK1 mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene BRAF/NCBI:673 906 AN4771-1 BRAF Amplification BRAF NCBI:673 gene colorectal cancer DOID:9256 risk 53844-7 PubMed:21098728 COLO201 and COLO206F cells harboring BRAF V600E mutations were cloned to be MEK inhibitor (AZD6244 [selumetinib]) resistant. The mechanism of this resistance was shown to be amplification of the BRAF V600E gene. BRAF V600E amplification was observed in 1/11 colorectal cancer patient samples evaluated, indicating this subclone (28% of cells) would be MEK inhibitor resistant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene BRAF/NCBI:673 906 AN4771-1 BRAF Amplification BRAF NCBI:673 gene colorectal cancer DOID:9256 risk 53844-7 CIViC:1243 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene BRAF/NCBI:673 906 AN4771-1 BRAF Amplification BRAF NCBI:673 gene colorectal cancer DOID:9256 risk 53844-7 CIViC:4173 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene BRAF/NCBI:673 906 AN4771-2 BRAF Amplification BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:25452114 In a retrospective study, authors analyzed BRAF V600 mutated melanoma metastases derived from 10 patients treated with the combination of dabrafenib and trametinib for resistance mechanisms and genetic correlates of response. An acquired resistance mechanism activating the MAPK pathway was identified in 9 tumors; BRAF amplification (n=4), MEK1/2 mutation (n=3), NRAS mutations (n=3). Among them, mutual exclusive alterations were BRAF amplification (n=4), MEK2 C125S (n=1), and NRAS Q61K (n=2). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene BRAF/NCBI:673 907 AN4771-2 BRAF Amplification BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:24265155 In a retrospective study of 44 relapsed melanoma patients harboring BRAF V600E or V600K (known BRAF inhibitor sensitizing mutations), MAPK pathway reactivation mechanisms were implicated in acquired resistance to BRAF inhibitor (vemurafenib or dabrafenib) monotherapy. The following MAPK pathway variants were found in progressive tumors with patient matched baseline tumors (some patients donated samples from multiple geographically/temporally distinct progressive tumors): NRAS mutations (G12D, G12R, G13R, Q61K, Q61R, Q61L) in 13/71 (18%) of progressive tumors, KRAS mutations (G12C, G12R, Q61H) in 5/71 (7%) of progressive tumors, mutant BRAF amplification (2-15 fold or 4-75 copies) in 11/57 (19%) of progressive tumors, mutant BRAF alternative splice variants (novel exon boundaries between 1/9, 1/11, 3/9) in 6/48 (13%) of progressive tumor RNA. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene BRAF/NCBI:673 907 AN4771-2 BRAF Amplification BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 CIViC:1243 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene BRAF/NCBI:673 907 AN4771-2 BRAF Amplification BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 CIViC:4174 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene BRAF/NCBI:673 907 AN4772-1 BRAF BRAF::CUL1 mutation BRAF NCBI:673 gene ovarian serous carcinoma DOID:0050933 risk 53844-7 PubMed:26324360 One patient with low-grade serous ovarian cancer had an in-frame fusion between the BRAF kinase domain and CUL1 identified by panel sequencing (MSK-IMPACT), with expression confirmed by whole-transcriptome sequencing. This patient with metastatic disease after treatment with carboplatin and paclitaxel, was enrolled onto a study of paclitaxel in combination with an oral MEK inhibitor and achieved a CR. She continued to receive therapy for 7 months, until discontinuation because of the development of pneumonitis. At publication, sustained CR had lasted > 18 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BRAF::CUL1 sequence variation in gene BRAF/NCBI:673 908 check_entity AN4772-1 BRAF BRAF::CUL1 mutation BRAF NCBI:673 gene ovarian serous carcinoma DOID:0050933 risk 53844-7 CIViC:652 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BRAF::CUL1 sequence variation in gene BRAF/NCBI:673 908 check_entity AN4773-1 BRAF CUX1::BRAF mutation BRAF NCBI:673 gene pancreatic cancer DOID:1793 risk 53844-7 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. One of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CUX1::BRAF sequence variation in gene BRAF/NCBI:673 909 check_entity AN4773-1 BRAF CUX1::BRAF mutation BRAF NCBI:673 gene pancreatic cancer DOID:1793 risk 53844-7 CIViC:2105 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CUX1::BRAF sequence variation in gene BRAF/NCBI:673 909 check_entity AN4774-1 BRAF D594A mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 PubMed:20141835 Preclinical study in melanoma cell lines. Inactivity of BRAF as mediated by specific mutation (D594A, D594V or K483M) or selective pharmacological inhibition leads to MEK hyperactivation through CRAF binding in NRAS mutant D04 cells. Either pan-RAF (e.g. sorafenib in the abscence of CRAF T421N gatekeeper mutation) or MEK inhibitors (e.g., trametinib) could instead block ERK pathway hyperactivation in RAS mutated cancers. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D594A sequence variation in gene BRAF/NCBI:673 910 check_entity AN4774-1 BRAF D594A mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 CIViC:575 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D594A sequence variation in gene BRAF/NCBI:673 910 check_entity AN4775-1 BRAF D594G mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 PubMed:28783719 RAF inhibitor vemurafenib failed to inhibit ERK signaling in tumor cells and NIH3T3 that express class 3 BRAF mutations (G466V, G466E, D594G, D594N, and G596R). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D594G sequence variation in gene BRAF/NCBI:673 911 check_entity AN4775-1 BRAF D594G mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 CIViC:607 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D594G sequence variation in gene BRAF/NCBI:673 911 check_entity AN4775-2 BRAF D594G mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:27404270 In a study of 908 patients with colorectal cancer, 7 patients had BRAF (D594G) mutations and 45 patients had BRAF (V600E) mutations. Overall clinicopathological implications of BRAF V600E and D594G mutant tumors were similar but BRAF D594G mutations were more likely to be left-sided tumors (85.7% vs. 31.1%; p<0.0098) and they were more likely to present as metastatic tumors (71.4% vs. 28.9%; p<0.04) than BRAF V600E mutant tumors. The overall log-rank was p < 0.001 when all three groups were calculated simultaneously; p < 0.0001 comparing BRAF wild-type and BRAF V600E survival, p = 0.015 comparing BRAF wild-type and BRAF D594G survival, and p = 0.98 comparing BRAF V600E and BRAF D594G. There was no statistically significant difference in OS between BRAF D594G and BRAF wt but BRAF V600E mutant patients had significantly worse survival when only stage IV patients (BRAF D594G N=5) were analyzed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D594G sequence variation in gene BRAF/NCBI:673 912 check_entity AN4775-2 BRAF D594G mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:20619739 One patient participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had a tumor which harbored BRAF D594G and was wildtype for KRAS, NRAS and PIK3CA. This patient was a 63 year old female treated with cetuximab and irinotecan (3rd line) who was one of two patients harboring a BRAF mutant tumor to experience a partial response. Progression free survival was 36 weeks and overall survival was 42 weeks from time of cetuximab administration. Authors note that cetuximab response is in accordance with cell line data suggesting that D594G cannot directly activate MAPK signaling, and that D594G mutants have low levels of p-MEK and are resistant to MEK inhibition. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D594G sequence variation in gene BRAF/NCBI:673 912 check_entity AN4775-2 BRAF D594G mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:26989027 In a retrospective study of 53, KRAS exon 2 wild-type, metastatic colorectal cancer patients, patients harboring BRAF G466A (n=1), G469A (n=2), D594G (n=1), or V600E (n=2) mutations were reported to be non-responders to cetuximab in combination with irinotecan, (BRAF mutation positive: responders vs. non-responders = 0 vs. 6; BRAF wild-type: responders vs. non-responders 30 vs. 17; P=0.004), as compared to patients with wild-type BRAF. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D594G sequence variation in gene BRAF/NCBI:673 912 check_entity AN4775-2 BRAF D594G mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 CIViC:607 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D594G sequence variation in gene BRAF/NCBI:673 912 check_entity AN4775-3 BRAF D594G mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 PubMed:18794803 In this preclinical study, melanoma cell lines harboring the kinase-dead G469E- and D594G mutations were identified. These cell lines were resitant to MEK-Inhibition but underwent apoptosis after shRNA-mediated CRAF knowdown or Treatment with the pan-RAF Inhibitor sorafenib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D594G sequence variation in gene BRAF/NCBI:673 913 check_entity AN4775-3 BRAF D594G mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 CIViC:607 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D594G sequence variation in gene BRAF/NCBI:673 913 check_entity AN4776-1 BRAF D594K mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 risk 53844-7 PubMed:19603024 The presence of BRAF V600E or D594K was associated with reduced progression-free survival in 5 patients with metastatic colorectal cancer treated with irinotecan-based first line therapy (3.5mo vs. 12.8mo, HR:4.1, 95%CI:1.5-11.3, P=0.006) when compared to 39 patients with wildtype BRAF. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D594K sequence variation in gene BRAF/NCBI:673 914 check_entity AN4776-1 BRAF D594K mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 risk 53844-7 CIViC:2271 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D594K sequence variation in gene BRAF/NCBI:673 914 check_entity AN4777-1 BRAF D594V mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 PubMed:20141835 Preclinical study in melanoma cell lines. Inactivity of BRAF as mediated by specific mutation (D594A, D594V or K483M) or selective pharmacological inhibition leads to MEK hyperactivation through CRAF binding in NRAS mutant D04 cells. Either pan-RAF (e.g. sorafenib in the abscence of CRAF T421N gatekeeper mutation) or MEK inhibitors could instead block ERK pathway hyperactivation in RAS mutated cancers. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D594V sequence variation in gene BRAF/NCBI:673 915 check_entity AN4777-1 BRAF D594V mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 CIViC:576 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D594V sequence variation in gene BRAF/NCBI:673 915 check_entity AN4778-1 BRAF DEL 485-490 BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 PubMed:26732095 Cells harboring in-frame deletions in BRAF in the L485-P490 amino acid region were found to be sensitive to the RAF dimer inhibitor LY3009120, but not sensitive to the BRAF-selective inhibitors vemurafenib or dabrafenib. These deletions were observed in KRAS wildtype pancreatic, ovarian, NSCLC, and thyroid cancers. In three cell lines H2405 (NSCLC with L485-P490>Y), BxPC-3 (pancreatic with V487-P492>A), and OV-90 (ovarian with N486-P490del), BRAF deletion–mediated MAPK activation was found to be sensitive to LY3009120 as evidenced by dose-dependent inhibition of phospho-MEK and ERK and cell growth inhibition with IC50 values of 0.04, 0.087, and 0.007 μmol/L in these three cell lines. LY3009120, but not vemurafenib, also inhibited tumor growth of both H2405 and BxPC-3 cells xenografted into mice. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRAF DEL 485-490 [biomarker_term_in_review] 916 not_mapped AN4778-1 BRAF DEL 485-490 BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 CIViC:518 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRAF DEL 485-490 [biomarker_term_in_review] 916 not_mapped AN4779-1 BRAF Exon 15 Mutation BRAF NCBI:673 gene gastrointestinal stromal tumor DOID:9253 risk 53844-7 PubMed:27371698 This phase II clinical trial of regorafenib (NCT01068769) examined the long term safety and efficacy of regorafenib monotherapy in patients with metastatic and/or unresectable gastrointestinal stromal tumors (GISTs) who failed previous treatments with imatinib. One patient's GIST harbored a BRAF exon 15 mutation.This patient experienced progressive disease and a progression free survival of 1.6 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:15:mutation sequence variation in gene BRAF/NCBI:673 917 check_entity AN4779-1 BRAF Exon 15 Mutation BRAF NCBI:673 gene gastrointestinal stromal tumor DOID:9253 risk 53844-7 PubMed:22614970 This retrospective study of a phase 2 clinical trial (NCT01068769) examined regorafenib safety and efficacy in advanced gastrointestinal stromal tumor (GIST) patients refractory to at least imatinib and sunitinib. One patient whose GIST harbored a BRAF exon 15 mutation and wildtype KIT and PDGFRA experienced rapid disease progression despite regorafenib administration. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:15:mutation sequence variation in gene BRAF/NCBI:673 917 check_entity AN4779-1 BRAF Exon 15 Mutation BRAF NCBI:673 gene gastrointestinal stromal tumor DOID:9253 risk 53844-7 CIViC:2519 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:15:mutation sequence variation in gene BRAF/NCBI:673 917 check_entity AN4780-1 BRAF G463E mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 PubMed:15035987 The BRAF mutation G463E resulted in elevated kinase activity relative to wild-type BRAF in vitro. B-RAF activity was determined using kinase dead MEK as a substrate. G463E activity was 28 times higher than basal WT BRAF. The authors classified G463E activity as intermediate since its kinase activity was between basal WT BRAF and G12V RAS-activated WT B-RAF cells. In comparison, some BRAF variants displayed high kinase activity above the G12V RAS-activated WT BRAF cells. NIH3T3 transformation assay yielded 24 +/- 14 foci/ng of transfected BRAF DNA, in comparison to WT, which yielded zero foci, indicating an oncogenic effect of BRAF G463E. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G463E sequence variation in gene BRAF/NCBI:673 918 check_entity AN4780-1 BRAF G463E mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 CIViC:3300 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G463E sequence variation in gene BRAF/NCBI:673 918 check_entity AN4781-1 BRAF G464V mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G464V sequence variation in gene BRAF/NCBI:673 919 check_entity AN4781-1 BRAF G464V mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 CIViC:1080 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G464V sequence variation in gene BRAF/NCBI:673 919 check_entity AN4782-1 BRAF G466V mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G466V sequence variation in gene BRAF/NCBI:673 920 check_entity AN4782-1 BRAF G466V mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 PubMed:28783719 RAF inhibitor vemurafenib failed to inhibit ERK signaling in tumor cells and NIH3T3 that express class 3 BRAF mutations (G466V, G466E, D594G, D594N, and G596R). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G466V sequence variation in gene BRAF/NCBI:673 920 check_entity AN4782-1 BRAF G466V mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 CIViC:2098 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G466V sequence variation in gene BRAF/NCBI:673 920 check_entity AN4782-2 BRAF G466V mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 risk 53844-7 PubMed:28783719 In the study with a tumor from a patient with metastatic colorectal cancer BRAF (G466V) and wild-type RAS and NF1. Treament with Panitumumab and irinotecan cause tumor regression. And in tumor cells of patient-derived xenograft generated from this patient, ERK signaling was sensitive to cetuximab and resistant to vemurafenib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G466V sequence variation in gene BRAF/NCBI:673 921 check_entity AN4782-2 BRAF G466V mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 risk 53844-7 CIViC:2098 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G466V sequence variation in gene BRAF/NCBI:673 921 check_entity AN4783-1 BRAF G469 mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:31580757 In a retrospective study from 20 institutes in 4 countries, the efficacy of BRAF inhibitor and/or MEK inhibitor in patients with melanoma harboring BRAF nonV600E/K mutations were evaluated. Treated with BRAF inhibitor monotherapy, response rate were 27%(4/15) for V600R, 100%(2/2) for V600D, 0% (0/2) for V600_K601>E, 0% (0/1) for V600G, 0% (0/1) for V600L, 0% (0/1) for V600_S602>DT, 0% (0/5) for L597, 0% (0/6) for K601E, 0% (0/2) for G469, 0% (0/1) for G593D,and 0% (0/1) for T599_V600insT Treated with MEK inhibitor monotherapy, response rate were 100% (1/1) for L597, and 0% (0/1) for K601E. Treated with BRAF inhibitor and MEK inhibitor combination thearpy, response rate were 55% (16/29) for V600R, 67% (2/3) for V600D, 50% (1/2) for V600_K601>E, 50% (1/2) for V600M, 22% (2/9) for L597,25% (1/4) for K601E, 67% (2/3) for G469, and 0% (0/1) for A598V. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G469 sequence variation in gene BRAF/NCBI:673 922 check_entity AN4783-1 BRAF G469 mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 CIViC:2691 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G469 sequence variation in gene BRAF/NCBI:673 922 check_entity AN4784-1 BRAF G469A mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G469A sequence variation in gene BRAF/NCBI:673 923 check_entity AN4784-1 BRAF G469A mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 CIViC:966 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G469A sequence variation in gene BRAF/NCBI:673 923 check_entity AN4785-1 BRAF G469E mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 PubMed:18794803 In this preclinical study, melanoma cell lines harboring the kinase-dead G469E- and D594G mutations were identified. These cell lines were resitant to MEK-Inhibition but underwent apoptosis after shRNA-mediated CRAF knowdown or Treatment with the pan-RAF Inhibitor sorafenib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G469E sequence variation in gene BRAF/NCBI:673 924 check_entity AN4785-1 BRAF G469E mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 CIViC:967 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G469E sequence variation in gene BRAF/NCBI:673 924 check_entity AN4786-1 BRAF G496A mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G496A sequence variation in gene BRAF/NCBI:673 925 check_entity AN4786-1 BRAF G496A mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 CIViC:2097 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G496A sequence variation in gene BRAF/NCBI:673 925 check_entity AN4787-1 BRAF G596C mutation BRAF NCBI:673 gene lung non-small cell carcinoma DOID:3908 risk 53844-7 PubMed:28947956 Non-V600 BRAF mutations occur in about half of BRAF-mutated lung cancers, and their sensitivity to Dabrafenib and Trametinib is not well documented. In a cohort of 229 NSCLC patients that underwent molecular testing, one was found to have a BRAF G596C mutation. This mutation had low kinase activity and reduced MEK/ERK activation compared to wtBRAF in transiently transfected HEK293T cells. Elevated MEK/ERK activation was seen when BRAF G596C was expressed in the presence of CRAF, and this activity was inhibited by both Dabrafenib and Trametinib. A lung epithelial cell line (BEAS-2B) expressing BRAF G596C showed reduced ERK activation when treated with combination Dabrafenib and Trametinib. These results support the use of Dabrafenib and Trametinib in MAPK pathway inhibition in the context of kinase-impaired BRAF mutants such as G596C. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G596C sequence variation in gene BRAF/NCBI:673 926 check_entity AN4787-1 BRAF G596C mutation BRAF NCBI:673 gene lung non-small cell carcinoma DOID:3908 risk 53844-7 CIViC:675 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G596C sequence variation in gene BRAF/NCBI:673 926 check_entity AN4788-1 BRAF G596R mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G596R sequence variation in gene BRAF/NCBI:673 927 check_entity AN4788-1 BRAF G596R mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 CIViC:1535 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G596R sequence variation in gene BRAF/NCBI:673 927 check_entity AN4788-2 BRAF G596R mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 risk 53844-7 PubMed:22180495 In an in vitro study, an NCI-H508 cell line expressing BRAF G596R demonstrated insensitivity to vemurafenib treatment compared to HT29 cells expressing BRAF V600E (a known vemurafenib sensitizing mutation; IC50 9.89 uM vs 0.025-0.35uM for BRAF V600E expressing cell lines). Note that NCI-H508 also expresses PIK3CA E545K. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G596R sequence variation in gene BRAF/NCBI:673 928 check_entity AN4788-2 BRAF G596R mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 risk 53844-7 CIViC:1535 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G596R sequence variation in gene BRAF/NCBI:673 928 check_entity AN4789-1 BRAF G606E mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G606E sequence variation in gene BRAF/NCBI:673 929 check_entity AN4789-1 BRAF G606E mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 CIViC:2099 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G606E sequence variation in gene BRAF/NCBI:673 929 check_entity AN4790-1 BRAF K483M mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 PubMed:20141835 Preclinical study in melanoma cell lines. Inactivity of BRAF as mediated by specific mutation (D594A, D594V or K483M) or selective pharmacological inhibition leads to MEK hyperactivation through CRAF binding in NRAS mutant D04 cells. Either pan-RAF (e.g. sorafenib in the abscence of CRAF T421N gatekeeper mutation) or MEK inhibitors (e.g., trametinib) could instead block ERK pathway hyperactivation in RAS mutated cancers. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K483M sequence variation in gene BRAF/NCBI:673 930 check_entity AN4790-1 BRAF K483M mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 CIViC:577 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K483M sequence variation in gene BRAF/NCBI:673 930 check_entity AN4791-1 BRAF K601E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 risk 53844-7 PubMed:36409971 This clinical study was conducted with 30 patients with colorectal cancer harboring BRAF V600E (n = 29) or BRAF K601E (n=1) mutations, treated with a combination of cobimetinib and vemurafenib. Of the 30 patients, only 27 were evaluable. An OR rate of 30% (95% CI; 14-50), and DC rate of 52% (95% CI; 35-65) was noted. Eight patients had a partial response with a median duration of 8.1 weeks (5.1-32.3 weeks) and six patients had SD16+ with a median duration of 29.1 weeks (28.1-44.0 weeks). The reported PFS was 15.7 weeks (95% CI; 12.1-18.1) and OS was 38.9 weeks (95% CI; 26.1-49.4). In 43% of the cohort, grade 3 AEs or SAEs were observed, likely associated with the treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K601E sequence variation in gene BRAF/NCBI:673 931 check_entity AN4791-1 BRAF K601E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 risk 53844-7 CIViC:4707 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K601E sequence variation in gene BRAF/NCBI:673 931 check_entity AN4791-2 BRAF K601E mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 PubMed:22798288 Preclinical study in 293H cell line. Ectopic expression of V600E, L597R/Q/S, and K601E mutants elevated phospho-MEK and ERK levels. Vemurafenib treatment of all of the BRAF mutant–expressing cells led to a decrease in phospho-MEK and ERK protein levels. Treatment with MEK inhibitor GSK1120212 led to a more dramatic decrease in phospho-ERK signaling. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K601E sequence variation in gene BRAF/NCBI:673 932 check_entity AN4791-2 BRAF K601E mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 CIViC:580 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K601E sequence variation in gene BRAF/NCBI:673 932 check_entity AN4792-1 BRAF KIAA1549::BRAF mutation BRAF NCBI:673 gene childhood low-grade glioma DOID:0080830 prognostic;risk 53844-7 PubMed:29948154 KIAA1549-BRAF fusion was identified in 87 of 272 patients with PLGGs using Fluorescence In situ hybridization (FISH) analysis. This mutation was strongly associated with a greater progression-free survival (p=0.0017) and overall survival (p=0.0029) [fusion-positive (n=64) vs fusion-negative (n=141)]. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KIAA1549::BRAF sequence variation in gene BRAF/NCBI:673 933 check_entity AN4792-1 BRAF KIAA1549::BRAF mutation BRAF NCBI:673 gene childhood low-grade glioma DOID:0080830 prognostic;risk 53844-7 PubMed:29156677 This preclinical study proposed to use a combination therapy of an MEK inhibitor (e.g. trametinib) and an mTOR inhibitor (e.g. everolimus) for the treatment of pediatric low-grade gliomas (PLGGs) with BRAF fusions to evade acquired resistance to MEK targeted therapy. The PI3K/Akt/mTOR pathway was identified as a resistance mechanism to MEKi treatment based on RNASeq and GSEA analysis. Using flank xenograft model, mice were injected with NIH3T3 cells expressing KIAA1549-BRAF fusions and treated daily with trametinib, everolimus either alone or combined with each other (n=~10 for each treatment arm). Combination therapy (Trametinib 1mg/kg+ Everolimus 10mg/kg) resulted in better suppression in tumor growth than single-agent treatment. Similarly, combination treatment strongly reduced colony formation as well as pERK and pS6 levels, showing on target effects. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KIAA1549::BRAF sequence variation in gene BRAF/NCBI:673 933 check_entity AN4792-1 BRAF KIAA1549::BRAF mutation BRAF NCBI:673 gene childhood low-grade glioma DOID:0080830 prognostic;risk 53844-7 PubMed:21610142 Hawkins et al. (2011) retrospectively studied 70 consecutive patient with incompletely resected pediatric low-grade astrocytomas (PLGA). KIAA1549-BRAF fusion was identified in 60% of cases in this cohort. Multi-variant analysis suggested that KIAA1549-BRAF fusion was the most significant favorable prognosis factor in incompletely resected PLGA and was independent of location, pathology, and age. Five-year PFS of fusion positive and fusion negative patients were 61% +/- 8% and 18% +/- 8% (P=0.0004), respectively. These results suggested that KIAA1549-BRAF fusion confers a less aggressive clinical phenotype on PLGA and may explain their tendency to growth arrest. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KIAA1549::BRAF sequence variation in gene BRAF/NCBI:673 933 check_entity AN4792-1 BRAF KIAA1549::BRAF mutation BRAF NCBI:673 gene childhood low-grade glioma DOID:0080830 prognostic;risk 53844-7 CIViC:614 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KIAA1549::BRAF sequence variation in gene BRAF/NCBI:673 933 check_entity AN4792-2 BRAF KIAA1549::BRAF mutation BRAF NCBI:673 gene childhood pilocytic astrocytoma DOID:6812 risk 53844-7 PubMed:28002790 A pilocytic astrocytoma (PA) cell line named DKFZ-BT66 was generated from a 2-year old patient with the disease. Expression of KIAA1549-BRAF fusion in this cell line was identified. Treatment with sorafenib or vemurafenib resulted in paradoxical activation of MAPK/ERK as seen by increased pERK in western blots. Authors note that their observation aligns with results from a phase II clinical trial wherein PA patients experienced tumor growth under sorafenib treatment induced by paradoxical MAPK activation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KIAA1549::BRAF sequence variation in gene BRAF/NCBI:673 934 check_entity AN4792-2 BRAF KIAA1549::BRAF mutation BRAF NCBI:673 gene childhood pilocytic astrocytoma DOID:6812 risk 53844-7 CIViC:614 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KIAA1549::BRAF sequence variation in gene BRAF/NCBI:673 934 check_entity AN4792-3 BRAF KIAA1549::BRAF mutation BRAF NCBI:673 gene pilocytic astrocytoma DOID:4851 diagnostic;risk 53844-7 PubMed:23817572 Genetic alterations in pilocytic astrocytoma (PA) were evaluated. Whole-genome sequencing of normal (blood) and tumor samples (n=96) was performed along with corresponding RNA-Seq (n=73) and mate-pair (MP) sequencing (n=68). Several known events activating the MAPK pathway were identified with KIAA1549-BRAF fusion being the most frequent variants (70 of 96 cases, 73%). Importantly, all but one of the cerebellar PA harbored a BRAF fusion (47 of 48 samples, 98%) with this one exception having a KRAS alteration. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KIAA1549::BRAF sequence variation in gene BRAF/NCBI:673 935 check_entity AN4792-3 BRAF KIAA1549::BRAF mutation BRAF NCBI:673 gene pilocytic astrocytoma DOID:4851 diagnostic;risk 53844-7 PubMed:18974108 This study identified a novel rearrangement event between the uncharacterized gene KIAA-1549 and BRAF in 66% (29 of 44) of pilocytic astrocytoma but not in 244 higher-grade astrocytomas that were evaluated. An in vitro study further showed that this fusion gene lacks the N-terminal BRAF auto-regulatory domain, leading to constitutive activation of BRAF. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KIAA1549::BRAF sequence variation in gene BRAF/NCBI:673 935 check_entity AN4792-3 BRAF KIAA1549::BRAF mutation BRAF NCBI:673 gene pilocytic astrocytoma DOID:4851 diagnostic;risk 53844-7 CIViC:614 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KIAA1549::BRAF sequence variation in gene BRAF/NCBI:673 935 check_entity AN4792-4 BRAF KIAA1549::BRAF mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 PubMed:26072686 A 65 yr old male patient with metastatic acral lentiginous melanoma (BRAF, NRAS, KIT negative) was found to harbor a KIAA1549-BRAF (intron 15-intron 8) fusion in a subcutaneous metastasis sample after disease progression. Trametinib was started and fatigue and ECOG status improved but imaging revealed slight disease progression after 2 weeks (15 sites measurable, 9 stable, 6 progressive). No new metastases were identified. The patient was switched to pembrolizumab and major disease progression was noted. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KIAA1549::BRAF sequence variation in gene BRAF/NCBI:673 936 check_entity AN4792-4 BRAF KIAA1549::BRAF mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 CIViC:614 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KIAA1549::BRAF sequence variation in gene BRAF/NCBI:673 936 check_entity AN4792-5 BRAF KIAA1549::BRAF mutation BRAF NCBI:673 gene spindle cell sarcoma DOID:4235 risk 53844-7 PubMed:24422672 A patient with a malignant spindle cell tumor of the chest wall treated as a soft tissue sarcoma was identified to harbor a KIAA1549-BRAF fusion. This patient responded to treatment with the pan-kinase inhibitor sorafenib in combination with bevacizumab and temsirolimus, achieving stable disease after 2 cycles extending into 11 cycles at which time she expired due to co-morbidities (acute myocardial infarction, hypotension). Of note, sequencing of 236 cancer-related genes identified CDKN2A A68fs*51, SUFU E283fs*3, MAP3K1 N325fs*3 and homozygous deletion of PTEN as well. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KIAA1549::BRAF sequence variation in gene BRAF/NCBI:673 937 check_entity AN4792-5 BRAF KIAA1549::BRAF mutation BRAF NCBI:673 gene spindle cell sarcoma DOID:4235 risk 53844-7 PubMed:26314551 A patients with malignant spindle cell tumor treated as as soft tissue sarcoma harboring KIAA1549-BRAF fusion were treated with sorafenib in combination with bevacizumab and temsirolimus. Tumor of the chest wall showed good response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KIAA1549::BRAF sequence variation in gene BRAF/NCBI:673 937 check_entity AN4792-5 BRAF KIAA1549::BRAF mutation BRAF NCBI:673 gene spindle cell sarcoma DOID:4235 risk 53844-7 CIViC:614 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KIAA1549::BRAF sequence variation in gene BRAF/NCBI:673 937 check_entity AN4793-1 BRAF L505H mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:24112705 Using a mutation screen in the BRAFV600E melanoma cell line A375, the L505H variant was identified as conferring resistance to vemurafenib. Analysis of the mutation in T293 cell lines found that the L505H mutant alone or with V600e had greater kinase activity and increased the levels of phospho-MEK. Finally, transduction of Ba/F3 cells with BRAF V600E/L505H IL3 independent proliferation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L505H sequence variation in gene BRAF/NCBI:673 938 check_entity AN4793-1 BRAF L505H mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:25515853 In this study, the investigators followed 10 patients treated with vemurafenib, and then they collected biopsies of lesions that progressed. In one of these patients, they identified the L505H mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L505H sequence variation in gene BRAF/NCBI:673 938 check_entity AN4793-1 BRAF L505H mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 CIViC:654 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L505H sequence variation in gene BRAF/NCBI:673 938 check_entity AN4794-1 BRAF L597Q mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L597Q sequence variation in gene BRAF/NCBI:673 939 check_entity AN4794-1 BRAF L597Q mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 CIViC:579 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L597Q sequence variation in gene BRAF/NCBI:673 939 check_entity AN4794-2 BRAF L597Q mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 PubMed:22798288 Preclinical study in 293H cell line. Ectopic expression of V600E, L597R/Q/S, and K601E mutants elevated phospho-MEK and ERK levels. Vemurafenib treatment of all of the BRAF mutant–expressing cells led to a decrease in phospho-MEK and ERK protein levels. Treatment with MEK inhibitor GSK1120212 led to a more dramatic decrease in phospho-ERK signaling. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L597Q sequence variation in gene BRAF/NCBI:673 940 check_entity AN4794-2 BRAF L597Q mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 PubMed:24933606 Case study report including one patient with L597Q mutation-positive metastatic melanoma (M1b disease) treated with the MEK inhibitor trametinib. The L597Q patient achieved a RECIST partial response and showed maximum tumor shrinkage of 33% with trametinib as the first-line treatment and had a partial response for 6.2 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L597Q sequence variation in gene BRAF/NCBI:673 940 check_entity AN4794-2 BRAF L597Q mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 CIViC:579 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L597Q sequence variation in gene BRAF/NCBI:673 940 check_entity AN4795-1 BRAF L597R mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:23715574 A case report of a patient with BRAF L597R mutation and clinical response to BRAF-inhibition (Vemurafenib) that correlated to in-vitro models. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L597R sequence variation in gene BRAF/NCBI:673 941 check_entity AN4795-1 BRAF L597R mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 CIViC:284 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L597R sequence variation in gene BRAF/NCBI:673 941 check_entity AN4795-2 BRAF L597R mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 PubMed:22798288 Preclinical study in 293H cell line. Ectopic expression of V600E, L597R/Q/S, and K601E mutants elevated phospho-MEK and ERK levels. Vemurafenib treatment of all of the BRAF mutant–expressing cells led to a decrease in phospho-MEK and ERK protein levels. Treatment with MEK inhibitor GSK1120212 led to a more dramatic decrease in phospho-ERK signaling. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L597R sequence variation in gene BRAF/NCBI:673 942 check_entity AN4795-2 BRAF L597R mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 CIViC:284 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L597R sequence variation in gene BRAF/NCBI:673 942 check_entity AN4796-1 BRAF L597S mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 PubMed:22798288 Preclinical study in 293H cell line. Ectopic expression of V600E, L597R/Q/S, and K601E mutants elevated phospho-MEK and ERK levels. Vemurafenib treatment of all of the BRAF mutant–expressing cells led to a decrease in phospho-MEK and ERK protein levels. Treatment with MEK inhibitor GSK1120212 led to a more dramatic decrease in phospho-ERK signaling. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L597S sequence variation in gene BRAF/NCBI:673 943 check_entity AN4796-1 BRAF L597S mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 CIViC:578 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L597S sequence variation in gene BRAF/NCBI:673 943 check_entity AN4797-1 BRAF L597V mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 PubMed:22805292 Case report of a phase 1 study in advanced melanoma patients. 97 patients with melanoma were enrolled and treated with trametinib. One patient with a BRAF Leu597Val had a confirmed partial response with 60% tumour reduction and received study treatment for more than 2 years. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L597V sequence variation in gene BRAF/NCBI:673 944 check_entity AN4797-1 BRAF L597V mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 CIViC:581 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L597V sequence variation in gene BRAF/NCBI:673 944 check_entity AN4798-1 BRAF MACF1::BRAF mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::MACF1::BRAF sequence variation in gene BRAF/NCBI:673 945 check_entity AN4798-1 BRAF MACF1::BRAF mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 CIViC:2103 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::MACF1::BRAF sequence variation in gene BRAF/NCBI:673 945 check_entity AN4799-1 BRAF Mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 PubMed:22169769 In this screen of 218 solid cancer cell lines, BRAF mutations were predictive of response to the MEK inhibitor GSK1120212. 26 of these cell lines had the BRAF V600E mutation, one cell line had a G469A mutation, one had G596R mutation and one had an unspecified mutation. Also of note, in RAF/RAS mutant colon cancer cell lines, co-occurring PIK3CA/PTEN mutations led to a cytostatic response rather than a cytotoxic response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRAF/NCBI:673 946 check_entity AN4799-1 BRAF Mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 CIViC:395 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRAF/NCBI:673 946 check_entity AN4799-2 BRAF Mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:25673558 A quantitative synthesis was performed on nine studies comparing treatment of metastatic colorectal cancer with cetuximab or panitumumab and chemotherapy, versus chemotherapy alone, or with other targeted inhibitors. It was found that in the patient subgroup with BRAF mutation (V600E in the majority of cases), there were no benefits to overall survival, progression free survival, or overall response rate with addition of cetuximab or panitumumab to treatment. This conclusion held in the first line treatment as well as general treatment setting. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRAF/NCBI:673 947 check_entity AN4799-2 BRAF Mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:22586653 A cohort of patient-derived xenografts (PDX) from 85 patients with metastatic colorectal cancer was created. PDX were treated with cetuximab and mechanisms of resistance investigated. None of the xenografts harboring KRAS (N=18), NRAS (N=7) or BRAF (N=3) mutations showed a response to cetuximab whereas 1 out of 4 xenografts with a PIK3CA mutation responded to cetuximab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRAF/NCBI:673 947 check_entity AN4799-2 BRAF Mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:20619739 This was a retrospective study of 350 patients with metastatic, chemotherapy refractory colorectal cancer treated with cetuximab + chemotherapy who had individual response data and whose tumors were KRAS wildtype and BRAF assessable. Patients harboring BRAF mutations (total n=24, V600E n=23, D594G n=1) had a lower response rate than did patients with wildtype BRAF (n=326; 2/24 [4.3%] vs 124/326 [38%], OR: 0.15, p=0.0012). BRAF mutant patients also experienced significantly lower disease control rate, PFS, and OS (median 26 vs 54 weeks, HR: 3.03 p<0.0001) in response to cetuximab treatment. In multivariate analysis, the significant associations between BRAF mutations and poor outcome were confirmed. The authors noted that two responders had the following genotypes: V600E mutation in low copy number, and BRAF D594G, and suggested that mutation status of BRAF is more informative than those of NRAS and PIK3CA exon 20 for predicting cetuximab response (second only to KRAS). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRAF/NCBI:673 947 check_entity AN4799-2 BRAF Mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:19603024 This was a retrospective clinical study of 168 metastatic colorectal cancer patients who received first line chemotherapy (made up of 5-fluorouracil (5-FU) only, 5-FU + oxaliplatin, 5-FU + irinotecan, or 5-FU + oxaliplatin + irinotecan) alone or with monoclonal antibodies (bevacizumab or cetuximab). It assessed the relationship between BRAF mutation status in primary tumors and post treatment PFS. Of 168 patients, 155 had wildtype BRAF and 13 had mutations in BRAF—including V600E and D594K. The study found that patients harboring a BRAF mutation had a significantly worse outcome than patients expressing wildtype BRAF, regardless of first line chemotherapy regimen or use of monoclonal antibody treatment (Median PFS: 4.3 and 12.5 months, respectively; p <.0001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRAF/NCBI:673 947 check_entity AN4799-2 BRAF Mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:21641636 In the Medical Research Council (MRC) COIN trial, ISRCTN27286448, patients who presented with advanced colorectal cancer were randomly assigned to chemotherapy (oxaliplatin and fluoropyrimidine; arm A), or chemotherapy plus cetuximab (arm B). Median overall survival was found to differ by mutation, regardless of treatment. Median overall survival was 8.8 months (IQR 4.5-27) for patients with BRAF variants, 14.4 months (IQR 8.5-24.0) for patients with KRAS variants, and 20.1 months (IQR 11.5-31.7) for wildtype patients. BRAF mutations were found in 102/1291 samples (7.90%), and of these, 12 were D594G and 90 V600E. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRAF/NCBI:673 947 check_entity AN4799-2 BRAF Mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:24112392 A meta analysis was performed using data from 21 published studies (n = 9885 patients) to assess prognostic value of BRAF mutations in colorectal cancer. When evaluating 14 studies (n = 7778 patients), the odds ratio (OR) of a proximal lesion, which is associated with greater mortality in colon cancer, was increased for patients with BRAF mutations (OR 5.222, 95% CI 3.801–7.174, P < 0.001). When evaluating 4 studies (n = 1526 patients), the odds ratio of T4 tumors, which indicates tumor growth past bowel lining, was increased for patients with BRAF mutations (OR 1.761, 95% CI 1.164–2.663, P = 0.007). When evaluating 8 studies (n = 2786 patients), the odds ratio of poor tumor differentiation was increased in patients with BRAF mutations (OR 3.816, 95% CI 2.714–5.365, P < 0.001). These results support that BRAF mutations indicate poor prognosis for patients with colorectal cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRAF/NCBI:673 947 check_entity AN4799-2 BRAF Mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 CIViC:395 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRAF/NCBI:673 947 check_entity AN4800-1 BRAF N486_P490del BRAF NCBI:673 gene pancreatic cancer DOID:1793 risk 53844-7 PubMed:29903880 In a case report, a patient with pancreatic cancer harboring BRAF N486-P490del was treated with trametinib. Within 4 weeks of initiating therapy, her serum CA19-9 had fallen from 36,000 to 8,100 U/mL, and the radiographic partial response was revealed by CT at 8 weeks after initiation of trametinib. cfDNA measurements for BRAF and TP53 alleles revealed a dramatic decline in response to trametinib. After 6 months of therapy, radiographic progression was identified. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRAF N486_P490del [biomarker_term_in_review] 948 not_mapped AN4800-1 BRAF N486_P490del BRAF NCBI:673 gene pancreatic cancer DOID:1793 risk 53844-7 CIViC:2663 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRAF N486_P490del [biomarker_term_in_review] 948 not_mapped AN4801-1 BRAF N581S mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N581S sequence variation in gene BRAF/NCBI:673 949 check_entity AN4801-1 BRAF N581S mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 CIViC:1160 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N581S sequence variation in gene BRAF/NCBI:673 949 check_entity AN4802-1 BRAF NRF1::BRAF mutation BRAF NCBI:673 gene transitional cell carcinoma DOID:2671 risk 53844-7 PubMed:31010895 In a case report, a patient with metastatic urothelial carcinoma harboring an NRF1-BRAF fusion was treated with trametinib. After two and a half months of treatment, MRI revealed 48.4% decrease in size of liver metastasis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::NRF1::BRAF sequence variation in gene BRAF/NCBI:673 950 check_entity AN4802-1 BRAF NRF1::BRAF mutation BRAF NCBI:673 gene transitional cell carcinoma DOID:2671 risk 53844-7 CIViC:2752 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::NRF1::BRAF sequence variation in gene BRAF/NCBI:673 950 check_entity AN4803-1 BRAF Non-V600 mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 PubMed:31924734 In a phase II basket trial (NCI-MATCH), patients with solid tumors or hematologic malignancies harboring BRAF non-V600 mutations were treated with trametinib. Among 50 patients assigned, 32 were eligible and received therapy with trametinib. Most common tumor histopathologic subtypes were GI cancers (n=8, of which 7 were colorectal adenocarcinoma), lung adenocarcinoma (n=9), prostate adenocarcinoma (n=4), gynecologic cancer (n=4), BRAF alterations included BRAF fusion (n=1), G464 (n=2), G466 (n=4), G469 (n=7), N581 (n=3), D594 (n=11), L597 (n=2) and K601 (n=1). Of the 32 patients evaluable for efficacy endpoints, the response rate was 3% (3/32). The patient with a partial response had invasive breast cancer with a BRAF G469E mutation. The median PFS was 1.8 months and the median OS was 5.7 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::non-v600:mutation sequence variation in gene BRAF/NCBI:673 951 check_entity AN4803-1 BRAF Non-V600 mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 CIViC:2281 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::non-v600:mutation sequence variation in gene BRAF/NCBI:673 951 check_entity AN4803-2 BRAF Non-V600 mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic 53844-7 PubMed:28486044 This study of 9,643 patients characterized clinical implications of non-V600 BRAF mutations in metastatic CRC. Of the patients with metastatic CRC that underwent NGS testing, 208 patients had non-V600 BRAF mutations (22% of BRAF mutations identified and 2.2% of total patients tested ). When compared to V600 BRAF mutations, tumors without V600 BRAF mutations were more prevalent in younger patients (58 v 68 years, respectively) and male patients (65% vs 46%, respectively). Additionally, non-V600 BRAF mutations were less prevalent in high-grade tumors (13% v 64%, respectively) and right-sided primary tumors (36% v 81%, respectively). Median overall survival was significantly longer in patients with non-V600 BRAF-mutant metastatic CRC compared with those with both V600E BRAF-mutant and wild-type BRAF metastatic CRC (60.7 v 11.4 v 43.0 months). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::non-v600:mutation sequence variation in gene BRAF/NCBI:673 952 check_entity AN4803-2 BRAF Non-V600 mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic 53844-7 CIViC:2281 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::non-v600:mutation sequence variation in gene BRAF/NCBI:673 952 check_entity AN4804-1 BRAF P731T mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P731T sequence variation in gene BRAF/NCBI:673 953 check_entity AN4804-1 BRAF P731T mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 CIViC:2100 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P731T sequence variation in gene BRAF/NCBI:673 953 check_entity AN4805-1 BRAF PAPSS1::BRAF mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:24345920 'BRAF-fusion in ''pan-negative'' melanomas were identified in TCGA data. Cell-lines with PAPSS1-BRAF fusion were resistant to treatment with Vemurafenib.' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PAPSS1::BRAF sequence variation in gene BRAF/NCBI:673 954 check_entity AN4805-1 BRAF PAPSS1::BRAF mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 CIViC:282 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PAPSS1::BRAF sequence variation in gene BRAF/NCBI:673 954 check_entity AN4806-1 BRAF PPFIBP2::BRAF mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 PubMed:26072686 Case report of a 47year old female patient with metastatic melanoma (BRAF, NRAS, KIT negative). A PPFIBP2-BRAF fusion was identified from DNA from a brain metastasis (inton 3 of PPFIBP2 fused to intron 10 of BRAF). Trametinib was introduced and anemia and ECOG status improved. Imaging revealed a 90% decrease in extracranial and 19% decrease in intracranial metastases with no new metastases and no progressing sites at 6 weeks. Trametinib was stopped and pembrolizumab introduced at this time. Progressive disease was noted after 5 cycles of pembrolizumab but re-introduction of trametinib did not show an effect. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PPFIBP2::BRAF sequence variation in gene BRAF/NCBI:673 955 check_entity AN4806-1 BRAF PPFIBP2::BRAF mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 CIViC:613 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PPFIBP2::BRAF sequence variation in gene BRAF/NCBI:673 955 check_entity AN4807-1 BRAF TRIM24::BRAF mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:24345920 'A TRIM24-BRAF fusion was identified in a single patient with metastatic melanoma that was ''pan-negative'' for driver mutations. A cell-line (293H) ectopically expressing the TRIM24-BRAF fusion was found to be sensitive to the MEK-inhibitor Trametinib.' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::TRIM24::BRAF sequence variation in gene BRAF/NCBI:673 956 check_entity AN4807-1 BRAF TRIM24::BRAF mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 CIViC:283 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::TRIM24::BRAF sequence variation in gene BRAF/NCBI:673 956 check_entity AN4807-2 BRAF TRIM24::BRAF mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 PubMed:24345920 Foundation One NGS assay and targeted RNAseq identified PAPSS1-BRAF fusion in a melanoma sample. Further BRAF fusions (TRIM24-BRAF) were identified in TCGA and additional samples. Ectopic expression of engineered cDNA in 293H cells showed that trametinib led to reduced ERK1/2 phosphorylation in fusion positive cells whereas vemurafenib was not effective. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::TRIM24::BRAF sequence variation in gene BRAF/NCBI:673 957 check_entity AN4807-2 BRAF TRIM24::BRAF mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 CIViC:283 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::TRIM24::BRAF sequence variation in gene BRAF/NCBI:673 957 check_entity AN4808-1 BRAF V600 mutation BRAF NCBI:673 gene cholangiocarcinoma DOID:4947 risk 53844-7 PubMed:26287849 Eight patients with BRAF V600 (7 with V600E, 1 with V600 unknown) mutated cholangiocarcinoma received vemurafenib. Only one patients showed partial response and duration of response of this patient was longer than 12 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 958 check_entity AN4808-1 BRAF V600 mutation BRAF NCBI:673 gene cholangiocarcinoma DOID:4947 risk 53844-7 CIViC:17 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 958 check_entity AN4808-2 BRAF V600 mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 risk 53844-7 PubMed:23325582 In metastatic colorectal cancer patients with wildtype KRAS, BRAF mutations were associated with poor progression free survival regardless of treatment (panitumumab with best supportive care or best supportive care alone). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 959 check_entity AN4808-2 BRAF V600 mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 risk 53844-7 PubMed:26392102 In clinical trial NCT01072175, 43 patients with BRAF V600 metastatic colorectal cancer (CRC) received mutant BRAF inhibitor dabrafenib and MEK inhibitor trametinib. Only 12% of patients showed partial response or better, with one complete response lasting 36 months and ongoing after data cutoff. 56% of patients achieved stable disease. The median progression free survival (PFS) was 3.5 months, longer than the median PFS (2.5 months) reported for metastatic CRC treated with standard chemotherapy. The authors conclude that MAPK targeting in CRC is a valid approach that can produce meaningful responses but additional work is required to more effectively inhibit the pathway. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 959 check_entity AN4808-2 BRAF V600 mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 risk 53844-7 PubMed:26287849 Patients with BRAF-V600 mutated cancers were identified (n=122) and clinical response to vemurafenib was evaluated. Of the 10 patients with colorectal cancer (80% BRAF V600E, 20% V600 unknown status), no responses were observed and overall survival was 9.3 months with a median progression-free survival of 4.5 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 959 check_entity AN4808-2 BRAF V600 mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 risk 53844-7 PubMed:28363909 In a Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab, Twenty-six patients with refractory BRAF V600 mutant metastatic CRC (mCRC) were treated with a selective RAF kinase inhibitor (encorafenib) plus a monoclonal antibody targeting EGFR (cetuximab). Confirmed overall response rates of 19% were observed and median progression-free survival was 3.7 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 959 check_entity AN4808-2 BRAF V600 mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 risk 53844-7 PubMed:147167 A randomized clinical trial was done with metastatic colorectal cancer (mCRC) patients (50 in the control group, 49 in the experimental group) with BRAF V600 mutations and RAS wild type that were enrolled from December 2014 to April 2016. The patients were randomized into groups with irinotecan and cetuximab with vemurafenib (VIC group) or without (IC group). The VIC group showed an improvement of progression of free survival (HR 0.42, 95% CI: 0.26 to 0.66, p < 0.001) with a median value of 4.4 months compared to 2.0 months for the IC group. In addition, for the VIC group, there was a 16% drug response rate while the IC group had a 4% drug response rate (p-value = 0.08). Some grade 3/4 adverse events were higher in the experimental arm, and skin toxicity and fatigue showed no increase. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 959 check_entity AN4808-2 BRAF V600 mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 risk 53844-7 CIViC:17 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 959 check_entity AN4808-3 BRAF V600 mutation BRAF NCBI:673 gene Langerhans-cell histiocytosis DOID:2571 risk 53844-7 PubMed:26287849 Patients with BRAF-V600 mutated cancers were identified (n=122) and clinical response to vemurafenib was evaluated. Of the 14 patients with Langerhans’-cell histiocytosis, 43% of patients had a response to vemurafenib (1 complete and 5 partial responses), disease regression was observed in 12/14 patients, all patients detailed improvement in disease-related symptoms, 0 patients had progressive disease during treatment, 12-month progression free survival was 91%, and overall survival rate was 100%. Among all 18 patients with Erdheim-Chester disease or Langerhans histiocytosis, 94% had BRAF V600E mutations and the remaining 6 percent (1 patient) had an unknown V600 mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 960 check_entity AN4808-3 BRAF V600 mutation BRAF NCBI:673 gene Langerhans-cell histiocytosis DOID:2571 risk 53844-7 CIViC:17 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 960 check_entity AN4808-4 BRAF V600 mutation BRAF NCBI:673 gene lung non-small cell carcinoma DOID:3908 risk 53844-7 PubMed:26287849 Patients with BRAF-V600 mutated cancers were identified (n=122) and clinical response to vemurafenib was evaluated. Of the 20 patients with non-small-cell-lung cancer (17 with BRAF V600E, one with BRAF V600G and one with BRAF V600 unknown status), 19 were evaluable and the response rate to vemurafenib was 42%, tumor regression was observed in 14/19 patients, progression-free survival was 7.3 months, and 12-month overall survival was 66%. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 961 check_entity AN4808-4 BRAF V600 mutation BRAF NCBI:673 gene lung non-small cell carcinoma DOID:3908 risk 53844-7 CIViC:17 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 961 check_entity AN4808-5 BRAF V600 mutation BRAF NCBI:673 gene melanoma DOID:1909 diagnostic;risk 53844-7 PubMed:21166657 BRAF mutations are associated with melanoma arising in non-chronic sun damaged skin and with superficial spreading melanoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 962 check_entity AN4808-5 BRAF V600 mutation BRAF NCBI:673 gene melanoma DOID:1909 diagnostic;risk 53844-7 PubMed:23020132 This was a Phase I and II study (NCT01072175) of dabrafenib and trametinib combination therapy vs. dabrafenib monotherapy in patients with metastatic melanoma. Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination therapy in contrast to 19% in those receiving monotherapy (P = 0.09). Of 162 patients with V600E or V600K mutation, 108 were given combination therapy and 54 monotherapy. After 1 year, 41% of patients in the combination group were alive and progression free whereas this was 9% in the monotherapy group (P<0.001). Median progression-free survival was 9.4 months with combination and 5.8 months with monotherapy. Hazard ratio for progression or death was 0.39 (95% CI, 0.25 to 0.62; P<0.001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 962 check_entity AN4808-5 BRAF V600 mutation BRAF NCBI:673 gene melanoma DOID:1909 diagnostic;risk 53844-7 PubMed:23434733 Phase I trial of the mitogen-activated protein kinase 1/2 inhibitor BAY 86-9766. 2 of 2 patients with BRAF mutant melanoma had moderate progressive disease (despite receiving the highest doses administered in the study). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 962 check_entity AN4808-5 BRAF V600 mutation BRAF NCBI:673 gene melanoma DOID:1909 diagnostic;risk 53844-7 PubMed:22608338 In the NCT00880321 trial using mutant BRAF inhibitor dabrafenib in solid tumors, 10 cases of melanoma brain metastases were assessed for dabrafenib response. In nine patients a decrease in size of metastases was seen, and in four cases a complete resolution of brain lesions was observed. This subset of patients had median progression free survival of 4.2 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 962 check_entity AN4808-5 BRAF V600 mutation BRAF NCBI:673 gene melanoma DOID:1909 diagnostic;risk 53844-7 PubMed:25265494 In a randomized phase 3 study, previously untreated advanced or metastatic BRAF V600 mutation-positive melanoma patients treated with combination vemurafenib and cobimetinib showed improved progression free survival (9.9 vs 6.2 months), increased rate of complete or partial response (68% vs 45%), and improved overall survival at 9 months ( 81% vs 73%) compared to the vemurafenib and placebo control group. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 962 check_entity AN4808-5 BRAF V600 mutation BRAF NCBI:673 gene melanoma DOID:1909 diagnostic;risk 53844-7 PubMed:22663011 Patients who had histologically confirmed, unresectable stage IIIC or IV cutaneous melanoma with a V600E or V600K BRAF mutation were eligible for the study. 322 eligible patients (281 with the V600E mutation, 40 with the V600K mutation, and 1 with both mutations) in a 2:1 ratio to receive oral trametinib (2 mg once daily) or intravenous chemotherapy consisting of either dacarbazine (1000 mg per square meter of body-surface area) or paclitaxel (175 mg per square meter), at the discretion of the investigator, every 3 weeks. The primary end point was progression-free survival; secondary end points included overall survival, overall response rate, duration of response, and safety. Treatment continued until disease progression, death, or withdrawal from the study. In the intention-to-treat population, the median duration of progression-free survival was 4.8 months in the trametinib group as compared with 1.5 months in the chemotherapy group (hazard ratio for progression, 0.45; 95% confidence interval [CI], 0.33 to 0.63; P<0.001). The 6-month overall survival rate in the intention-to-treat population was 81% in the trametinib group and 67% in the chemotherapy group. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 962 check_entity AN4808-5 BRAF V600 mutation BRAF NCBI:673 gene melanoma DOID:1909 diagnostic;risk 53844-7 PubMed:27480103 In this double-blind, randomized, placebo-controlled, multicentre study, adult patients with histologically confirmed BRAF(V600) mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) to receive cobimetinib or placebo, in combination with oral vemurafenib. Progression-free survival was the primary endpoint. Between Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). Investigator-assessed median progression-free survival was 12.3 months for cobimetinib and vemurafenib versus 7.2 months for placebo and vemurafenib (HR 0.58 [95% CI 0.46-0.72], p<0.0001). Median overall survival was 22.3 months for cobimetinib and vemurafenib versus 17.4 months for placebo and vemurafenib (HR 0.70, 95% CI 0.55-0.90; p=0.005). The safety profile for cobimetinib and vemurafenib was tolerable and manageable, and no new safety signals were observed with longer follow-up. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 962 check_entity AN4808-5 BRAF V600 mutation BRAF NCBI:673 gene melanoma DOID:1909 diagnostic;risk 53844-7 PubMed:28891408 Combination Dabrafenib and Trametinib treatment was assessed for adjuvant treatment of stage III resected BRAF V600 mutant melanoma in the COMBI-AD trial NCT01682083. Patients were treated with combination therapy or placebo for 12 months. The estimated 3-year rate of relapse-free survival was 58% in the treated group and 39% in the placebo group with hazard ratio for relapse or death of 0.47 (95% CI, 0.39 to 0.58; P<0.001). 3-year overall survival rate for treated group was 86%, and 77% in the placebo group (hazard ratio for death, 0.57; 95% CI, 0.42-0.79; P=0.0006). The level of improvement observed did not cross the prespecified interim analysis boundary of P=0.000019. Distant metastasis-free survival and freedom from relapse was higher in the combination-treated group. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 962 check_entity AN4808-5 BRAF V600 mutation BRAF NCBI:673 gene melanoma DOID:1909 diagnostic;risk 53844-7 PubMed:25265492 In this Phase III trial (NCT01584648 COMBI-d), 423 previously untreated patients with unresectable stage IIIC or IV BRAF V600E or V600K mutant melanoma received dabrafenib and trametinib or dabrafenib alone with primary endpoint of progression free survival with secondary endpoints including disease response. The hazard ratio for progression or death in the dabrafenib–trametinib group was 0.75 (95% confidence interval, 0.57 to 0.99; P=0.03). Of 210 patients in the dabrafenib + trametinib group, 67% of patients had a response, which was 16 percentage points higher than in the dabrafenib-alone group (95% CI, 6 to 25; P=0.002). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 962 check_entity AN4808-5 BRAF V600 mutation BRAF NCBI:673 gene melanoma DOID:1909 diagnostic;risk 53844-7 PubMed:25037139 In this Phase 1b study, 129 patients with unresectable or metastatic melanoma were verified for BRAF V600 mutation using the cobas 4800 mutation test were selected who had progressed on vemurafenib (66 patients) or never received BRAF inhibitor (63 patients). The combination of vemurafenib and cobimetinib was deemed safe and tolerable. Confirmed objective responses were seen in 15% of vemurafenib progressed patients and median progression-free survival was 2.8 months (95% CI 2·6–3·4). Confirmed objective responses were seen in 87% of patients who had never received BRAF inhibitor, including 10% with complete response. Median progression-free survival was 13.7 months (95% CI 10·1–17·5). The majority of patients had BRAF V600E mutation. Post-hoc sequencing of 94 tumor samples indicated seven tumors with a mutation other than BRAF V600E. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 962 check_entity AN4808-5 BRAF V600 mutation BRAF NCBI:673 gene melanoma DOID:1909 diagnostic;risk 53844-7 PubMed:29573941 In a phase 3 trial, patients with melanoma with BRAF V600E or V600K mutation were randomly assigned to encorafenib plus binimetinib or vemurafenib or encorafenib. mPFS was 14·9 months (95% CI 11·0-18·5) in the encorafenib plus binimetinib group and 7·3 months (5·6-8·2) in the vemurafenib group (hazard ratio [HR] 0·54, 95% CI 0·41-0·71; two-sided p<0·0001) assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 962 check_entity AN4808-5 BRAF V600 mutation BRAF NCBI:673 gene melanoma DOID:1909 diagnostic;risk 53844-7 PubMed:32534646 In this phase 3, randomised, double-blind, placebo-controlled trial, 514 patients with unresectable stage IIIc–IV, BRAFV600 mutation-positive melanoma were randomly assigned to either 28-day cycles of the atezolizumab, vemurafenib, and cobimetinib group or atezolizumab placebo, vemurafenib, and cobimetinib control group on a 1:1 basis. The trials primary outcome was progression-free survival. It was discovered at the median follow-up of 18.9 months (IQR: 10·4 – 23·8), that progression-free survival was significantly prolonged with atezolizumab versus control (15.1 vs 10.6 months; hazard ratio: 0.78; 95% CI: 0·63 – 0·97; p = 0·025). 13% of patients in the treatment cohort and 16% in the control cohort stopped all treatment due to adverse events. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 962 check_entity AN4808-5 BRAF V600 mutation BRAF NCBI:673 gene melanoma DOID:1909 diagnostic;risk 53844-7 CIViC:17 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 962 check_entity AN4808-6 BRAF V600 mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 PubMed:25399551 The Combi-v (NCT01597908) open-label, randomized phase 3 trial had 704 patients with metastatic melanoma with a BRAF V600 mutation. Patients were randomized to receive either a combination of dabrafenib and trametinib or vemurafenib orally as first-line therapy. At preplanned interim analysis the overall survival rate at 12 months was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P=0.005). Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). Cutaneous squamous-cell carcinoma and keratoacanthoma occurred at 1% with combination-therapy and 18% in the vemurafenib group. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 963 check_entity AN4808-6 BRAF V600 mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 CIViC:17 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600 sequence variation in gene BRAF/NCBI:673 963 check_entity AN4809-1 BRAF V600D mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:23463675 Patients with other BRAF V600 mutations also respond well to the V600E drug dabrafenib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600D sequence variation in gene BRAF/NCBI:673 964 check_entity AN4809-1 BRAF V600D mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:18287029 In an in vitro study, WM2664, a BRAF V600D expressing cell line, demonstrated improved sensitivity to vemurafenib treatment, compared to BRAF wild-type expressing cells. Sensitivity was determined by assessing cell proliferation (WM2664, GI50: 1.5uM; vs. BRAF expressing cells (n=9) GI50: 10-41uM). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600D sequence variation in gene BRAF/NCBI:673 964 check_entity AN4809-1 BRAF V600D mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:20551065 In an in vitro study, the WM2664 and WM239A cell lines expressing BRAF V600D were associated with increased sensitivity to vemurafenib treatment, as compared to cell lines expressing BRAF wild-type. Sensitivity was determined by proliferation assay. In addition, vemurafenib treatment strongly inhibited MEK and ERK phosphorylation in WM2664 cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600D sequence variation in gene BRAF/NCBI:673 964 check_entity AN4809-1 BRAF V600D mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:31580757 In a retrospective study from 20 institutes in 4 countries, the efficacy of BRAF inhibitor and/or MEK inhibitor in patients with melanoma harboring BRAF nonV600E/K mutations were evaluated. Treated with BRAF inhibitor monotherapy, response rate were 27%(4/15) for V600R, 100%(2/2) for V600D, 0% (0/2) for V600_K601>E, 0% (0/1) for V600G, 0% (0/1) for V600L, 0% (0/9) for V600_S602>DT, 0% (0/5) for L597, 0% (0/6) for K601E, 0% (0/2) for G469, 0% (0/1) for G593D,and 0% (0/1) for T599_V600insT Treated with MEK inhibitor monotherapy, response rate were 100% (1/1) for L597, and 0% (0/1) for K601E. Treated with BRAF inhibitor and MEK inhibitor combination thearpy, response rate were 55% (16/29) for V600R, 67% (2/3) for V600D, 50% (1/2) for V600_K601>E, 50% (1/2) for V600M, 22% (2/9) for L597,25% (1/4) for K601E, 67% (2/3) for G469, and 0% (0/1) for A598V. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600D sequence variation in gene BRAF/NCBI:673 964 check_entity AN4809-1 BRAF V600D mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 CIViC:11 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600D sequence variation in gene BRAF/NCBI:673 964 check_entity AN4810-1 BRAF V600E BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:24265155 In a retrospective study of 44 relapsed melanoma patients harboring BRAF V600E or V600K (known BRAF inhibitor sensitizing mutations), MAPK pathway reactivation mechanisms were implicated in acquired resistance to BRAF inhibitor (vemurafenib or dabrafenib) monotherapy. The following MAPK pathway variants were found in progressive tumors with patient matched baseline tumors (some patients donated samples from multiple geographically/temporally distinct progressive tumors): NRAS mutations (G12D, G12R, G13R, Q61K, Q61R, Q61L) in 13/71 (18%) of progressive tumors, KRAS mutations (G12C, G12R, Q61H) in 5/71 (7%) of progressive tumors, mutant BRAF amplification (2-15 fold or 4-75 copies) in 11/57 (19%) of progressive tumors, mutant BRAF alternative splice variants (novel exon boundaries between 1/9, 1/11, 3/9) in 6/48 (13%) of progressive tumor RNA. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 965 check_entity AN4810-1 BRAF V600E BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 CIViC:4174 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 965 check_entity AN4811-1 BRAF V600E mutation BRAF NCBI:673 gene biliary tract cancer DOID:4607 risk 53844-7 PubMed:169315 In a phase II trial, 33 patients with advanced or metastatic biliary tract cancer (BTC) received dabrafenib (D) and trametinib (T) in a second or higher line therapeutic context. Of the 33 patients, 30 had BRAF V600E mutated tumors, and 32 were evaluable. Objective response rate was 41% (13/32; 95% CI, 24 - 59%). Median PFS was 7.2 months (95% CI, 4.6 - 10.1 months), and median OS was 11.3 months (95% CI, 7.3 - 17.6 months). The author concluded that D+T therapy should be considered for patients with BRAF V600E mutated BTC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 966 check_entity AN4811-1 BRAF V600E mutation BRAF NCBI:673 gene biliary tract cancer DOID:4607 risk 53844-7 CIViC:12 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 966 check_entity AN4811-2 BRAF V600E mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 PubMed:23934108 Preclinical study analyzing the differential response to MEK inhibitors in KRAS and BRAF mutant cancer cell lines and mouse xenografts. Inhibition of active, phosphorylated MEK by GDC-0973 (cobimetinib) is required for strong inhibition of the MAPK pathway in BRAF-mutant tumours. This study provides mechanistic rationale for improved efficacy of cobimetinib in BRAF-mutant models compared to MEK inhibitors acting through an alternative mechanism (GDC-0623 and G-573). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 967 check_entity AN4811-2 BRAF V600E mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 PubMed:32758030 This NCI-MATCH trial was conducted in 35 patients of which 29 were included in the primary efficacy analysis with tumors with BRAF V600E mutations, and treated with a combination of dabrafenib and trametinib. The ORR was 37.9% (90% CI, 22.9-54.9). The median PFS and median OS were 11.4 months (90% CI, 8.4-16.3) and 28.6 months respectively. Meaningful results were achieved with this treatment with an overall DCR of 75.9%. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 967 check_entity AN4811-2 BRAF V600E mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 PubMed:35363510 In this phase II study of the arm E of the NCI-COG pediatric MATCH trial, 20 patients (median age: 14) were treated with Selumetinib. High-grade glioma (n=7) and rhabdomyosarcoma (n=7) were the most common types of cancers in this cohort. There was no objective response (PR or CR), the best overall response being SD, in three patients. The 6-month PFS rate was 15% (95% CI; 4-34). 25% of the patients had grade 3 or higher AEs, possibly attributed to selumetinib treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 967 check_entity AN4811-2 BRAF V600E mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 CIViC:12 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 967 check_entity AN4811-2 BRAF V600E mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 CIViC:4715 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 967 check_entity AN4811-2 BRAF V600E mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 CIViC:4748 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 967 check_entity AN4811-3 BRAF V600E mutation BRAF NCBI:673 gene childhood low-grade glioma DOID:0080830 prognostic 53844-7 PubMed:29948154 Using Sanger sequencing, BRAFV600E mutations were identified in 21 of 285 patients with PLGGs (7.4%). This mutation was enriched in hemispheric tumors (p<0.007) and was associated with shorter progression-free survival (p=0.011) and overall survival (p=0.032) [mt (n=18) vs wt (n=166)]. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 968 check_entity AN4811-3 BRAF V600E mutation BRAF NCBI:673 gene childhood low-grade glioma DOID:0080830 prognostic 53844-7 CIViC:12 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 968 check_entity AN4811-4 BRAF V600E mutation BRAF NCBI:673 gene childhood pilocytic astrocytoma DOID:6812 risk 53844-7 PubMed:25524464 In a case report, a 28 month old patient with a cervicomedullary low grade glioma compatible with pilocytic astrocytoma which was resected had a second lesion consistent with a ganglioglioma 3 years later. This mass progressed under treatment at which point PCR amplification of BRAF exon 15 and subsequent Sanger sequencing the initial biopsy revealed the tumor harbored a BRAF V600E mutation. Based on these results, vemurafenib monotherapy was started and radiological and clinical response was noted after 3 months of treatment, which was sustained after 6 months of therapy. Prior to vemurafenib treatment, the patient had undergone tracheotomy, was treated with standard chemotherapy and underwent another surgery, but had developed progressive disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 969 check_entity AN4811-4 BRAF V600E mutation BRAF NCBI:673 gene childhood pilocytic astrocytoma DOID:6812 risk 53844-7 CIViC:12 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 969 check_entity AN4811-5 BRAF V600E mutation BRAF NCBI:673 gene cholangiocarcinoma DOID:4947 risk 53844-7 PubMed:28480077 Chemotherapy-refractory, metastatic cholangiocarcinoma with CNS involvement and a BRAF V600E mutation had a partial response at 8 weeks to dabrafenib and trametinib combination with complete radiologic regression at 12 weeks. At 6 months the patient was still on treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 970 check_entity AN4811-5 BRAF V600E mutation BRAF NCBI:673 gene cholangiocarcinoma DOID:4947 risk 53844-7 PubMed:26687137 A 31 year old patient with metastatic cholangiocarcinoma with BRAF V600E was treated with vemurafenib, panitumumab and irinotecan triplet therapy. By 2 months, 50% reduction of tumor volume was noted, including multiple lung metastases, complete clinical response was noted by CT 6 months post therapy and this treatment was continued. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 970 check_entity AN4811-5 BRAF V600E mutation BRAF NCBI:673 gene cholangiocarcinoma DOID:4947 risk 53844-7 CIViC:12 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 970 check_entity AN4811-6 BRAF V600E mutation BRAF NCBI:673 gene colorectal adenocarcinoma DOID:0050861 risk 53844-7 PubMed:29431699 In this trial, 142 patients with metastatic, BRAF V600E mutant colorectal cancer were randomized to receive either BRAF inhibitor dabrafenib (D) + EGFR inhibitor panitumumab (P); or a triple therapy of D + P and MEK inhibition with trametinib (T) or T + P. Confirmed response rates for D+P (n=20), D+T+P (n=91), and T+P (n=31) were 10%, 21%, and 0%, respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 971 check_entity AN4811-6 BRAF V600E mutation BRAF NCBI:673 gene colorectal adenocarcinoma DOID:0050861 risk 53844-7 CIViC:12 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 971 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:19001320 Cetuximab or panitumumab may be ineffective in patients with BRAF mutation unless BRAF inhibitor such as Sorafenib is introduced. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:23845441 Combined PI3K inhibitor GDC0941 and BRAF inhibitor PLX4720 administration to NSG mice subcutanousely injected with colorectal cell lines with a BRAF V600E mutation effectively inhibited tumor growth and reduced cellular proliferation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:23812671 Combined nutlin-3 and PLX4720 administration to athymic nude mice subcutanousely injected with the A357 colorectal cell line with a BRAF V600E mutation effectively inhibited tumor growth significantly more than single agent therapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:22180495 This in vivo study examined the efficacy of various treatments on athymic nude mice xenografted with colorectal cancer HT29 cells, which harbor BRAF V600E. The authors sought to understand whether the addition of vemurafenib (a BRAF V600E inhibitor) to agents approved for the treatment of metastatic colorectal cancer increased therapeutic efficacy, and which combinations worked best. Capecitabine, bevacizumab and vemurafenib combination therapy resulted in 100% tumor growth inhibition (TGI) and 190% increased lifespan (ILS) compared to vehicle treated controls. Seven mice experienced partial response and two experienced complete response. Triplet therapy resulted in better TGI and ILS compared to any agent in isolation or capecitabine + vemurafenib doublet therapy (p <0.05, p <0.0001, for all comparisons). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:24594804 V600E is associated with adverse pathological features of colorectal cancer. This can be concluded as a marker of poor prognosis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:20619739 This was a retrospective study of 691 cetuximab treated patients with metastatic, chemotherapy refractory colorectal cancer. Of those, 30 patients harbored BRAF V600E, were KRAS, NRAS and PIK3CA wt, and had individual response data. One patient (who harbored BRAF V600E in low copy number) responded, 11 had stable disease, and 18 progressed. Treatments included cetuximab + irinotecan (n=20), cetuximab monotherapy (n=5), cetuximab + FOLFIRI (n=4), and cetuximab + oxaliplatin + 5FU (n=1). Median PFS was 8 weeks (2-32 weeks), median OS was 25 weeks (4-237 weeks), and median number of previous chemotherapy lines was 2 (0-4). Median age was 61 years old (42-78) and there were 16 males and 14 females. Authors concluded that BRAF mutation (23/24 of mutants were BRAF V600E) was strongly associated with poor response to cetuximab and suggested that mutation status of BRAF is more informative than those of NRAS and PIK3CA exon 20 for predicting cetuximab response (second only to KRAS). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:25989278 This meta-analysis of 7 randomized control trials evaluating overall survival (OS) (8 for progression free survival) could not definitely state that survival benefit of anti-EGFR monoclonal antibodies is limited to patients with wild type BRAF. In other words, the authors believe that there is insufficient data to justify the exclusion of anti-EGFR monoclonal antibody therapy for patients with mutant BRAF. In these studies, mutant BRAF specifically meant the V600E mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:26460303 In this Phase II pilot study (NCT00405587) of BRAF V600 inhibitor vemurafenib in 21 metastatic colorectal cancer (CRC) patients with BRAF V600E, one patient had a durable 21 week partial response, and seven patients had 8 week stable disease as best response. Median progression free survival was 2.1 months and median overall survival was 7.7 months. The authors conclude that single agent vemurafenib did not show meaningful activity in V600E CRC, in contrast to the significant vemurafenib activity against V600 in melanoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:22608338 In trial NCT00880321, dabrafenib was tested in various solid tumor types harboring mutant BRAF after establishing dosage of 150 mg twice daily. In nine colorectal cancer patients with established V600E mutation, 1 confirmed response, 7 instances of stable disease, and 1 case of progressive disease was seen, which contrasted strongly with a 56% confirmed response rate seen in metastatic V600E melanoma patients similarly treated in the same study. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:22281684 5 of 7 colorectal cancer (CRC) cell lines with BRAF V600E mutation were resistant to treatment with the BRAF inhibitor vemurafenib. An RNAi screen in the WiDr cell line (a V600E CRC line) identified EGFR as an enhancer for survival when exposed to vemurafenib. Treatment with vemurafenib and EGFR inhibitor (cetuximab or gefitinib) in V600E CRC cells (WiDr, VACO432 and KM20) showed inhibited growth as well as induction of the cleaved PARP apoptotic marker. WiDr and VACO432 cells were injected into immunodeficient mice. Modest response was seen with vemurafenib treatment, while combination treatment showed considerable tumor growth inhibition as compared to control. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:25589621 Treatment response to mutant BRAF inhibitor vemurafenib and EGFR inhibitor panitumumab was assayed in 12 patients with metastatic colorectal cancer (CRC) who had progressed on chemotherapy. Two patients had confirmed partial responses, and 2 showed stable disease over 6 months. The authors conclude that although some efficacy is seen, only a small subset of patients respond to this treatment and the responses are not durable. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:23549875 In a mouse model of BRAF V600E colorectal cancer, western blots from tumors in mice treated with BRAF inhibitor GDC-0879 and PI3K/mTOR inhibitor BEZ235 showed stronger reduction in phospho-Akt and phospho-S6 than PI3K/mTOR inhibitor alone, and combination inhibition also resulted in stronger phospho-ERK inhibition in tumors than did BRAF inhibition alone. Increased apoptosis in tumors was seen in dual treatment conditions with increased TUNEL-positive cells. In vehicle treated mice, area of colon covered by tumor increased, while treatment with single agent inhibitors caused growth inhibition resulting in no change in colon area covered by tumors. Administration of dual inhibitors induced tumor regression apparent in a decrease of colonic area covered by tumors over the course of treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:27404270 In a study of 908 patients with colorectal cancer, 45 patients had BRAF V600E mutations and 589 patients were BRAF wild type. BRAF V600E mutations were more likely to be proximal tumors (68.9%, 20.7%; p<0.0001), they were more likely to be poorly differentiated (17.7%, 1.9%; p<0.0001), they were more likely to be mucinous carcinoma type (20.0%, 4.2%; p=0.0003), they were more likely to have lymphatic invasion (77.6%, 49.9%; p=0.0003), and they had a shorter survival time (31.1 mo, 41.6 mo; p=0.001). The 3-year survival rate was significantly poorer in the V600E group when compared to the wild type group (63.8%, 87.9%; p<0.0001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:27325282 Case report of a patient with BRAF V600E mutant metastatic colorectal cancer. Combined EGFR and BRAF inhibition (panitumumab and vemurafenib) showed an initial partial response for 4 months with subsequent disease progression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:27729313 Phase 1b study of vemurafenib, cetuximab and irinotecan in 19 patients with colorectal cancer (1 with appendiceal cancer). Six of 17 evaluable patients achieved an objective response, 15 patients total had either stable disease or radiographic response (the patient with appendiceal cancer had disease progression). Estimated median PFS was 7.7 months. Effect of the combined treatment was also observed in xenograft and cell line studies. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:27302369 In a study of 468 colorectal cancer samples, 61 patients had micro-satellite instability and there was a statistically significantly better prognosis for BRAF WT patients relative to BRAF (V600E)-mutated patients (Log-rank P=0.0903). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:19603024 In a study of metastatic colorectal cancer patients who received 5-FU-based first-line chemotherapy, those with BRAF V600E mutations had reduced progression-free survival (4.3mo vs. 12.5mo, HR:4.9, 95%CI:2.7-9.0, P<0.0001, univariate analysis; HR:4.0, 95%CI:2.2-7.4, P<0.0001, multivariate analysis) and reduced overall survival (10.9mo vs. 40.5mo, HR:4.5, 95%CI:2.4-8.4, P<0.0001, univariate analysis; HR:4.1, 95%CI:2.1-8.0, P<0.0001, multivariate analysis) compared to those with wildtype BRAF. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:19571295 In a study of metastatic colorectal cancer patients treated with capecitabine, oxaliplatin, and bevacizumab, those with BRAF V600E mutations had reduced progression-free survival (5.9mo vs. 12.2mo, P=0.003) and reduced overall survival (15.0mo vs. 24.6mo, P=0.002) compared to those with wildtype BRAF. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:19903786 This study examined outcomes of 240 rectum cancer patients treated with total mesorectal excision therapy. Tumor samples were obtained at the time of surgery and genotyped for BRAF exon 15 mutations. BRAF V600E was identified in 5 cases. The authors reported that no differences were found in overall survival between patients with and without BRAF mutations (P > 0.1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:25666295 In a retrospective study of 148 treatment naive metastatic colorectal cancer patients, patients with BRAF V600E and wildtype NRAS/KRAS (n=14) mutation treated with FOLFOX4 plus cetuximab were associated with a decreased progression free survival (7.2mo vs. 9.7mo, HR:0.39, 95% CI:0.21-0.72, P=0.0017), and decreased overall survival (11.7mo vs. 28.5mo, HR:0.23, 95% CI:0.12-0.41, P<0.0001), as compared to patients with wildtype BRAF, NRAS and KRAS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Among 2 patients with BRAF V600E mutant colorectal cancer, 1 had a partial response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:29431699 In this trial, 142 patients with metastatic, BRAF V600E mutant colorectal cancer were randomized to receive either BRAF inhibitor dabrafenib (D) + EGFR inhibitor panitumumab (P); or a triple therapy of D + P and MEK inhibition with trametinib (T) or T + P. Confirmed response rates for D+P (n=20), D+T+P (n=91), and T+P (n=31) were 10%, 21%, and 0%, respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:20008640 Patients with completely resected colorectal adenocarcinoma (Stage II-III) were treated with fluorouracil and leucovorin +/- ironotecan. Of the 1,307 FFPE samples tested, V600E was observed in 31 Stage II samples (7.6%) and 72 Stage III samples (7.9%). V600E was prognostic for overall survival, but not for relapse-free survival, in patients with stages II and III combined, and in stage III alone. For all MSI low and stable tumors, BRAF V600E positive samples had a hazard ratio (HR) of 2.19 (95% CI, 1.43 to 3.37, P=0.00034). For all samples in the cohort (MSI-H and MSI-L) BRAF V600E positive samples had a 1.66 HR (95% CI, 1.15 to 2.40, P=0.0069). The authors note prognostic value for BRAF V600E, especially in non-MSI high tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:21502544 The CRYSTAL Phase III Trial evaluated efficacy of irinotecan, fluorouracil, and leucovorin (FOLFIRI) with or without Cetuximab for colorectal cancer patients who presented with unresectable metastatic disease. BRAF mutation status (V600E) was analyzed via LightMix BRAF V600E Kit. V600E mutations were detected in 60/999 tumor samples (6%), 59 of which were wild-type for KRAS. When comparing patients with wildtype KRAS (n=625), BRAF V600E tumors had worse outcomes relative to BRAF wildtype. For patients with BRAF V600E tumors (n=566), median overall survival (OS) was 25.1 months with cetuximab and 21.6 months without cetuximab. For patients with wildtype BRAF (n=59), median OS was 14.1 months with cetuximab and 10.3 months without cetuximab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:168986 In a phase III trial, patients with BRAF V600E mutated metastatic colorectal cancer received triplet combination with encorafenib + binimetinib + cetuximab in a second or third-line setting. In the safety-lead in part of this trial, 30 patients were given triplet therapy, of which 29 with V600E mutation were included in the efficacy analysis. The objective response rate was 48% [95%CI: 29.4 - 67.5], median PFS was 8.0 mo [95%CI: 5.6 - 9.3], and median OS was 15.3 mo [95%CI: 9.6 - not reached]. The author concluded that triplet therapy was well tolerated and PFS and OS were substantially improved over historical standard of care. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:31566309 665 patients with BRAF V600E-mutated metastatic CRC were enrolled In this open-label, phase 3 trial. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators’ choice of either cetuximab and irinotecan or cetuximab and FOLFIRI. The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (triplet group vs. control P<0.001). The median progression-free survival in the triplet-therapy group was 4.3 months (95% CI, 4.1 to 5.2) and 1.5 months (95% CI, 1.5 to 1.7) in the control group (hazard ratio for disease progression or death, 0.38; 95% CI, 0.29 to 0.49; P<0.001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:21098728 COLO201 and COLO206F cells harboring BRAF V600E mutations were cloned to be MEK inhibitor (AZD6244 [selumetinib]) resistant. The mechanism of this resistance was shown to be amplification of the BRAF V600E gene. BRAF V600E amplification was observed in 1/11 colorectal cancer patient samples evaluated, indicating this subclone (28% of cells) would be MEK inhibitor resistant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 PubMed:36409971 This clinical study was conducted with 30 patients with colorectal cancer harboring BRAF V600E (n = 29) or BRAF K601E (n=1) mutations, treated with a combination of cobimetinib and vemurafenib. Of the 30 patients, only 27 were evaluable. An OR rate of 30% (95% CI; 14-50), and DC rate of 52% (95% CI; 35-65) was noted. Eight patients had a partial response with a median duration of 8.1 weeks (5.1-32.3 weeks) and six patients had SD16+ with a median duration of 29.1 weeks (28.1-44.0 weeks). The reported PFS was 15.7 weeks (95% CI; 12.1-18.1) and OS was 38.9 weeks (95% CI; 26.1-49.4). In 43% of the cohort, grade 3 AEs or SAEs were observed, likely associated with the treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 CIViC:12 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 CIViC:4173 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-7 BRAF V600E mutation BRAF NCBI:673 gene colorectal cancer DOID:9256 prognostic;risk 53844-7 CIViC:4707 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 972 check_entity AN4811-8 BRAF V600E mutation BRAF NCBI:673 gene gastrointestinal neuroendocrine tumor DOID:0050626 risk 53844-7 PubMed:27048246 BRAF mutations were identified in 9% of 108 cases of high-grade colorectal neuroendocrine tumors (80% V600E). Two patients were treated with a combination of BRAF and MEK inhibition and exhibited durable response (beyond 7 and 9 months, respectively). Urinary BRAF V600E tumor DNA correlated with disease response in one of the patients. BRAF and MEK inhibition was either dabrafenib+trametinib (case 1) or vemurafenib+trametinib (case 2). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 973 check_entity AN4811-8 BRAF V600E mutation BRAF NCBI:673 gene gastrointestinal neuroendocrine tumor DOID:0050626 risk 53844-7 CIViC:12 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 973 check_entity AN4811-9 BRAF V600E mutation BRAF NCBI:673 gene hairy cell leukemia DOID:285 diagnostic;risk 53844-7 PubMed:21663470 In 47 patients with Hairy Cell Leukemia, sequencing discovered a V600E mutation in all 47 of the sequenced patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 974 check_entity AN4811-9 BRAF V600E mutation BRAF NCBI:673 gene hairy cell leukemia DOID:285 diagnostic;risk 53844-7 PubMed:26352686 Two clinical trials evaluated the effects of vemurafenib in 54 patients with BRAF (V600E) positive hairy-cell leukemia. The overall response rate was 98% with 19/54 having a complete response and 34/54 having a partial response. In the Italian study (n=25), the median relapse-free survival was 9 months and in the U.S. study (n=24), rate of progression-free survival was 73% with overall survival rate of 91%. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 974 check_entity AN4811-9 BRAF V600E mutation BRAF NCBI:673 gene hairy cell leukemia DOID:285 diagnostic;risk 53844-7 CIViC:12 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 974 check_entity AN4811-10 BRAF V600E mutation BRAF NCBI:673 gene intrahepatic cholangiocarcinoma DOID:4928 risk 53844-7 PubMed:28078132 Two cases of patients with BRAF V600E positive, refractory intrahepatic cholangiocarcinoma showed excellent clinical and radiographic response to combination dabrafenib and trametinib treatment. One patient achieved complete remission at 6 months with progression at 9 months and the other partial remission at 2 months and no progression as of 5 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 975 check_entity AN4811-10 BRAF V600E mutation BRAF NCBI:673 gene intrahepatic cholangiocarcinoma DOID:4928 risk 53844-7 PubMed:25435907 Dabrafenib and trametinib combination showed durable response for a patient with standard chemotherapy and radiation refractory, poorly differentiated, intrahepatic cholangiocarcinoma harboring BRAF V600E. At time of publication, 8.5 months, the patient was still on treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 975 check_entity AN4811-10 BRAF V600E mutation BRAF NCBI:673 gene intrahepatic cholangiocarcinoma DOID:4928 risk 53844-7 CIViC:12 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 975 check_entity AN4811-11 BRAF V600E mutation BRAF NCBI:673 gene Langerhans cell sarcoma DOID:7146 risk 53844-7 PubMed:31513482 Off-label use of vemurafenib to treat BRAF V600E mutation-positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated. Fifty-four patients from 12 countries were treated with vemurafenib 20 mg/kg/day. Because LCH is a heterogeneous systemic disease, the quantitative Disease Activity Score (DAS), which reflects overall LCH extension, was used as an evaluation criterion. At 8 weeks, 38 patients had CRs (non-active disease) and 16 had PRs (active disease better). DAS decreased from a median value of 7 to 0 between VMF initiation and day 60 (P < 0.001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 976 check_entity AN4811-11 BRAF V600E mutation BRAF NCBI:673 gene Langerhans cell sarcoma DOID:7146 risk 53844-7 CIViC:12 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 976 check_entity AN4811-12 BRAF V600E mutation BRAF NCBI:673 gene laryngeal squamous cell carcinoma DOID:2876 risk 53844-7 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. One patient with BRAF V600E mutant laryngeal cancer had a partial response with vemurafenib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 977 check_entity AN4811-12 BRAF V600E mutation BRAF NCBI:673 gene laryngeal squamous cell carcinoma DOID:2876 risk 53844-7 CIViC:12 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 977 check_entity AN4811-13 BRAF V600E mutation BRAF NCBI:673 gene low grade glioma DOID:0080829 risk 53844-7 PubMed:32523649 In this trial, 19 patients with pediatric brain tumours (1 patient with Astrocytoma, 1 with Fibrillary Astrocytoma, 10 with Pilocytic Astrocytoma, 5 with Ganglioglioma and 2 with Pleomorphic Xanthoastrocytoma) harbouring BRAF V600E were treated with vemurafenib. The study reported a positive response to the treatment, with 1 complete response, 5 partial responses, and 13 patients with stable disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 978 check_entity AN4811-13 BRAF V600E mutation BRAF NCBI:673 gene low grade glioma DOID:0080829 risk 53844-7 CIViC:12 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 978 check_entity AN4811-14 BRAF V600E mutation BRAF NCBI:673 gene lung non-small cell carcinoma DOID:3908 risk 53844-7 PubMed:27283860 Patients with BRAF V600E-mutant NSCLC (n=57) were enrolled into a phase 2, multicentre, non-randomised, open-label study, administering dabrafenib plus trametinib. The overall response rate was 36/57 (63.2%, [95% CI 49.3-75.6]) and the median progression-free survival was 9.7 months (95% CI 6.9-19.6). At data cutoff (11.6 months of follow-up), 18/36 (50%) confirmed responses were ongoing and 23/57 (40%) of patients had died. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 979 check_entity AN4811-14 BRAF V600E mutation BRAF NCBI:673 gene lung non-small cell carcinoma DOID:3908 risk 53844-7 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Within the BRAF mutant group, fourteen patients had refractory BRAF V600E-mutated NSCLC (adenocarcinoma, n = 13; sarcomatoid, n = 1). Six patients (43%; 95% CI, 18% to 71%) had objective responses (one CR, five PR), and two additional patients had SD > 120 days. The median DOR was 5 months (range, 4 to 14 months). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 979 check_entity AN4811-14 BRAF V600E mutation BRAF NCBI:673 gene lung non-small cell carcinoma DOID:3908 risk 53844-7 CIViC:12 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 979 check_entity AN4810-1 BRAF V600E mutation BRAF NCBI:673 gene melanoma DOID:1909 prognostic;risk 53844-7 PubMed:24586605 BRAF status does not predict outcome in patients treated with dacarbazine or temozolomide. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 980 check_entity AN4810-1 BRAF V600E mutation BRAF NCBI:673 gene melanoma DOID:1909 prognostic;risk 53844-7 PubMed:24576830 In the setting of BRAF(V600E), NF1 loss resulted in elevated activation of RAS-GTP but does not show resistance to MEK inhibitors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 980 check_entity AN4810-1 BRAF V600E mutation BRAF NCBI:673 gene melanoma DOID:1909 prognostic;risk 53844-7 PubMed:24583796 Dabrafenib with trametinib provides higher response rate and lower toxicity (as compared to chemotherapy) in patients with melanoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 980 check_entity AN4810-1 BRAF V600E mutation BRAF NCBI:673 gene melanoma DOID:1909 prognostic;risk 53844-7 PubMed:24388723 BRAF V600E is correlated with shorter disease-free and overall Survival in a Spanish cohort of melanoma patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 980 check_entity AN4810-1 BRAF V600E mutation BRAF NCBI:673 gene melanoma DOID:1909 prognostic;risk 53844-7 PubMed:25370471 One patient with BRAF V600E mutated melanoma (with no detected PI3K pathway deregulation) had a partial response on treatment with pictilisib, a PI3K inhibitor, for 9.5 months. Study was a phase-1 with 60 patients enrolled. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 980 check_entity AN4810-1 BRAF V600E mutation BRAF NCBI:673 gene melanoma DOID:1909 prognostic;risk 53844-7 PubMed:24947927 This was a phase I expansion and pharmacodynamic study of oral MEK inhibitor RO4987655 on advanced cancer. Of 17 patients with BRAF V600E melanoma, 4 achieved partial response, 5 experienced stable disease lasting longer than 16 weeks, and 8 experienced disease progression (including 2 with prior vemurafenib treatment). One of the partial responders had a concomitant EGFR mutation, and two of the stable disease patients had other concomitant mutations (in RET or MET). The median days on treatment was 113 (18-366) for BRAF V600E melanoma patients and 107 (17-323) for BRAF V600 wildtype patients (n=23). Patients with BRAF V600E mutant melanoma experienced similar response rates (24% vs 20%) and rates of metabolic response measured by decrease in FDG uptake assessed by FDG-PET (86% vs 75%) compared to non-BRAF mutant patients. Patients with melanoma, either BRAF wt or V600E, experienced significant decreases in Ki67 expression by day 15 of MEK inhibitor treatment (P<0.02). The authors conclude that RO4987655 has clinical activity in BRAF V600E and BRAF wt melanoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 980 check_entity AN4810-1 BRAF V600E mutation BRAF NCBI:673 gene melanoma DOID:1909 prognostic;risk 53844-7 PubMed:26678033 49 BRAF-mutant melanoma cell lines from patients not previously treated with BRAF inhibition were analyzed. 21 exhibited primary resistance to BRAF inhibition using PLX4720. Inhibition of MEK1/2 (AZD6244 [selumetinib]) and PI3K/mTOR (BEZ235 [dactolisib]) was the most effective approach to counteract resistance in comparison to inhibition with the PLX4720 (progenitor of vemurafenib)-BEZ235 (where response was assessed by apoptosis, viability, p-ERK, p-Akt inhibition). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 980 check_entity AN4810-1 BRAF V600E mutation BRAF NCBI:673 gene melanoma DOID:1909 prognostic;risk 53844-7 PubMed:24508103 The BRIM-3 Phase III trial NCT01006980 assessed BRAF inhibitor vemurafenib versus dacarbazine in 598 patients with treatment naive metastatic melanoma and confirmed V600E mutation. Significant differences were seen in overall survival (13.3 months with vemurafenib vs. 10.0 months with dacarbazine) and median progression free survival (6.9 months with vemurafenib vs. 1.6 months with dacarbazine) assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 980 check_entity AN4810-1 BRAF V600E mutation BRAF NCBI:673 gene melanoma DOID:1909 prognostic;risk 53844-7 PubMed:25265494 In this Phase III trial (coBRIM, NCT01689519) of 495 V600 mutant melanoma patients, 344 had V600E mutation. 174 patients were treated with vemurafenib and placebo, and 170 were treated with vemurafenib and cobimetinib and tested for progression free survival. 88 of 174 monotherapy group patients had an event with median progression free survival of 6.5 months. In the combination group 58 of 174 patients had an event with median progression-free survival not met, however, when in combination with other V600 mutations median progression-free survival was 9.9 months with combination treatment. Median time to followup for the whole cohort was 7.3 months. Hazard Ratio for progression or death was 0.57 (0.41-0.80). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 980 check_entity AN4810-1 BRAF V600E mutation BRAF NCBI:673 gene melanoma DOID:1909 prognostic;risk 53844-7 PubMed:20818844 Multicenter, phase 1, dose-escalation trial of PLX4032 (Vemurafenib). Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients (N=37/48). Patients without the V600E mutation had evidence of tumor regression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 980 check_entity AN4810-1 BRAF V600E mutation BRAF NCBI:673 gene melanoma DOID:1909 prognostic;risk 53844-7 PubMed:22663011 In a study of 322 advanced melanoma patients with BRAF-V600E (N=281), BRAF-V600K (N=40), or both mutations (N=1), treatment with trametinib was associated with improved progression-free survival (4.8mo vs. 1.5mo; HR: 0.45, 95% CI: 0.33-0.63, P<0.001) compared to chemotherapy control group. Additionally, treatment with trametinib was associated with increased 6-month overall survival (HR: 0.54, 95% CI: 0.32-0.92, P=0.01). The authors note similar outcomes for the primary efficacy population (V600E only) and the intention-to-treat population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 980 check_entity AN4810-1 BRAF V600E mutation BRAF NCBI:673 gene melanoma DOID:1909 prognostic;risk 53844-7 PubMed:23569304 In a phase 2 clinical trial (NCT00949702) of 132 BRAF mutation positive metastatic melanoma patients treated with vemurafenib monotherapy, patients harboring BRAF V600E (n=123) or V600K (n=9) mutations were associated with a favorable objective response rate (53% per RECIST v1.1 criteria, 70/132), with 6% (8/132) and 47% (62/132) of patients achieving complete response and partial response, respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 980 check_entity AN4810-1 BRAF V600E mutation BRAF NCBI:673 gene melanoma DOID:1909 prognostic;risk 53844-7 PubMed:26557775 In a clinical study (NCT01307397) of Polish, stage IIIC/IV, melanoma patients with metastases (n=75) harboring BRAF V600 mutation (as detected by cobas 4800 BRAF V600 Mutation Test), median overall survival was 61.9% (95% CI: 50.1-73.6) and median progression free survival was 7.4 months (95% CI: 5.5-9.2). Median duration of response was 7.4 months (95% CI: 5.7-9.2), with 3% (2/75) and 43% (29/75) of patients achieving a complete and partial response, respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 980 check_entity AN4810-1 BRAF V600E mutation BRAF NCBI:673 gene melanoma DOID:1909 prognostic;risk 53844-7 PubMed:25524477 In a retrospective study of 300 stage IV melanoma patients, patients with BRAF V600E mutation (n=175) were associated with a 4.8% (8/167) complete response, a 58.1% (97/167) partial response and stable disease in 22.2% (37/167) of cases, while 15% (25/167) of patients harboring BRAF V600E experienced progressive disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 980 check_entity AN4810-1 BRAF V600E mutation BRAF NCBI:673 gene melanoma DOID:1909 prognostic;risk 53844-7 PubMed:28891408 Adjuvant dual treatment with BRAF inhibitor dabrafenib and MEK inhibitor trametinib was administered to patients with stage III resected melenoma with V600E or V600K mutation in this stage III trial (COMBO-AD, NCT01682083). 792 (91%) patients had V600E, and were administered dabrafenib and trametinib or placebo for 12 months. In subsequent analysis, relapse or death occurred in 150/397 patients (38%) in the treatment group and 229/395 patients (58%) in the placebo group for a 95% CI Hazard Ratio of 0.48 (0.39-0.58). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 980 check_entity AN4810-1 BRAF V600E mutation BRAF NCBI:673 gene melanoma DOID:1909 prognostic;risk 53844-7 PubMed:25265492 In this Phase III trial (NCT01584648 COMBI-d), previously untreated patients with unresectable stage IIIC or IV melanoma with BRAF V600E (359 patients) or V600K (61 patients) received dabrafenib and trametinib or dabrafenib alone with primary endpoint of progression free survival and secondary endpoints including disease response. The hazard ratio for progression or death in the V600E group was 0.81 for dabrafenib-trametinib vs dabrafenib-alone. Of 179 V600E patients in the dabrafenib-trametinib group, 68% of patients had a response, which was 15 percentage points higher than in the dabrafenib-alone group (95% CI, 4 to 24; P=0.006). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 980 check_entity AN4810-1 BRAF V600E mutation BRAF NCBI:673 gene melanoma DOID:1909 prognostic;risk 53844-7 PubMed:23020132 In this Phase I and II study (NCT01072175) patients with metastatic melanoma were given dabrafenib and trametinib combination therapy vs. dabrafenib monotherapy. From V600E patients, 45 received monotherapy and 92 received combination therapy. Hazard ratio for progression or death was 0.43 (95% CI, 0.27-0.71). Both patients with the BRAF V600E and V600K mutation showed significant improvement in progression-free survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 980 check_entity AN4810-1 BRAF V600E mutation BRAF NCBI:673 gene melanoma DOID:1909 prognostic;risk 53844-7 PubMed:23031422 A single 66-year old male patient with advanced melanoma thought to have concomitant BRAF V600E and V600M mutations responded rapidly to dabrafenib. His shoulder lesion reduced by 60% after 1 week of therapy and was gone after 1 month. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 980 check_entity AN4810-1 BRAF V600E mutation BRAF NCBI:673 gene melanoma DOID:1909 prognostic;risk 53844-7 CIViC:12 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 980 check_entity AN4810-1 BRAF V600E mutation BRAF NCBI:673 gene melanoma DOID:1909 prognostic;risk 53844-7 CIViC:4170 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 980 check_entity AN4811-16 BRAF V600E mutation BRAF NCBI:673 gene multiple myeloma DOID:9538 prognostic;risk 53844-7 PubMed:23612012 In patients with multiple myeloma, those with BRAF V600E had shorter overall survival than wild-type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 981 check_entity AN4811-16 BRAF V600E mutation BRAF NCBI:673 gene multiple myeloma DOID:9538 prognostic;risk 53844-7 PubMed:24997557 A 65-year-old man presented with stage II myeloma. He was initially treated with chemotherapy and he received an autologous stem cell transplant. Sequencing of the recurrent tumor harbored BRAF V600E mutation and he was treated with vemurafenib. After 7 weeks of treatment, the patient relapsed and died. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 981 check_entity AN4811-16 BRAF V600E mutation BRAF NCBI:673 gene multiple myeloma DOID:9538 prognostic;risk 53844-7 CIViC:12 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 981 check_entity AN4811-17 BRAF V600E mutation BRAF NCBI:673 gene ovarian cancer DOID:2394 risk 53844-7 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Among 4 patients with BRAF V600E mutant ovarian cancer, 2 had a partial response and one had stable disease > 120days. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 982 check_entity AN4811-17 BRAF V600E mutation BRAF NCBI:673 gene ovarian cancer DOID:2394 risk 53844-7 CIViC:12 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 982 check_entity AN4811-18 BRAF V600E mutation BRAF NCBI:673 gene ovarian serous carcinoma DOID:0050933 risk 53844-7 PubMed:26490654 A stage 4B, low-grade papillary serous ovarian adenocarcinoma patient, harboring a BRAF V600E mutation was associated with response to vemurafenib monotherapy. The patient was treated with standard chemotherapy, hormone therapy and bevacizumab prior to the identification of the BRAF V600E mutation; next, the patient was treated with paclitaxel and an anti-HER3 antibody and finally with vemurafenib, obtaining a partial response of greater than 1 year. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 983 check_entity AN4811-18 BRAF V600E mutation BRAF NCBI:673 gene ovarian serous carcinoma DOID:0050933 risk 53844-7 CIViC:12 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 983 check_entity AN4811-19 BRAF V600E mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 PubMed:21639808 Phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. A relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression was observed with vemurafenib as compared with dacarbazine (P<0.001 for both comparisons). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 984 check_entity AN4811-19 BRAF V600E mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 PubMed:22356324 Phase 2 trial in 132 patients with previously treated metastatic melanoma with BRAF V600E mutation. Confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Median overall survival was 15.9 months (95% CI, 11.6 to 18.3). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 984 check_entity AN4811-19 BRAF V600E mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 PubMed:25399551 In a clinical trial (NCT01597908) of 704 metastatic melanoma patients, patients harboring a BRAF V600E mutation and treated with vemurafenib (n=317) were associated with a 51% response rate, as compared to a 64% response rate (p<0.001) in V600E mutation positive patients treated with dabrafenib and trametinib combination therapy (n=312). Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 984 check_entity AN4811-19 BRAF V600E mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 PubMed:27135738 Experiment with immunodeficient mice transplanted with melanoma cell lines indicates EZH2 inhibitor JQEZ5 might be effective in combination with a B-RAF inhibitor in RAF-mutant melanoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 984 check_entity AN4811-19 BRAF V600E mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 CIViC:12 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 984 check_entity AN4811-19 BRAF V600E mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 CIViC:4241 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 984 check_entity AN4811-20 BRAF V600E mutation BRAF NCBI:673 gene thyroid cancer DOID:1781 diagnostic 53844-7 PubMed:21594703 BRAF V600E is shown to be associated with the tall-cell variant of papillary thyroid cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 985 check_entity AN4811-20 BRAF V600E mutation BRAF NCBI:673 gene thyroid cancer DOID:1781 diagnostic 53844-7 CIViC:12 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 985 check_entity AN4811-21 BRAF V600E mutation BRAF NCBI:673 gene thyroid gland anaplastic carcinoma DOID:0080522 risk 53844-7 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. One patient with BRAF V600E mutant anaplastic thyroid cancer had a complete response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 986 check_entity AN4811-21 BRAF V600E mutation BRAF NCBI:673 gene thyroid gland anaplastic carcinoma DOID:0080522 risk 53844-7 PubMed:26287849 In a phase 2 “basket” study of vemurafenib in BRAF V600-positive non-melanoma cancers, seven patients with anaplastic thyroid cancer were enrolled. All 7 patients had V600E mutations. One complete response and one partial response was observed, for a response rate of 29%. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 986 check_entity AN4811-21 BRAF V600E mutation BRAF NCBI:673 gene thyroid gland anaplastic carcinoma DOID:0080522 risk 53844-7 PubMed:29072975 Interim analysis of a basket trial evaluating the combination of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) in previously treated V600E-mutated patients showed 11/16 patients with anaplastic thyroid carcinoma responded to treatment (overall response rate 69%; 95% CI, 41% to 89%). Seven patients had ongoing responses. Median duration of response, progression-free survival, and overall survival were not reached after 120 weeks. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 986 check_entity AN4811-21 BRAF V600E mutation BRAF NCBI:673 gene thyroid gland anaplastic carcinoma DOID:0080522 risk 53844-7 CIViC:12 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 986 check_entity AN4811-22 BRAF V600E mutation BRAF NCBI:673 gene thyroid gland papillary carcinoma DOID:3969 diagnostic;prognostic;risk 53844-7 PubMed:24570209 Thyroid nodule with BRAF V600E mutation is highly correlated with papillary thyroid cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 987 check_entity AN4811-22 BRAF V600E mutation BRAF NCBI:673 gene thyroid gland papillary carcinoma DOID:3969 diagnostic;prognostic;risk 53844-7 PubMed:24354346 Unlike other studies that suggest a poorer outcome, BRAF mutation in this study was not correlated with poorer prognosis in papillary thyroid cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 987 check_entity AN4811-22 BRAF V600E mutation BRAF NCBI:673 gene thyroid gland papillary carcinoma DOID:3969 diagnostic;prognostic;risk 53844-7 PubMed:21594703 BRAF mutation correlated with poor prognosis in papillary thyroid cancer in both older (>65 yo) and younger (<65 yo) cohorts. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 987 check_entity AN4811-22 BRAF V600E mutation BRAF NCBI:673 gene thyroid gland papillary carcinoma DOID:3969 diagnostic;prognostic;risk 53844-7 PubMed:24396464 BRAF V600E is correlated with poor prognosis in papillary thyroid cancer in a study of 187 patients with PTC and other thyroid diseases. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 987 check_entity AN4811-22 BRAF V600E mutation BRAF NCBI:673 gene thyroid gland papillary carcinoma DOID:3969 diagnostic;prognostic;risk 53844-7 PubMed:25024077 In patients with papillary thyroid cancer harboring both BRAF V600E and the TERT promotor mutation C228T (N=35), recurrence-free survival is worse than in patients harboring one of these mutations (N=159 BRAF, N=26 TERT promoter mutated) or no mutations in either gene (N=287)(P<0.001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 987 check_entity AN4811-22 BRAF V600E mutation BRAF NCBI:673 gene thyroid gland papillary carcinoma DOID:3969 diagnostic;prognostic;risk 53844-7 PubMed:24987354 A 73 year old patient with prior history of breast cancer presented with metastatic papillary thyroid carcinoma. After two treatments of I-131 a comprehensive tumor profile revealed BRAF V600E as the only genetic alteration on a near diploid genome with trisomy 1q. Vemurafenib treatment resulted in improvement of symptoms and considerable reductions in tumor mass, and after 23 months the patient remained on therapy with well controlled disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 987 check_entity AN4811-22 BRAF V600E mutation BRAF NCBI:673 gene thyroid gland papillary carcinoma DOID:3969 diagnostic;prognostic;risk 53844-7 PubMed:27460442 Open-label non-randomised phase 2 trial in patients with recurrent or metastatic BRAF V600E mutant papillary thyroid cancer refractory to radioactive iodine. Patients had (cohort 2) or had not (cohort 1) previously been treated with VEGFR inhibitors. 51 patients were enrolled (26 cohort 1, 25 cohort 2). In cohort 1, partial response was achieved in ten (38.5%) patients. Nine patients achieved stable disease for at least 6 months (35%). Median PFS was 18.2 months and median OS not reached after a median follow-up pf 18.8 months. In cohort 2, six patients (27.3%) achieved a partial response and another six patients achieved stable disease for at least six months. Median PFS was 8.9 months and median OS was 14.4. months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 987 check_entity AN4811-22 BRAF V600E mutation BRAF NCBI:673 gene thyroid gland papillary carcinoma DOID:3969 diagnostic;prognostic;risk 53844-7 PubMed:18682506 In a study of 102 papillary thyroid cancer patients with a 15 year median follow-up time, those with BRAF V600E mutations had reduced overall survival compared to those with wildtype BRAF (P=0.015, log-rank test). The presence of BRAF V600E was associated with poorer outcome as defined by persistent disease or death (Odds ratio:14.63, 95%CI:1.28-167.29, P=0.03, multivariate analysis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 987 check_entity AN4811-22 BRAF V600E mutation BRAF NCBI:673 gene thyroid gland papillary carcinoma DOID:3969 diagnostic;prognostic;risk 53844-7 PubMed:21882184 In a meta-analysis of 8 studies, papillary thyroid cancer patients with BRAF V600E mutation had a higher frequency of recurrence and persistent disease compared to those with wildtype BRAF (28.5% vs. 12.8% , Risk ratio:2.14, 95%CI:1.67-2.74, P<0.00001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 987 check_entity AN4811-22 BRAF V600E mutation BRAF NCBI:673 gene thyroid gland papillary carcinoma DOID:3969 diagnostic;prognostic;risk 53844-7 PubMed:16174717 Clinical study including 219 patients with papillary thyroid cancer (PTC) to determine a correlation between the BRAF V600E mutation and poor oncological outcome. This study found that 107 of the 219 (49%) patients had this mutation signifying that the BRAF V600E mutation is one of the most commonly occurring among PTC patients. This cohort was split into two groups—BRAF+ and BRAF-. Of the 107 patients that were BRAF+, 25% had tumor reoccurrence compared with 9% in the BRAF- group (P=0.004). Multivariate analysis was performed to assess BRAF correlation independent of known contributing factors to cancer such as age, gender, and multifocality. The results showed that the BRAF mutation is indicative/contributes to lymph node metastasis, associated with tumor reoccurrence, stage, and that recurrent disease was more extensive and required more aggressive treatments in BRAF+ patients compared with BRAF- patients. The authors conclude that PTC patients with the BRAF V600E mutation have worse clinicopathological outcomes, and that the BRAF mutation can be used to assess risk stratification in patients with PTC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 987 check_entity AN4811-22 BRAF V600E mutation BRAF NCBI:673 gene thyroid gland papillary carcinoma DOID:3969 diagnostic;prognostic;risk 53844-7 CIViC:12 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600E sequence variation in gene BRAF/NCBI:673 987 check_entity AN4812-1 BRAF V600K ) BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:24265155 In a retrospective study of 44 relapsed melanoma patients harboring BRAF V600E or V600K (known BRAF inhibitor sensitizing mutations), MAPK pathway reactivation mechanisms were implicated in acquired resistance to BRAF inhibitor (vemurafenib or dabrafenib) monotherapy. The following MAPK pathway variants were found in progressive tumors with patient matched baseline tumors (some patients donated samples from multiple geographically/temporally distinct progressive tumors): NRAS mutations (G12D, G12R, G13R, Q61K, Q61R, Q61L) in 13/71 (18%) of progressive tumors, KRAS mutations (G12C, G12R, Q61H) in 5/71 (7%) of progressive tumors, mutant BRAF amplification (2-15 fold or 4-75 copies) in 11/57 (19%) of progressive tumors, mutant BRAF alternative splice variants (novel exon boundaries between 1/9, 1/11, 3/9) in 6/48 (13%) of progressive tumor RNA. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600K sequence variation in gene BRAF/NCBI:673 988 check_entity AN4812-1 BRAF V600K ) BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 CIViC:4174 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600K sequence variation in gene BRAF/NCBI:673 988 check_entity AN4812-1 BRAF V600K mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:24508103 In the Phase III study of vemurafenib versus dacarbazine BRIM-3 (NCT01006980) in metastatic melanoma, 57 patients were confirmed to have V600K mutation. In this subgroup of treatment-naive patients, significant differences were seen in overall survival (14.5 months with vemurafenib vs. 7.6 months with dacarbazine), as well as median progression free survival (5.9 months with vemurafenib vs. 1.7 months with dacarbazine). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600K sequence variation in gene BRAF/NCBI:673 989 check_entity AN4812-1 BRAF V600K mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:26989536 A 53 year old male presented with a scalp lesion which was incompletely excised. Metastases were seen in lymph node biopsy and subsequently in CT. BRAF inhibitor vemurafenib was then administered at 960 mg twice daily and later at 720 mg twice daily and reduction in metastases was observed. After 2 years complete radiological response was seen, while treatment was discontinued due to cardiomyopathy. 12 months after stopping vemurafenib patient did not show evidence of metastatic melanoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600K sequence variation in gene BRAF/NCBI:673 989 check_entity AN4812-1 BRAF V600K mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:21343559 Patients were treated with a specific RAF inhibitor (dabrafenib), which improved overall survival of patients with BRAF mutations (P<0.003), compared to non-treated patients with BRAF mutations. Patients having BRAF mutations were associated with reduced overall survival (11.1 mo vs. 46.1 mo for wild-type, P=0.006). BRAF mutations were more frequent in tumors with superficially spreading histological sub-type (43% vs. 19% , P<0.001) compared to BRAF wild-type tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600K sequence variation in gene BRAF/NCBI:673 989 check_entity AN4812-1 BRAF V600K mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:22663011 In a study of 322 advanced melanoma patients with BRAF-V600E (N=281), BRAF-V600K (N=40), or both mutations (N=1), treatment with trametinib was associated with improved progression-free survival (4.8mo vs. 1.5mo; HR: 0.45, 95% CI: 0.33-0.63, P<0.001) compared to chemotherapy control group. Additionally, treatment with trametinib was associated with increased 6-month overall survival (HR: 0.54, 95% CI: 0.32-0.92, P=0.01). The authors note similar outcomes for the primary efficacy population (V600E only) and the intention-to-treat population, however, sub-group analysis for patients with V600K did not show significant improvement in PFS (HR: 0.50, 95% CI:0.18-1.35). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600K sequence variation in gene BRAF/NCBI:673 989 check_entity AN4812-1 BRAF V600K mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:25524477 In a retrospective study of 300 stage IV melanoma patients, patients with BRAF V600K mutation (n=18) were associated with a 5.6% (1/18) complete response, a 22.2% (4/18) partial response and stable disease in 44.4% (8/18) of cases; however, 27.8% (5/18) of patients harboring BRAF V600K experienced progressive disease and patients with BRAF V600E mutation achieved a more impressive clinical benefit, as compared to patients with BRAF V600K mutation (P=0.016). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600K sequence variation in gene BRAF/NCBI:673 989 check_entity AN4812-1 BRAF V600K mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:28891408 Adjuvant dual treatment with BRAF inhibitor dabrafenib and MEK inhibitor trametinib was administered to patients with stage III resected melenoma with V600E or V600K mutation in this stage III trial (COMBO-AD, NCT01682083). 78 (9%) patients had V600K, and were administered dabrafenib and trametinib or placebo for 12 months. In subsequent analysis, relapse or death occurred in 16/41 patients (39%) in the treatment group and 19/37 patients (51%) in the placebo group for a 95% CI Hazard Ratio of 0.54 (0.27-1.06). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600K sequence variation in gene BRAF/NCBI:673 989 check_entity AN4812-1 BRAF V600K mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:25265494 In this Phase III trial (coBRIM, NCT01689519) of 495 V600 mutant melanoma patients, 56 had V600K mutation. 32 patients were treated with vemurafenib and placebo, and 24 were treated with vemurafenib and cobimetinib and tested for progression free survival. 17 of 32 monotherapy group patients had an event with median progression free survival of 5.3 months. In the combination group 4 of 24 patients had an event with median progression-free survival not met, however, when in combination with other V600 mutations median progression-free survival was 9.9 months with combination treatment. Median time to followup for the whole cohort was 7.3 months. Hazard Ratio for progression or death was 0.27 (0.09-0.81). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600K sequence variation in gene BRAF/NCBI:673 989 check_entity AN4812-1 BRAF V600K mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 CIViC:559 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600K sequence variation in gene BRAF/NCBI:673 989 check_entity AN4813-2 BRAF V600K mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 PubMed:25399551 In a clinical trial (NCT01597908) of 704 metastatic melanoma patients, patients harboring a BRAF V600K mutation and treated with vemurafenib (n=34) were associated with a 44% response rate, as compared to a 65% response rate in V600E mutation positive patients treated with dabrafenib and trametinib combination therapy (n=34). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600K sequence variation in gene BRAF/NCBI:673 990 check_entity AN4813-2 BRAF V600K mutation BRAF NCBI:673 gene skin melanoma DOID:8923 risk 53844-7 CIViC:559 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600K sequence variation in gene BRAF/NCBI:673 990 check_entity AN4814-1 BRAF V600M mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:23031422 A single 66-year old male patient with advanced melanoma thought to have concomitant BRAF V600E and V600M mutations responded rapidly to dabrafenib. His shoulder lesion reduced by 60% after 1 week of therapy and was gone after 1 month. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600M sequence variation in gene BRAF/NCBI:673 991 check_entity AN4814-1 BRAF V600M mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 CIViC:4170 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V600M sequence variation in gene BRAF/NCBI:673 991 check_entity AN4815-1 BRAF V600_K601>E mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:31580757 In a retrospective study from 20 institutes in 4 countries, the efficacy of BRAF inhibitor and/or MEK inhibitor in patients with melanoma harboring BRAF nonV600E/K mutations were evaluated. Treated with BRAF inhibitor monotherapy, response rate were 27%(4/15) for V600R, 100%(2/2) for V600D, 0% (0/2) for V600_K601>E, 0% (0/1) for V600G, 0% (0/1) for V600L, 0% (0/1) for V600_S602>DT, 0% (0/5) for L597, 0% (0/6) for K601E, 0% (0/2) for G469, 0% (0/1) for G593D,and 0% (0/1) for T599_V600insT Treated with MEK inhibitor monotherapy, response rate were 100% (1/1) for L597, and 0% (0/1) for K601E. Treated with BRAF inhibitor and MEK inhibitor combination thearpy, response rate were 55% (16/29) for V600R, 67% (2/3) for V600D, 50% (1/2) for V600_K601>E, 50% (1/2) for V600M, 22% (2/9) for L597,25% (1/4) for K601E, 67% (2/3) for G469, and 0% (0/1) for A598V. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::v600_k601>e:mutation sequence variation in gene BRAF/NCBI:673 992 check_entity AN4815-1 BRAF V600_K601>E mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 CIViC:2689 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::v600_k601>e:mutation sequence variation in gene BRAF/NCBI:673 992 check_entity AN4816-1 BRAF WASFL::BRAF mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::WASFL::BRAF sequence variation in gene BRAF/NCBI:673 993 check_entity AN4816-1 BRAF WASFL::BRAF mutation BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 CIViC:2104 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::WASFL::BRAF sequence variation in gene BRAF/NCBI:673 993 check_entity AN4817-1 BRAF Wildtype BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:24947927 Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655. Among 12 patients with melanoma BRAF wild type and non-NRAS or NRAS unknown status, seven patients experienced partial response (n=3) or stable disease (n=4). Authors conclude that RO4987655 has clinical activity in BRAF V600-wt (and BRAF V600E) melanoma. They suggest that other drugs such as immune check point inhibitors are preferred in BRAF wt melanoma, so the role of RO4987655 as a single agent is limited for BRAF WT patients with the possible exception of a small window of opportunity for combinations with MEK inhibitors after immunotherapy progression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRAF Wildtype [biomarker_term_in_review] 994 not_mapped AN4817-1 BRAF Wildtype BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 CIViC:422 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRAF Wildtype [biomarker_term_in_review] 994 not_mapped AN4818-1 BRAF ZKSCAN1::BRAF mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:26314551 Analysis of BRAF fusions in 20,573 tumors, across 12 distinct tumor types. BRAF fusions were identified in 55 (0.3%) patients and enriched in spitzoid melanoma, pilocytic astrocytomas, pancreatic acinar and papillary thyroid cancers. Clinical data were available for two patients. Among them one 46-year old woman with spitzoid melanoma that harbored a ZKSCAN1-BRAF fusion responded to treatment with the MEK inhibitor trametinib. Subcutaneous tumor nodules exhibited clinical responses within 14 days of therapy, and her dominant bulky right lung metastases showed significant response by Day 45. Subsequent robotic-assisted lobectomy was able to remove the previously unresectable tumor with clean surgical margins. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ZKSCAN1::BRAF sequence variation in gene BRAF/NCBI:673 995 check_entity AN4818-1 BRAF ZKSCAN1::BRAF mutation BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 CIViC:653 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ZKSCAN1::BRAF sequence variation in gene BRAF/NCBI:673 995 check_entity AN4819-1 BRAF intron 10 rearrangement BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::intron:10:rearrangement sequence variation in gene BRAF/NCBI:673 996 check_entity AN4819-1 BRAF intron 10 rearrangement BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 CIViC:2102 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::intron:10:rearrangement sequence variation in gene BRAF/NCBI:673 996 check_entity AN4819-2 BRAF intron 10 rearrangement BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:24265155 In a retrospective study of 44 relapsed melanoma patients harboring BRAF V600E or V600K (known BRAF inhibitor sensitizing mutations), MAPK pathway reactivation mechanisms were implicated in acquired resistance to BRAF inhibitor (vemurafenib or dabrafenib) monotherapy. The following MAPK pathway variants were found in progressive tumors with patient matched baseline tumors (some patients donated samples from multiple geographically/temporally distinct progressive tumors): NRAS mutations (G12D, G12R, G13R, Q61K, Q61R, Q61L) in 13/71 (18%) of progressive tumors, KRAS mutations (G12C, G12R, Q61H) in 5/71 (7%) of progressive tumors, mutant BRAF amplification (2-15 fold or 4-75 copies) in 11/57 (19%) of progressive tumors, mutant BRAF alternative splice variants (novel exon boundaries between 1/9, 1/11, 3/9) in 6/48 (13%) of progressive tumor RNA. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::intron:10:rearrangement sequence variation in gene BRAF/NCBI:673 997 check_entity AN4819-2 BRAF intron 10 rearrangement BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 CIViC:2102 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::intron:10:rearrangement sequence variation in gene BRAF/NCBI:673 997 check_entity AN4820-1 BRAF intron 9 rearrangement BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Of 26 patients with BRAF V600E mutations, objective responses were seen in 12 patients (46%; 95% CI, 27% to 67%). Only one of 23 patients (4%; 95% CI, 0% to 22%) with other non-V600 BRAF mutations had a PR (pancreas cancer with a CUX1-BRAF fusion). Nonresponding BRAF mutations included: K601E (n = 6), G464V (n = 2), G469A (n = 2), G496A (n = 2), N581S (n = 2), and one each for G466V, G596R, G606E, L597Q, P731T, intron 9 rearrangement, intron 10 rearrangement, and MACF1- and WASFL-BRAF fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::intron:9:rearrangement sequence variation in gene BRAF/NCBI:673 998 check_entity AN4820-1 BRAF intron 9 rearrangement BRAF NCBI:673 gene cancer DOID:162 risk 53844-7 CIViC:2101 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::intron:9:rearrangement sequence variation in gene BRAF/NCBI:673 998 check_entity AN4820-2 BRAF intron 9 rearrangement BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 PubMed:24265155 In a retrospective study of 44 relapsed melanoma patients harboring BRAF V600E or V600K (known BRAF inhibitor sensitizing mutations), MAPK pathway reactivation mechanisms were implicated in acquired resistance to BRAF inhibitor (vemurafenib or dabrafenib) monotherapy. The following MAPK pathway variants were found in progressive tumors with patient matched baseline tumors (some patients donated samples from multiple geographically/temporally distinct progressive tumors): NRAS mutations (G12D, G12R, G13R, Q61K, Q61R, Q61L) in 13/71 (18%) of progressive tumors, KRAS mutations (G12C, G12R, Q61H) in 5/71 (7%) of progressive tumors, mutant BRAF amplification (2-15 fold or 4-75 copies) in 11/57 (19%) of progressive tumors, mutant BRAF alternative splice variants (novel exon boundaries between 1/9, 1/11, 3/9) in 6/48 (13%) of progressive tumor RNA. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::intron:9:rearrangement sequence variation in gene BRAF/NCBI:673 999 check_entity AN4820-2 BRAF intron 9 rearrangement BRAF NCBI:673 gene melanoma DOID:1909 risk 53844-7 CIViC:2101 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::intron:9:rearrangement sequence variation in gene BRAF/NCBI:673 999 check_entity AN4821-1 BRCA1 Alu insertion BRCA1 NCBI:672 gene breast cancer DOID:1612 diagnostic 21636-6 PubMed:16088935 In a Portuguese family with 6 cases of breast cancer and 1 of ovarian cancer, a 46 year old woman was diagnosed with breast cancer. She was negative for BRCA1/2 mutations using standard methods but a Southern blot identified a ~350bp Alu element (AluYa5 subtype) insertion in exon 3. RT-PCR revealed exon 3 was excluded from the spliced transcript in this patient. Blood samples from 24 family members were collected and the Alu element was identified in the 3 with ovarian or breast cancer that had evaluable samples. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::alu:insertion sequence variation in gene BRCA1/NCBI:672 1000 check_entity AN4821-1 BRCA1 Alu insertion BRCA1 NCBI:672 gene breast cancer DOID:1612 diagnostic 21636-6 CIViC:690 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::alu:insertion sequence variation in gene BRCA1/NCBI:672 1000 check_entity AN4822-1 BRCA1 Expression BRCA1 NCBI:672 gene malignant mesothelioma DOID:1790 risk 21636-6 PubMed:22190288 Expression of BRCA1 in 6 mesothelioma cell lines was associated with sensitivity to vinorelbine in functional studies. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene BRCA1/NCBI:672 1001 AN4822-1 BRCA1 Expression BRCA1 NCBI:672 gene malignant mesothelioma DOID:1790 risk 21636-6 CIViC:393 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene BRCA1/NCBI:672 1001 AN4823-1 BRCA1 Loss-of-function BRCA1 NCBI:672 gene breast cancer DOID:1612 risk 21636-6 PubMed:28211448 The authors show that in the CX-5461 and CX-3543, G-quadruplex stabilizing agents, demonstrate specific toxicity against BRCA deficient breast cancer derived cells and polyclonal patient-derived xenograft models. Xenografts harbored both a germline BRCA and a somatic BRCA mutation leading to disruption of both. The BRCA and NHEJ pathways are required for the repair of CX-5461 and CX-3543-induced DNA damage and failure to do so leads to lethality. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA1 Loss-of-function [biomarker_term_in_review] 1002 not_mapped AN4823-1 BRCA1 Loss-of-function BRCA1 NCBI:672 gene breast cancer DOID:1612 risk 21636-6 PubMed:28242752 In part 2 of a two-part dose-escalation phase I trial (NCT01286987), 71 patients with Ewings sarcoma, breast, ovarian, small cell lung, or pancreatic cancers received 1.0 mg/day talazoparib treatment. Of patients with BRCA mutation-associated breast and ovarian cancers, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients, respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA1 Loss-of-function [biomarker_term_in_review] 1002 not_mapped AN4823-1 BRCA1 Loss-of-function BRCA1 NCBI:672 gene breast cancer DOID:1612 risk 21636-6 CIViC:131 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA1 Loss-of-function [biomarker_term_in_review] 1002 not_mapped AN4823-2 BRCA1 Loss-of-function BRCA1 NCBI:672 gene Her2-receptor negative breast cancer DOID:0060080 risk 21636-6 PubMed:28578601 302 patients (234 with progression events) with HER2-negative metastatic breast cancer and with a confirmed deleterious or suspected deleterious germline BRCA mutation (164 BRCA1, 129 BRCA2) had significantly improved progression-free survival and better response rate to olaparib (PARP inhibitor) than standard therapy (7.0 mo vs 4.2 mo, hazard ratio 0.58, 95% CI 0.43-0.8) in this randomized phase 3 trial (NCT02000622). For BRCA1 patients specifically, the hazard ratio was 0.54, 95% CI 0.37-0.79). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA1 Loss-of-function [biomarker_term_in_review] 1003 not_mapped AN4823-2 BRCA1 Loss-of-function BRCA1 NCBI:672 gene Her2-receptor negative breast cancer DOID:0060080 risk 21636-6 PubMed:34081848 Report of OlympiA (NCT02032823), a randomized, double-blind, placebo-controlled study of 1836 patients with HER2-negative breast cancer with germline pathogenic or likely pathogenic mutations in BRCA1 or BRCA2. Patients were early stage but had completed chemotherapy; ER/PR+ patients could also have concurrent hormone therapy. 82% of patients were triple negative. 72% of patients had BRCA1 germline mutations, 27% had BRCA2, and 0.4% both. 921 patients received olaparib and 915 placebo. Invasive disease-free survival (IDFS) showed improvement with olaparib treatment (86% vs 77%, HR 0.58 [0.41 to 0.82], P<0.001). For overall survival, deaths in the olaparib arm were lower (59 vs 86, HR 0.68 [0.44 to 1.05], P=0.02). The IDFS benefit was independent of whether mutation was in BRCA1 (HR=0.52, 0.39-0.70) or BRCA2 (HR 0.52, 0.30-0.86). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA1 Loss-of-function [biomarker_term_in_review] 1003 not_mapped AN4823-2 BRCA1 Loss-of-function BRCA1 NCBI:672 gene Her2-receptor negative breast cancer DOID:0060080 risk 21636-6 CIViC:131 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA1 Loss-of-function [biomarker_term_in_review] 1003 not_mapped AN4823-3 BRCA1 Loss-of-function BRCA1 NCBI:672 gene ovarian cancer DOID:2394 risk 21636-6 PubMed:23346317 The combination of PARP inhibition (Olaparib) with BRCA mutation results in irreparable and lethal DNA damage. Response rates are higher in BRCA1 mutation positive women with high grade serous or undifferentiated ovarian cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA1 Loss-of-function [biomarker_term_in_review] 1004 not_mapped AN4823-3 BRCA1 Loss-of-function BRCA1 NCBI:672 gene ovarian cancer DOID:2394 risk 21636-6 PubMed:28242752 In part 2 of a two-part dose-escalation phase I trial (NCT01286987), 71 patients with Ewings sarcoma, breast, ovarian, small cell lung, or pancreatic cancers received 1.0 mg/day talazoparib treatment. Of patients with BRCA mutation-associated breast and ovarian cancers, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients, respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA1 Loss-of-function [biomarker_term_in_review] 1004 not_mapped AN4823-3 BRCA1 Loss-of-function BRCA1 NCBI:672 gene ovarian cancer DOID:2394 risk 21636-6 CIViC:131 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA1 Loss-of-function [biomarker_term_in_review] 1004 not_mapped AN4823-4 BRCA1 Loss-of-function BRCA1 NCBI:672 gene pancreatic adenocarcinoma DOID:4074 risk 21636-6 PubMed:31157963 In the phase 3 POLO trial patients who had germline BRCA1/2 mutation and metastatic pancreatic adenocarcinoma that had not progressed during first-line platinum-based chemotherapy were allocated to maintenance olaparib or placebo. BRCA1/2 mutation was determine by the BRAC-Analysis CDx test. Median progression free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% CI, 0.35 to 0.82; p=0.004). BRCA1 mutations were present in 29/92 patients in the olaparib group and 16/62 patients in the placebo group, while one patient receiving olaparib had both BRCA1 and BRCA2 germline mutations. Responses were seen in 18 (20%) patients in the olaparib group, including two complete responses. The safety profile of olaparib was similar to that observed in other patient populations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA1 Loss-of-function [biomarker_term_in_review] 1005 not_mapped AN4823-4 BRCA1 Loss-of-function BRCA1 NCBI:672 gene pancreatic adenocarcinoma DOID:4074 risk 21636-6 CIViC:131 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA1 Loss-of-function [biomarker_term_in_review] 1005 not_mapped AN4823-5 BRCA1 Loss-of-function BRCA1 NCBI:672 gene prostate cancer DOID:10283 prognostic;risk 21636-6 PubMed:26510020 1/1 patients with BRCA1 homozygous deletion had a response to olaparib in this phase 2 study. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA1 Loss-of-function [biomarker_term_in_review] 1006 not_mapped AN4823-5 BRCA1 Loss-of-function BRCA1 NCBI:672 gene prostate cancer DOID:10283 prognostic;risk 21636-6 PubMed:23569316 In a study of 2,019 patients with prostate cancer, 18 had germline BRCA1 mutations, 61 had germline BRCA2 mutations and 1,940 were non-carriers. Patients with BRCA1/2 mutations had a 2-fold higher incidence of poorly differentiated cancer (Gleason score >8), a higher incidence of advanced stage (37% vs. 28%; P=0.003), a higher incidence of nodal involvement (15% vs. 5%; P=0.0005), and a higher incidence of metastatic spread (18% vs. 9%; P=0.005). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA1 Loss-of-function [biomarker_term_in_review] 1006 not_mapped AN4823-5 BRCA1 Loss-of-function BRCA1 NCBI:672 gene prostate cancer DOID:10283 prognostic;risk 21636-6 CIViC:131 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA1 Loss-of-function [biomarker_term_in_review] 1006 not_mapped AN4823-6 BRCA1 Loss-of-function BRCA1 NCBI:672 gene triple-receptor negative breast cancer DOID:0060081 risk 21636-6 PubMed:34081848 Report of OlympiA (NCT02032823), a randomized, double-blind, placebo-controlled study of 1836 patients with HER2-negative breast cancer with germline pathogenic or likely pathogenic mutations in BRCA1 or BRCA2. Patients were early stage but had completed chemotherapy; ER/PR+ patients could also have concurrent hormone therapy. 82% of patients were triple negative. 72% of patients had BRCA1 germline mutations, 27% had BRCA2, and 0.4% both. 921 patients received olaparib and 915 placebo. Invasive disease-free survival (IDFS) showed improvement with olaparib treatment (86% vs 77%, HR 0.58 [0.41 to 0.82], P<0.001). For overall survival, deaths in the olaparib arm were lower (59 vs 86, HR 0.68 [0.44 to 1.05], P=0.02). The IDFS benefit was independent of whether mutation was in BRCA1 (HR=0.52, 0.39-0.70) or BRCA2 (HR 0.52, 0.30-0.86). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA1 Loss-of-function [biomarker_term_in_review] 1007 not_mapped AN4823-6 BRCA1 Loss-of-function BRCA1 NCBI:672 gene triple-receptor negative breast cancer DOID:0060081 risk 21636-6 CIViC:131 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA1 Loss-of-function [biomarker_term_in_review] 1007 not_mapped AN4824-1 BRCA1 Mutation BRCA1 NCBI:672 gene cancer DOID:162 risk 21636-6 PubMed:19553641 In this phase 1 trial, 60 patients with advanced solid tumors (ovarian, breast, colorectal, melanoma, sarcoma, prostate) were treated with PARP inhibitor olaparib. Durable antitumor activity was only observed in BRCA1/2 mutation carriers. 19 BRCA carriers had ovarian, breast, or prostate cancers; 12 of these (63%) had a clinical benefit from treatment with olaparib: radiologic or tumor-marker responses or meaningful disease stabilization (stable disease for a period of 4 months or more). Nine BRCA carriers had a response according to RECIST, with the response sustained for more than 76 weeks in one patient. No responses were seen in patients without BRCA mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1008 check_entity AN4824-1 BRCA1 Mutation BRCA1 NCBI:672 gene cancer DOID:162 risk 21636-6 CIViC:185 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1008 check_entity AN4824-2 BRCA1 Mutation BRCA1 NCBI:672 gene castration-resistant prostate carcinoma DOID:0080909 risk 21636-6 PubMed:32343890 This randomized, open-label, phase 3 trial evaluated the PARP inhibitor olaparib in 387 men with metastatic castration-resistant prostate cancer (mCRPC) who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). The study found that in men with mCRPC who had somatic or germline deleterious alterations (irrespective of zygosity) in any of the following HRR genes (BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L), olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone (PFS HR 0.49 [0.38, 0.63]). For 15 patients with BRCA1 mutations specifically, PFS HR 0.41 [0.13-1.39]. . Based on the results of this study, on May 19, 2020, the Food and Drug Administration approved olaparib (LYNPARZA) for adult patients with deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC, who have progressed following prior treatment with enzalutamide or abiraterone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1009 check_entity AN4824-2 BRCA1 Mutation BRCA1 NCBI:672 gene castration-resistant prostate carcinoma DOID:0080909 risk 21636-6 CIViC:185 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1009 check_entity AN4824-3 BRCA1 Mutation BRCA1 NCBI:672 gene ovary epithelial cancer DOID:2152 prognostic;risk 21636-6 PubMed:22274685 In patients with invasive epithelial ovarian cancer, those with mutations in BRCA1 had better five-year overall survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1010 check_entity AN4824-3 BRCA1 Mutation BRCA1 NCBI:672 gene ovary epithelial cancer DOID:2152 prognostic;risk 21636-6 CIViC:185 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1010 check_entity AN4824-3 BRCA1 Mutation BRCA1 NCBI:672 gene ovary epithelial cancer DOID:2152 prognostic;risk 21636-6 PubMed:27717299 In a randomized, double-blind, phase 3 trial, 553 patients with ovarian cancer, fallopian tube cancer, or primary peritoneal cancer with predominantly high-grade serous histologic features were enrolled. Of the 553 enrolled, 203 had germline BRCA1/2 mutations and 350 had non-germline BRCA1/2 mutations (including both somatic mutant and wildtype BRCA1/2); BRCA1/2 mutation status was determined via BRACAnalysis testing (Myriad Genetics). The patients were randomized in a 2:1 ratio to receive niraparib 300 mg or placebo once daily. Patients in the niraparib group had a significantly longer median duration of progression-free survival than the placebo group: 21.0 vs. 5.5 months in the gBRCA cohort (hazard ratio, 0.27; 95% CI: 0.17 - 0.41; p < 0.001) and 9.3 months vs. 3.9 months in the overall non-gBRCA cohort (hazard ratio, 0.45; 95% CI: 0.34 - 0.61; p < 0.001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1010 check_entity AN4824-3 BRCA1 Mutation BRCA1 NCBI:672 gene ovary epithelial cancer DOID:2152 prognostic;risk 21636-6 CIViC:4409 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1010 check_entity AN4824-4 BRCA1 Mutation BRCA1 NCBI:672 gene Her2-receptor negative breast cancer DOID:0060080 risk 21636-6 PubMed:28792849 Randomized, open-label, phase 3 trial in which olaparib monotherapy was compared with standard therapy in patients with a germline BRCA mutation HER2–negative metastatic breast cancer. 205 patients were assigned to receive olaparib and 97 were assigned to receive standard therapy. Median progression-free survival was significantly longer in the olaparib group than in the standard-therapy group (7.0 months vs. 4.2 months; hazard ratio 0.58; 95%CI 0.43 to 0.80; P<0.001). A response to treatment occurred in 100 of the 167 patients who had measurable disease in the olaparib group (59.9%; 95% CI, 52.0 to 67.4) and in 19 of the 66 patients in the standard-therapy group (28.8%; 95% CI, 18.3 to 41.3). A complete response was seen in 9.0% of the patients who had measurable disease in the olaparib group and in 1.5% in the standard-therapy group. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1011 check_entity AN4824-4 BRCA1 Mutation BRCA1 NCBI:672 gene Her2-receptor negative breast cancer DOID:0060080 risk 21636-6 CIViC:185 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1011 check_entity AN4824-5 BRCA1 Mutation BRCA1 NCBI:672 gene ovarian cancer DOID:2394 prognostic;risk 21636-6 PubMed:26740259 664 patients with non-bulky FIGO Stage II-IV ovarian cancer were evaluated for PFS when treated with Pazopanib versus placebo. Of the 664 patients, 10% (n=68) were BRCA1+, 4% were BRCA 2+ (n=29) and 85% (n=567) were BCRA1/2 negative. Longer progression free survival was observed in BRCA1/2 positive carriers versus BRCA1/2 negative carriers in both the Pazopanib arm and the placebo arm, however, due to small sample size, the PFS increase in the Pazopanib arm was not statistically significant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1012 check_entity AN4824-5 BRCA1 Mutation BRCA1 NCBI:672 gene ovarian cancer DOID:2394 prognostic;risk 21636-6 PubMed:25218906 46 women with platinum-sensitive, high-grade, BRCA1/2+ ovarian cancer received either olaparib monotherapy or olaparib/cediranib combination therapy. Median PFS was increased in combination therapy (17.7 months versus 9.0 months; HR=0.42; 95%CI 0.23-0.76; p=0.005); overall response rate was increased in the combination therapy (79.6% versus 47.8%; p=0.002); and total deaths were reduced in combination therapy (6 patients versus 10 patients). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1012 check_entity AN4824-5 BRCA1 Mutation BRCA1 NCBI:672 gene ovarian cancer DOID:2394 prognostic;risk 21636-6 PubMed:21862407 In a study of 63 patients with ovarian cancer, 17 patients had BRCA1 or BRCA2 mutations and 46 patients had no BRCA mutations. Of the BRCA-positive patients, 7/17(41%; 95%CI 22-64) showed objective response to olaparib whereas only 11/46 BRCA-negative patients (24%; 95%CI 14-38) showed objective response to olaparib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1012 check_entity AN4824-5 BRCA1 Mutation BRCA1 NCBI:672 gene ovarian cancer DOID:2394 prognostic;risk 21636-6 PubMed:27908594 A phase 2 trial on patients with relapsed, platinum-sensitive high grade ovarian, fallopian tube or primary peritoneal carcinoma (ARIEL2 Part1, NCT01891344) was held to assess PARP inhibitor rucaparib on 3 genetically defined subsets of patients. Out of 40 BRCA mutant (BRCA1 or BRCA2) patients, 14 had homozygous somatic BRCA1 mutation or deletion. Confirmed objective response was seen in 71% (10/14) of the somatic BRCA1 mutant subgroup. Authors note that response rate was similar regardless of whether the BRCA mutation was somatic or germline, in BRCA 1 or BRCA 2. In a BRCA wild-type subgroup, with low levels of loss of heterozygosity (LOH), confirmed objective response was observed in 10% (7/70) of the patients. Patients with BRCA mutant tumors experienced significantly longer median progression free survival than patients with BRCA wildtype, LOH low tumors (12.8 vs 5.2 mo, HR: 0.27, P<0.0001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1012 check_entity AN4824-5 BRCA1 Mutation BRCA1 NCBI:672 gene ovarian cancer DOID:2394 prognostic;risk 21636-6 PubMed:30345884 In the phase 3 SOLO1 trial 390 patients with newly diagnosed advanced ovarian cancer with a mutation in BRCA1 or BRCA2 who had complete or partial response after platinum-based chemotherapy were randomized 2:1 to receive olaparib or placebo. The olaparib arm had 191 patients with BRCA1 mutation, 66 BRCA2, and 3 patients with both BRCA1 and BRCA2, while the placebo arm had 91 BRCA1 and 40 BRCA2 mutant patients. Analysis of PFS by blinded independent review found freedom from disease progression or death at 3 years was 69% in the olaparib arm compared with 35% in the placebo arm (hazard ratio for disease progression or death, 0.28; 95% CI, 0.20 to 0.39; P<0.001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1012 check_entity AN4824-5 BRCA1 Mutation BRCA1 NCBI:672 gene ovarian cancer DOID:2394 prognostic;risk 21636-6 PubMed:28882436 Combined meta-analysis of Study 10 (NCT01482715, phase I/II) and ARIEL2 (NCT01891344, phase II), both multi-centre, open-label, single-arm trials evaluating rucaparib in ovarian cancer with BRCA1 or BRCA2 deleterious germline or somatic mutations. Mutation status was determined by local testing or by central Foundation Medicine sequencing. Of 106 patients, OR was 53.8% (95% CI, 43.8-63.5); 8.5% and 45.3% of patients achieved complete and partial responses, respectively. Median duration of response was 9.2 months (95% CI, 6.6-11.6). Response rates by gene/mutation: BRCA1/2 germline (n=88, OR 53.4); BRCA1/2 somatic (n=18, OR 55.6); BRCA1 (n=67, OR 53.7); BRCA2 (n=39, OR 53.8). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1012 check_entity AN4824-5 BRCA1 Mutation BRCA1 NCBI:672 gene ovarian cancer DOID:2394 prognostic;risk 21636-6 CIViC:185 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1012 check_entity AN4824-6 BRCA1 Mutation BRCA1 NCBI:672 gene ovarian carcinoma DOID:4001 risk 21636-6 PubMed:24240112 In a study of ovarian carcinomas, 81% of tumors with germline BRCA1/2 mutations were platinum sensitive, whereas only 60% of tumors with non-BRCA1/2 mutations were platinum sensitive (N=47; N=158; P=0.01). Sensitivity was defined by maintenance of complete response greater than 6 months post platinum-based therapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1013 check_entity AN4824-6 BRCA1 Mutation BRCA1 NCBI:672 gene ovarian carcinoma DOID:4001 risk 21636-6 CIViC:185 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1013 check_entity AN4824-7 BRCA1 Mutation BRCA1 NCBI:672 gene pancreatic cancer DOID:1793 risk 21636-6 PubMed:25366685 Twenty-three patients with pancreatic cancer havoring BRCA1/2 germline mutations received olaparib. Five (21.7%) patients had a BRCA1 mutation. All but one had received prior gemcitabine, and 65% had received prior platinum. Tumor response rate was 21.7% and stable disease more than 8 weeks was 35%. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1014 check_entity AN4824-7 BRCA1 Mutation BRCA1 NCBI:672 gene pancreatic cancer DOID:1793 risk 21636-6 PubMed:25072261 Patients with BRCA1/2 associated pancreatic adenocarcinoma were evaluated retrospectively. In patients with stage 3 and 4, the median overall survival (mOS) was 22 months for the platinum exposed (n=22), compared with 9 months for the non-platinum (n=21) treatment groups (p<0.039) assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1014 check_entity AN4824-7 BRCA1 Mutation BRCA1 NCBI:672 gene pancreatic cancer DOID:1793 risk 21636-6 PubMed:29338080 In Phase I study for pancreatic cancer patients GEM 600 mg/m2 + CDDP 25 mg/m2 + Veliparib 20 - 80 mg twice daily showed response rate of 77.8% (7/9) and mOS of 23.3 months in germline BRCA mutation-positive patients with stage IV disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1014 check_entity AN4824-7 BRCA1 Mutation BRCA1 NCBI:672 gene pancreatic cancer DOID:1793 risk 21636-6 PubMed:29223478 Veliparib 400mg BID was administered to patients with germline BRCA1/2-mutated pancreatic cancer. Sixteen patients were enrolled. All except two (12.5%) had previously been treated with platinum therapy. No confirmed partial response was observed. One patient who had received prior single-agent gemcitabine only had an unconfirmed PR. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1014 check_entity AN4824-7 BRCA1 Mutation BRCA1 NCBI:672 gene pancreatic cancer DOID:1793 risk 21636-6 CIViC:185 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1014 check_entity AN4824-8 BRCA1 Mutation BRCA1 NCBI:672 gene prostate cancer DOID:10283 risk 21636-6 PubMed:36753688 A clinical study was conducted in 30 patients with Metastatic Prostate Cancer harboring BRCA1/2 mutations treated with olaparib. A disease control rate of 69% (95% CI, 51-81) and an objective response rate of 58% (95% CI, 37-77) were noted. The PFS and OS were 38.4 weeks (95% CI, 16.3 - 52.1) and 76.4 weeks (95% CI, 49.3-106.0) respectively. Grade 3 or 4 serious adverse affects were reported in six out of the thirty patients, likely related to olaparib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1015 check_entity AN4824-8 BRCA1 Mutation BRCA1 NCBI:672 gene prostate cancer DOID:10283 risk 21636-6 CIViC:4409 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1015 check_entity AN4824-9 BRCA1 Mutation BRCA1 NCBI:672 gene triple-receptor negative breast cancer DOID:0060081 risk 21636-6 PubMed:25847936 In an evaluation of 77 patients, those who had BRCA1/2 germline mutations (n=11) had an increase response rate to cisplatin when compared to those without germline mutations (54.5% versus 19.7%; P=0.022) although progression free survival and overall survival was not significantly different. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1016 check_entity AN4824-9 BRCA1 Mutation BRCA1 NCBI:672 gene triple-receptor negative breast cancer DOID:0060081 risk 21636-6 PubMed:21862407 In a study of 26 patients with breast cancer, 10 patients were BRCA-positive and 16 patients were BRCA-negative. Regardless of BRCA status, none showed objective response when treated with olaparib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1016 check_entity AN4824-9 BRCA1 Mutation BRCA1 NCBI:672 gene triple-receptor negative breast cancer DOID:0060081 risk 21636-6 CIViC:185 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA1/NCBI:672 1016 check_entity AN4825-1 BRCA1 P968FS mutation BRCA1 NCBI:672 gene breast cancer DOID:1612 diagnostic 21636-6 PubMed:24137399 A 55-year-old non-Ashkenazi Spanish female diagnosed with breast cancer (at 51 years old) and ovarian cancer. Sequencing of BRCA1 and BRCA2 revealed a 2-base frameshift insertion in BRCA1 (labeled 3020insCT/c.2901insCT in this paper, with the data shown corresponding to a GA insertion, reading left to right in the reference genome, between chr17:43092628-43092629 in GRCh38). This mutation ultimately causes a downstream premature stop codon and truncated BRCA1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::p968fs:mutation sequence variation in gene BRCA1/NCBI:672 1017 check_entity AN4825-1 BRCA1 P968FS mutation BRCA1 NCBI:672 gene breast cancer DOID:1612 diagnostic 21636-6 CIViC:473 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::p968fs:mutation sequence variation in gene BRCA1/NCBI:672 1017 check_entity AN4825-2 BRCA1 P968FS mutation BRCA1 NCBI:672 gene ovarian cancer DOID:2394 diagnostic 21636-6 PubMed:24137399 A 55-year-old non-Ashkenazi Spanish female diagnosed with breast cancer (at 51 years old) and ovarian cancer. Sequencing of BRCA1 and BRCA2 revealed a 2-base frameshift insertion in BRCA1 (labeled 3020insCT/c.2901insCT in this paper, with the data shown corresponding to a GA insertion, reading left to right in the reference genome, between chr17:43092628-43092629 in GRCh38). This mutation ultimately causes a downstream premature stop codon and truncated BRCA1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::p968fs:mutation sequence variation in gene BRCA1/NCBI:672 1018 check_entity AN4825-2 BRCA1 P968FS mutation BRCA1 NCBI:672 gene ovarian cancer DOID:2394 diagnostic 21636-6 CIViC:473 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::p968fs:mutation sequence variation in gene BRCA1/NCBI:672 1018 check_entity AN4826-1 BRCA1 Q1467* mutation BRCA1 NCBI:672 gene ovarian cancer DOID:2394 risk 21636-6 PubMed:27908594 In a phase 2 study of 206 recurrent, platinum-sensitive, high-grade ovarian cancer patients, patients with germline or somatic BRCA1 or BRCA2 mutation (n=40) were associated with improved progression free survival (HR 0.27, 95% CI: 0.16-0.44, p<0.0001) as compared to BRCA1/2 wild-type, loss of heterozygosity low patients (n=71) treated with rucaparib monotherapy; further, BRCA1/2 mutation patients achieved a longer median duration of response (9.2 months, 95% CI: 6.4-12.9, p=0.013 vs. 5.6 months, 95% CI: 4.6-8.5). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q1467* sequence variation in gene BRCA1/NCBI:672 1019 check_entity AN4826-1 BRCA1 Q1467* mutation BRCA1 NCBI:672 gene ovarian cancer DOID:2394 risk 21636-6 CIViC:1220 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q1467* sequence variation in gene BRCA1/NCBI:672 1019 check_entity AN4827-1 BRCA1 Underexpression BRCA1 NCBI:672 gene ovarian cancer DOID:2394 risk 21636-6 PubMed:21920589 Absent/low expression of BRCA1 (IHC) was associated with improved response to chemotherapy in 292 patients with sporadic ovarian cancer compared to patients with high expression (odds ratio 2.47: 95%CI 1.10-5.55, p=0.029). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene BRCA1/NCBI:672 1020 AN4827-1 BRCA1 Underexpression BRCA1 NCBI:672 gene ovarian cancer DOID:2394 risk 21636-6 CIViC:399 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene BRCA1/NCBI:672 1020 AN4828-1 BRCA1 W1815X mutation BRCA1 NCBI:672 gene endometrioid ovary carcinoma DOID:5828 risk 21636-6 PubMed:23415752 In an in vitro study, a SNU-251 cell line expressing BRCA1 W1815X truncating mutation demonstrated increased sensitivity to olaparib treatment with long-term exposure, compared to ovarian cell lines expressing BRCA1 wild-type. Sensitivity was determined by assessing cytotoxicity and doubling time. The authors note that the slow doubling time of SNU-251 cells was compensated for with a 2 week cytotoxicity assay as compared to the 1 week assay used for all other cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::W1815X sequence variation in gene BRCA1/NCBI:672 1021 check_entity AN4828-1 BRCA1 W1815X mutation BRCA1 NCBI:672 gene endometrioid ovary carcinoma DOID:5828 risk 21636-6 CIViC:1463 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::W1815X sequence variation in gene BRCA1/NCBI:672 1021 check_entity AN4829-1 BRCA2 D3095E mutation BRCA2 NCBI:675 gene breast cancer DOID:1612 diagnostic 38530-2 PubMed:18951446 49-year old woman diagnosed with breast cancer was assessed for BRCA2 mutations. Algorithms including Align-GVGD predicted pathogenicity, however PolyPhen predicted that this variant was benign. The author’s assessment of the factors predicts a pathogenicity probability of 0.73 and an Odds Ratio of 2.7. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D3095E sequence variation in gene BRCA2/NCBI:675 1022 check_entity AN4829-1 BRCA2 D3095E mutation BRCA2 NCBI:675 gene breast cancer DOID:1612 diagnostic 38530-2 CIViC:657 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D3095E sequence variation in gene BRCA2/NCBI:675 1022 check_entity AN4830-1 BRCA2 K3326* mutation BRCA2 NCBI:675 gene glioblastoma DOID:3068 risk 38530-2 PubMed:32043779 In a case report, a 3‐year‐old girl with glioblastoma harboring a probable germline heterozygous BRCA2 Lys3326Ter (K3326*) nonsense variant. After debulking surgery, the patient received standard‐of‐care treatment with radiation and temozolomide. Nine months later the PARP inhibitor olaparib was administered in combination with temozolomide for 16 cycles. This regimen was well tolerated by the patient and serial imaging showed a reduction in tumor size. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K3326* sequence variation in gene BRCA2/NCBI:675 1023 check_entity AN4830-1 BRCA2 K3326* mutation BRCA2 NCBI:675 gene glioblastoma DOID:3068 risk 38530-2 CIViC:2740 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K3326* sequence variation in gene BRCA2/NCBI:675 1023 check_entity AN4831-1 BRCA2 Loss-of-function BRCA2 NCBI:675 gene breast cancer DOID:1612 risk 38530-2 PubMed:28211448 The authors show that in the CX-5461 and CX-3543, G-quadruplex stabilizing agents, demonstrate specific toxicity against BRCA deficient breast cancer derived cells and polyclonal patient-derived xenograft models. The BRCA and NHE J pathways are required for the repair of CX-5461 and CX-3543-induced DNA damage and failure to do so leads to lethality. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA2 Loss-of-function [biomarker_term_in_review] 1024 not_mapped AN4831-1 BRCA2 Loss-of-function BRCA2 NCBI:675 gene breast cancer DOID:1612 risk 38530-2 PubMed:28242752 In part 2 of a two-part dose-escalation phase I trial (NCT01286987), 71 patients with Ewings sarcoma, breast, ovarian, small cell lung, or pancreatic cancers received 1.0 mg/day talazoparib treatment. Of patients with BRCA mutation-associated breast and ovarian cancers, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients, respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA2 Loss-of-function [biomarker_term_in_review] 1024 not_mapped AN4831-1 BRCA2 Loss-of-function BRCA2 NCBI:675 gene breast cancer DOID:1612 risk 38530-2 CIViC:132 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA2 Loss-of-function [biomarker_term_in_review] 1024 not_mapped AN4831-2 BRCA2 Loss-of-function BRCA2 NCBI:675 gene Her2-receptor negative breast cancer DOID:0060080 risk 38530-2 PubMed:28578601 302 patients (234 with progression events) with HER2-negative metastatic breast cancer and with a confirmed deleterious or suspected deleterious germline BRCA mutation (164 BRCA1, 129 BRCA2) had significantly improved progression-free survival and better response rate to olaparib (PARP inhibitor) than standard therapy (7.0 mo vs 4.2 mo, hazard ratio 0.58, 95% CI 0.43-0.8) in this randomized phase 3 trial (NCT02000622). For BRCA2 patients specifically, the hazard ratio was 0.68, 95% CI 0.45-0.1.07. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA2 Loss-of-function [biomarker_term_in_review] 1025 not_mapped AN4831-2 BRCA2 Loss-of-function BRCA2 NCBI:675 gene Her2-receptor negative breast cancer DOID:0060080 risk 38530-2 PubMed:34081848 Report of OlympiA (NCT02032823), a randomized, double-blind, placebo-controlled study of 1836 patients with HER2-negative breast cancer with germline pathogenic or likely pathogenic mutations in BRCA1 or BRCA2. Patients were early stage but had completed chemotherapy; ER/PR+ patients could also have concurrent hormone therapy. 82% of patients were triple negative. 72% of patients had BRCA1 germline mutations, 27% had BRCA2, and 0.4% both. 921 patients received olaparib and 915 placebo. Invasive disease-free survival (IDFS) showed improvement with olaparib treatment (86% vs 77%, HR 0.58 [0.41 to 0.82], P<0.001). For overall survival, deaths in the olaparib arm were lower (59 vs 86, HR 0.68 [0.44 to 1.05], P=0.02). The IDFS benefit was independent of whether mutation was in BRCA1 (HR=0.52, 0.39-0.70) or BRCA2 (HR 0.52, 0.30-0.86). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA2 Loss-of-function [biomarker_term_in_review] 1025 not_mapped AN4831-2 BRCA2 Loss-of-function BRCA2 NCBI:675 gene Her2-receptor negative breast cancer DOID:0060080 risk 38530-2 CIViC:132 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA2 Loss-of-function [biomarker_term_in_review] 1025 not_mapped AN4831-3 BRCA2 Loss-of-function BRCA2 NCBI:675 gene ovarian cancer DOID:2394 risk 38530-2 PubMed:23346317 The combination of PARP inhibition (Olaparib) with BRCA mutation results in irreparable and lethal DNA damage. Response rates are higher in BRCA2 mutation positive women with high grade serous or undifferentiated ovarian cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA2 Loss-of-function [biomarker_term_in_review] 1026 not_mapped AN4831-3 BRCA2 Loss-of-function BRCA2 NCBI:675 gene ovarian cancer DOID:2394 risk 38530-2 PubMed:28242752 In part 2 of a two-part dose-escalation phase I trial (NCT01286987), 71 patients with Ewings sarcoma, breast, ovarian, small cell lung, or pancreatic cancers received 1.0 mg/day talazoparib treatment. Of patients with BRCA mutation-associated breast and ovarian cancers, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients, respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA2 Loss-of-function [biomarker_term_in_review] 1026 not_mapped AN4831-3 BRCA2 Loss-of-function BRCA2 NCBI:675 gene ovarian cancer DOID:2394 risk 38530-2 CIViC:132 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA2 Loss-of-function [biomarker_term_in_review] 1026 not_mapped AN4831-4 BRCA2 Loss-of-function BRCA2 NCBI:675 gene pancreatic adenocarcinoma DOID:4074 risk 38530-2 PubMed:31157963 In the phase 3 POLO trial patients who had germline BRCA1/2 mutation and metastatic pancreatic adenocarcinoma that had not progressed during first-line platinum-based chemotherapy were allocated to maintenance olaparib or placebo. BRCA1/2 mutation was determine by the BRAC-Analysis CDx test. Median progression free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% CI, 0.35 to 0.82; p=0.004). BRCA2 mutations were present in 62/92 patients in the olaparib group and 46/62 patients in the placebo group, while one patient receiving olaparib had both BRCA1 and BRCA2 germline mutations. Responses were seen in 18 (20%) patients in the olaparib group, including two complete responses. The safety profile of olaparib was similar to that observed in other patient populations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA2 Loss-of-function [biomarker_term_in_review] 1027 not_mapped AN4831-4 BRCA2 Loss-of-function BRCA2 NCBI:675 gene pancreatic adenocarcinoma DOID:4074 risk 38530-2 CIViC:132 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA2 Loss-of-function [biomarker_term_in_review] 1027 not_mapped AN4831-5 BRCA2 Loss-of-function BRCA2 NCBI:675 gene pancreatic cancer DOID:1793 risk 38530-2 PubMed:16243825 In pancreatic cell lines PL11 (FANCC-deficient) and CAPAN1 (BRCA2-mutated), sensitivity to DNA cross-linking agents was observed compared to FANCC/BRCA2 wildtype cell lines (Su86.86, CFPAC, AsPc1, and MiaPaCa2). Mitomycin C specifically led to regression in 8/11 xenografts of the CAPAN1 cell line compared to 2/9 in the CFPAC (BRCA2 wildtype) cell line. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA2 Loss-of-function [biomarker_term_in_review] 1028 not_mapped AN4831-5 BRCA2 Loss-of-function BRCA2 NCBI:675 gene pancreatic cancer DOID:1793 risk 38530-2 CIViC:132 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA2 Loss-of-function [biomarker_term_in_review] 1028 not_mapped AN4831-6 BRCA2 Loss-of-function BRCA2 NCBI:675 gene prostate cancer DOID:10283 prognostic;risk 38530-2 PubMed:26510020 In a phase 2 trial of patients with metastatic, castration-resistant prostate cancer, treated with olaparib tablets at a dose of 400 mg twice a day, all 7 patients harbouring BRCA2 loss of function alleles (biallelic somatic loss or germline mutations in combination with somatic copy loss or copy neutral LOH) demonstrated a clinical response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA2 Loss-of-function [biomarker_term_in_review] 1029 not_mapped AN4831-6 BRCA2 Loss-of-function BRCA2 NCBI:675 gene prostate cancer DOID:10283 prognostic;risk 38530-2 PubMed:23569316 In a study of 2,019 patients with prostate cancer, 18 had germ-line BRCA1 mutations, 61 had germ-line BRCA2 mutations and 1,940 were non-carriers. Patients with BRCA1/2 mutations had a 2-fold higher incidence of poorly differentiated cancer (Gleason score >8), a higher incidence of advanced stage (37% vs. 28%; P=0.003), a higher incidence of nodal involvement (15% vs. 5%; P=0.0005), and a higher incidence of metastatic spread (18% vs. 9%; P=0.005). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA2 Loss-of-function [biomarker_term_in_review] 1029 not_mapped AN4831-6 BRCA2 Loss-of-function BRCA2 NCBI:675 gene prostate cancer DOID:10283 prognostic;risk 38530-2 CIViC:132 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA2 Loss-of-function [biomarker_term_in_review] 1029 not_mapped AN4831-7 BRCA2 Loss-of-function BRCA2 NCBI:675 gene triple-receptor negative breast cancer DOID:0060081 risk 38530-2 PubMed:34081848 Report of OlympiA (NCT02032823), a randomized, double-blind, placebo-controlled study of 1836 patients with HER2-negative breast cancer with germline pathogenic or likely pathogenic mutations in BRCA1 or BRCA2. Patients were early stage but had completed chemotherapy; ER/PR+ patients could also have concurrent hormone therapy. 82% of patients were triple negative. 72% of patients had BRCA1 germline mutations, 27% had BRCA2, and 0.4% both. 921 patients received olaparib and 915 placebo. Invasive disease-free survival (IDFS) showed improvement with olaparib treatment (86% vs 77%, HR 0.58 [0.41 to 0.82], P<0.001). For overall survival, deaths in the olaparib arm were lower (59 vs 86, HR 0.68 [0.44 to 1.05], P=0.02). The IDFS benefit was independent of whether mutation was in BRCA1 (HR=0.52, 0.39-0.70) or BRCA2 (HR 0.52, 0.30-0.86). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA2 Loss-of-function [biomarker_term_in_review] 1030 not_mapped AN4831-7 BRCA2 Loss-of-function BRCA2 NCBI:675 gene triple-receptor negative breast cancer DOID:0060081 risk 38530-2 CIViC:132 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition BRCA2 Loss-of-function [biomarker_term_in_review] 1030 not_mapped AN4832-1 BRCA2 M1I mutation BRCA2 NCBI:675 gene ovarian cancer DOID:2394 risk 38530-2 PubMed:27908594 In a phase 2 study of 206 recurrent, platinum-sensitive, high-grade ovarian cancer patients, patients with germline or somatic BRCA1 or BRCA2 mutation (n=40) were associated with improved progression free survival (HR 0.27, 95% CI: 0.16-0.44, p<0.0001) as compared to BRCA1/2 wild-type, loss of heterozygosity low patients (n=71) treated with rucaparib monotherapy; further, BRCA1/2 mutation patients achieved a longer median duration of response (9.2 months, 95% CI: 6.4-12.9, p=0.013 vs. 5.6 months, 95% CI: 4.6-8.5). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M1I sequence variation in gene BRCA2/NCBI:675 1031 check_entity AN4832-1 BRCA2 M1I mutation BRCA2 NCBI:675 gene ovarian cancer DOID:2394 risk 38530-2 CIViC:1222 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M1I sequence variation in gene BRCA2/NCBI:675 1031 check_entity AN4833-1 BRCA2 M1R mutation BRCA2 NCBI:675 gene ovarian cancer DOID:2394 risk 38530-2 PubMed:27908594 In a phase 2 study of 206 recurrent, platinum-sensitive, high-grade ovarian cancer patients, patients with germline or somatic BRCA1 or BRCA2 mutation (n=40) were associated with improved progression free survival (HR 0.27, 95% CI: 0.16-0.44, p<0.0001) as compared to BRCA1/2 wild-type, loss of heterozygosity low patients (n=71) treated with rucaparib monotherapy; further, BRCA1/2 mutation patients achieved a longer median duration of response (9.2 months, 95% CI: 6.4-12.9, p=0.013 vs. 5.6 months, 95% CI: 4.6-8.5). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M1R sequence variation in gene BRCA2/NCBI:675 1032 check_entity AN4833-1 BRCA2 M1R mutation BRCA2 NCBI:675 gene ovarian cancer DOID:2394 risk 38530-2 CIViC:1221 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M1R sequence variation in gene BRCA2/NCBI:675 1032 check_entity AN4834-1 BRCA2 Mutation BRCA2 NCBI:675 gene breast cancer DOID:1612 risk 38530-2 PubMed:28792849 Randomized, open-label, phase 3 trial in which olaparib monotherapy was compared with standard therapy in patients with a germline BRCA mutation HER2–negative metastatic breast cancer. 205 patients were assigned to receive olaparib and 97 were assigned to receive standard therapy. Median progression-free survival was significantly longer in the olaparib group than in the standard-therapy group (7.0 months vs. 4.2 months; hazard ratio 0.58; 95%CI 0.43 to 0.80; P<0.001). A response to treatment occurred in 100 of the 167 patients who had measurable disease in the olaparib group (59.9%; 95% CI, 52.0 to 67.4) and in 19 of the 66 patients in the standard-therapy group (28.8%; 95% CI, 18.3 to 41.3). A complete response was seen in 9.0% of the patients who had measurable disease in the olaparib group and in 1.5% in the standard-therapy group. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1033 check_entity AN4834-1 BRCA2 Mutation BRCA2 NCBI:675 gene breast cancer DOID:1612 risk 38530-2 CIViC:186 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1033 check_entity AN4834-2 BRCA2 Mutation BRCA2 NCBI:675 gene cancer DOID:162 risk 38530-2 PubMed:19553641 In this phase 1 trial 60 patients with advanced solid tumors (ovarian, breast, colorectal, melanoma, sarcoma, prostate) were treated with PARP inhibitor olaparib. Durable antitumor activity was only observed in BRCA1/2 mutation carriers.19 BRCA carriers had ovarian, breast, or prostate cancers; 12 of these (63%) had a clinical benefit from treatment with olaparib: radiologic or tumor-marker responses or meaningful disease stabilization (stable disease for a period of 4 months or more). Nine BRCA carriers had a response according to RECIST, with the response sustained for more than 76 weeks in one patient. No responses were seen in patients without BRCA mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1034 check_entity AN4834-2 BRCA2 Mutation BRCA2 NCBI:675 gene cancer DOID:162 risk 38530-2 CIViC:186 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1034 check_entity AN4834-3 BRCA2 Mutation BRCA2 NCBI:675 gene castration-resistant prostate carcinoma DOID:0080909 risk 38530-2 PubMed:32343890 In phase 3 trial of 387 patients comparing olaparib and new hormonal agent (enzalutamide or abiraterone) therapy for patients with metastatic castration-resistant prostate cancer harboring homologous recombinant repair-related gene mutation detected from a tumor sample, olaparib showed significant PFS benefit in an ITT population (HR [95%CI] 0.49 [0.38, 0.63]). But in subgroup analysis, the treatment effect differed in each mutated genes. Among them, patients with BRCA2 mutations (olaparib: n=92, control: n=53) showed a prominent benefit of olaparib (PFS HR [95%CI] 0.21 [0.13, 0.32]). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1035 check_entity AN4834-3 BRCA2 Mutation BRCA2 NCBI:675 gene castration-resistant prostate carcinoma DOID:0080909 risk 38530-2 CIViC:186 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1035 check_entity AN4834-4 BRCA2 Mutation BRCA2 NCBI:675 gene ovary epithelial cancer DOID:2152 prognostic;risk 38530-2 PubMed:22274685 In patients with invasive epithelial ovarian cancer, those with mutations in BRCA2 had better five-year overall survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1036 check_entity AN4834-4 BRCA2 Mutation BRCA2 NCBI:675 gene ovary epithelial cancer DOID:2152 prognostic;risk 38530-2 CIViC:186 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1036 check_entity AN4834-4 BRCA2 Mutation BRCA2 NCBI:675 gene ovary epithelial cancer DOID:2152 prognostic;risk 38530-2 PubMed:27717299 In a randomized, double-blind, phase 3 trial, 553 patients with ovarian cancer, fallopian tube cancer, or primary peritoneal cancer with predominantly high-grade serous histologic features were enrolled. Of the 553 enrolled, 203 had germline BRCA1/2 mutations and 350 had non-germline BRCA1/2 mutations (including both somatic mutant and wildtype BRCA1/2); BRCA1/2 mutation status was determined via BRACAnalysis testing (Myriad Genetics). The patients were randomized in a 2:1 ratio to receive niraparib 300 mg or placebo once daily. Patients in the niraparib group had a significantly longer median duration of progression-free survival than the placebo group: 21.0 vs. 5.5 months in the gBRCA cohort (hazard ratio, 0.27; 95% CI: 0.17 - 0.41; p < 0.001) and 9.3 months vs. 3.9 months in the overall non-gBRCA cohort (hazard ratio, 0.45; 95% CI: 0.34 - 0.61; p < 0.001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1036 check_entity AN4834-4 BRCA2 Mutation BRCA2 NCBI:675 gene ovary epithelial cancer DOID:2152 prognostic;risk 38530-2 CIViC:4409 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1036 check_entity AN4834-5 BRCA2 Mutation BRCA2 NCBI:675 gene ovarian cancer DOID:2394 prognostic;risk 38530-2 PubMed:26740259 664 patients with non-bulky FIGO Stage II-IV ovarian cancer were evaluated for PFS when treated with Pazopanib versus placebo. Of the 664 patients, 10% (n=68) were BRCA1+, 4% were BRCA 2+ (n=29) and 85% (n=567) were BCRA1/2 negative. Longer progression free survival was observed in BRCA1/2 positive carriers versus BRCA1/2 negative carriers in both the Pazopanib arm and the placebo arm, however, due to small sample size, the PFS increase in the Pazopanib arm was not statistically significant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1037 check_entity AN4834-5 BRCA2 Mutation BRCA2 NCBI:675 gene ovarian cancer DOID:2394 prognostic;risk 38530-2 PubMed:25218906 46 women with platinum-sensitive, high-grade, BRCA1/2+ ovarian cancer received either olaparib monotherapy or olaparib/cediranib combination therapy. Median PFS was increased in combination therapy (17.7 months versus 9.0 months; HR=0.42; 95%CI 0.23-0.76; p=0.005); overall response rate was increased in the combination therapy (79.6% versus 47.8%; p=0.002); and total deaths were reduced in combination therapy (6 patients versus 10 patients). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1037 check_entity AN4834-5 BRCA2 Mutation BRCA2 NCBI:675 gene ovarian cancer DOID:2394 prognostic;risk 38530-2 PubMed:21862407 In a study of 63 patients with ovarian cancer, 17 patients had BRCA1 or BRCA2 mutations and 46 patients had no BRCA mutations. Of the BRCA-positive patients, 7/17(41%; 95%CI 22-64) showed objective response to olaparib whereas only 11/46 BRCA-negative patients (24%; 95%CI 14-38) showed objective response to olaparib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1037 check_entity AN4834-5 BRCA2 Mutation BRCA2 NCBI:675 gene ovarian cancer DOID:2394 prognostic;risk 38530-2 PubMed:27908594 A phase 2 trial on patients with relapsed, platinum-sensitive high grade ovarian, fallopian tube or primary peritoneal carcinoma (ARIEL2 Part1, NCT01891344) was held to assess PARP inhibitor rucaparib on 3 genetically defined subsets of patients. Out of 40 BRCA (BRCA1 or BRCA2) mutant patients, 5 had somatic BRCA2 mutation, 4 of which were homozygous mutations and one had unknown zygosity. Confirmed objective response was seen in 80% (4/5) of the somatic BRCA2 mutant subgroup. Authors note that response rate was similar regardless of whether the BRCA mutation was somatic or germline, in BRCA 1 or BRCA 2. In a BRCA wild-type subgroup, with low levels of loss of heterozygosity (LOH), confirmed objective response was observed in 10% (7/70) of the patients. Patients with BRCA mutant tumors experienced significantly longer median progression free survival than patients with BRCA wildtype, LOH low tumors (12.8 vs 5.2 mo, HR: 0.27, P<0.0001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1037 check_entity AN4834-5 BRCA2 Mutation BRCA2 NCBI:675 gene ovarian cancer DOID:2394 prognostic;risk 38530-2 PubMed:30345884 In the phase 3 SOLO1 trial 390 patients with newly diagnosed advanced ovarian cancer with a mutation in BRCA1 or BRCA2 who had complete or partial response after platinum-based chemotherapy were randomized 2:1 to receive olaparib or placebo. The olaparib arm had 191 patients with BRCA1 mutation, 66 BRCA2, and 3 patients with both BRCA1 and BRCA2, while the placebo arm had 91 BRCA1 and 40 BRCA2 mutant patients. Analysis of PFS by blinded independent review found freedom from disease progression or death at 3 years was 69% in the olaparib arm compared with 35% in the placebo arm (hazard ratio for disease progression or death, 0.28; 95% CI, 0.20 to 0.39; P<0.001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1037 check_entity AN4834-5 BRCA2 Mutation BRCA2 NCBI:675 gene ovarian cancer DOID:2394 prognostic;risk 38530-2 PubMed:28882436 Combined meta-analysis of Study 10 (NCT01482715, phase I/II) and ARIEL2 (NCT01891344, phase II), both multi-centre, open-label, single-arm trials evaluating rucaparib in ovarian cancer with BRCA1 or BRCA2 deleterious germline or somatic mutations. Mutation status was determined by local testing or by central Foundation Medicine sequencing. Of 106 patients, OR was 53.8% (95% CI, 43.8-63.5); 8.5% and 45.3% of patients achieved complete and partial responses, respectively. Median duration of response was 9.2 months (95% CI, 6.6-11.6). Response rates by gene/mutation: BRCA1/2 germline (n=88, OR 53.4); BRCA1/2 somatic (n=18, OR 55.6); BRCA1 (n=67, OR 53.7); BRCA2 (n=39, OR 53.8). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1037 check_entity AN4834-5 BRCA2 Mutation BRCA2 NCBI:675 gene ovarian cancer DOID:2394 prognostic;risk 38530-2 CIViC:186 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1037 check_entity AN4834-6 BRCA2 Mutation BRCA2 NCBI:675 gene ovarian carcinoma DOID:4001 risk 38530-2 PubMed:24240112 In a study of ovarian carcinomas, 81% of tumors with germline BRCA1/2 mutations were platinum sensitive, whereas only 60% of tumors with non-BRCA1/2 mutations were platinum sensitive (N=47; N=158; P=0.01). Sensitivity was defined by maintenance of complete response greater than 6 months post platinum-based therapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1038 check_entity AN4834-6 BRCA2 Mutation BRCA2 NCBI:675 gene ovarian carcinoma DOID:4001 risk 38530-2 CIViC:186 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1038 check_entity AN4834-7 BRCA2 Mutation BRCA2 NCBI:675 gene pancreatic cancer DOID:1793 risk 38530-2 PubMed:25366685 Twenty-three patients with pancreatic cancer havoring BRCA1/2 germline mutations received olaparib. Eighteen (78%) patients had a BRCA2 mutation. In total of patients with BRCA1/2 mutation , all but one had received prior gemcitabine, and 65% had received prior platinum. Tumor response rate was 21.7% and stable disease more than 8 weeks was 35%. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1039 check_entity AN4834-7 BRCA2 Mutation BRCA2 NCBI:675 gene pancreatic cancer DOID:1793 risk 38530-2 PubMed:25072261 Patients with BRCA1/2 associated pancreatic adenocarcinoma were evaluated retrospectively. In patients with stage 3 and 4, the median overall survival (mOS) was 22 months for the platinum exposed (n=22), compared with 9 months for the non-platinum (n=21) treatment groups (p<0.039) assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1039 check_entity AN4834-7 BRCA2 Mutation BRCA2 NCBI:675 gene pancreatic cancer DOID:1793 risk 38530-2 PubMed:29338080 In Phase I study for pancreatic cancer patients GEM 600 mg/m2 + CDDP 25 mg/m2 + Veliparib 20 - 80 mg twice daily showed response rate of 77.8% (7/9) and mOS of 23.3 months in germline BRCA mutation-positive patients with stage IV disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1039 check_entity AN4834-7 BRCA2 Mutation BRCA2 NCBI:675 gene pancreatic cancer DOID:1793 risk 38530-2 PubMed:29223478 Veliparib 400mg bid was administered to patients with germline BRCA1/2 mutated pancreatic cancer. Sixteen pts was enrolled. All except two pts (12.5%) had previously been treated with platinum therapy. No confirmed PR was observed. One patient who had received prior single-agent gemcitabine only had an unconfirmed PR. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1039 check_entity AN4834-7 BRCA2 Mutation BRCA2 NCBI:675 gene pancreatic cancer DOID:1793 risk 38530-2 PubMed:21508395 Patient with germline BRCA2 mutation underwent resection of pancreatic cancer. Around three years later, tumor recurrence was detected by MRI and PET-CT confirmed it. She was treated with gemcitabine plus iniparib in clinical trial. Excellent response to therapy was observed and surgery was performed but no residual tumor tissue was detected assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1039 check_entity AN4834-7 BRCA2 Mutation BRCA2 NCBI:675 gene pancreatic cancer DOID:1793 risk 38530-2 CIViC:186 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1039 check_entity AN4834-8 BRCA2 Mutation BRCA2 NCBI:675 gene prostate cancer DOID:10283 risk 38530-2 PubMed:36753688 A clinical study was conducted in 30 patients with Metastatic Prostate Cancer harboring BRCA1/2 mutations treated with olaparib. A disease control rate of 69% (95% CI, 51-81) and an objective response rate of 58% (95% CI, 37-77) were noted. The PFS and OS were 38.4 weeks (95% CI, 16.3 - 52.1) and 76.4 weeks (95% CI, 49.3-106.0) respectively. Grade 3 or 4 serious adverse affects were reported in six out of the thirty patients, likely related to olaparib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1040 check_entity AN4834-8 BRCA2 Mutation BRCA2 NCBI:675 gene prostate cancer DOID:10283 risk 38530-2 CIViC:4409 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1040 check_entity AN4834-9 BRCA2 Mutation BRCA2 NCBI:675 gene triple-receptor negative breast cancer DOID:0060081 risk 38530-2 PubMed:25847936 In an evaluation of 77 patients, those who had BRCA1/2 germline mutations (n=11) had an increase response rate to cisplatin when compared to those without germline mutations (54.5% versus 19.7%; P=0.022) although progression free survival and overall survival was not significantly different. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1041 check_entity AN4834-9 BRCA2 Mutation BRCA2 NCBI:675 gene triple-receptor negative breast cancer DOID:0060081 risk 38530-2 PubMed:21862407 In a study of 26 patients with breast cancer, 10 patients were BRCA-positive and 16 patients were BRCA-negative. Regardless of BRCA status, none showed objective response when treated with olaparib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1041 check_entity AN4834-9 BRCA2 Mutation BRCA2 NCBI:675 gene triple-receptor negative breast cancer DOID:0060081 risk 38530-2 CIViC:186 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRCA2/NCBI:675 1041 check_entity AN4835-1 BRCA2 R2336P mutation BRCA2 NCBI:675 gene ovarian cancer DOID:2394 risk 38530-2 PubMed:27908594 In a phase 2 study of 206 recurrent, platinum-sensitive, high-grade ovarian cancer patients, patients with germline or somatic BRCA1 or BRCA2 mutation (n=40) were associated with improved progression free survival (HR 0.27, 95% CI: 0.16-0.44, p<0.0001) as compared to BRCA1/2 wild-type, loss of heterozygosity low patients (n=71) treated with rucaparib monotherapy; further, BRCA1/2 mutation patients achieved a longer median duration of response (9.2 months, 95% CI: 6.4-12.9, p=0.013 vs. 5.6 months, 95% CI: 4.6-8.5). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R2336P sequence variation in gene BRCA2/NCBI:675 1042 check_entity AN4835-1 BRCA2 R2336P mutation BRCA2 NCBI:675 gene ovarian cancer DOID:2394 risk 38530-2 CIViC:1226 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R2336P sequence variation in gene BRCA2/NCBI:675 1042 check_entity AN4836-1 BRCA2 TRUNCATING MUTATION BRCA2 NCBI:675 gene breast cancer DOID:1612 diagnostic 38530-2 PubMed:16088935 De novo Alu element insertions were identified within the BRCA2 coding sequences in 3 out of 50 Portuguese families. However, the segregation data and mRNA results in this study were conflicting or inconclusive. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::truncating:mutation sequence variation in gene BRCA2/NCBI:675 1043 check_entity AN4836-1 BRCA2 TRUNCATING MUTATION BRCA2 NCBI:675 gene breast cancer DOID:1612 diagnostic 38530-2 CIViC:689 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::truncating:mutation sequence variation in gene BRCA2/NCBI:675 1043 check_entity AN4837-1 BRCA2 V159M mutation BRCA2 NCBI:675 gene ovarian cancer DOID:2394 risk 38530-2 PubMed:27908594 In a phase 2 study of 206 recurrent, platinum-sensitive, high-grade ovarian cancer patients, patients with germline or somatic BRCA1 or BRCA2 mutation (n=40) were associated with improved progression free survival (HR 0.27, 95% CI: 0.16-0.44, p<0.0001) as compared to BRCA1/2 wild-type, loss of heterozygosity low patients (n=71) treated with rucaparib monotherapy; further, BRCA1/2 mutation patients achieved a longer median duration of response (9.2 months, 95% CI: 6.4-12.9, p=0.013 vs. 5.6 months, 95% CI: 4.6-8.5). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V159M sequence variation in gene BRCA2/NCBI:675 1044 check_entity AN4837-1 BRCA2 V159M mutation BRCA2 NCBI:675 gene ovarian cancer DOID:2394 risk 38530-2 CIViC:1223 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V159M sequence variation in gene BRCA2/NCBI:675 1044 check_entity AN4838-1 BRCA2 V211I mutation BRCA2 NCBI:675 gene ovarian cancer DOID:2394 risk 38530-2 PubMed:27908594 In a phase 2 study of 206 recurrent, platinum-sensitive, high-grade ovarian cancer patients, patients with germline or somatic BRCA1 or BRCA2 mutation (n=40) were associated with improved progression free survival (HR 0.27, 95% CI: 0.16-0.44, p<0.0001) as compared to BRCA1/2 wild-type, loss of heterozygosity low patients (n=71) treated with rucaparib monotherapy; further, BRCA1/2 mutation patients achieved a longer median duration of response (9.2 months, 95% CI: 6.4-12.9, p=0.013 vs. 5.6 months, 95% CI: 4.6-8.5). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V211I sequence variation in gene BRCA2/NCBI:675 1045 check_entity AN4838-1 BRCA2 V211I mutation BRCA2 NCBI:675 gene ovarian cancer DOID:2394 risk 38530-2 CIViC:1225 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V211I sequence variation in gene BRCA2/NCBI:675 1045 check_entity AN4839-1 BRCA2 V211L mutation BRCA2 NCBI:675 gene ovarian cancer DOID:2394 risk 38530-2 PubMed:27908594 In a phase 2 study of 206 recurrent, platinum-sensitive, high-grade ovarian cancer patients, patients with germline or somatic BRCA1 or BRCA2 mutation (n=40) were associated with improved progression free survival (HR 0.27, 95% CI: 0.16-0.44, p<0.0001) as compared to BRCA1/2 wild-type, loss of heterozygosity low patients (n=71) treated with rucaparib monotherapy; further, BRCA1/2 mutation patients achieved a longer median duration of response (9.2 months, 95% CI: 6.4-12.9, p=0.013 vs. 5.6 months, 95% CI: 4.6-8.5). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V211L sequence variation in gene BRCA2/NCBI:675 1046 check_entity AN4839-1 BRCA2 V211L mutation BRCA2 NCBI:675 gene ovarian cancer DOID:2394 risk 38530-2 CIViC:1224 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V211L sequence variation in gene BRCA2/NCBI:675 1046 check_entity AN4840-1 BRD4 BRD4::NUTM1 mutation BRD4 NCBI:23476 gene NUT midline carcinoma DOID:0060463 diagnostic;risk PubMed:20871596 Treatment of the patient-derived 797 NMC cell line for 48 hours with JQ1 (500 nM) provoked terminal differentiation which was accompanied by growth arrest and sustained inhibition of proliferation. Non-BRD4-dependent cell lines including a squamous carcinoma cell line (TE10) failed to exhibit differentiation effects when treated with JQ1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BRD4::NUTM1 sequence variation in gene BRD4/NCBI:23476 1047 check_entity AN4840-1 BRD4 BRD4::NUTM1 mutation BRD4 NCBI:23476 gene NUT midline carcinoma DOID:0060463 diagnostic;risk PubMed:26976114 In the clinic, compassionate use of the BET inhibitor birabresib (also known as OTX015 or MK-8628) induced rapid tumor regression in 2 of 4 patients with confirmed BRD4-NUTM1 fusions and significant disease stabilization in a third patient. This study provides the first clinical evidence that a BET inhibitor can induce impressive and rapid antitumor activity in this rare and exceptionally aggressive disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BRD4::NUTM1 sequence variation in gene BRD4/NCBI:23476 1047 check_entity AN4840-1 BRD4 BRD4::NUTM1 mutation BRD4 NCBI:23476 gene NUT midline carcinoma DOID:0060463 diagnostic;risk PubMed:18391746 5 of 28 cases of undifferentiated carcinomas of the upper aerodigestive tract (UCUAT) not associated with EBV infection were found to have NUTM1 rearrangements suggesting NUT midline carcinoma may be underdiagnosed and more prevalent than previously thought. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BRD4::NUTM1 sequence variation in gene BRD4/NCBI:23476 1047 check_entity AN4840-1 BRD4 BRD4::NUTM1 mutation BRD4 NCBI:23476 gene NUT midline carcinoma DOID:0060463 diagnostic;risk CIViC:700 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BRD4::NUTM1 sequence variation in gene BRD4/NCBI:23476 1047 check_entity AN4841-1 BRIP1 Mutation BRIP1 NCBI:83990 gene castration-resistant prostate carcinoma DOID:0080909 risk PubMed:32343890 This randomized, open-label, phase 3 trial evaluated the PARP inhibitor olaparib in 387 men with metastatic castration-resistant prostate cancer (mCRPC) who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). The study found that in men with mCRPC who had somatic or germline deleterious alterations (irrespective of zygosity) in any of the following HRR genes (BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L), olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone (PFS HR 0.49 [0.38, 0.63]). A total of 4 patients had BRIP1 mutations, 2 in each arm. Based on the results of this study, on May 19, 2020, the Food and Drug Administration approved olaparib (LYNPARZA) for adult patients with deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC, who have progressed following prior treatment with enzalutamide or abiraterone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRIP1/NCBI:83990 1048 check_entity AN4841-1 BRIP1 Mutation BRIP1 NCBI:83990 gene castration-resistant prostate carcinoma DOID:0080909 risk CIViC:4389 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BRIP1/NCBI:83990 1048 check_entity AN4842-1 BTK C481S mutation BTK NCBI:695 gene chronic lymphocytic leukemia DOID:1040 risk 35295-5 PubMed:24869598 Whole exome sequencing of 6 chronic lymphocytic leukemia patients with acquired resistance to ibrutinib determined 5/6 patients harbored a C481S mutation in BTK. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C481S sequence variation in gene BTK/NCBI:695 1049 check_entity AN4842-1 BTK C481S mutation BTK NCBI:695 gene chronic lymphocytic leukemia DOID:1040 risk 35295-5 PubMed:26182309 In a trial of 308 patients with chronic lymphocytic leukemia treated with ibrutinib, 31 discontinued treatment due to disease progression (13 CLL progression, 18 Richter’s transformation). 11/13 patients were deep sequenced for BTK and PLCG2. 9 patients were identified with BTK mutations (C481S in 8 patients). In 5 patients, C481S was the sole abnormality. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C481S sequence variation in gene BTK/NCBI:695 1049 check_entity AN4842-1 BTK C481S mutation BTK NCBI:695 gene chronic lymphocytic leukemia DOID:1040 risk 35295-5 CIViC:168 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C481S sequence variation in gene BTK/NCBI:695 1049 check_entity AN4843-1 BTK MUTATION BTK NCBI:695 gene chronic lymphocytic leukemia DOID:1040 prognostic 35295-5 PubMed:28418267 A patient cohort of 308 individuals was created from trials of Ibrutinib in CLL (see Maddocks 2015, PMID: 26182309). A secondary cohort was created from a prospective collection of 112 patients. 83/308 patients discontinued because of disease progression (27 Richter's transformation; 1 prolymphocytic leukemia; 55 progressive CLL). 46/55 progressive patients had a relapse sample available for sequencing of BTK and PLCG2. 31 patients only had BTK C481(F/R/A/S) mutations, 3 patients only had PLCG2 mutations, and 6 patients had both BTK C481 and PLCG2 mutations. In the 112 patients sequencing of BTK and PLGC2 coding regions was performed every 3 months. At publication at 8 patients had experienced relapse. All 8 had BTK C481S mutations with clonal expansion before relapse. 8 additional patients did not have clinical relapse but had BTK C481S mutations with VAF >1% and increasing CLL cells in peripheral blood. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BTK/NCBI:695 1050 check_entity AN4843-1 BTK MUTATION BTK NCBI:695 gene chronic lymphocytic leukemia DOID:1040 prognostic 35295-5 CIViC:2045 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene BTK/NCBI:695 1050 check_entity AN4844-1 BTK T316A mutation BTK NCBI:695 gene chronic lymphocytic leukemia DOID:1040 risk 35295-5 PubMed:27626698 Case report of a patient with CLL and Richter-transformed relapse under ibrutinib (after an initial partial response for 10 months). Sequencing of sequential samples of this patient revealed a novel BTK T316 mutation at relapse (allele frequency of 75%). Characterization of this mutation showed that is was located on the SH2 domain, not associated with Ibrutinib binding. Introduction of this mutation in an Ibrutinib-sensitive lymphoma cell line showed resistance comparable to the known C481 resistance mutations, which was also confirmed by absence of downstream signaling. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T316A sequence variation in gene BTK/NCBI:695 1051 check_entity AN4844-1 BTK T316A mutation BTK NCBI:695 gene chronic lymphocytic leukemia DOID:1040 risk 35295-5 CIViC:844 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T316A sequence variation in gene BTK/NCBI:695 1051 check_entity AN4845-1 CALR EXON 9 FRAMESHIFT CALR NCBI:811 gene essential thrombocythemia DOID:2224 risk 77174-1 PubMed:26486786 Study explored the hematologic and molecular responses in a cohort of 31 patients presenting with thrombocythemia and CALR exon 9 frameshift mutations. All 31 patients exhibited a hematologic response at the time of followup (European LeukemiaNet criteria). In regards to molecular response, before treatment the CALR mutant allele displayed a median frequency of 41% across the cohort, during treatment a significant decrease was observed in comparison to controls treated with hydroxyurea and aspirin. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CALR EXON 9 FRAMESHIFT [biomarker_term_in_review] 1052 not_mapped AN4845-1 CALR EXON 9 FRAMESHIFT CALR NCBI:811 gene essential thrombocythemia DOID:2224 risk 77174-1 CIViC:555 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CALR EXON 9 FRAMESHIFT [biomarker_term_in_review] 1052 not_mapped AN4845-2 CALR EXON 9 FRAMESHIFT CALR NCBI:811 gene myelofibrosis DOID:4971 prognostic 77174-1 PubMed:25037629 Study of 428 patients with primary Myelofibrosis found that those patients harboring CALR exon 9 mutations displayed significantly longer survival than those with JAK2 mutations (HR: 2.5, median survival yrs: CALR 15.9, JAK2 5.9) assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CALR EXON 9 FRAMESHIFT [biomarker_term_in_review] 1053 not_mapped AN4845-2 CALR EXON 9 FRAMESHIFT CALR NCBI:811 gene myelofibrosis DOID:4971 prognostic 77174-1 PubMed:24496303 In patients with primary myelofibrosis CALR mutations were associated with improved median survival. For 277 patients, CALR mutated, ASXL1 wildtype patients (median survival, 10.4 years, N=46); CALR wildtype, ASXL1 mutant patients (2.3 years; HR, 5.9; 95% CI, 3.5–10.0, N=62); and either CALR/ASXL1wildtype or CALR/ASXL1 mutant patients (5.8 years; HR, 2.5; 95% CI, 1.5–4.0, N=169). These results were independent of DIPSS-plus risk but added prognostic information to this risk categorization. These results were also validated in an independent cohort of 293 patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CALR EXON 9 FRAMESHIFT [biomarker_term_in_review] 1053 not_mapped AN4845-2 CALR EXON 9 FRAMESHIFT CALR NCBI:811 gene myelofibrosis DOID:4971 prognostic 77174-1 CIViC:555 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CALR EXON 9 FRAMESHIFT [biomarker_term_in_review] 1053 not_mapped AN4846-1 CALR Mutation CALR NCBI:811 gene essential thrombocythemia DOID:2224 diagnostic 77174-1 PubMed:27069254 Diagnostic criterion for essential thrombocytemia according to the World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues 2016. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CALR/NCBI:811 1054 check_entity AN4846-1 CALR Mutation CALR NCBI:811 gene essential thrombocythemia DOID:2224 diagnostic 77174-1 CIViC:2261 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CALR/NCBI:811 1054 check_entity AN4847-1 CASP8 D302H mutation CASP8 NCBI:841 gene neuroblastoma DOID:769 prognostic PubMed:25502557 21 SNPs were analyzed using qRT-PCR genotyping assays in 500 Neuroblastoma tumor samples, and the CASP8 D302H missense variant was found to be associated with worse overall survival (P = 0.0006; Q = 0.049) and worse event-free survival (P = 0.0002; Q = 0.042) in those samples that had MYCN amplification (N = 94). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D302H sequence variation in gene CASP8/NCBI:841 1055 check_entity AN4847-1 CASP8 D302H mutation CASP8 NCBI:841 gene neuroblastoma DOID:769 prognostic CIViC:646 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D302H sequence variation in gene CASP8/NCBI:841 1055 check_entity AN4848-1 CASP8 Overexpression CASP8 NCBI:841 gene Ewing sarcoma of bone DOID:3368 risk PubMed:26291055 In-vitro and in-vivo sensitivity to DR5 antibody conatumumab was correlated with expression of caspase-8. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CASP8/NCBI:841 1056 AN4848-1 CASP8 Overexpression CASP8 NCBI:841 gene Ewing sarcoma of bone DOID:3368 risk CIViC:342 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CASP8/NCBI:841 1056 AN4849-1 CBFB CBFB::MYH11 mutation CBFB NCBI:865 gene acute myeloid leukemia DOID:9119 prognostic PubMed:22180162 The CBFB-MYH11 fusion has been shown to be associated with favorable prognosis in acute myeloid leukemia. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CBFB::MYH11 sequence variation in gene CBFB/NCBI:865 1057 check_entity AN4849-1 CBFB CBFB::MYH11 mutation CBFB NCBI:865 gene acute myeloid leukemia DOID:9119 prognostic CIViC:427 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CBFB::MYH11 sequence variation in gene CBFB/NCBI:865 1057 check_entity AN4850-1 CBL Y371H mutation CBL NCBI:867 gene juvenile myelomonocytic leukemia DOID:0050458 diagnostic PubMed:20543203 Three patients displayed variable developmental conditions with predisposition to JMML. All cases included a copy neutral loss of heterozygosity of the 11q23 chromosomal region, encompassing the CBL locus. A heterozygous germline CBL p.Y371H substitution was found in each of them and was inherited from the father in one patient. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y371H sequence variation in gene CBL/NCBI:867 1058 check_entity AN4850-1 CBL Y371H mutation CBL NCBI:867 gene juvenile myelomonocytic leukemia DOID:0050458 diagnostic CIViC:2507 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y371H sequence variation in gene CBL/NCBI:867 1058 check_entity AN4851-1 CBLB RS2305035 mutation CBLB NCBI:868 gene lung non-small cell carcinoma DOID:3908 prognostic PubMed:26732495 Samples from 393 patients with NSCLC were evaluated for 3 SNPs in CBLB (rs1042852, rs2305035, and rs7649466). Genotypes rs7649466 and rs1042852 were not associated with a change in clinical outcome compared to wildtype however, rs2305035 A genotype (A/A or A/G) had better local recurrence-free survival, metastasis-free survival and overall survival when compared to GG genotype (n=186). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS2305035 sequence variation in gene CBLB/NCBI:868 1059 check_entity AN4851-1 CBLB RS2305035 mutation CBLB NCBI:868 gene lung non-small cell carcinoma DOID:3908 prognostic CIViC:639 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS2305035 sequence variation in gene CBLB/NCBI:868 1059 check_entity AN4852-1 CBLC EXPRESSION CBLC NCBI:23624 gene cancer DOID:162 risk PubMed:25883215 The E3 ubiquitin ligase, CBLC, was identified as a candidate biomarker for olaparib sensitivity in a siRNA screen and further validated in-vitro. In other words, expression of CBLC is predicted to confer resistance to olaparib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CBLC/NCBI:23624 1060 AN4852-1 CBLC EXPRESSION CBLC NCBI:23624 gene cancer DOID:162 risk CIViC:322 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CBLC/NCBI:23624 1060 AN4853-1 CCND1 Amplification CCND1 NCBI:595 gene breast cancer DOID:1612 risk 42780-7 PubMed:24367492 In this retrospective analysis, CCND1 amplification was analyzed in 442 patients. No interaction with treatment was observed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CCND1/NCBI:595 1061 AN4853-1 CCND1 Amplification CCND1 NCBI:595 gene breast cancer DOID:1612 risk 42780-7 PubMed:19874578 A panel of 47 breast cancer cell lines was tested for sensitivty/resistance to CDK4/6 inhibitor Palbociclib (PD0332991), where IC50 below 150nM was sensitive, and above 1000nM resistant. Cyclin D1 had higher expression levels in sensitive cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CCND1/NCBI:595 1061 AN4853-1 CCND1 Amplification CCND1 NCBI:595 gene breast cancer DOID:1612 risk 42780-7 CIViC:18 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CCND1/NCBI:595 1061 AN4853-2 CCND1 Amplification CCND1 NCBI:595 gene cancer DOID:162 risk 42780-7 PubMed:36853016 This Phase 2 NCI-MATCH Trial subprotocol Z1B was conducted in 32 patients with either CCND1, 2 or 3 amplification, and were treated with Palbociclib. Squamous cell lung cancer (n=5), adenocarcinoma of the prostate (n=3), squamous cell carcinoma of the head and the neck (n = 3) and adenocarcinoma of the colon (n=3) were the four most common malignancies. The median PFS was 1.8 months and the median OS was 7.7 months, with no PR and only SD (n=12) as the best response. Additionally, there were 7 deaths in the study due to disease progression. Overall, no meaningful antitumor activity was reported. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CCND1/NCBI:595 1062 AN4853-2 CCND1 Amplification CCND1 NCBI:595 gene cancer DOID:162 risk 42780-7 CIViC:4709 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CCND1/NCBI:595 1062 AN4853-3 CCND1 Amplification CCND1 NCBI:595 gene lung non-small cell carcinoma DOID:3908 prognostic 42780-7 PubMed:17070615 Inceased copy number of CCND1 is associated with poorer overall survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CCND1/NCBI:595 1063 AN4853-3 CCND1 Amplification CCND1 NCBI:595 gene lung non-small cell carcinoma DOID:3908 prognostic 42780-7 CIViC:18 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CCND1/NCBI:595 1063 AN4853-4 CCND1 Amplification CCND1 NCBI:595 gene ovarian cancer DOID:2394 risk 42780-7 PubMed:21278246 A panel of 40 ovarian cancer cell lines with varied mutation profiles was assayed for sensitivity to the cdk4/6 inhibitor palbociclib (PD0332991) via measurement of IC50 values for inhibition of proliferation. Large variation in palbociclib sensitivity was observed and cell lines (N=40) were classified as above (resistant) or below (sensitive) the mean log of all IC50 values. 6/18 (33%) of the resistant lines and in only 1/22 (5%) of the sensitive lines (P = 0.017) had CCND1 copy number gain. Increased CCND1 expression was not correlated with sensitivity to palbociclib (p=0.671). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CCND1/NCBI:595 1064 AN4853-4 CCND1 Amplification CCND1 NCBI:595 gene ovarian cancer DOID:2394 risk 42780-7 CIViC:18 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CCND1/NCBI:595 1064 AN4853-5 CCND1 Amplification CCND1 NCBI:595 gene renal cell carcinoma DOID:4450 risk 42780-7 PubMed:23898052 28 renal cell carcinoma cell lines were tested for sensitivity to CDK4/6 inhibitor Palbociclib (PD0332991). 19 were reported sensitive, and 9 resistant. 15 of the 28 cell lines had high levels of Cyclin D1 (CCND1) expression which did not correlate significantly with palbociclib sensitivity (p=0.348). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CCND1/NCBI:595 1065 AN4853-5 CCND1 Amplification CCND1 NCBI:595 gene renal cell carcinoma DOID:4450 risk 42780-7 CIViC:18 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CCND1/NCBI:595 1065 AN4853-6 CCND1 Amplification CCND1 NCBI:595 gene skin melanoma DOID:8923 risk 42780-7 PubMed:26307133 Retrospective analysis of somatic mutations and copy number changes in 119 patient treated with carboplatin, paclitaxel, ± sorafenib (CPS) in the E2603 trial. CPS therapy was associated with improved progression-free survival (PFS) compared with CP in patients with tumors with CCND1 gene copy gains (HR, 0.45; P = 0.035). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CCND1/NCBI:595 1066 AN4853-6 CCND1 Amplification CCND1 NCBI:595 gene skin melanoma DOID:8923 risk 42780-7 CIViC:18 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CCND1/NCBI:595 1066 AN4854-1 CCND1 Expression CCND1 NCBI:595 gene lung non-small cell carcinoma DOID:3908 prognostic 42780-7 PubMed:17070615 Three studies have found no significant survival impact for CCND1 in lung cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CCND1/NCBI:595 1067 AN4854-1 CCND1 Expression CCND1 NCBI:595 gene lung non-small cell carcinoma DOID:3908 prognostic 42780-7 CIViC:19 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CCND1/NCBI:595 1067 AN4855-1 CCND1 Overexpression CCND1 NCBI:595 gene breast cancer DOID:1612 diagnostic;prognostic 42780-7 PubMed:15961768 Cyclin D1 overexpression is associated with the ER-positive subtype of breast cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CCND1/NCBI:595 1068 AN4855-1 CCND1 Overexpression CCND1 NCBI:595 gene breast cancer DOID:1612 diagnostic;prognostic 42780-7 CIViC:20 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CCND1/NCBI:595 1068 AN4855-2 CCND1 Overexpression CCND1 NCBI:595 gene childhood B-cell acute lymphoblastic leukemia DOID:0080146 prognostic 42780-7 PubMed:29408328 Reverse phase protein array (RPPA) revealed upregulation of CCND1 at diagnosis in B-ALL relapse patients (n=27) versus patients that did not relapse (n=86, p>.01). 5-year cumulative incidence of relapse analysis showed B-ALL patients within this cohort with CCND1 expression at diagnosis above the 75th percentile had a higher incidence of relapse versus those below the 75th percentile. CCND1 upregulation appears to impact relapse 500 days post initial diagnosis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CCND1/NCBI:595 1069 AN4855-2 CCND1 Overexpression CCND1 NCBI:595 gene childhood B-cell acute lymphoblastic leukemia DOID:0080146 prognostic 42780-7 CIViC:20 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CCND1/NCBI:595 1069 AN4855-3 CCND1 Overexpression CCND1 NCBI:595 gene estrogen-receptor positive breast cancer DOID:0060075 risk 42780-7 PubMed:15138475 The authors performed a tissue microarray analysis of 167 postmenopausal breast cancers that had been randomized to treatment with or without tamoxifen. ER +ve patients with high CCND1 tumor expression did not show any difference in survival between tamoxifen and no treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CCND1/NCBI:595 1070 AN4855-3 CCND1 Overexpression CCND1 NCBI:595 gene estrogen-receptor positive breast cancer DOID:0060075 risk 42780-7 CIViC:20 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CCND1/NCBI:595 1070 AN4855-4 CCND1 Overexpression CCND1 NCBI:595 gene head and neck squamous cell carcinoma DOID:5520 prognostic 42780-7 PubMed:16309541 Cyclin D1 overexpression is associated with shorter overall survival and increased metastasis in head and neck squamous cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CCND1/NCBI:595 1071 AN4855-4 CCND1 Overexpression CCND1 NCBI:595 gene head and neck squamous cell carcinoma DOID:5520 prognostic 42780-7 CIViC:20 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CCND1/NCBI:595 1071 AN4855-5 CCND1 Overexpression CCND1 NCBI:595 gene mantle cell lymphoma DOID:0050746 prognostic;risk 42780-7 PubMed:17891190 Cyclin D1 overexpression is associated with shorter overall survival and increased metastasis in mantle cell lymphoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CCND1/NCBI:595 1072 AN4855-5 CCND1 Overexpression CCND1 NCBI:595 gene mantle cell lymphoma DOID:0050746 prognostic;risk 42780-7 PubMed:22383795 A pharmacodynamic study (NCT00420056) of 17 mantle cell lymphoma MCL patients was performed using the CDK4/6 inhibitor palbociclib (PD0332991). Patients were verified by IHC, FISH or molecular testing for the t(11:14) rearrangement causing Cyclin D overexpression in MCL. 1 patient demonstrated complete response, and 2 showed partial response for an 18% overall response rate. 7 patients showed stable disease. Patient population was heavily pretreated. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CCND1/NCBI:595 1072 AN4855-5 CCND1 Overexpression CCND1 NCBI:595 gene mantle cell lymphoma DOID:0050746 prognostic;risk 42780-7 PubMed:16690963 In Mantle Cell Lymphoma (MCL), t(11:14)-induced overexpression of cyclin D1 was targeted by CDK4/6 inhibitor Palbociclib (PD0332991). Palbociclib caused Rb dephosphorylation in MCL cell lines and patient derived tumor cells. MCL cell lines overexpressing cyclin D1 showed growth inhibition with Palbociclib. The VAL DLBCL cell line was used as control to verify cyclin D1 overexpression but was not used as a control in Palbociclib inhibitor experiments. Instead, the investigators report that other publications report cell lines without cyclin D1 overexpression had higher IC50 values for palbociclib, suggesting overexpresssed cyclin D1 targetability in MCL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CCND1/NCBI:595 1072 AN4855-5 CCND1 Overexpression CCND1 NCBI:595 gene mantle cell lymphoma DOID:0050746 prognostic;risk 42780-7 CIViC:20 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CCND1/NCBI:595 1072 AN4856-1 CCND2 Amplification CCND2 NCBI:894 gene cancer DOID:162 risk PubMed:36853016 This Phase 2 NCI-MATCH Trial subprotocol Z1B was conducted in 32 patients with either CCND1, 2 or 3 amplification, and were treated with Palbociclib. Squamous cell lung cancer (n=5), adenocarcinoma of the prostate (n=3), squamous cell carcinoma of the head and the neck (n = 3) and adenocarcinoma of the colon (n=3) were the four most common malignancies. The median PFS was 1.8 months and the median OS was 7.7 months, with no PR and only SD (n=12) as the best response. Additionally, there were 7 deaths in the study due to disease progression. Overall, no meaningful antitumor activity was reported. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CCND2/NCBI:894 1073 AN4856-1 CCND2 Amplification CCND2 NCBI:894 gene cancer DOID:162 risk CIViC:4709 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CCND2/NCBI:894 1073 AN4857-1 CCND2 OVEREXPRESSION CCND2 NCBI:894 gene stomach cancer DOID:10534 prognostic PubMed:10547574 Cyclin D2 overexpression is associated with poor prognosis in gastric cancers. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CCND2/NCBI:894 1074 AN4857-1 CCND2 OVEREXPRESSION CCND2 NCBI:894 gene stomach cancer DOID:10534 prognostic CIViC:21 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CCND2/NCBI:894 1074 AN4858-1 CCND2 PROMOTER DEMETHYLATION CCND2 NCBI:894 gene stomach cancer DOID:10534 diagnostic PubMed:14612939 CCND2 hypomethylation is seen to be more common in stage III and IV gastric tumors than stage I and II. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CCND2 PROMOTER DEMETHYLATION [biomarker_term_in_review] 1075 not_mapped AN4858-1 CCND2 PROMOTER DEMETHYLATION CCND2 NCBI:894 gene stomach cancer DOID:10534 diagnostic CIViC:22 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CCND2 PROMOTER DEMETHYLATION [biomarker_term_in_review] 1075 not_mapped AN4859-1 CCND3 Amplification CCND3 NCBI:896 gene cancer DOID:162 risk PubMed:36853016 This Phase 2 NCI-MATCH Trial subprotocol Z1B was conducted in 32 patients with either CCND1, 2 or 3 amplification, and were treated with Palbociclib. Squamous cell lung cancer (n=5), adenocarcinoma of the prostate (n=3), squamous cell carcinoma of the head and the neck (n = 3) and adenocarcinoma of the colon (n=3) were the four most common malignancies. The median PFS was 1.8 months and the median OS was 7.7 months, with no PR and only SD (n=12) as the best response. Additionally, there were 7 deaths in the study due to disease progression. Overall, no meaningful antitumor activity was reported. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CCND3/NCBI:896 1076 AN4859-1 CCND3 Amplification CCND3 NCBI:896 gene cancer DOID:162 risk CIViC:4709 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CCND3/NCBI:896 1076 AN4860-1 CCND3 Loss CCND3 NCBI:896 gene obsolete T-cell lymphoblastic leukemia/lymphoma DOID:715 risk PubMed:23079656 Treatment of Notch-driven T-cell leukemia in Ccnd3 knockout mice with Palbociclib (PD-0332991) significantly increased median survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CCND3 Loss [biomarker_term_in_review] 1077 not_mapped AN4860-1 CCND3 Loss CCND3 NCBI:896 gene obsolete T-cell lymphoblastic leukemia/lymphoma DOID:715 risk CIViC:23 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CCND3 Loss [biomarker_term_in_review] 1077 not_mapped AN4861-1 CCNE1 Amplification CCNE1 NCBI:898 gene estrogen-receptor positive breast cancer DOID:0060075 risk PubMed:27020857 Preclinical study in breast cancer cell lines treated with CDK4/6 inhibitor palbociclib. Cell lines with acquired resistance to palbociclib were developed. Two palbociclib-resistant cell lines were derived through chronic exposure to 1 μmol/L palbociclib during 3 to 4 months. Copy number profiling from exome sequencing of MCF-7 and MCF-7pR, confirmed relative amplification of CCNE1. Silencing of CCNE1 or CDK2 alone in MCF-7pR cells had no effect on cell-cycle arrest, but resulted in substantially increased cell-cycle arrest and reduction in cell growth in combination with palbociclib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CCNE1/NCBI:898 1078 AN4861-1 CCNE1 Amplification CCNE1 NCBI:898 gene estrogen-receptor positive breast cancer DOID:0060075 risk CIViC:187 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CCNE1/NCBI:898 1078 AN4861-2 CCNE1 Amplification CCNE1 NCBI:898 gene ovarian carcinoma DOID:4001 prognostic PubMed:20336784 In a retrospective study of 88 ovarian carcinomas, 18 had amplification of CCNE1. Those with amplification had worse overall and disease-free survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CCNE1/NCBI:898 1079 AN4861-2 CCNE1 Amplification CCNE1 NCBI:898 gene ovarian carcinoma DOID:4001 prognostic CIViC:187 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CCNE1/NCBI:898 1079 AN4861-3 CCNE1 Amplification CCNE1 NCBI:898 gene ovarian serous cystadenocarcinoma DOID:5746 risk PubMed:27663592 A high throughput compound screen identified synergistic combinations in CCNE1 amplified high grade serous ovarian carcinoma, including dinaciclib and AKT inhibitors assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CCNE1/NCBI:898 1080 AN4861-3 CCNE1 Amplification CCNE1 NCBI:898 gene ovarian serous cystadenocarcinoma DOID:5746 risk CIViC:187 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CCNE1/NCBI:898 1080 AN4862-1 CCNE1 Overexpression CCNE1 NCBI:898 gene breast cancer DOID:1612 prognostic PubMed:12432043 Patients with high expression of total cyclin E and low-molecular weight cyclin E is strongly associated with poor prognosis in breast cancer, and the hazard ratio for these patients in 13.3 times higher than those with normal cyclin E levels. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CCNE1/NCBI:898 1081 AN4862-1 CCNE1 Overexpression CCNE1 NCBI:898 gene breast cancer DOID:1612 prognostic CIViC:24 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CCNE1/NCBI:898 1081 AN4862-2 CCNE1 Overexpression CCNE1 NCBI:898 gene gastric adenosquamous carcinoma DOID:5635 prognostic PubMed:10224221 Elevated levels of CCNE1 mRNA has been shown to be correlated with advanced stage gastric carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CCNE1/NCBI:898 1082 AN4862-2 CCNE1 Overexpression CCNE1 NCBI:898 gene gastric adenosquamous carcinoma DOID:5635 prognostic CIViC:24 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CCNE1/NCBI:898 1082 AN4862-3 CCNE1 Overexpression CCNE1 NCBI:898 gene ovarian cancer DOID:2394 risk PubMed:26204491 Four ovarian cancer cell lines with elevated CCNE1 expression were 40x more sensitive to Cdk2 inhibitor SNS-032 than four cell lines without CCNE1 overexpression. SNS-032 greatly prolonged the survival of mice with CCNE1 overexpressing xenografts. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CCNE1/NCBI:898 1083 AN4862-3 CCNE1 Overexpression CCNE1 NCBI:898 gene ovarian cancer DOID:2394 risk CIViC:24 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CCNE1/NCBI:898 1083 AN4863-1 CD274 Expression CD274 NCBI:29126 gene breast cancer DOID:1612 prognostic PubMed:28079291 A meta-analysis of the role of PD-L1 expression in breast cancer found nine relevant studies with a total 8583 patients. PD-L1 expression was found to be associated with several poor prognostic indicators, such as ductal cancer, high tumor grade, ER negativity, PR negativity, HER2 positivity and aggressive molecular subtypes. PD-L1 overexpression had no significant impact on metastasis-free survival (HR 0.924, 95% CI = 0.747-1.141, p = 0.462), disease-free survival (HR 1.122, 95% CI = 0.878-1.434, p = 0.357) and overall specific survival (HR 0.837, 95% CI = 0.640-1.093, p = 0.191), but significantly correlated with shortened overall survival (HR 1.573, 95% CI = 1.010-2.451, p = 0.045). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1084 AN4863-1 CD274 Expression CD274 NCBI:29126 gene breast cancer DOID:1612 prognostic PubMed:28430626 In this meta-analysis, 5 studies totalling 2,546 cases were combined to assess the prognostic association of PD-L1 expression in breast cancer. The combined hazard ratio (HR) for PD-L1 overexpression was 1.76 (OS). The pooled odds ratios (ORs) indicated that PD-L1 expression was associated with positive lymph node metastasis, higher histological grades, estrogen receptor (ER)-negativity, and triple-negative breast cancer (TNBC). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1084 AN4863-1 CD274 Expression CD274 NCBI:29126 gene breast cancer DOID:1612 prognostic CIViC:272 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1084 AN4863-2 CD274 Expression CD274 NCBI:29126 gene cancer DOID:162 prognostic;risk PubMed:22658127 Trial NCT00730639 tested monoclonal antibody nivolumab against the PD-1 immune checkpoint receptor in pretreated patients with various cancer types. PD-L1 expression was tested in 42 patients by ICH from tumor FFPE biopsies. (18 melanoma, 10 NSCLC, 7 colorectal cancer, 5 renal cell cancer, 2 prostate cancer). 9 of 25 PD-L1 expressing patients showed objective response, and zero of 17 PD-L1 negative patients showed objective response (p=0.006). Biopsies were optional, and therefore not fully randomized. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1085 AN4863-2 CD274 Expression CD274 NCBI:29126 gene cancer DOID:162 prognostic;risk PubMed:28453554 PD-L1 is not only expressed in tumor cells (TCs) but also upregulated in tumor-infiltrating immune cells (TIICs). This meta-analysis evaluated the prognostic value of PD-L1 expression in TIICs in different types of cancers. 18 studies involving 3674 patients were included. PD-L1 positivity in TIICs related to a lower risk of death (HR = 0.784, p=0.047), and TIICs indicated a better prognosis especially in breast cancer patients (HR = 0.359, p=0.002). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1085 AN4863-2 CD274 Expression CD274 NCBI:29126 gene cancer DOID:162 prognostic;risk PubMed:28471952 A meta analysis of 60 research studies involving 10,310 solid tumors indicated that CD274 over expression results in poor overall survival (HR = 1.58, P <.001) and poor disease free/progression free survival (DFS/PFS) (HR = 1.72, P =0 .001). When split into sub groups by cancer type overall survival was poor for breast (HR = 1.98, P =0 .014), urothelial (HR = 2.24, P <0.001), renal (HR = 3.30, P <0.001), and gastric cancers (HR = 1.56, P =0 .040). DFS/PFS was poor in patients with hepatocellular carcinoma (HR = 1.72, P = 0.003), melanoma (HR = 3.39, P <0.001), and renal carcinoma, (HR = 5.04, P <0.001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1085 AN4863-2 CD274 Expression CD274 NCBI:29126 gene cancer DOID:162 prognostic;risk CIViC:272 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1085 AN4863-3 CD274 Expression CD274 NCBI:29126 gene head and neck squamous cell carcinoma DOID:5520 risk PubMed:28476872 Radiation-resistant cell lines exhibited upregulation and increased activation of Axl, PI3 kinase signalling as well as increased expression of PD-L1. In 3 cohorts of HPV-negative head and neck squamous cell carcinoma patient samples evaluated with different methods [reverse phase protein array (N=68), mRNA expression array (N=97) or immunohistochemistry (N=114), respectively], increased expression of PD-L1 was also correlated with local failure following radiotherapy as compared to the PD-L1–low expression group (P = 0.01, 1.9 × 10−3, and 9 × 10−4, respectively). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1086 AN4863-3 CD274 Expression CD274 NCBI:29126 gene head and neck squamous cell carcinoma DOID:5520 risk CIViC:272 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1086 AN4863-4 CD274 Expression CD274 NCBI:29126 gene lung non-small cell carcinoma DOID:3908 prognostic;risk PubMed:26664143 This meta-analysis did not find a significant connection between expression of PD-L1 and overall survival in patients with NSCLC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1087 AN4863-4 CD274 Expression CD274 NCBI:29126 gene lung non-small cell carcinoma DOID:3908 prognostic;risk PubMed:26086854 Based on a meta-analysis of 20 trials (1475 patients), PD-L1 expression was associated with a higher ORR rate in patients with NSCLC. Active drugs were Nivolumab and Pembrolizumab, PD-1 receptor targeting antibodies. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1087 AN4863-4 CD274 Expression CD274 NCBI:29126 gene lung non-small cell carcinoma DOID:3908 prognostic;risk PubMed:26771872 74 patients with stage III NSCLC treated with concurrent chemoradiotherapy were retrospectively analyzed for PD-L1 expression and CD8+ tumour-infiltrating lymphocytes (TILs) density (IHC). CD8+ TIL density was an independent predictor of progression free survival (PFS) and overall survival (OS). Only when both TIL density and PD-L1 expression were both considered, was PD-L1 expression associated with survival. The subgroup, PD-L1+/CD8 low tumors had the shortest PFS (8.6 months, p = 0.02) and shortest, but not significantly different, OS (13.9 months, p = 0.11). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1087 AN4863-4 CD274 Expression CD274 NCBI:29126 gene lung non-small cell carcinoma DOID:3908 prognostic;risk PubMed:26918451 Meta-Analysis of PD-L1 (CD274) Expression Status in 914 patients (7 studies) and response to PD-1/PD-L1 monoclonal antibodies. Patients with PD-L1 positive tumors (PD-L1 tumor cell staining ≥1%), had a significantly higher ORR, compared to patients with PD-L1 negative tumors (OR: 2.44; 95% CIs: 1.61-3.68). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1087 AN4863-4 CD274 Expression CD274 NCBI:29126 gene lung non-small cell carcinoma DOID:3908 prognostic;risk PubMed:26970723 Exploratory biomarker analysis from a phase-II randomized trial comparing atezolizumab (PD-L1) and docetaxel in previously treated, advanced or metastatic non-small cell lung cancer. Baseline PD-L1 expression (IHC) was assessed in tumour cells (as percentage of PD-L1-expressing tumour cells TC3≥50%, TC2≥5% and <50%, TC1≥1% and <5%, and TC0<1%) and tumour-infiltrating immune cells (as percentage of tumour area: IC3≥10%, IC2≥5% and <10%, IC1≥1% and <5%, and IC0<1%). Increasing PD-L1 Expression was associated with improved overall survival (TC3 or IC3 HR 0·49 [0·22-1·07; p=0·068], TC2/3 or IC2/3 HR 0·54 [0·33-0·89; p=0·014], TC1/2/3 or IC1/2/3 HR 0·59 [0·40-0·85; p=0·005], TC0 and IC0 HR 1·04 [0·62-1·75; p=0·871]) but not progression free survival or overall response rate. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1087 AN4863-4 CD274 Expression CD274 NCBI:29126 gene lung non-small cell carcinoma DOID:3908 prognostic;risk PubMed:27718847 This open-label, randomized, phase-3 clinical trial compared pembrolizumab to chemotherapy in treating NSCLC patients with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of EGFR or translocation of ALK. Patients in the pembrolizumab group exhibited significantly better progression-free survival and overall survival compared to patients in the chemotherapy group. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1087 AN4863-4 CD274 Expression CD274 NCBI:29126 gene lung non-small cell carcinoma DOID:3908 prognostic;risk PubMed:28472902 In this meta-analysis of 14 studies with 2857 patients, the immunotherapy response rate was higher among PD-L1-positive patients (RR: 2.19, 95% CI: 1.63-2.94). PD-L1 expression was also related to better progression-free survival (HR: 0.69, 95% CI: 0.57-0.85) and better overall survival (HR: 0.77, 95% CI: 0.67-0.89). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1087 AN4863-4 CD274 Expression CD274 NCBI:29126 gene lung non-small cell carcinoma DOID:3908 prognostic;risk PubMed:25891174 PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy of pembrolizumab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1087 AN4863-4 CD274 Expression CD274 NCBI:29126 gene lung non-small cell carcinoma DOID:3908 prognostic;risk CIViC:272 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1087 AN4863-5 CD274 Expression CD274 NCBI:29126 gene lung squamous cell carcinoma DOID:3907 prognostic PubMed:26313362 In this study, PD-L1 expression (measured by IHC) was associated with better overall survival in the subgroup of Lung Squamous Cell Carcinomas (149 of 321 patients in the study). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1088 AN4863-5 CD274 Expression CD274 NCBI:29126 gene lung squamous cell carcinoma DOID:3907 prognostic CIViC:272 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1088 AN4863-6 CD274 Expression CD274 NCBI:29126 gene melanoma DOID:1909 risk PubMed:26086854 Based on a meta-analysis of 20 trials (1475 patients), of which 7 studies (636 patients) included melanoma, PD-L1 expression was associated with a higher ORR rate in patients with melanoma. Active drugs were Nivolumab and Pembrolizumab, PD-1 receptor targeting antibodies. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1089 AN4863-6 CD274 Expression CD274 NCBI:29126 gene melanoma DOID:1909 risk PubMed:23724867 A clinical trial of 86 patients evaluated concurrent (n=53) or sequential (n=33) treatment of ipilimumab (anti-CTLA4) and nivolumab (anti-PD1). In the concurrent regimen cohort, 65% of patients showed clinical activity with no correlation between PD-L1 expression and response (6 of 13 patients were PD-L1 positive versus 9 of 22 patients were PD-L1 negative). In the sequential regimen cohort, 20% of patients had an objective response with a potential correlation between PD-L1 expression and response (4 of 8 patients were PD-L1 positive versus 1 of 13 patients were PD-L1 negative). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1089 AN4863-6 CD274 Expression CD274 NCBI:29126 gene melanoma DOID:1909 risk CIViC:272 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1089 AN4863-7 CD274 Expression CD274 NCBI:29126 gene Merkel cell carcinoma DOID:3965 risk PubMed:27093365 Patients with Merkel Cell Carcinoma (n=26) were enrolled to receive pembrolizumab. Of these patients, 25 were evaluated for response rate to pembrolizumab and PD-L1 (CD274) expression. The response rate to pembrolizumab was 56% (95%CI: 35-76%), however, there was no correlation between PD-L1 expression (cutoff >1%) on tumor cells or on infiltrating immune cells and clinical response to pembrolizumab (P=0.61). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1090 AN4863-7 CD274 Expression CD274 NCBI:29126 gene Merkel cell carcinoma DOID:3965 risk CIViC:272 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1090 AN4863-8 CD274 Expression CD274 NCBI:29126 gene ovarian serous carcinoma DOID:0050933 prognostic PubMed:26625204 High expression of PD-L1 and PD-1 were associated with a favorable prognosis in patients with high grade serous ovarian carcinoma (n = 215 cases). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1091 AN4863-8 CD274 Expression CD274 NCBI:29126 gene ovarian serous carcinoma DOID:0050933 prognostic CIViC:272 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1091 AN4863-9 CD274 Expression CD274 NCBI:29126 gene stomach carcinoma DOID:5517 prognostic PubMed:27009855 465 gastric cancer samples and 15 corresponding liver metastases underwent IHC for PD1/PD-L1 protein expression. PD-L1 positivity in tumor cells was defined by at least 2% tumor cells with membranous positivity, PD-L1 positivity in immune cells by at least 10% PD-L1 positive immune cells. Patients with PD-L1 positive tumor cells had a significant better overall (p=0.028) and tumor specific survival (p=0.018). The same applied for patients with PD-L1 positive immune cells (p<0.001 each). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1092 AN4863-9 CD274 Expression CD274 NCBI:29126 gene stomach carcinoma DOID:5517 prognostic CIViC:272 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1092 AN4863-10 CD274 Expression CD274 NCBI:29126 gene thyroid gland papillary carcinoma DOID:3969 prognostic PubMed:27086918 Immunohistochemical analyses of PD-L1 protein was retrospectively performed on 251 archived FFPE surgical tissues (66 benign thyroid nodules and 185 papillary thyroid carcinomas PTC, E1L3N antibody). Patients with increased PD-L1 protein had significantly shorter median DFS (36 months [membranous staining] and 49 months [cytoplasmic staining] vs. 186 months [negative], p < 0.001 and p < 0.01, respectively). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1093 AN4863-10 CD274 Expression CD274 NCBI:29126 gene thyroid gland papillary carcinoma DOID:3969 prognostic CIViC:272 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD274/NCBI:29126 1093 AN4864-1 CD44 CD44s Expression CD44 NCBI:960 gene cancer DOID:162 risk PubMed:25762343 CD44 isoform expression (especially CD44s) was identified to predict response to CD44 antibody RG7356 preclinically. Retrospective evaluation of 13 patients from a phase 1 study, treated with RG7356, identified 3 patients with CD44s isoform. 2/3 patients with CD44s had SD as best response. Overall, 5 patients had an OR. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD44/NCBI:960 1094 AN4864-1 CD44 CD44s Expression CD44 NCBI:960 gene cancer DOID:162 risk CIViC:337 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CD44/NCBI:960 1094 AN4865-1 CD44 CD44v6 mutation CD44 NCBI:960 gene ovarian cancer DOID:2394 prognostic PubMed:26250934 In a clinical study including 59 stage III-IV ovarian cancer patients with peritoneal disseminated tumors, Kaplan-Meier analysis showed a significant association between CD44v6 high expression and worse OS (P=0.0059), but not PFS (P=0.4290). Similarly, high CD44v6 expression was found to be a predictive factor by univariate (P = 0.007; HR, 2.930; 95% CI, 1.334–6.436) and multivariate (P = 0.022; HR, 2.568; 95% CI, 1.149–5.738) analyses. In vivo experiments showed that CD44v6-positive ES-2 cells produced larger tumors and more frequent metastases than CD44v6-negative cells, when implanted in nude mice. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::cd44v6:mutation sequence variation in gene CD44/NCBI:960 1095 check_entity AN4865-1 CD44 CD44v6 mutation CD44 NCBI:960 gene ovarian cancer DOID:2394 prognostic CIViC:3241 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::cd44v6:mutation sequence variation in gene CD44/NCBI:960 1095 check_entity AN4866-1 CDH1 MUTATION CDH1 NCBI:999 gene stomach carcinoma DOID:5517 prognostic 21652-3 PubMed:27313181 285 intestinal-type tumors and 183 diffuse-type tumors were evaluated for mutational profiles. CDH1 mutations are associated with diffuse type mucinous gastric carcinoma, which indicate worse prognosis when compared to intestinal type (p<0.001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CDH1/NCBI:999 1096 check_entity AN4866-1 CDH1 MUTATION CDH1 NCBI:999 gene stomach carcinoma DOID:5517 prognostic 21652-3 CIViC:660 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CDH1/NCBI:999 1096 check_entity AN4867-1 CDK12 Loss-of-function CDK12 NCBI:51755 gene ovarian serous carcinoma DOID:0050933 risk PubMed:24240700 In models of high-grade serous ovarian cancer (HGS-OVCa), CDK12 attenuation was sufficient to confer sensitivity to PARP1/2 inhibition, suppression of DNA repair via homologous recombination, and reduced expression of BRCA1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDK12 Loss-of-function [biomarker_term_in_review] 1097 not_mapped AN4867-1 CDK12 Loss-of-function CDK12 NCBI:51755 gene ovarian serous carcinoma DOID:0050933 risk CIViC:232 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDK12 Loss-of-function [biomarker_term_in_review] 1097 not_mapped AN4868-1 CDK12 Mutation CDK12 NCBI:51755 gene castration-resistant prostate carcinoma DOID:0080909 risk PubMed:32343890 This randomized, open-label, phase 3 trial evaluated the PARP inhibitor olaparib in 387 men with metastatic castration-resistant prostate cancer (mCRPC) who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). The study found that in men with mCRPC who had somatic or germline deleterious alterations (irrespective of zygosity) in any of the following HRR genes (BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L), olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone (PFS HR 0.49 [0.38, 0.63]). For 99 patients with CDK12 mutations specifically, PFS HR 0.74 [0.44-1.31]. Based on the results of this study, on May 19, 2020, the Food and Drug Administration approved olaparib (LYNPARZA) for adult patients with deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC, who have progressed following prior treatment with enzalutamide or abiraterone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CDK12/NCBI:51755 1098 check_entity AN4868-1 CDK12 Mutation CDK12 NCBI:51755 gene castration-resistant prostate carcinoma DOID:0080909 risk CIViC:2633 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CDK12/NCBI:51755 1098 check_entity AN4869-1 CDK4 Amplification CDK4 NCBI:1019 gene liposarcoma DOID:3382 risk 57927-6 PubMed:23569312 In a phase 2 clinical trial, NCT01209598, 30 patients with CDK4-amplified and RB-expressing well differentiated and dedifferentiated liposarcomas (WDLS/DDLS) were treated with a selective CDK 4/6 inhibitor, PD0332991. Treatment with PD0332991 was associated with favorable progression free survival rates (66% PFS rate, primary end point being greater than 40%) suggesting that CDK4 amplification is predictive of sensitivity to CDK4 inhibitor therapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CDK4/NCBI:1019 1099 AN4869-1 CDK4 Amplification CDK4 NCBI:1019 gene liposarcoma DOID:3382 risk 57927-6 PubMed:27124835 A total of 59 patients with well-differentiated or dedifferentiated liposarcomas were enrolled in a phase 2 study to evaluate palbociclib efficacy. Half of the patients had received prior treatment and half were treatment naive. Of the 59 patients, at least 34 conferred CDK4 amplification and the remaining were not tested for CDK4 amplification. In the initial cohort (n=28), where all patients had confirmed CDK4 amplification, at least 14 of the patients were progression free at 12 weeks. Overall progression-free survival at 12 weeks was 57.2% and overall median PFS was 17.9 weeks. There was 1 complete response. Toxic effects were primarily hematologic and included neutropenia (grade 3, n = 20 [33%]; grade 4, n = 2 [3%]) but no neutropenic fever. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CDK4/NCBI:1019 1099 AN4869-1 CDK4 Amplification CDK4 NCBI:1019 gene liposarcoma DOID:3382 risk 57927-6 CIViC:549 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene CDK4/NCBI:1019 1099 AN4870-1 CDK4 EXPRESSION CDK4 NCBI:1019 gene childhood B-cell acute lymphoblastic leukemia DOID:0080146 risk 57927-6 PubMed:29408328 CDK4 was found to be significantly overexpressed in the bone marrow of MLL-rearranged B-ALL patients (n=70) compared to normal bone marrow (n=74, p<.001). Combination treatment with dexamethasone (glucocorticoid) and Ribociclib (a highly selective CDK4 / CDK6 inhibitor) of both glucocorticoid sensitive (Rs4;11 & NALM6) and glucocorticoid resistant (RCH-ACV & SEM) B-ALL cell lines synergistically reduced cell viability of all four lines greater than individual drug exposures. Combination therapy also synergistically reduced the cell viability of 5 primary B-ALL lines derived from diagnosis bone marrow compared to individual treatment. (Note: Expression of CDK4 was not quantitatively measured in the derived and primary B-ALL lines used). Further investigation in RCH-ACV and SEM lines revealed dexamethasone and Ribociclib combined increased apoptosis (annexin-V) and increased G1 arrest along with increased p16 (a CDK4 & CDK6 inhibitor) and decreased phosphorylation of downstream G1 to S cell cycle progression markers compared to single treatments. Combination treatment also led to the increase of NR3C1 expression. Knockdown of CDK4 and CDK6 by siRNAs in RCH-ACV sensitized these cells to dexamethasone treatment and increased NR3C1 expression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDK4/NCBI:1019 1100 AN4870-1 CDK4 EXPRESSION CDK4 NCBI:1019 gene childhood B-cell acute lymphoblastic leukemia DOID:0080146 risk 57927-6 CIViC:25 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDK4/NCBI:1019 1100 AN4870-2 CDK4 EXPRESSION CDK4 NCBI:1019 gene estrogen-receptor positive breast cancer DOID:0060075 risk 57927-6 PubMed:25002028 In mouse xenograft studies of PIK3CA mutant breast cancers, the combination of PI3K and CDK4/6 inhibitors overcomes intrinsic and adaptive resistance leading to tumor regressions. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDK4/NCBI:1019 1101 AN4870-2 CDK4 EXPRESSION CDK4 NCBI:1019 gene estrogen-receptor positive breast cancer DOID:0060075 risk 57927-6 CIViC:25 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDK4/NCBI:1019 1101 AN4870-3 CDK4 EXPRESSION CDK4 NCBI:1019 gene sarcoma DOID:1115 risk 57927-6 PubMed:26528855 A preclinical study to explore the efficacy of CDK4/6 inhibition with palbociclib, in a panel of sarcoma cell lines and sarcoma tumor xenografts (PDXs). The responsiveness of these cell lines correlated with their levels of CDK4 mRNA as well as in vivo PDX, but not against sarcomas displaying low levels of CDK4 and high levels of p16ink4a (CDKN2A). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDK4/NCBI:1019 1102 AN4870-3 CDK4 EXPRESSION CDK4 NCBI:1019 gene sarcoma DOID:1115 risk 57927-6 CIViC:25 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDK4/NCBI:1019 1102 AN4871-1 CDK4 R24C mutation CDK4 NCBI:1019 gene skin melanoma DOID:8923 risk 57927-6 PubMed:24495407 In a cohort of 143 patients with primary invasive melanoma, copy-number gain of CDK4 was observed (FISH) in 37% of cases. PD0332991 efficacy (proliferation assay) was assessed in a panel of 47 melanoma cell lines. Four cell lines had an R24C activating mutation in CDK4, three of these were sensitive to PD0332991 (palbociclib). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R24C sequence variation in gene CDK4/NCBI:1019 1103 check_entity AN4871-1 CDK4 R24C mutation CDK4 NCBI:1019 gene skin melanoma DOID:8923 risk 57927-6 CIViC:552 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R24C sequence variation in gene CDK4/NCBI:1019 1103 check_entity AN4872-1 CDK6 EXPRESSION CDK6 NCBI:1021 gene childhood B-cell acute lymphoblastic leukemia DOID:0080146 risk PubMed:29408328 CDK6 was found to be significantly overexpressed in the bone marrow of B-ALL patients (n=299) compared to normal bone marrow (n=74, p<.001). Combination treatment with dexamethasone (glucocorticoid) and Ribociclib (a highly selective CDK4 / CDK6 inhibitor) of both glucocorticoid sensitive (Rs4;11 & NALM6) and glucocorticoid resistant (RCH-ACV & SEM) B-ALL cell lines synergistically reduced cell viability of all four lines greater than individual drug exposures. Combination therapy synergistically reduced the cell viability of 5 primary B-ALL lines derived from diagnosis bone marrow compared to individual treatment. (Note: Expression of CDK6 was not quantitatively measured in the derived and primary B-ALL lines used). Further investigation in RCH-ACV and SEM revealed dexamethasone and Ribociclib combined increased apoptosis (annexin-V) and increased G1 arrest along with increased p16 (a CDK4 & CDK6 inhibitor) expression and decreased phosphorylation of downstream G1 to S cell cycle progression markers compared to single treatments. Combination treatment also led to the increase of NR3C1 expression. Knockdown of CDK4 and CDK6 by siRNAs in RCH-ACV sensitized these cells to dexamethasone treatment and increased NR3C1 expression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDK6/NCBI:1021 1104 AN4872-1 CDK6 EXPRESSION CDK6 NCBI:1021 gene childhood B-cell acute lymphoblastic leukemia DOID:0080146 risk CIViC:2911 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDK6/NCBI:1021 1104 AN4873-1 CDK6 Overexpression CDK6 NCBI:1021 gene estrogen-receptor positive breast cancer DOID:0060075 risk PubMed:27252418 In two cohorts (n=45 and n=46) of ER+ breast cancer patients who had received fulvestrant, CDK6 overexpression correlated with shorter median time to progression in both cohorts (2.5 vs. 8.2 months and 3.4 vs. 8.9 months for CDK6 overexpression vs. normal expression). CDK6 expression did not correlate with other lines of treatment (N=68, tamoxifen or endocrine therapy). Four fulvestrant-resistant cell lines were derived from estrogen responsive and fulvestrant sensitive parental breast cancer cell line MCF-7/SO.5. Gene expression profiling showed upregulation of CDK6 in the fulvestrant resistant derivatives. Knockdown of CDK6 in these derivative cells resulted in fulvestrant sensitivity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CDK6/NCBI:1021 1105 AN4873-1 CDK6 Overexpression CDK6 NCBI:1021 gene estrogen-receptor positive breast cancer DOID:0060075 risk CIViC:598 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CDK6/NCBI:1021 1105 AN4873-2 CDK6 Overexpression CDK6 NCBI:1021 gene glioblastoma proneural subtype DOID:0050804 risk PubMed:28903422 In this study twelve GBM cell lines and normal human astrocytes (NHA) were treated with the CDK4/6 inhibitor palbociclib. NHA and several GBM cell lines were resistant to palbociclib with IC50 values greater than 1000 nM, while six of seven proneural subtype GBM lines were highly sensitive (IC50 9-210 nM). Palbociclib treatment induced cell accumulation in G1 phase in 3 sensitive proneural lines, but not in 3 resistant lines. Treatment with vehicle versus oral palbociclib (150 mg/kg/day) was compared in mice with intracranial implantation of proneural GBM stem cell-like G448 cells, which are shown to have higher than normal expression of CDK6. Mice receiving palbociclib had significantly longer survival time (p=0.038). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CDK6/NCBI:1021 1106 AN4873-2 CDK6 Overexpression CDK6 NCBI:1021 gene glioblastoma proneural subtype DOID:0050804 risk CIViC:598 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CDK6/NCBI:1021 1106 AN4874-1 CDKN1A EXPRESSION CDKN1A NCBI:1026 gene colorectal cancer DOID:9256 risk PubMed:24708484 112 patients with rectal cancer who received 5-FU based chemotherapy and surgery were retrospectively analyzed for expression of Ki67, TS, BAX, EpCAM, p53, p21, EGFR, CD44, CD133, CD166, HIF1α and ALDH1. High pretreatment p21 (CDKN1A) expression was significantly associated with non-pCR (p = 0.022) and poor disease free survival (median DFS - low vs high p21: 75.8 vs 58.1 months, p = 0.002). Multivariate analysis was also significant (p = 0.001, HR 6.14; 95% CI 2.03, 18.55). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDKN1A/NCBI:1026 1107 AN4874-1 CDKN1A EXPRESSION CDKN1A NCBI:1026 gene colorectal cancer DOID:9256 risk CIViC:351 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDKN1A/NCBI:1026 1107 AN4875-1 CDKN1A rs1059234 mutation CDKN1A NCBI:1026 gene retinoblastoma DOID:768 diagnostic PubMed:24045412 This study examined two CDKN1A polymorphisms (rs1801270 and rs1059234) in 141 carriers of RB1 variants and 120 unrelated healthy individuals. Authors found that RB1 carriers were more likely to have the non-wildtype CT genotype for rs1059234 than healthy controls (p=0.0065), and the chance of developing retinoblastoma increased 2.15 fold with the CT genotype compared to the wildtype CC genotype (OR: 2.15, 95% CI: 1.23-3.76). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::rs1059234 sequence variation in gene CDKN1A/NCBI:1026 1108 check_entity AN4875-1 CDKN1A rs1059234 mutation CDKN1A NCBI:1026 gene retinoblastoma DOID:768 diagnostic CIViC:3181 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::rs1059234 sequence variation in gene CDKN1A/NCBI:1026 1108 check_entity AN4876-1 CDKN1A rs1801270 mutation CDKN1A NCBI:1026 gene retinoblastoma DOID:768 diagnostic PubMed:24045412 This study examined two CDKN1A polymorphisms (rs1801270 and rs1059234) in 141 carriers of RB1 variants and 120 unrelated healthy individuals. Authors found that RB1 carriers were more likely to have the non-wildtype CA genotype for rs1801270 than healthy controls (p=0.0117), and the chance of developing retinoblastoma increased 1.98 fold with the CA genotype compared to the wildtype CC genotype (OR: 1.98, 95% CI: 1.16-3.37). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::rs1801270 sequence variation in gene CDKN1A/NCBI:1026 1109 check_entity AN4876-1 CDKN1A rs1801270 mutation CDKN1A NCBI:1026 gene retinoblastoma DOID:768 diagnostic CIViC:2540 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::rs1801270 sequence variation in gene CDKN1A/NCBI:1026 1109 check_entity AN4877-1 CDKN1B CYTOPLASMIC MISLOCALIZATION CDKN1B NCBI:1027 gene breast cancer DOID:1612 risk 75388-9 PubMed:25587029 Cytoplasmic localization of p27 (CDKN1B) leads to lapatinib resistance in HER2+ breast cancer cell lines. p27 knockout resensitiuzed cells to lapatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN1B CYTOPLASMIC MISLOCALIZATION [biomarker_term_in_review] 1110 not_mapped AN4877-1 CDKN1B CYTOPLASMIC MISLOCALIZATION CDKN1B NCBI:1027 gene breast cancer DOID:1612 risk 75388-9 CIViC:356 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN1B CYTOPLASMIC MISLOCALIZATION [biomarker_term_in_review] 1110 not_mapped AN4878-1 CDKN1B EXPRESSION CDKN1B NCBI:1027 gene head and neck squamous cell carcinoma DOID:5520 risk 75388-9 PubMed:24239278 41 HNSSC were analyzed by IHC for expression of EGFR, p53, CCND1, p16, p21, p27 (CDKN2B), p-AKT, HIF-1a, Caspase 3 and BCL2. p27 was the only protein that served as a predictive biomarker of response after multivariate analysis (p=0.025; n=41 patients). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDKN1B/NCBI:1027 1111 AN4878-1 CDKN1B EXPRESSION CDKN1B NCBI:1027 gene head and neck squamous cell carcinoma DOID:5520 risk 75388-9 CIViC:368 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDKN1B/NCBI:1027 1111 AN4879-1 CDKN2A Deletion CDKN2A NCBI:1029 gene childhood low-grade glioma DOID:0080830 prognostic 57927-6 PubMed:29948154 CDKN2A deletion was identified in 24 of 273 patients with PLGGs using FISH analysis. An association between this alteration and BRAFV600E was detected (p=0.0001). Hemispheric tumors with CDKN2A deletion were associated with shorter progression-free survival (p=0.0073) but did not affect overall survival (p=0.5) [mt (n=10) vs wt (n=59)]. CDKN2A deletion remained an independent prognostic factor in multivariate analysis for PFS [HR 4.38 (95% CI 1.05–18.23); p = 0.043]. CDKN2A deletion was not a prognostic factor in midline or cerebellar tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene CDKN2A/NCBI:1029 1112 check_entity AN4879-1 CDKN2A Deletion CDKN2A NCBI:1029 gene childhood low-grade glioma DOID:0080830 prognostic 57927-6 CIViC:2523 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene CDKN2A/NCBI:1029 1112 check_entity AN4880-1 CDKN2A Loss CDKN2A NCBI:1029 gene acute lymphoblastic leukemia DOID:9952 prognostic 57927-6 PubMed:30592434 A total of thirteen studies including 2857 patients were combined in a meta-analysis. Combined HRs suggested that CDKN2A/B deletions were poor prognostic factors for both overall survival (OS) (HR = 2.15, 95% CI 1.82-2.54) and event-free survival (EFS)/disease-free survival (DFS)/relapse-free survival (RFS) (HR = 2.16, 95% CI 1.73-2.69). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Loss [biomarker_term_in_review] 1113 not_mapped AN4880-1 CDKN2A Loss CDKN2A NCBI:1029 gene acute lymphoblastic leukemia DOID:9952 prognostic 57927-6 CIViC:550 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Loss [biomarker_term_in_review] 1113 not_mapped AN4880-2 CDKN2A Loss CDKN2A NCBI:1029 gene biliary tract cancer DOID:4607 risk 57927-6 PubMed:35100714 A phase II clinical study conducted in 10 patients with biliary cancer with CDKN2A loss or mutation, that were treated with palbociclib. No clinical activity demonstrated in patients with CDKN2A mutated/deleted biliary cancer at 16 weeks. A PFS of 7.3 weeks (90% CI; 3.9 - 7.9) and OS of 11.1 weeks (90% CI; 5.1 - 14) noted in the patients with no unexpected toxicities from palbociclib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Loss [biomarker_term_in_review] 1114 not_mapped AN4880-2 CDKN2A Loss CDKN2A NCBI:1029 gene biliary tract cancer DOID:4607 risk 57927-6 CIViC:4716 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Loss [biomarker_term_in_review] 1114 not_mapped AN4880-3 CDKN2A Loss CDKN2A NCBI:1029 gene dermatofibrosarcoma protuberans DOID:3507 risk 57927-6 PubMed:25852058 An imatinib-resistant cell line, DFSP105, was established from a dermatofibrosarcoma protuberans which had progressed to a high-grade fibrosarcomatous DFSP. The disease-associated COL1A1-PDGFB fusion was consistent with the most common form, a supernumerary ring chromosome. Genetic characterization of the cell line with a SNP array identified a homozygous CDKN2A/B deletion. Treatment of this cell line with CDK4/6 inhibitor palbociclib led to growth inhibition and reduced RB1 phosphorylation in vitro and in-vivo. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Loss [biomarker_term_in_review] 1115 not_mapped AN4880-3 CDKN2A Loss CDKN2A NCBI:1029 gene dermatofibrosarcoma protuberans DOID:3507 risk 57927-6 CIViC:550 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Loss [biomarker_term_in_review] 1115 not_mapped AN4880-4 CDKN2A Loss CDKN2A NCBI:1029 gene Ewing sarcoma DOID:3369 risk 57927-6 PubMed:27286459 A patient-derived xenograft (PDX) from a patient with cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) loss and FUS-ERG fusion positive Ewing's sarcoma was created. The PDX was treated in four cohorts (each N=6) with control, doxorubicin, CDK4/6 inhibitor palbociclib or IGF-1R inhibitor linsitinib. Both linsitinib and palbociclib cohorts were significantly more effective than control and doxorubicin. Doxorubicin was part of the patient's treatment (Neoadjuvant chemotherapy with DOX, vincristine, and cyclophosphamide) and was noted by authors as failing to control tumor growth. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Loss [biomarker_term_in_review] 1116 not_mapped AN4880-4 CDKN2A Loss CDKN2A NCBI:1029 gene Ewing sarcoma DOID:3369 risk 57927-6 CIViC:550 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Loss [biomarker_term_in_review] 1116 not_mapped AN4880-5 CDKN2A Loss CDKN2A NCBI:1029 gene Her2-receptor negative breast cancer DOID:0060080 risk 57927-6 PubMed:26715889 A patient with metastatic ER-positive, her2-negative breast cancer with CDKN2A loss experienced a short-lived (~3-month) clinical response to palbociclib when given in combination with letrozole. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Loss [biomarker_term_in_review] 1117 not_mapped AN4880-5 CDKN2A Loss CDKN2A NCBI:1029 gene Her2-receptor negative breast cancer DOID:0060080 risk 57927-6 CIViC:550 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Loss [biomarker_term_in_review] 1117 not_mapped AN4880-6 CDKN2A Loss CDKN2A NCBI:1029 gene lung non-small cell carcinoma DOID:3908 risk 57927-6 PubMed:174591 TAPUR, a phase II basket trial, included a cohort of patients with advanced non-small lung cell carcinoma (NSCLC) harboring with CDKN2A loss or mutation and no RB mutations. Twenty-nine patients were treated with CDK4/6 inhibitor palbociclib; one experienced a partial response and 6 experienced stable disease lasting longer than 16 weeks (disease control rate: 29%). Median PFS was 7.9 weeks and median OS was 20.6 weeks. Authors concluded that palbociclib is worthy of further study in advanced NSCLC when standard treatment options aren't available. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Loss [biomarker_term_in_review] 1118 not_mapped AN4880-6 CDKN2A Loss CDKN2A NCBI:1029 gene lung non-small cell carcinoma DOID:3908 risk 57927-6 PubMed:35050752 A phase II clinical study was conducted with 29 patients with Non-Small-Cell Lung Cancer harboring CDKN2A alterations and wild-type Rb. The study reported one patient with a partial response, and six patients with SD for a duration of at least 16 weeks. The disease control rate was 31% (90% CI, 19-40). The PFS and OS observed were 8.1 weeks (95% CI, 7.1 - 16.0) and 21.6 weeks (95% CI. 14.1-41.1) respectively. At least one grade 3 or 4 adverse event or serious adverse event was reported in 11 patients, likely associated with palbociclib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Loss [biomarker_term_in_review] 1118 not_mapped AN4880-6 CDKN2A Loss CDKN2A NCBI:1029 gene lung non-small cell carcinoma DOID:3908 risk 57927-6 CIViC:550 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Loss [biomarker_term_in_review] 1118 not_mapped AN4880-6 CDKN2A Loss CDKN2A NCBI:1029 gene lung non-small cell carcinoma DOID:3908 risk 57927-6 CIViC:4750 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Loss [biomarker_term_in_review] 1118 not_mapped AN4880-7 CDKN2A Loss CDKN2A NCBI:1029 gene ovarian cancer DOID:2394 risk 57927-6 PubMed:21278246 Preclinical study of the effects of PD-0332991 on proliferation, cell-cycle, apoptosis, and Rb phosphorylation in a panel of 40 human ovarian cancer cell lines. Concentration-dependent antiproliferative effects of PD-0332991 were seen in all ovarian cancer cell lines, but varied significantly between individual lines. Rb-proficient cell lines with low p16 expression were significantly more sensitive to PD-0332991 (as defined by IC50 < mean) in mRNA expression (Agilent), protein level (Western Blot) and copy number (Array CGH) analyses. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Loss [biomarker_term_in_review] 1119 not_mapped AN4880-7 CDKN2A Loss CDKN2A NCBI:1029 gene ovarian cancer DOID:2394 risk 57927-6 CIViC:550 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Loss [biomarker_term_in_review] 1119 not_mapped AN4880-8 CDKN2A Loss CDKN2A NCBI:1029 gene pancreatic cancer DOID:1793 risk 57927-6 PubMed:35100714 A phase II clinical study conducted with 12 patients with pancreatic cancer with CDKN2A loss or mutation treated with palbociclib. No clinical activity demonstrated in patients with CDKN2A mutated/deleted pancreatic adenocarcinoma. A PFS of 7.2 weeks (90% CI; 4 - 8) and OS of 12.4 weeks (90% CI; 4.7 - 23.1) noted in the patients with no unexpected toxicities from palbociclib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Loss [biomarker_term_in_review] 1120 not_mapped AN4880-8 CDKN2A Loss CDKN2A NCBI:1029 gene pancreatic cancer DOID:1793 risk 57927-6 CIViC:4716 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Loss [biomarker_term_in_review] 1120 not_mapped AN4880-9 CDKN2A Loss CDKN2A NCBI:1029 gene renal cell carcinoma DOID:4450 risk 57927-6 PubMed:23898052 Preclinical study of CDK4/6 inhibitor PD-0332991 in 28 renal carcinoma cell lines (25 malignant RCC and three non-malignant, transformed cell lines derived from kidney epithelium). Both p15 and p16 loss (CGH) were tested for association with response to PD-0332991 using Fisher's exact test. Cell lines with p16 and p15 losses were significantly more likely to be classified as responders (defined by pharmacokinetic data-based concentration of <=400nM) to PD-0332991 (p=0.027, relative risk (RR)=2.06 and p=0.047, RR=1.71, respectively). Four cell lines had homozygous deletions of CDKN2A but not CDKN2B, and three of these lines were classified as being sensitive to PD-0332991. There were no cell lines with only CDKN2B deletion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Loss [biomarker_term_in_review] 1121 not_mapped AN4880-9 CDKN2A Loss CDKN2A NCBI:1029 gene renal cell carcinoma DOID:4450 risk 57927-6 CIViC:550 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Loss [biomarker_term_in_review] 1121 not_mapped AN4880-10 CDKN2A Loss CDKN2A NCBI:1029 gene skin melanoma DOID:8923 risk 57927-6 PubMed:12777976 Preclinical study in 9 melanoma cell lines. Three cell lines did not have CDKN2A (p16) mutations and showed expression of the protein on western blot analysis. Two of the other six cell lines had stop codons leading to a truncated protein, and three had missense mutations with evidence of protein expression on western blot (two cell lines with a P114L mutation and one with an E88K mutation). Mean IC50s of flavopiridol were significantly lower in cell lines with a mutated or non-expressed p16 (p16-) (mean 50% inhibitory concentration [IC(50)] = 12.5 nM), than in cell lines with intact p16 (p16+) (mean IC(50) = 25 nM). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Loss [biomarker_term_in_review] 1122 not_mapped AN4880-10 CDKN2A Loss CDKN2A NCBI:1029 gene skin melanoma DOID:8923 risk 57927-6 PubMed:24495407 In a cohort of 143 patients with primary invasive melanoma hemizygous or homozygous loss of CDKN2A was observed (FISH) in 56% of cases. PD0332991 efficacy (proliferation assay) was assessed in a panel of 47 melanoma cell lines. Loss of functional p16INK4A (CDKN2A) due to gene deletion (49% of cells), methylation (4% of cells), or mutation (19% of cells) was the most prevalent alteration occurring in 71% of cell lines, and significantly correlated with PD0332991 sensitivity (Fisher's exact test P < 0.02). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Loss [biomarker_term_in_review] 1122 not_mapped AN4880-10 CDKN2A Loss CDKN2A NCBI:1029 gene skin melanoma DOID:8923 risk 57927-6 CIViC:550 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Loss [biomarker_term_in_review] 1122 not_mapped AN4881-1 CDKN2A Mutation CDKN2A NCBI:1029 gene biliary tract cancer DOID:4607 risk 57927-6 PubMed:35100714 A phase II clinical study conducted in 10 patients with biliary cancer with CDKN2A loss or mutation, that were treated with palbociclib. No clinical activity demonstrated in patients with CDKN2A mutated/deleted biliary cancer at 16 weeks. A PFS of 7.3 weeks (90% CI; 3.9 - 7.9) and OS of 11.1 weeks (90% CI; 5.1 - 14) noted in the patients with no unexpected toxicities from palbociclib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CDKN2A/NCBI:1029 1123 check_entity AN4881-1 CDKN2A Mutation CDKN2A NCBI:1029 gene biliary tract cancer DOID:4607 risk 57927-6 CIViC:4716 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CDKN2A/NCBI:1029 1123 check_entity AN4881-2 CDKN2A Mutation CDKN2A NCBI:1029 gene cholangiocarcinoma DOID:4947 risk 57927-6 PubMed:158598 In a phase 2 trial, patients with gallbladder cancer or bile duct cancer with CDKN2A loss or mutation were received palbociclib. Among 10 patients, no overall response or stable disease at 16 weeks were observed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CDKN2A/NCBI:1029 1124 check_entity AN4881-2 CDKN2A Mutation CDKN2A NCBI:1029 gene cholangiocarcinoma DOID:4947 risk 57927-6 CIViC:2573 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CDKN2A/NCBI:1029 1124 check_entity AN4881-3 CDKN2A Mutation CDKN2A NCBI:1029 gene pancreatic cancer DOID:1793 risk 57927-6 PubMed:158598 In a phase 2 trial, patients with pancreatic cancer with CDKN2A loss or mutation were received palbociclib. Among 12 patients no overall response or stable disease at 16 weeks were observed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CDKN2A/NCBI:1029 1125 check_entity AN4881-3 CDKN2A Mutation CDKN2A NCBI:1029 gene pancreatic cancer DOID:1793 risk 57927-6 PubMed:35100714 A phase II clinical study conducted with 12 patients with pancreatic cancer with CDKN2A loss or mutation treated with palbociclib. No clinical activity demonstrated in patients with CDKN2A mutated/deleted pancreatic adenocarcinoma. A PFS of 7.2 weeks (90% CI; 4 - 8) and OS of 12.4 weeks (90% CI; 4.7 - 23.1) noted in the patients with no unexpected toxicities from palbociclib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CDKN2A/NCBI:1029 1125 check_entity AN4881-3 CDKN2A Mutation CDKN2A NCBI:1029 gene pancreatic cancer DOID:1793 risk 57927-6 CIViC:2573 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CDKN2A/NCBI:1029 1125 check_entity AN4881-3 CDKN2A Mutation CDKN2A NCBI:1029 gene pancreatic cancer DOID:1793 risk 57927-6 CIViC:4716 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CDKN2A/NCBI:1029 1125 check_entity AN4881-4 CDKN2A Mutation ) CDKN2A NCBI:1029 gene lung non-small cell carcinoma DOID:3908 risk 57927-6 PubMed:35050752 A phase II clinical study was conducted with 29 patients with Non-Small-Cell Lung Cancer harboring CDKN2A alterations and wild-type Rb. The study reported one patient with a partial response, and six patients with SD for a duration of at least 16 weeks. The disease control rate was 31% (90% CI, 19-40). The PFS and OS observed were 8.1 weeks (95% CI, 7.1 - 16.0) and 21.6 weeks (95% CI. 14.1-41.1) respectively. At least one grade 3 or 4 adverse event or serious adverse event was reported in 11 patients, likely associated with palbociclib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation:) sequence variation in gene CDKN2A/NCBI:1029 1126 check_entity AN4881-4 CDKN2A Mutation ) CDKN2A NCBI:1029 gene lung non-small cell carcinoma DOID:3908 risk 57927-6 CIViC:4750 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation:) sequence variation in gene CDKN2A/NCBI:1029 1126 check_entity AN4882-1 CDKN2A Promoter Hypermethylation CDKN2A NCBI:1029 gene lung non-small cell carcinoma DOID:3908 prognostic 57927-6 PubMed:23111194 In NSCLC patients younger than 60 years at age of diagnosis, p16 (CDKN2A) promoter hypermethylation is associated with shorter time to recurrence and shorter overall survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Promoter Hypermethylation [biomarker_term_in_review] 1127 not_mapped AN4882-1 CDKN2A Promoter Hypermethylation CDKN2A NCBI:1029 gene lung non-small cell carcinoma DOID:3908 prognostic 57927-6 CIViC:27 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2A Promoter Hypermethylation [biomarker_term_in_review] 1127 not_mapped AN4883-1 CDKN2A RS3814960 mutation CDKN2A NCBI:1029 gene esophagus squamous cell carcinoma DOID:3748 prognostic 57927-6 PubMed:27414035 124 esophageal squamous cell carcinoma patients with radical resection were genotyped using MassArray. The TC/CC genotype of p14ARF at rs3814960 had decreased overall survival (HR = 2.77, 95% CI: 1.33–5.75, P = 0.006, Pc = 0.030) and decreased disease-free survival (DFS) (HR = 2.45, 95% CI: 1.30–4.61, P = 0.005) compared to patients without this mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS3814960 sequence variation in gene CDKN2A/NCBI:1029 1128 check_entity AN4883-1 CDKN2A RS3814960 mutation CDKN2A NCBI:1029 gene esophagus squamous cell carcinoma DOID:3748 prognostic 57927-6 CIViC:637 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS3814960 sequence variation in gene CDKN2A/NCBI:1029 1128 check_entity AN4884-1 CDKN2A c.151-1G>C mutation CDKN2A NCBI:1029 gene melanoma DOID:1909 diagnostic 57927-6 PubMed:11433531 Skipping of exon 2 of both the CDKN2A p14 and p16 isoform transcripts was detected by RT-PCR in a lymphoblastoid cell line derived from a patient carrying the c.151-1G>C variant. The novel CDKN2A splicing variant segregated with disease in a displastic nevous family. The authors state this finding provides further evidence that the disruption of CDKN2A can be predisposing for nervous system tumors, melanomas and displastic nevi. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.151-1g>c:mutation sequence variation in gene CDKN2A/NCBI:1029 1129 check_entity AN4884-1 CDKN2A c.151-1G>C mutation CDKN2A NCBI:1029 gene melanoma DOID:1909 diagnostic 57927-6 CIViC:2753 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.151-1g>c:mutation sequence variation in gene CDKN2A/NCBI:1029 1129 check_entity AN4885-1 CDKN2A p16 Expression CDKN2A NCBI:1029 gene head and neck squamous cell carcinoma DOID:5520 prognostic;risk 57927-6 PubMed:24577117 In this retrospective analysis of the SPECTRUM trial, p16 (CDKN2A) expression (and HPV-infection) was not predictive of response to EGFR-targeted therapy in combination with chemotherapy (n = 416 patient tumors). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDKN2A/NCBI:1029 1130 AN4885-1 CDKN2A p16 Expression CDKN2A NCBI:1029 gene head and neck squamous cell carcinoma DOID:5520 prognostic;risk 57927-6 PubMed:24799460 p16 positivity, as a surrogate marker for HPV-associated HNSSC was a favorable prognostic marker in recurrent or metastatic carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDKN2A/NCBI:1029 1130 AN4885-1 CDKN2A p16 Expression CDKN2A NCBI:1029 gene head and neck squamous cell carcinoma DOID:5520 prognostic;risk 57927-6 PubMed:23746666 In this retrospective analysis of p16 status as surrogate marker for HPV in the SPECTRUM trial, p16 (CDKN2A) expression was not associated with improved response to EGFR-directed therapy (Panitumumab) in combination with chemotherapy compared to chemotherapy alone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDKN2A/NCBI:1029 1130 AN4885-1 CDKN2A p16 Expression CDKN2A NCBI:1029 gene head and neck squamous cell carcinoma DOID:5520 prognostic;risk 57927-6 PubMed:24577089 In this study response to EGFR-inhibition by cetuximab was independent of HPV-status, represented by expression of p16 (CDKN2A, an established biomarker of HPV infection). Expression of p16 was assayed in 69 HNSCC patients by IHC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDKN2A/NCBI:1029 1130 AN4885-1 CDKN2A p16 Expression CDKN2A NCBI:1029 gene head and neck squamous cell carcinoma DOID:5520 prognostic;risk 57927-6 PubMed:25267748 Patients from three studies (RTOG 0129, 0234, and 0522; 85, 95 and 142 patients, respectively) were retrospectively analyzed for p16 (CDKN2A) expression (IHC) and HPV-high risk status (ISH). p16 expression in non-oropharyngeal HNSSC was also prognostic and associated with a better outcome. However, p16-positive oropharyngeal HNSSC still had better PFS and OS than p16-positive non-oropharyngeal HNSSC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDKN2A/NCBI:1029 1130 AN4885-1 CDKN2A p16 Expression CDKN2A NCBI:1029 gene head and neck squamous cell carcinoma DOID:5520 prognostic;risk 57927-6 PubMed:25892145 Phase III trial to compare afatinib or metothrexate in recurrent or metastatic head and neck squamous cell carcinoma. 483 patients were randomized to either afatinib (n=322) or methotrexate (n=161). 285 patients were assessed for p16 Status (IHC). In the post-hoc analysis, benefit of afatinib compared with methotrexate was more pronounced in p16-negative disease (HR 0·69 [95% CI 0·50–0·96], p=0.022) than in p16-positive disease (HR 0·95 [CI 0·51–1·75], p=0.67, interaction test p=0·32). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDKN2A/NCBI:1029 1130 AN4885-1 CDKN2A p16 Expression CDKN2A NCBI:1029 gene head and neck squamous cell carcinoma DOID:5520 prognostic;risk 57927-6 CIViC:268 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDKN2A/NCBI:1029 1130 AN4885-2 CDKN2A p16 Expression CDKN2A NCBI:1029 gene lung non-small cell carcinoma DOID:3908 prognostic 57927-6 PubMed:22619677 In a cohort of 73 patients with stage I or stage II NSCLC it was discovered that the CDKN2A protein (p16-INK4A) retrospectively evaluated via IHC was associated with adverse outcomes (p=0.004). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDKN2A/NCBI:1029 1131 AN4885-2 CDKN2A p16 Expression CDKN2A NCBI:1029 gene lung non-small cell carcinoma DOID:3908 prognostic 57927-6 CIViC:268 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDKN2A/NCBI:1029 1131 AN4885-3 CDKN2A p16 Expression CDKN2A NCBI:1029 gene oropharynx cancer DOID:8557 prognostic;risk 57927-6 PubMed:20530316 720 patients with stage III/IV oropharyngeal cancer were retrospectively analyzed for p16 and HPV status. p16 and HPV-positivity correlated well and both showed improved overall-survival compared to patients with HPV-negative/p16 negative tumors. HPV/p16 status was shown to be a strong and independent risk factor in oropharyngeal carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDKN2A/NCBI:1029 1132 AN4885-3 CDKN2A p16 Expression CDKN2A NCBI:1029 gene oropharynx cancer DOID:8557 prognostic;risk 57927-6 PubMed:26712222 This study shows that benefit of EGFR inhibition in addition to radiotherapy was independent of p16/HPV status. 182 patients were evaluated. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDKN2A/NCBI:1029 1132 AN4885-3 CDKN2A p16 Expression CDKN2A NCBI:1029 gene oropharynx cancer DOID:8557 prognostic;risk 57927-6 CIViC:268 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDKN2A/NCBI:1029 1132 AN4886-1 CDKN2B Loss CDKN2B NCBI:1030 gene Ewing sarcoma DOID:3369 risk PubMed:27286459 A patient-derived xenograft (PDX) from a patient with cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) loss and FUS-ERG fusion positive Ewing's sarcoma was created. The PDX was treated in four cohorts (each N=6) with control, doxorubicin, CDK4/6 inhibitor palbociclib or IGF-1R inhibitor linsitinib. Both linsitinib and palbociclib cohorts were significantly more effective than control and doxorubicin. Doxorubicin was part of the patient's treatment (Neoadjuvant chemotherapy with DOX, vincristine, and cyclophosphamide) and was noted by authors as failing to control tumor growth. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2B Loss [biomarker_term_in_review] 1133 not_mapped AN4886-1 CDKN2B Loss CDKN2B NCBI:1030 gene Ewing sarcoma DOID:3369 risk CIViC:551 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2B Loss [biomarker_term_in_review] 1133 not_mapped AN4886-2 CDKN2B Loss CDKN2B NCBI:1030 gene renal cell carcinoma DOID:4450 risk PubMed:23898052 Preclinical study of CDK4/6 inhibitor PD-0332991 in 28 renal carcinoma cell lines (25 malignant RCC and three non-malignant, transformed cell lines derived from kidney epithelium). Both p15 and p16 loss (CGH) were tested for association with response to PD-0332991 using Fisher's exact test. Cell lines with p16 and p15 losses were significantly more likely to be classified as responders (defined by pharmacokinetic data-based concentration of <=400nM) to PD-0332991 (p=0.027, relative risk (RR)=2.06 and p=0.047, RR=1.71, respectively). Four cell lines had homozygous deletions of CDKN2A but not CDKN2B, and three of these lines were classified as being sensitive to PD-0332991. There were no cell lines with only CDKN2B deletion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2B Loss [biomarker_term_in_review] 1134 not_mapped AN4886-2 CDKN2B Loss CDKN2B NCBI:1030 gene renal cell carcinoma DOID:4450 risk CIViC:551 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2B Loss [biomarker_term_in_review] 1134 not_mapped AN4887-1 CDKN2B METHYLATION CDKN2B NCBI:1030 gene acute promyelocytic leukemia DOID:0060318 prognostic PubMed:16307009 This study analyses 45 new acute promyelocytic leukemia patients (22 male and 23 female). CDKN2B was found to be a negative prognostic biomarker for disease free survival (DFS). The 5-year DFS was 9.6% in methylated and 62.5% in unmethylated samples. While methylation also associated with young age, a multivariate analysis found CDKN2B methylation to be the only independent marker with significance (P=0.008) for DFS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2B METHYLATION [biomarker_term_in_review] 1135 not_mapped AN4887-1 CDKN2B METHYLATION CDKN2B NCBI:1030 gene acute promyelocytic leukemia DOID:0060318 prognostic CIViC:765 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CDKN2B METHYLATION [biomarker_term_in_review] 1135 not_mapped AN4888-1 CDX2 EXPRESSION CDX2 NCBI:1045 gene colorectal cancer DOID:9256 prognostic PubMed:26789870 Patients with stage II/III colorectal cancer were analyzed for expression of CDX2 (by microarray and IHC). In the discovery (466 patients) and validation sets (314 patients), 5-year DFS was lower among patients with CDX2 negative tumors (discovery set:hazard ratio for disease recurrence, 3.44; 95% confidence interval [CI], 1.60 to 7.38; P=0.002; validation set: hazard ratio, 2.42; 95% CI, 1.36 to 4.29; P=0.003). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDX2/NCBI:1045 1136 AN4888-1 CDX2 EXPRESSION CDX2 NCBI:1045 gene colorectal cancer DOID:9256 prognostic CIViC:406 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CDX2/NCBI:1045 1136 AN4889-1 CEBPA BIALLELIC INACTIVATION CEBPA NCBI:1050 gene acute myeloid leukemia DOID:9119 prognostic 64012-8 PubMed:27276561 In a study of 1,540 patients with Acute Myeloid Leukemia, 66 patients (4%) had a CEBPA (biallelic) mutation. In the absence of gene fusion products, patients with biallelic CEBPA mutations showed the highest rate of survival (~78%) when compared to IDH2 (R172) mutations, NPM1(W288fs) mutations, chromatin-spliceosome mutations and TP53–aneuploidy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CEBPA BIALLELIC INACTIVATION [biomarker_term_in_review] 1137 not_mapped AN4889-1 CEBPA BIALLELIC INACTIVATION CEBPA NCBI:1050 gene acute myeloid leukemia DOID:9119 prognostic 64012-8 CIViC:590 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CEBPA BIALLELIC INACTIVATION [biomarker_term_in_review] 1137 not_mapped AN4890-1 CEBPA Mutation CEBPA NCBI:1050 gene acute myeloid leukemia DOID:9119 prognostic;risk 64012-8 PubMed:19965647 In a randomized trial of previously untreated younger (<60) patients with acute myeloid leukemia (excluding acute promyelocytic leukemia) and high-risk myelodysplastic syndrome CEBPA mutation status had no significant impact on patient response to ATRA (N=20) compared to randomized control (N=15). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CEBPA/NCBI:1050 1138 check_entity AN4890-1 CEBPA Mutation CEBPA NCBI:1050 gene acute myeloid leukemia DOID:9119 prognostic;risk 64012-8 PubMed:18450602 In young patients (age 16-60) with previously untreated, cytogenetically normal acute myeloid leukemia, CEBPA mutation was significantly associated with complete remission in multivariate analysis (odds ratio, 1.33; 95% confidence interval [CI], 1.01 to 1.74). Multivariate analysis was performed on all patients that were evaluated for a mutation in at least 1 gene (CEBPA, FLT3-ITD or NPM1) totaling 693/872 patients in the study. Only 509 patients in the study were evaluated for CEBPA, 67 of which had a mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CEBPA/NCBI:1050 1138 check_entity AN4890-1 CEBPA Mutation CEBPA NCBI:1050 gene acute myeloid leukemia DOID:9119 prognostic;risk 64012-8 PubMed:14726504 Overall survival and remission duration were significantly longer (p=0.01 and p=0.05, respectively) in younger (16-60), cytogenetically normal acute myeloid leukemia patients with CEBPA mutations (21/236 patients). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CEBPA/NCBI:1050 1138 check_entity AN4890-1 CEBPA Mutation CEBPA NCBI:1050 gene acute myeloid leukemia DOID:9119 prognostic;risk 64012-8 PubMed:19304957 In children with acute myeloid leukemia, those with mutations in CEBPA had better overall and event-free survival and decreased cummulative incidence of relapse. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CEBPA/NCBI:1050 1138 check_entity AN4890-1 CEBPA Mutation CEBPA NCBI:1050 gene acute myeloid leukemia DOID:9119 prognostic;risk 64012-8 PubMed:25014773 In a set of 315 pediatric patients with acute myeloid leukemia, 47 had mutations in CEBPA. Those with mutations had better overall survival than wild-type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CEBPA/NCBI:1050 1138 check_entity AN4890-1 CEBPA Mutation CEBPA NCBI:1050 gene acute myeloid leukemia DOID:9119 prognostic;risk 64012-8 CIViC:29 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CEBPA/NCBI:1050 1138 check_entity AN4891-1 CEBPA N-TERMINAL FRAME SHIFT CEBPA NCBI:1050 gene acute myeloid leukemia DOID:9119 prognostic;risk 64012-8 PubMed:14726504 Remission duration was significantly longer in younger (16-60), cytogenetically normal AML patients with CEBPA assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CEBPA N-TERMINAL FRAME SHIFT [biomarker_term_in_review] 1139 not_mapped AN4891-1 CEBPA N-TERMINAL FRAME SHIFT CEBPA NCBI:1050 gene acute myeloid leukemia DOID:9119 prognostic;risk 64012-8 PubMed:26167872 This preclinical study establishes that the p30 isoform of CEBPA expressed as a result of N-terminal truncating mutations preferentially interacts with WRD5, a component of the SET/MLL complex. Knockdown of WRD5 in 32D cells (mouse hematopoietic cell line) or transplanted primary mouse bone marrow expressing the p30 isoform restored myeloid differentiation in these cells. OICR-9429, a small molecule inhibitor of WRD5, and anti-WRD5 siRNAs selectively inhibited colony formation of mouse fetal liver cells homozygous for N-terminal CEBPA mutations but not wildtype colony formation. Finally, OICR-9429 reduced viability of primary human AML blasts harboring N-terminal domain CEBPA mutations in culture but not AML blasts with other mutations. Taken together, WRD5 inhibition is a potential therapeutic method for patients harboring N-terminal CEBPA mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CEBPA N-TERMINAL FRAME SHIFT [biomarker_term_in_review] 1139 not_mapped AN4891-1 CEBPA N-TERMINAL FRAME SHIFT CEBPA NCBI:1050 gene acute myeloid leukemia DOID:9119 prognostic;risk 64012-8 CIViC:28 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CEBPA N-TERMINAL FRAME SHIFT [biomarker_term_in_review] 1139 not_mapped AN4892-1 CFLAR EXPRESSION CFLAR NCBI:8837 gene prostate cancer DOID:10283 risk PubMed:22623731 Expression of c-FLIP (CFLAR) in 50 prostate specimens (assessed by IHC) was increased in castrate-resistant prostate cancer. In-vitro, silencing of CFLAR led to sensitization of two cell lines to bicalutamide. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CFLAR/NCBI:8837 1140 AN4892-1 CFLAR EXPRESSION CFLAR NCBI:8837 gene prostate cancer DOID:10283 risk CIViC:388 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CFLAR/NCBI:8837 1140 AN4893-1 CHEK1 Mutation CHEK1 NCBI:1111 gene castration-resistant prostate carcinoma DOID:0080909 risk PubMed:32343890 This randomized, open-label, phase 3 trial evaluated the PARP inhibitor olaparib in 387 men with metastatic castration-resistant prostate cancer (mCRPC) who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). The study found that in men with mCRPC who had somatic or germline deleterious alterations (irrespective of zygosity) in any of the following HRR genes (BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L), olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone (PFS HR 0.49 [0.38, 0.63]). A total of 3 patients had CHEK1 mutations, 2 in olaparib arm and 1 in control arm. Based on the results of this study, on May 19, 2020, the Food and Drug Administration approved olaparib (LYNPARZA) for adult patients with deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC, who have progressed following prior treatment with enzalutamide or abiraterone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CHEK1/NCBI:1111 1141 check_entity AN4893-1 CHEK1 Mutation CHEK1 NCBI:1111 gene castration-resistant prostate carcinoma DOID:0080909 risk CIViC:4391 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CHEK1/NCBI:1111 1141 check_entity AN4894-1 CHEK1 Overexpression CHEK1 NCBI:1111 gene lung small cell carcinoma DOID:5409 risk PubMed:28490518 A preclinical study to evaluate the efficacy of targeting the overexpressed CHEK1 cell cycle chekpoint kinase, including both miRNA and Prexasertib-induced inhibition. Both in vitro and in vivo, Prexasertib had strong single agent efficacy and augmented the effect of Olaparib or Cisplatin in either combination, including platinum-resistant models. CHEK1 and MYC overexpression were predictors of response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CHEK1/NCBI:1111 1142 AN4894-1 CHEK1 Overexpression CHEK1 NCBI:1111 gene lung small cell carcinoma DOID:5409 risk CIViC:1601 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CHEK1/NCBI:1111 1142 AN4895-1 CHEK2 1100DELC CHEK2 NCBI:11200 gene prostate cancer DOID:10283 diagnostic 89038-4 PubMed:26629066 Meta-analysis linking CHEK2 1100delC to a higher risk of prostate cancer (OR 3.29; 95% confidence interval: 1.85-5.85; P = 0.00). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CHEK2 1100DELC [biomarker_term_in_review] 1143 not_mapped AN4895-1 CHEK2 1100DELC CHEK2 NCBI:11200 gene prostate cancer DOID:10283 diagnostic 89038-4 CIViC:766 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CHEK2 1100DELC [biomarker_term_in_review] 1143 not_mapped AN4896-1 CHEK2 I157T mutation CHEK2 NCBI:11200 gene prostate cancer DOID:10283 diagnostic 89038-4 PubMed:26629066 Meta-analysis of 4 retrospective studies linked CHEK2 I157T to a higher risk of prostate cancer (OR 1.80; 95% confidence interval: 1.51-2.14; P = 0.00). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I157T sequence variation in gene CHEK2/NCBI:11200 1144 check_entity AN4896-1 CHEK2 I157T mutation CHEK2 NCBI:11200 gene prostate cancer DOID:10283 diagnostic 89038-4 CIViC:768 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I157T sequence variation in gene CHEK2/NCBI:11200 1144 check_entity AN4897-1 CHEK2 IVS2+1G>A mutation CHEK2 NCBI:11200 gene prostate cancer DOID:10283 diagnostic 89038-4 PubMed:26629066 Meta-analysis of 2 studies of CHEK2 and prostate cancer showing that the IVS2+1G>A mutation is irrelevant as a predictor of prostate cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::ivs2+1g>a:mutation sequence variation in gene CHEK2/NCBI:11200 1145 check_entity AN4897-1 CHEK2 IVS2+1G>A mutation CHEK2 NCBI:11200 gene prostate cancer DOID:10283 diagnostic 89038-4 CIViC:769 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::ivs2+1g>a:mutation sequence variation in gene CHEK2/NCBI:11200 1145 check_entity AN4898-1 CHEK2 Loss-of-function CHEK2 NCBI:11200 gene cancer DOID:162 diagnostic 89038-4 PubMed:10617473 Heterozygous germline truncating (frameshift) and missense mutations confer highly penetrant predisposition to multiple cancer types including sarcoma, breast cancer, and brain tumors. Screening of individuals with Li-Fraumeni syndrome but lacking TP53 mutations identified 1/4 classical and 2/18 LFS variant presentation. This included 1 large family pedigree with strong co-segregation of the mutation with cancer development. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CHEK2 Loss-of-function [biomarker_term_in_review] 1146 not_mapped AN4898-1 CHEK2 Loss-of-function CHEK2 NCBI:11200 gene cancer DOID:162 diagnostic 89038-4 CIViC:227 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CHEK2 Loss-of-function [biomarker_term_in_review] 1146 not_mapped AN4899-1 CHEK2 R474C c.1420C>T CHEK2 NCBI:11200 gene cancer DOID:162 diagnostic 89038-4 PubMed:27900359 Siblings (brother and sister) each were diagnosed with multiple primary lung cancer at the age of 60, along with various other cancers in their lifetimes. Homozygosity mapping revealed their parents (who also had cancer) had a consanguineous union. Each sibling was homozygous for CHEK2 R474C. The brother also had a son who died of neuroblastoma at 22 months of age. Amino acid R474 is highly conserved (98%) and forms a salt bridge in both the inactive and active CHEK2 homodimer. Modeling reveals R474C likely negatively affects the saltbridge and destabilizes the protein. Calcium phosphate DNA precipitation to overexpress CHEK2 WT or R474C in NIH3T3 cells revealed limited expression of R474C and limited activation through phosphorylation after UV exposure compared to the WT CHEK2 controls. ACMG codes as follows: Mutation in critical and well established functional domain (saltbridge) (PM1). Absent from control databases (ESP, dnSNP) except 1000 genomes with 1/2503 cases (.02%)(PM2). Predicted deleterious/damaging by multiple (4; SIFT, PolyPhen, MutationTaster2, Align GCGD) in silico algorithms (PP3). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R474C sequence variation in gene CHEK2/NCBI:11200 1147 check_entity AN4899-1 CHEK2 R474C c.1420C>T CHEK2 NCBI:11200 gene cancer DOID:162 diagnostic 89038-4 CIViC:2828 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R474C sequence variation in gene CHEK2/NCBI:11200 1147 check_entity AN4900-1 CHEK2 mutation CHEK2 NCBI:11200 gene castration-resistant prostate carcinoma DOID:0080909 risk 89038-4 PubMed:32343890 This randomized, open-label, phase 3 trial evaluated the PARP inhibitor olaparib in 387 men with metastatic castration-resistant prostate cancer (mCRPC) who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). The study found that in men with mCRPC who had somatic or germline deleterious alterations (irrespective of zygosity) in any of the following HRR genes (BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L), olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone (PFS HR 0.49 [0.38, 0.63]). For 17 patients with CHEK2 mutations specifically, PFS HR 0.87 [0.23-4.13]. Based on the results of this study, on May 19, 2020, the Food and Drug Administration approved olaparib (LYNPARZA) for adult patients with deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC, who have progressed following prior treatment with enzalutamide or abiraterone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CHEK2/NCBI:11200 1148 check_entity AN4900-1 CHEK2 mutation CHEK2 NCBI:11200 gene castration-resistant prostate carcinoma DOID:0080909 risk 89038-4 CIViC:4386 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CHEK2/NCBI:11200 1148 check_entity AN4901-1 CIC CIC::DUX4 mutation CIC NCBI:23152 gene CIC-rearranged sarcoma DOID:0081250 diagnostic;risk PubMed:28346326 This study consists of a cohort of 115 patients with a class of sarcomas that had similar morphology to Ewing sarcoma. The presence of a CIC rearrangement was detected in all the cases by FISH. Previously, it was unclear whether this class of sarcomas should be classified as a separate entity or be classified as a variant of Ewing sarcoma. CIC-rearranged sarcomas showed a male predominance with an average age of 32 years old. A CIC::DUX4 fusion was found by additional FISH testing for DUX4 loci in 57% of the cases, with either a translocation between chromosomes 4 and 19 or between chromosomes 10 and 19. 57 patients were followed clinically and showed a 5-year survival rate of 43%, which was significantly lower than the 77% 5-year survival rate of Ewing sarcoma patients (p=0.002). In histologic evaluation, stromal myxoid change was a common finding in CIC-positive tumors, while this is not usually found in Ewing sarcoma. CIC-positive tumors showed a diffuse CD99 immunohistochemical staining pattern in only 23% of the cases, in contrast to that found in Ewing sarcoma, which showed a diffuse CD99 staining pattern in almost all of the cases. Therefore, this study provides evidence that sarcomas that contain CIC::DUX4 fusion should be considered a separate entity, distinct from Ewing sarcoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CIC::DUX4 sequence variation in gene CIC/NCBI:23152 1149 check_entity AN4901-1 CIC CIC::DUX4 mutation CIC NCBI:23152 gene CIC-rearranged sarcoma DOID:0081250 diagnostic;risk PubMed:16717057 Kawamura-Saito, et al. (2006) presented 2 soft tissue Ewing-like sarcoma cases (62 years of age female who deceased 10 months after biopsy; 31 years of age male who was without recurrence 30 months after operation) with CIC–DUX4 t(4;19)(q35;q13) fusion. The authors used chromosome analysis (FISH) as well as RT-PCR to analyze the fusion. The authors also carried out multiple in vitro studies. The CIC-DUX4 region inserted in NIH 3T3 cells resulted in an increase of anchorage-independent colonies in comparison to the wild-type (indicating potential oncogenic transcription effect). The CIC-DUX4 construct transfected into HeLa cells showed 130 times higher transcriptional activities in comparison to the wild-type. The authors isolated RNA from U2OS cells with CIC-DUX4 fusion, and showed increased expression of 22 genes. Increased expression of ETV1 and ERM was seen in tumor tissue of case 1. The segment including potential ERM gene promoter region (TATA box) was transfected into HeLa and cell line from case 2 tumor tissue (ECD1). The result showed 235 times stronger promoter activity in ECD1 in comparison to the HeLa cell line. Also, the authors co-transfected the promoter region of the ETV1 gene and CIC-DUX4 into HeLa cell lines, which resulted in recognition of the region by the CIC-DUX4. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CIC::DUX4 sequence variation in gene CIC/NCBI:23152 1149 check_entity AN4901-1 CIC CIC::DUX4 mutation CIC NCBI:23152 gene CIC-rearranged sarcoma DOID:0081250 diagnostic;risk PubMed:35151033 The authors recognize that differentiating between Ewing sarcoma and CIC::DUX4 fusion associated sarcoma can be challenging due to overlapping histological and immunohistochemical phenotypes. In this study, 70 patients with undifferentiated round cell sarcoma or Ewing-like sarcoma were examined by EWSR1 break apart FISH, CIC break apart FISH, and CIC::DUX4 RT-PCR. 6 cases (8.6%) of CIC::DUX4 sarcoma were identified and tended to exhibit cytologic pleomorphism with bizarre nuclei and multinucleated cells and myxoid stoma. Although there wasn't a difference in overall survival, CIC::DUX4 sarcomas showed shorter disease-free survival and poorer response to treatment than Ewing sarcomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CIC::DUX4 sequence variation in gene CIC/NCBI:23152 1149 check_entity AN4901-1 CIC CIC::DUX4 mutation CIC NCBI:23152 gene CIC-rearranged sarcoma DOID:0081250 diagnostic;risk PubMed:22072439 In this 2012 paper, 22 small blue round cell tumors that remained unclassified after screening for known sarcoma-related translocations, were analyzed for CIC and FUS rearrangements. 68% (15/22) were positive for CIC rearrangements by FISH. Further analysis (RACE, RT-PCR, and/or long-range DNA PCR) on 2 cases revealed CIC was fused to DUX4 (with duplicate copies found on 4q35 and10q26.3). FISH confirmed the fused signals of CIC with either 4q35 or 10q26.3 in 6 cases.The authors suggest this is a newly defined subgroup of primitive round cell sarcomas characterized by CIC rearrangements, distinct from Ewing sarcoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CIC::DUX4 sequence variation in gene CIC/NCBI:23152 1149 check_entity AN4901-1 CIC CIC::DUX4 mutation CIC NCBI:23152 gene CIC-rearranged sarcoma DOID:0081250 diagnostic;risk CIViC:3121 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CIC::DUX4 sequence variation in gene CIC/NCBI:23152 1149 check_entity AN4902-1 CIP2A EXPRESSION CIP2A NCBI:57650 gene pancreatic ductal adenocarcinoma DOID:3498 prognostic PubMed:26894380 Expression of the protein CIP2A was investigated in 72 cases of pancreatic ductal adenocarcinoma and 27 cases of adjacent tissues. Immunohistochemistry revealed a significant difference in expression between tumor and adjacent normal samples. Furthermore, a statistically significant decrease in overall survival was discovered between positive and negative CIP2A expression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CIP2A/NCBI:57650 1150 AN4902-1 CIP2A EXPRESSION CIP2A NCBI:57650 gene pancreatic ductal adenocarcinoma DOID:3498 prognostic CIViC:470 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CIP2A/NCBI:57650 1150 AN4903-1 CIP2A Underexpression CIP2A NCBI:57650 gene pancreatic ductal adenocarcinoma DOID:3498 risk PubMed:26894380 Researchers studied the effect of CIP2A expression in relation to gemcitabine sensitivity via SW1990 cell lines. SW1990 cells with CIP2A expression knocked-down displayed lower IC50 (p=.024), indicating a sensitivity to gemcitabine. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene CIP2A/NCBI:57650 1151 AN4903-1 CIP2A Underexpression CIP2A NCBI:57650 gene pancreatic ductal adenocarcinoma DOID:3498 risk CIViC:471 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene CIP2A/NCBI:57650 1151 AN4904-1 CRBN Mutation CRBN NCBI:51185 gene multiple myeloma DOID:9538 risk PubMed:23480694 A 37 year old, heavily pretreated (including thalidomide and lenalidomide) patient with IgG-kappa multiple myeloma was sequenced following extramedullary relapse. A high number of alterations were observed including 38 rearrangements, 35 translocations, 4 indels, and 271 nonsynonymous point mutations. Two mutations altering CRBN (Q99* and R283K), a gene previously described as being necessary for immunomodulatory drug response, were observed and thought to be responsible for resistance to the pomalidomide and dexamethasone treatment she received but failed to respond to following sequencing. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CRBN/NCBI:51185 1152 check_entity AN4904-1 CRBN Mutation CRBN NCBI:51185 gene multiple myeloma DOID:9538 risk CIViC:694 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CRBN/NCBI:51185 1152 check_entity AN4905-1 CRLF2 IGH::CRLF2 mutation CRLF2 NCBI:64109 gene B-cell adult acute lymphocytic leukemia DOID:0060592 prognostic PubMed:20018760 CRLF2 overexpression was examined in 90 adult B-ALL patients with demographic data that lacked characteristic rearrangements and identified overexpression in 15/90 (16.67%). Disease-free survival was significantly shorter among patients with CRLF2 overexpression (median 17.8 mo vs. 37.8 mo; P<0.03). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::IGH::CRLF2 sequence variation in gene CRLF2/NCBI:64109 1153 check_entity AN4905-1 CRLF2 IGH::CRLF2 mutation CRLF2 NCBI:64109 gene B-cell adult acute lymphocytic leukemia DOID:0060592 prognostic CIViC:2532 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::IGH::CRLF2 sequence variation in gene CRLF2/NCBI:64109 1153 check_entity AN4905-2 CRLF2 IGH::CRLF2 mutation CRLF2 NCBI:64109 gene childhood B-cell acute lymphoblastic leukemia DOID:0080146 prognostic PubMed:20139093 Gene expression profiling of 207 uniformly treated children with high-risk B-progenitor acute lymphoblastic leukemia enrolled in COG P9906 study identified 29/207 (14%) with increased expression of CRLF2. All 29 patients demonstrated a CRLF2 rearrangement. Patients with CRLF2 rearrangements had a predicted relapse-free survival (RFS) at 4 years of 35.3% (+/- 9.5%) in contrast to 71.3% (+/- 3.6%) (P=0.001) for patients without CRLF2 rearrangements. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::IGH::CRLF2 sequence variation in gene CRLF2/NCBI:64109 1154 check_entity AN4905-2 CRLF2 IGH::CRLF2 mutation CRLF2 NCBI:64109 gene childhood B-cell acute lymphoblastic leukemia DOID:0080146 prognostic CIViC:2532 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::IGH::CRLF2 sequence variation in gene CRLF2/NCBI:64109 1154 check_entity AN4906-1 CSF1R MEF2D::CSF1R mutation CSF1R NCBI:1436 gene acute lymphoblastic leukemia DOID:9952 risk PubMed:24186003 Cell lines with MEF2D-CSF1R fusion show sensitivity to the tyrosine kinase inhibitors Imatinib and GW-2580. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::MEF2D::CSF1R sequence variation in gene CSF1R/NCBI:1436 1155 check_entity AN4906-1 CSF1R MEF2D::CSF1R mutation CSF1R NCBI:1436 gene acute lymphoblastic leukemia DOID:9952 risk CIViC:30 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::MEF2D::CSF1R sequence variation in gene CSF1R/NCBI:1436 1155 check_entity AN4906-2 CSF1R MEF2D::CSF1R mutation CSF1R NCBI:1436 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 risk PubMed:31434701 This study describes a cohort of 24 patients with BCR-ABL1-like B-ALL and ABL-class kinase rearrangement exposed to TKI frontline or at relapse, who showed favorable MRD response and outcome. Specifically, one 34-year-old man with MEF2D-CSF1R identified by RNAseq was prescribed an unspecified dose of imatinib as adjuvant to his frontline chemotherapy (protocol GRAALL-2014). His initial MRD analysis at 94 days remained positive for blasts (1 x 10^-4), but was consistent with continuous complete remission at day 147. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::MEF2D::CSF1R sequence variation in gene CSF1R/NCBI:1436 1156 check_entity AN4906-2 CSF1R MEF2D::CSF1R mutation CSF1R NCBI:1436 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 risk CIViC:30 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::MEF2D::CSF1R sequence variation in gene CSF1R/NCBI:1436 1156 check_entity AN4907-1 CSF1R TBL1XR1::CSF1R mutation CSF1R NCBI:1436 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic PubMed:28408464 This study included 1389 cases of high-risk pediatric B-ALL, of which 284 were identified by TaqMan Low Density Array to have a BCR-ABL1-like (Ph-like) gene expression signature. RT-PCR or RNAseq performed on Ph-like, CRLF2 negative patients revealed one case of the novel TBL1XR1-CSF1R fusion. No clinical information pertaining to this individual was disclosed. Considering the previously confirmed Ph-like expression signature in the tested cases, the results suggest that the presence of the TBL1XR1-CSF1R fusion in B-ALL may indicate the BCR-ABL1-like (Ph-like) subtype of the disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::TBL1XR1::CSF1R sequence variation in gene CSF1R/NCBI:1436 1157 check_entity AN4907-1 CSF1R TBL1XR1::CSF1R mutation CSF1R NCBI:1436 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic CIViC:3227 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::TBL1XR1::CSF1R sequence variation in gene CSF1R/NCBI:1436 1157 check_entity AN4908-1 CSF3R Mutation CSF3R NCBI:1441 gene atypical chronic myeloid leukemia, BCR-ABL1 negative DOID:0060597 diagnostic 92674-1 PubMed:23656643 Study found that mutations in CSF3R are enriched in patients with Chronic Neutrophilic Leukemia (CNL) or Atypical Chronic Myeloid Leukemia (16/27, 59%) when compared to other blood disorders (AML=1/292, t-cell ALL=0/8, B-cell ALL=0/41) assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CSF3R/NCBI:1441 1158 check_entity AN4908-1 CSF3R Mutation CSF3R NCBI:1441 gene atypical chronic myeloid leukemia, BCR-ABL1 negative DOID:0060597 diagnostic 92674-1 CIViC:556 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CSF3R/NCBI:1441 1158 check_entity AN4908-2 CSF3R Mutation CSF3R NCBI:1441 gene chronic neutrophilic leukemia DOID:0080187 diagnostic 92674-1 PubMed:23656643 Study found that mutations in CSF3R are enriched in patients with Chronic Neutrophilic Leukemia (CNL) or Atypical Chronic Myeloid Leukemia (16/27, 59%) when compared to other blood disorders (AML=1/292, t-cell ALL=0/8, B-cell ALL=0/41) assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CSF3R/NCBI:1441 1159 check_entity AN4908-2 CSF3R Mutation CSF3R NCBI:1441 gene chronic neutrophilic leukemia DOID:0080187 diagnostic 92674-1 CIViC:556 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene CSF3R/NCBI:1441 1159 check_entity AN4909-1 CSF3R T618I mutation CSF3R NCBI:1441 gene chronic neutrophilic leukemia DOID:0080187 risk 92674-1 PubMed:24081659 Demonstrates that activating mutations in CSF3R are sufficient to drive a myeloproliferative disorder resembling aCML and CNL that is sensitive to pharmacologic JAK inhibition. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T618I sequence variation in gene CSF3R/NCBI:1441 1160 check_entity AN4909-1 CSF3R T618I mutation CSF3R NCBI:1441 gene chronic neutrophilic leukemia DOID:0080187 risk 92674-1 PubMed:25180155 Case report of a patient treated with ruxolitinib, an FDA-approved JAK1/2 inhibitor, which resulted in dramatic improvement of his blood counts. He also had significant reduction of spleen volume and constitutional symptoms. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T618I sequence variation in gene CSF3R/NCBI:1441 1160 check_entity AN4909-1 CSF3R T618I mutation CSF3R NCBI:1441 gene chronic neutrophilic leukemia DOID:0080187 risk 92674-1 CIViC:2260 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T618I sequence variation in gene CSF3R/NCBI:1441 1160 check_entity AN4910-1 CTAG1B Overexpression CTAG1B NCBI:1485 gene multiple myeloma DOID:9538 risk PubMed:26193344 Clinical responses to NY-ESO-1/LAGE-1 TCR-engineered T-cells were observed in 16 of 20 patients (80%) with advanced multiple myeloma expressing NY-ESO-1 and/or LAGE-1 in this Phase 1/2a trial showing a median progression free survival of 19.1 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CTAG1B/NCBI:1485 1161 AN4910-1 CTAG1B Overexpression CTAG1B NCBI:1485 gene multiple myeloma DOID:9538 risk CIViC:1247 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CTAG1B/NCBI:1485 1161 AN4911-1 CTAG2 Overexpression CTAG2 NCBI:30848 gene multiple myeloma DOID:9538 risk PubMed:26193344 Clinical responses to NY-ESO-1/LAGE-1 TCR-engineered T-cells were observed in 16 of 20 patients (80%) with advanced multiple myeloma expressing NY-ESO-1 and/or LAGE-1 in this Phase 1/2a trial showing a median progression free survival of 19.1 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CTAG2/NCBI:30848 1162 AN4911-1 CTAG2 Overexpression CTAG2 NCBI:30848 gene multiple myeloma DOID:9538 risk CIViC:1248 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene CTAG2/NCBI:30848 1162 AN4912-1 CTLA4 CTLA4::CD28 mutation CTLA4 NCBI:1493 gene Sezary's disease DOID:8541 risk PubMed:25802883 A 67-year-old Caucasian female with stage IVA Sezary syndrome presented refractory to traditional therapy and was enrolled in a whole genome study trial. Sequencing revealed a CTLA4-CD28 fusion protein such that the inhibitory CTLA4 receptor activated a stimulatory CD28 intracellular domain that promoted proliferation. The patient was treated with iplimumab, a CTLA4 receptor inhibitor, and after 10 days, there was a reduction in erythema and ulceration by 50%, a reduction in tumor size by 75%, and overall improved quality of life. However, during the sixth week of therapy, the patient rapidly developed skin tumors and died 3 months later. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CTLA4::CD28 sequence variation in gene CTLA4/NCBI:1493 1163 check_entity AN4912-1 CTLA4 CTLA4::CD28 mutation CTLA4 NCBI:1493 gene Sezary's disease DOID:8541 risk CIViC:595 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CTLA4::CD28 sequence variation in gene CTLA4/NCBI:1493 1163 check_entity AN4913-1 CTNNB1 Activating Mutation CTNNB1 NCBI:1499 gene melanoma DOID:1909 risk 21659-8 PubMed:25970248 Activation of melanoma-cell-intrinsic WNT/β-catenin signalling pathway contributes to a lack of T-cell infiltration in melanoma. Molecular analysis of human metastatic melanoma samples revealed a correlation between activation of the WNT/β-catenin signalling pathway and absence of a T-cell gene expression signature. In autochthonous mouse melanoma models active β-catenin signalling results in T-cell exclusion and resistance to anti-PD-L1/anti-CTLA-4 monoclonal antibody therapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::activating:mutation sequence variation in gene CTNNB1/NCBI:1499 1164 check_entity AN4913-1 CTNNB1 Activating Mutation CTNNB1 NCBI:1499 gene melanoma DOID:1909 risk 21659-8 CIViC:1270 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::activating:mutation sequence variation in gene CTNNB1/NCBI:1499 1164 check_entity AN4914-1 CTNNB1 Exon 3 Mutation CTNNB1 NCBI:1499 gene childhood medulloblastoma DOID:3869 diagnostic 21659-8 PubMed:19197950 A series of 72 pediatric medulloblastomas were evaluated for CTNNB1 mutations (by direct sequencing), copy number alterations (by array-comparative genomic hybridization), and beta-catenin protein expression (by immunohistochemistry). CTNNB1 mutations were detected in all six cases with extensive (>50% of the tumor cells) nuclear staining of beta-catenin. Remarkably, five out of these six tumors demonstrated a loss of chromosome 6, a cytogenetic event that is absent in CTNNB1-wildtype tumors (p <0.0001, Fisher’s exact test). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:3:mutation sequence variation in gene CTNNB1/NCBI:1499 1165 check_entity AN4914-1 CTNNB1 Exon 3 Mutation CTNNB1 NCBI:1499 gene childhood medulloblastoma DOID:3869 diagnostic 21659-8 PubMed:17172831 A total of 51 medulloblastomas from two independent cohorts (19 and 32 cases) were assessed for evidence of Wnt/Wg pathway activation, alongside a genome-wide analysis of associated copy-number aberrations. Cases displaying evidence of Wnt/Wg activation (CTNNB1 mutation and/or beta-catenin nuclear stabilization) were exclusively associated with a distinct genomic signature involving loss of an entire copy of chromosome 6 but few other aberrations. Loss of chromosome 6 was exclusively observed in Wnt/Wg-activated medulloblastoma, as evidenced by 3 of 3 cases with nuclear immune-positivity for b-catenin in the first cohort (19 cases). In the second cohort (32 cases), loss of chromosome 6 is observed in Wnt/Wg-active tumors and absence in Wnt/Wg-negative cases (8/13 vs. 0/19; p=0.0001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:3:mutation sequence variation in gene CTNNB1/NCBI:1499 1165 check_entity AN4914-1 CTNNB1 Exon 3 Mutation CTNNB1 NCBI:1499 gene childhood medulloblastoma DOID:3869 diagnostic 21659-8 CIViC:2761 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:3:mutation sequence variation in gene CTNNB1/NCBI:1499 1165 check_entity AN4914-2 CTNNB1 Exon 3 Mutation CTNNB1 NCBI:1499 gene desmoid tumor DOID:0080366 prognostic 21659-8 PubMed:23960186 This study illustrates the prevalence of CTNNB1 mutations in sporadic desmoid tumors, and examines whether the presence of CTNNB1 mutations correlates with the disease outcome. CTNNB1 mutations (including specific exon 3 mutations T41A, S45F, S45P, and S45C) were found in 106 out of 145 desmoid tumor specimens, and in 86 out of 115 specimens from patients who had undergone complete surgical resection. At a median follow-up of 31 months, the 5-year recurrence free survival rate of patients with the beta-catenin mutated tumors was worse than that of the patients with wild-type tumors (58% vs 74%), however, the difference was not statistically significant (p = 0.285). Thus, the study shows that there is no statistically significant correlation between the CTNNB1 mutation and the recurrence risk of sporadic desmoid tumors, even though specific exon 3 CTNNB1 mutations are commonly identified in these tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:3:mutation sequence variation in gene CTNNB1/NCBI:1499 1166 check_entity AN4914-2 CTNNB1 Exon 3 Mutation CTNNB1 NCBI:1499 gene desmoid tumor DOID:0080366 prognostic 21659-8 CIViC:2761 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:3:mutation sequence variation in gene CTNNB1/NCBI:1499 1166 check_entity AN4915-1 CTNNB1 S45F mutation CTNNB1 NCBI:1499 gene desmoid tumor DOID:0080366 diagnostic;prognostic;risk 21659-8 PubMed:18832571 Desmoid fibromatosis is a rare, nonmetastatic neoplasm marked by local invasiveness and relentless recurrence. Beta-Catenin deregulation has been commonly identified in sporadic desmoids. CTNNB1 mutations were observed in 117 of 138 (85%) of desmoids. Three discrete mutations in two codons of CTNNB1 exon 3 were identified: T41A (59%), S45F (33%), and S45P (8%). Five-year recurrence-free survival was significantly poorer in S45F-mutated desmoids (23%, P < 0.0001) versus either T41A (57%) or nonmutated tumors (65%). In conclusion, CTNNB1 mutations are highly common in desmoid tumors. Furthermore, patients harboring CTNNB1 (S45F) mutations are at particular risk for recurrence and therefore may especially benefit from adjuvant therapeutic approaches. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S45F sequence variation in gene CTNNB1/NCBI:1499 1167 check_entity AN4915-1 CTNNB1 S45F mutation CTNNB1 NCBI:1499 gene desmoid tumor DOID:0080366 diagnostic;prognostic;risk 21659-8 PubMed:22766794 In this study a collection of 254 sporadic desmoid tumors were analysed for presence of mutations in CTNNB1. A mutation in exon 3 of the CTNNB1 gene was identified in 223 (88%) of the 254 cases. The CTNNB1 mutation spectra concerned mainly three point mutations in two codons (41 and 45): T41A was identified in 132 cases (59%); S45F was identified in 49 samples (22%); and S45P was identified in 27 samples (12%). None of the 175 lesions mimicking desmoid tumors analyzed harbored any CTNNB1 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S45F sequence variation in gene CTNNB1/NCBI:1499 1167 check_entity AN4915-1 CTNNB1 S45F mutation CTNNB1 NCBI:1499 gene desmoid tumor DOID:0080366 diagnostic;prognostic;risk 21659-8 PubMed:24788118 Of the 33 patients with desmoid fibromatosis treated with meloxicam, a COX-2 selective inhibitor, one showed complete remission (CR), 7 partial remission (PR), 12 stable disease (SD), and 13 progressive disease (PD). The following 3 point mutations were identified in 21 of the 33 cases (64%): T41A (16 cases), S45F (4 cases) and S45P (one case). All four cases with S45F mutation exhibited strong nuclear expression of β-catenin. S45F mutation was significantly associated with a poor response (all cases; PD) (p = 0.017) assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S45F sequence variation in gene CTNNB1/NCBI:1499 1167 check_entity AN4915-1 CTNNB1 S45F mutation CTNNB1 NCBI:1499 gene desmoid tumor DOID:0080366 diagnostic;prognostic;risk 21659-8 PubMed:25341748 This was a multi-institutional retrospective cohort study which looked at the prognostic value of CTNNB1 gene mutations in aggressive fibromatosis (also known as desmoid tumor). The study analyzed 101 patients who had undergone surgical resection of confirmed primary extra-abdominal or abdominal wall aggressive fibromatosis. Specimens were reviewed for the presence of T41A, S45F, and 45P mutations on the CTNNB1 gene. Mutations were found in 76 patients, with T41A being most common (n = 49), followed by S45F (n = 18), and 45P (n = 3). The 5-year cumulative risk of recurrence was 22.8%. Further analysis revealed that patients with an S45F mutation had a 5-year recurrence risk of 63.8% and an 8.5-fold higher risk of recurrence compared to patients with wild type tumors (P=0.006). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S45F sequence variation in gene CTNNB1/NCBI:1499 1167 check_entity AN4915-1 CTNNB1 S45F mutation CTNNB1 NCBI:1499 gene desmoid tumor DOID:0080366 diagnostic;prognostic;risk 21659-8 CIViC:1260 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S45F sequence variation in gene CTNNB1/NCBI:1499 1167 check_entity AN4916-1 CTNNB1 S45P mutation CTNNB1 NCBI:1499 gene desmoid tumor DOID:0080366 diagnostic;prognostic 21659-8 PubMed:18832571 Desmoid fibromatosis is a rare, nonmetastatic neoplasm marked by local invasiveness and relentless recurrence. Beta-Catenin deregulation has been commonly identified in sporadic desmoids. CTNNB1 mutations were observed in 117 of 138 (85%) of desmoids. Three discrete mutations in two codons of CTNNB1 exon 3 were identified: T41A (59%), S45F (33%), and S45P (8%). In conclusion, CTNNB1 mutations are highly common in desmoid tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S45P sequence variation in gene CTNNB1/NCBI:1499 1168 check_entity AN4916-1 CTNNB1 S45P mutation CTNNB1 NCBI:1499 gene desmoid tumor DOID:0080366 diagnostic;prognostic 21659-8 PubMed:22766794 In this study a collection of 254 sporadic desmoid tumors were analysed for presence of mutations in CTNNB1. A mutation in exon 3 of the CTNNB1 gene was identified in 223 (88%) of the 254 cases. The CTNNB1 mutation spectra concerned mainly three point mutations in two codons (41 and 45): T41A was identified in 132 cases (59%); S45F was identified in 49 samples (22%); and S45P was identified in 27 samples (12%). None of the 175 lesions mimicking desmoid tumors analyzed harbored any CTNNB1 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S45P sequence variation in gene CTNNB1/NCBI:1499 1168 check_entity AN4916-1 CTNNB1 S45P mutation CTNNB1 NCBI:1499 gene desmoid tumor DOID:0080366 diagnostic;prognostic 21659-8 CIViC:1261 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S45P sequence variation in gene CTNNB1/NCBI:1499 1168 check_entity AN4917-1 CTNNB1 T41A mutation CTNNB1 NCBI:1499 gene desmoid tumor DOID:0080366 diagnostic;prognostic 21659-8 PubMed:18832571 Desmoid fibromatosis is a rare, nonmetastatic neoplasm marked by local invasiveness and relentless recurrence. Beta-Catenin deregulation has been commonly identified in sporadic desmoids. CTNNB1 mutations were observed in 117 of 138 (85%) of desmoids. Three discrete mutations in two codons of CTNNB1 exon 3 were identified: T41A (59%), S45F (33%), and S45P (8%). Five-year recurrence-free survival was significantly poorer in S45F-mutated desmoids (23%, P < 0.0001) versus either T41A (57%) or nonmutated tumors (65%). In conclusion, CTNNB1 mutations are highly common in desmoid tumors. Furthermore, patients harboring CTNNB1 (45F) mutations are at particular risk for recurrence and therefore may especially benefit from adjuvant therapeutic approaches. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T41A sequence variation in gene CTNNB1/NCBI:1499 1169 check_entity AN4917-1 CTNNB1 T41A mutation CTNNB1 NCBI:1499 gene desmoid tumor DOID:0080366 diagnostic;prognostic 21659-8 PubMed:22766794 In this study a collection of 254 sporadic desmoid tumors were analysed for presence of mutations in CTNNB1. A mutation in exon 3 of the CTNNB1 gene was identified in 223 (88%) of the 254 cases. The CTNNB1 mutation spectra concerned mainly three point mutations in two codons (41 and 45): T41A was identified in 132 cases (59%); S45F was identified in 49 samples (22%); and S45P was identified in 27 samples (12%). None of the 175 lesions mimicking desmoid tumors analyzed harbored any CTNNB1 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T41A sequence variation in gene CTNNB1/NCBI:1499 1169 check_entity AN4917-1 CTNNB1 T41A mutation CTNNB1 NCBI:1499 gene desmoid tumor DOID:0080366 diagnostic;prognostic 21659-8 CIViC:1259 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T41A sequence variation in gene CTNNB1/NCBI:1499 1169 check_entity AN4918-1 CXCR4 EXPRESSION CXCR4 NCBI:7852 gene gastric adenocarcinoma DOID:3717 risk PubMed:20651371 CXCR4 expression as assessed by microarray analysis, was associated with resistance to docetaxel in 11 cancer cell lines (R^2 = 0.23, p = 0.019). Expression levels (by qtPCR) were also higher in resistant tumors among 25 patient samples. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CXCR4/NCBI:7852 1170 AN4918-1 CXCR4 EXPRESSION CXCR4 NCBI:7852 gene gastric adenocarcinoma DOID:3717 risk CIViC:401 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene CXCR4/NCBI:7852 1170 AN4919-1 CYP2D6 Loss-of-function CYP2D6 NCBI:1565 gene breast cancer DOID:1612 prognostic 21663-0 PubMed:24098545 Meta-analysis of 25 studies involving 13,629 women with tamoxifen treated breast cancer. The meta-analysis investigated the association between CYP2D6 genotypes and response to tamoxifen treatment (loss/reduced function vs. unchanged/increased function). The authors examine a prevailing hypothesis that individuals carrying a reduced function CYP2D6 allele have poorer outcomes due to less metabolism of tamoxifen to active metabolites. The study concludes that there is insufficient evidence to support use of CYP2D6 genotyping as a guide for tamoxifen use in breast cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CYP2D6 Loss-of-function [biomarker_term_in_review] 1171 not_mapped AN4919-1 CYP2D6 Loss-of-function CYP2D6 NCBI:1565 gene breast cancer DOID:1612 prognostic 21663-0 CIViC:702 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition CYP2D6 Loss-of-function [biomarker_term_in_review] 1171 not_mapped AN4920-1 DCC EXPRESSION DCC NCBI:1630 gene colorectal cancer DOID:9256 prognostic PubMed:8929264 Expression of DCC was a strong positive predictive factor for survival in both stage II and stage III colorectal carcinomas. In patients with stage II disease whose tumors expressed DCC, the five-year survival rate was 94.3 percent, whereas in patients with DCC-negative tumors, the survival rate was 61.6 percent (P<0.001). In patients with stage III disease, the respective survival rates were 59.3 percent and 33.2 percent (P=0.03). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene DCC/NCBI:1630 1172 AN4920-1 DCC EXPRESSION DCC NCBI:1630 gene colorectal cancer DOID:9256 prognostic CIViC:1258 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene DCC/NCBI:1630 1172 AN4921-1 DDIT3 EWSR1::DDIT3 mutation DDIT3 NCBI:1649 gene myxoid liposarcoma DOID:5363 diagnostic PubMed:8637704 Identified two cases of myxoid liposarcoma with translocations (between 12q13 and 22q12) giving rise to EWSR1-DDIT3 (EWS-CHOP) fusions instead of the more common FUS-DDIT3. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EWSR1::DDIT3 sequence variation in gene DDIT3/NCBI:1649 1173 check_entity AN4921-1 DDIT3 EWSR1::DDIT3 mutation DDIT3 NCBI:1649 gene myxoid liposarcoma DOID:5363 diagnostic CIViC:698 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EWSR1::DDIT3 sequence variation in gene DDIT3/NCBI:1649 1173 check_entity AN4922-1 DDIT3 FUS::DDIT3 mutation DDIT3 NCBI:1649 gene liposarcoma DOID:3382 diagnostic PubMed:20332486 Both RT-PCR and PCR were used to detect and confirm the presence of fusion transcripts in RNA extracted from the surgical resections of 74 liposarcomas and 98 lipomas. FUS-DDIT3 (TLS-CHOP) was found in 22/74 (30%) liposarcomas, but not detected in any of the 98 noncancerous lipomas. Within the liposarcomas FUS-DDIT3 was found in 1/12 (8%) well-differentiated, 1/4 (25%) de-differentiated, 1/17 (6%) unclassified, and 19/41 (46%) myxoid subtypes. The results demonstrate the specificity of FUS-DDIT3 fusions to liposarcomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FUS::DDIT3 sequence variation in gene DDIT3/NCBI:1649 1174 check_entity AN4922-1 DDIT3 FUS::DDIT3 mutation DDIT3 NCBI:1649 gene liposarcoma DOID:3382 diagnostic CIViC:703 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FUS::DDIT3 sequence variation in gene DDIT3/NCBI:1649 1174 check_entity AN4922-2 DDIT3 FUS::DDIT3 mutation DDIT3 NCBI:1649 gene myxoid liposarcoma DOID:5363 diagnostic PubMed:1568170 In this 1992 paper, 9 of 26 liposarcoma patients had a histopathologic diagnosis of myxoid liposarcoma. Cytogenetic analysis revealed 6 of these patients had t(12;16)(q13;p11). 2 patients had a cytogenic pattern more consistent with pleomorphic liposarcoma with high chromosome counts and multiple abnormalities. 1 patient had a cytogenetic pattern more consistent with well-differentiated liposarcoma. The t(12;16)(q13;p11) translocation was suggested to aid in the diagnosis of myxoid liposarcoma and is now know to correspond to the FUS::DDIT3 fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FUS::DDIT3 sequence variation in gene DDIT3/NCBI:1649 1175 check_entity AN4922-2 DDIT3 FUS::DDIT3 mutation DDIT3 NCBI:1649 gene myxoid liposarcoma DOID:5363 diagnostic CIViC:703 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FUS::DDIT3 sequence variation in gene DDIT3/NCBI:1649 1175 check_entity AN4923-1 DDR2 G253C mutation DDR2 NCBI:4921 gene lung non-small cell carcinoma DOID:3908 risk PubMed:22328973 In 3T3 fibroblasts expressing the G253C mutation have to be sensitive to the tyrosine kinase inhibitor dasatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G253C sequence variation in gene DDR2/NCBI:4921 1176 check_entity AN4923-1 DDR2 G253C mutation DDR2 NCBI:4921 gene lung non-small cell carcinoma DOID:3908 risk CIViC:141 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G253C sequence variation in gene DDR2/NCBI:4921 1176 check_entity AN4924-1 DDR2 G505S mutation DDR2 NCBI:4921 gene lung non-small cell carcinoma DOID:3908 risk PubMed:22328973 In 3T3 fibroblasts expressing the G505S mutation have to be sensitive to the tyrosine kinase inhibitor dasatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G505S sequence variation in gene DDR2/NCBI:4921 1177 check_entity AN4924-1 DDR2 G505S mutation DDR2 NCBI:4921 gene lung non-small cell carcinoma DOID:3908 risk CIViC:142 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G505S sequence variation in gene DDR2/NCBI:4921 1177 check_entity AN4925-1 DDR2 G774V mutation DDR2 NCBI:4921 gene lung non-small cell carcinoma DOID:3908 risk PubMed:22328973 In 3T3 fibroblasts expressing the G774V mutation have to be sensitive to the tyrosine kinase inhibitor dasatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G774V sequence variation in gene DDR2/NCBI:4921 1178 check_entity AN4925-1 DDR2 G774V mutation DDR2 NCBI:4921 gene lung non-small cell carcinoma DOID:3908 risk CIViC:144 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G774V sequence variation in gene DDR2/NCBI:4921 1178 check_entity AN4926-1 DDR2 I638F mutation DDR2 NCBI:4921 gene lung non-small cell carcinoma DOID:3908 risk PubMed:22328973 In 3T3 fibroblasts expressing the I638F mutation have to be sensitive to the tyrosine kinase inhibitor dasatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I638F sequence variation in gene DDR2/NCBI:4921 1179 check_entity AN4926-1 DDR2 I638F mutation DDR2 NCBI:4921 gene lung non-small cell carcinoma DOID:3908 risk CIViC:143 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I638F sequence variation in gene DDR2/NCBI:4921 1179 check_entity AN4927-1 DDR2 L239R mutation DDR2 NCBI:4921 gene lung non-small cell carcinoma DOID:3908 risk PubMed:22328973 In 3T3 fibroblasts expressing the L239R mutation have to be sensitive to the tyrosine kinase inhibitor dasatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L239R sequence variation in gene DDR2/NCBI:4921 1180 check_entity AN4927-1 DDR2 L239R mutation DDR2 NCBI:4921 gene lung non-small cell carcinoma DOID:3908 risk CIViC:140 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L239R sequence variation in gene DDR2/NCBI:4921 1180 check_entity AN4928-1 DDR2 L63V mutation DDR2 NCBI:4921 gene lung non-small cell carcinoma DOID:3908 risk PubMed:22328973 In 3T3 fibroblasts expressing the L63V mutation have to be sensitive to the tyrosine kinase inhibitor dasatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L63V sequence variation in gene DDR2/NCBI:4921 1181 check_entity AN4928-1 DDR2 L63V mutation DDR2 NCBI:4921 gene lung non-small cell carcinoma DOID:3908 risk CIViC:139 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L63V sequence variation in gene DDR2/NCBI:4921 1181 check_entity AN4929-1 DDR2 S768R mutation DDR2 NCBI:4921 gene lung non-small cell carcinoma DOID:3908 risk PubMed:22328973 In a patient expressing a DDR2 S768R mutation, treatment with dasatinib plus erlotinib acheived a partial response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S768R sequence variation in gene DDR2/NCBI:4921 1182 check_entity AN4929-1 DDR2 S768R mutation DDR2 NCBI:4921 gene lung non-small cell carcinoma DOID:3908 risk CIViC:145 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S768R sequence variation in gene DDR2/NCBI:4921 1182 check_entity AN4930-1 DDX41 R164W mutation DDX41 NCBI:51428 gene hematologic cancer DOID:2531 diagnostic PubMed:26712909 Eight members of larger pedigree spanning four generations with inherited hematological cancers were sequenced with whole exome sequencing or sanger sequencing of DDX41 exons 5 and 6. A mutation c.490C>T or R164W was found in 5/5 members with Non Hodkin's lymphoma, Hodgkin lymphoma, or multiple myeloma but not in 3/3 unaffected individuals. The site of mutation is reported to potentially be important for DDX41 helicase activity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R164W sequence variation in gene DDX41/NCBI:51428 1183 check_entity AN4930-1 DDX41 R164W mutation DDX41 NCBI:51428 gene hematologic cancer DOID:2531 diagnostic CIViC:792 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R164W sequence variation in gene DDX41/NCBI:51428 1183 check_entity AN4931-1 DDX43 Overexpression DDX43 NCBI:55510 gene uveal melanoma DOID:6039 risk PubMed:24899684 MEK inhibitor-resistant (selumetinib, PD0325901, GSK1129212) uveal melanoma cell lines were created from two GNAQ Q209L mutant cell lines. Overexpression of DDX43 mediated RAS-induced selumetinib resistance as demonstrated by depletion of DDX43 decreasing RAS proteins and ectopic expression of DDX43 induced RAS protein levels. These results were confirmed using biopsies from liver metastases in 14 patients with uveal melanoma harboring GNAQ or GNA11 mutations who were treated on a phase II study of selumetinib. 6 patients with partial response or stable disease for ≥16 weeks, were defined as “responders” (R), 8 patients who had disease progression before 16 weeks were defined as “nonresponders” (NR). DDX43 Expression (qPCR) was higher in nonresponders (P = 0.045). Liver metastasis biopsy samples (3 R and 3 NR) were immunoblotted for DDX43, pERK and RAS proteins with consistent results. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene DDX43/NCBI:55510 1184 AN4931-1 DDX43 Overexpression DDX43 NCBI:55510 gene uveal melanoma DOID:6039 risk CIViC:477 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene DDX43/NCBI:55510 1184 AN4932-1 DEFA1 EXPRESSION DEFA1 NCBI:1667 gene prostate cancer DOID:10283 risk PubMed:26261420 Blood mRNA levels of DEFA1, DEFA1B and DEFA3 were associated with response to docetaxel treatment in castration resistant prostate cancer. The discovery cohort consisted of 6 patients, results were validated in 10 patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene DEFA1/NCBI:1667 1185 AN4932-1 DEFA1 EXPRESSION DEFA1 NCBI:1667 gene prostate cancer DOID:10283 risk CIViC:324 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene DEFA1/NCBI:1667 1185 AN4933-1 DICER1 D1709E mutation DICER1 NCBI:23405 gene glandular pattern ovarian yolk sac tumor DOID:6511 risk PubMed:22187960 DICER1 mutations in the RNase IIIb domain were found in 29% of nonepithelial ovarian tumors (n=103). There was one Yolk sac tumor that had a somatic mutation in D1709E. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D1709E sequence variation in gene DICER1/NCBI:23405 1186 check_entity AN4933-1 DICER1 D1709E mutation DICER1 NCBI:23405 gene glandular pattern ovarian yolk sac tumor DOID:6511 risk CIViC:2072 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D1709E sequence variation in gene DICER1/NCBI:23405 1186 check_entity AN4933-2 DICER1 D1709E mutation DICER1 NCBI:23405 gene Sertoli-Leydig cell tumor DOID:2997 diagnostic PubMed:22187960 DICER1 mutations in the RNase IIIb domain were found in 29% of nonepithelial ovarian tumors (n=103) with high predominance in Sertoli-Lydig cell tumors (26/43; 60%). There were two mutations in D1709E. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D1709E sequence variation in gene DICER1/NCBI:23405 1187 check_entity AN4933-2 DICER1 D1709E mutation DICER1 NCBI:23405 gene Sertoli-Leydig cell tumor DOID:2997 diagnostic CIViC:2072 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D1709E sequence variation in gene DICER1/NCBI:23405 1187 check_entity AN4934-1 DICER1 D1709G mutation DICER1 NCBI:23405 gene granulosa cell tumor DOID:2999 risk PubMed:22187960 DICER1 mutations in the RNase IIIb domain were found in 29% of nonepithelial ovarian tumors (n=103) with one mutation in a Juvenile ovarian granulosa-cell tumor (1/14; 7%). This individual had a somatic mutation in D1709G. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D1709G sequence variation in gene DICER1/NCBI:23405 1188 check_entity AN4934-1 DICER1 D1709G mutation DICER1 NCBI:23405 gene granulosa cell tumor DOID:2999 risk CIViC:2071 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D1709G sequence variation in gene DICER1/NCBI:23405 1188 check_entity AN4934-2 DICER1 D1709G mutation DICER1 NCBI:23405 gene Sertoli-Leydig cell tumor DOID:2997 diagnostic PubMed:22187960 DICER1 mutations in the RNase IIIb domain were found in 29% of nonepithelial ovarian tumors (n=103) with high predominance in Sertoli-Lydig cell tumors (26/43; 60%). There was one mutation in D1709G. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D1709G sequence variation in gene DICER1/NCBI:23405 1189 check_entity AN4934-2 DICER1 D1709G mutation DICER1 NCBI:23405 gene Sertoli-Leydig cell tumor DOID:2997 diagnostic CIViC:2071 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D1709G sequence variation in gene DICER1/NCBI:23405 1189 check_entity AN4935-1 DICER1 D1709N mutation DICER1 NCBI:23405 gene glandular pattern ovarian yolk sac tumor DOID:6511 risk PubMed:22187960 DICER1 mutations in the RNase IIIb domain were found in 29% of nonepithelial ovarian tumors (n=103). There was one Yolk sac tumor that had a somatic mutation in D1709N. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D1709N sequence variation in gene DICER1/NCBI:23405 1190 check_entity AN4935-1 DICER1 D1709N mutation DICER1 NCBI:23405 gene glandular pattern ovarian yolk sac tumor DOID:6511 risk CIViC:1927 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D1709N sequence variation in gene DICER1/NCBI:23405 1190 check_entity AN4935-2 DICER1 D1709N mutation DICER1 NCBI:23405 gene Sertoli-Leydig cell tumor DOID:2997 diagnostic PubMed:26428316 In this exploratory study of Sertoli-Leydig cell tumors, DICER1 mutations were found in over half of the samples sequenced, but were not found to have any role in tumorigenesis, contrary to what was previously believed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D1709N sequence variation in gene DICER1/NCBI:23405 1191 check_entity AN4935-2 DICER1 D1709N mutation DICER1 NCBI:23405 gene Sertoli-Leydig cell tumor DOID:2997 diagnostic PubMed:22187960 DICER1 mutations in the RNase IIIb domain were found in 29% of nonepithelial ovarian tumors (n=103) with high predominance in Sertoli-Lydig cell tumors (26/43; 60%). There were ten mutations in D1709N. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D1709N sequence variation in gene DICER1/NCBI:23405 1191 check_entity AN4935-2 DICER1 D1709N mutation DICER1 NCBI:23405 gene Sertoli-Leydig cell tumor DOID:2997 diagnostic CIViC:1927 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D1709N sequence variation in gene DICER1/NCBI:23405 1191 check_entity AN4936-1 DICER1 E1705K mutation DICER1 NCBI:23405 gene Sertoli-Leydig cell tumor DOID:2997 diagnostic PubMed:26428316 Sanger sequencing identified DICER1 hotspot mutations in 20 of 32 (63%) ovarian Sertoli–Leydig cell tumors. These mutations were unrelated to tumor differentiation and mostly (16/20, 80%) were E1705K. Additionally, DICER1 E1705K mutations were identified in 5/8 (63%) Sertoli cell tumors and 2/5 (40%) gynandroblastomas. However, no mutations were identified in 15 testicular sex cord-stromal tumors (8 classical Sertoli cell tumors, 3 Sertoli cell tumors-large cell calcifying variant, 4 sex cord-stromal tumors not otherwise specified). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E1705K sequence variation in gene DICER1/NCBI:23405 1192 check_entity AN4936-1 DICER1 E1705K mutation DICER1 NCBI:23405 gene Sertoli-Leydig cell tumor DOID:2997 diagnostic CIViC:1926 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E1705K sequence variation in gene DICER1/NCBI:23405 1192 check_entity AN4937-1 DICER1 E1813Q mutation DICER1 NCBI:23405 gene Sertoli-Leydig cell tumor DOID:2997 diagnostic;risk PubMed:26428316 In this exploratory study of Sertoli-Leydig cell tumors, DICER1 mutations were found in over half of the samples sequenced, but were not found to have any role in tumorigenesis, contrary to what was previously believed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E1813Q sequence variation in gene DICER1/NCBI:23405 1193 check_entity AN4937-1 DICER1 E1813Q mutation DICER1 NCBI:23405 gene Sertoli-Leydig cell tumor DOID:2997 diagnostic;risk PubMed:22187960 DICER1 mutations in the RNase IIIb domain were found in 29% of nonepithelial ovarian tumors (n=103) with high predominance in Sertoli-Lydig cell tumors (26/43; 60%). There were two patients with E1813Q. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E1813Q sequence variation in gene DICER1/NCBI:23405 1193 check_entity AN4937-1 DICER1 E1813Q mutation DICER1 NCBI:23405 gene Sertoli-Leydig cell tumor DOID:2997 diagnostic;risk CIViC:1928 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E1813Q sequence variation in gene DICER1/NCBI:23405 1193 check_entity AN4938-1 DKK1 NUCLEAR EXPRESSION DKK1 NCBI:22943 gene colorectal cancer DOID:9256 risk PubMed:25788273 Nuclear expression of DICKKOPF-1 was identified in 15% of 699 patients with colorectal cancer and was associated with decreased progression-free survival (PFS) and overall survival (OS) after chemotherapy (FOLFOX, FOLFIRI, or 5-FU) [adjusted HR, 1.65; 95% confidence interval (CI), 1.23-2.21; P = 0.002)]. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene DKK1/NCBI:22943 1194 AN4938-1 DKK1 NUCLEAR EXPRESSION DKK1 NCBI:22943 gene colorectal cancer DOID:9256 risk CIViC:336 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene DKK1/NCBI:22943 1194 AN4939-1 DNMT1 EXPRESSION DNMT1 NCBI:1786 gene gastric adenocarcinoma DOID:3717 risk PubMed:21458988 High DNMT1 expression was found in 105/127 (83%) or patients (by qPCR assay). Low DNMT1 expression was associated with improved histopathological and clinical response and OS in patients with gastric cancer (P=0.03/P=0.008, P(log-rank)=0.001, respectively). In one cisplatin resistant cell line, DAC treatment and cisplatin had a synergistic effect. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene DNMT1/NCBI:1786 1195 AN4939-1 DNMT1 EXPRESSION DNMT1 NCBI:1786 gene gastric adenocarcinoma DOID:3717 risk CIViC:331 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene DNMT1/NCBI:1786 1195 AN4939-2 DNMT1 EXPRESSION DNMT1 NCBI:1786 gene ovarian cancer DOID:2394 risk PubMed:25968887 DNMT1 expression (mRNA expression from an independent study) correlated with sensitivity to decitabine (ρ, −0.443, Pearson regression analysis) in this preclinical study of 45 solid tumor cell lines. DNMT1 protein expression was also evaluated in two KRAS-mutant ovarian cancer cell lines pre and post-decitabine treatment showing downregulation following treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene DNMT1/NCBI:1786 1196 AN4939-2 DNMT1 EXPRESSION DNMT1 NCBI:1786 gene ovarian cancer DOID:2394 risk CIViC:331 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene DNMT1/NCBI:1786 1196 AN4940-1 DNMT3A Mutation DNMT3A NCBI:1788 gene acute myeloid leukemia DOID:9119 prognostic;risk PubMed:22490330 Young AML patients (415 patients; <60 years old) with any DNMT3A mutation (n=96) have shorter overall survival and relapse-free survival than patients with wildtype DNMT3A. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene DNMT3A/NCBI:1788 1197 check_entity AN4940-1 DNMT3A Mutation DNMT3A NCBI:1788 gene acute myeloid leukemia DOID:9119 prognostic;risk PubMed:27288520 In AML patients aged <60years, presence of a DNMT3A mutation associated with inferior CR rate (HR, 0.54; P=.05) and shorter OS (HR, 1.84; P<.001) in multivariate analyses. Mutated DNMT3A associated with shorter RFS (HR 1.38; P=.034) irrespective of patient age. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene DNMT3A/NCBI:1788 1197 check_entity AN4940-1 DNMT3A Mutation DNMT3A NCBI:1788 gene acute myeloid leukemia DOID:9119 prognostic;risk PubMed:27276561 DNMT3A mutations associate with adverse overall survival in acute myeloid leukemia patients if they occur in the context of mutated NPM1 and FLT3-ITD (NPM1-FLT3ITD-DNMT3A phenotype), and in the context of IDH2 codon R140 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene DNMT3A/NCBI:1788 1197 check_entity AN4940-1 DNMT3A Mutation DNMT3A NCBI:1788 gene acute myeloid leukemia DOID:9119 prognostic;risk PubMed:22124213 Among 46 AML patients treated with decitabine, the response rate was 75% (6/8) among DNMT3A mutated and 34% (13/38) among DNMT3A wild-type patients (P=.008) assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene DNMT3A/NCBI:1788 1197 check_entity AN4940-1 DNMT3A Mutation DNMT3A NCBI:1788 gene acute myeloid leukemia DOID:9119 prognostic;risk CIViC:189 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene DNMT3A/NCBI:1788 1197 check_entity AN4940-2 DNMT3A Mutation DNMT3A NCBI:1788 gene cancer DOID:162 risk PubMed:28351930 'A subset of patients receiving PD1/PD-L1 inhibition appear to be ''hyper-progressors,'' with a greatly accelerated rate of tumor growth and clinical deterioration compared to pre-therapy. The current study investigated potential genomic markers associated with ''hyper-progression''. Consecutive stage IV cancer patients who received immunotherapies (CTLA-4, PD-1/PD-L1 inhibitors or other [investigational] agents) and had their tumor evaluated by next-generation sequencing Amongst 155 patients, TTF (time to treatment failure) <2 months was seen in 4/5 individuals harbouring DNMT3A alteration.' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene DNMT3A/NCBI:1788 1198 check_entity AN4940-2 DNMT3A Mutation DNMT3A NCBI:1788 gene cancer DOID:162 risk CIViC:189 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene DNMT3A/NCBI:1788 1198 check_entity AN4940-3 DNMT3A Mutation DNMT3A NCBI:1788 gene myelodysplastic syndrome DOID:0050908 prognostic PubMed:21415852 12/150 patients with de novo myelodysplastic syndrome screened for DNMT3A mutations (bone marrow and paired normal skin) had heterozygous mutations with predicted translational consequences. 1 patient was identified with 2 nonsynonymous coding mutations. R882 mutations accounted for 4/13 reported mutations, P904L for 2/13 mutations and the remaining had not been previously reported at the time of this report. Overall and event-free survival were worse for DNMT3A mutant patients although transplantation status was not considered (log-rank p=0.005 and p=0.009). Transformation to AML was increased for mutant 7/12 (58%) versus wildtype 39/138 (28%) patients (p=0.007). The authors note larger cohorts will be required to confirm these results. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene DNMT3A/NCBI:1788 1199 check_entity AN4940-3 DNMT3A Mutation DNMT3A NCBI:1788 gene myelodysplastic syndrome DOID:0050908 prognostic CIViC:189 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene DNMT3A/NCBI:1788 1199 check_entity AN4940-4 DNMT3A Mutation DNMT3A NCBI:1788 gene T-cell acute lymphoblastic leukemia DOID:5603 prognostic PubMed:23341344 In adult patients with early (n = 30), cortical (n = 30), mature (n = 3) or unknown (n = 8) T-cell acute lymphoblastic leukemia, those with mutations in DNMT3A (n=12) had shorter overall survival than wild-type patients (n=59; p=0.011). This was also true for the subset of patients with early T-ALL DNMT3A-mutated (n = 8) compared to wild-type patients (n = 22; p=0.005). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene DNMT3A/NCBI:1788 1200 check_entity AN4940-4 DNMT3A Mutation DNMT3A NCBI:1788 gene T-cell acute lymphoblastic leukemia DOID:5603 prognostic CIViC:189 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene DNMT3A/NCBI:1788 1200 check_entity AN4941-1 DNMT3A R882 mutation DNMT3A NCBI:1788 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk PubMed:22081665 DNMT3A R882 mutations occur most often in de novo AML patients with intermediate risk cytogenetics (39/194 intermediate risk patients vs 0/89 low and high risk). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R882 sequence variation in gene DNMT3A/NCBI:1788 1201 check_entity AN4941-1 DNMT3A R882 mutation DNMT3A NCBI:1788 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk PubMed:22490330 Young AML patients (<60 years old) with DNMT3A mutations (60% of which were R882) were older in age, had higher white blood cell counts and had higher platelet counts than patients wildtype for DNMT3A. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R882 sequence variation in gene DNMT3A/NCBI:1788 1201 check_entity AN4941-1 DNMT3A R882 mutation DNMT3A NCBI:1788 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk PubMed:21067377 De novo AML patients with DNMT3A D882 mutation showed worse survival (event-free and overall) outcome than those without DNMT3A mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R882 sequence variation in gene DNMT3A/NCBI:1788 1201 check_entity AN4941-1 DNMT3A R882 mutation DNMT3A NCBI:1788 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk PubMed:24512939 DNMT3A R882 mutations were associated with older age, higher white blood cell count, and FAB M4 and M5 subtypes compared to wildtype DNMT3A in a cohort of cytogenetically normal AML patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R882 sequence variation in gene DNMT3A/NCBI:1788 1201 check_entity AN4941-1 DNMT3A R882 mutation DNMT3A NCBI:1788 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk PubMed:23632886 In a large cohort of AML patients (mean = 48 years), DNMT3A mutation (64.5% of which were R882) had no prognostic value on overall, relapse free and event free survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R882 sequence variation in gene DNMT3A/NCBI:1788 1201 check_entity AN4941-1 DNMT3A R882 mutation DNMT3A NCBI:1788 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk PubMed:22291079 In older cytogenetically normal AML patients (>59 years), DNMT3A R882 mutation is prognostic for shorter disease free survival and overall survival compared to patients without the mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R882 sequence variation in gene DNMT3A/NCBI:1788 1201 check_entity AN4941-1 DNMT3A R882 mutation DNMT3A NCBI:1788 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk CIViC:32 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R882 sequence variation in gene DNMT3A/NCBI:1788 1201 check_entity AN4942-1 DPYD DPYD*13 HOMOZYGOSITY DPYD NCBI:1806 gene cancer DOID:162 risk 45284-7 PubMed:23988873 The Clinical Pharmacogenomics Implementation Consortium Guidelines for DPYD genotype and 5-FU dosing does not recommend the use of 5-FU or capecitabine in patients with homozygous DPYD*2A, *13 or rs67376798 and the FDA drug labels warn to use precautions in this patient population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition DPYD DPYD*13 HOMOZYGOSITY [biomarker_term_in_review] 1202 not_mapped AN4942-1 DPYD DPYD*13 HOMOZYGOSITY DPYD NCBI:1806 gene cancer DOID:162 risk 45284-7 CIViC:719 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition DPYD DPYD*13 HOMOZYGOSITY [biomarker_term_in_review] 1202 not_mapped AN4943-1 DPYD DPYD*2A HOMOZYGOSITY DPYD NCBI:1806 gene cancer DOID:162 risk 45284-7 PubMed:23988873 The Clinical Pharmacogenomics Implementation Consortium Guidelines for DPYD genotype and 5-FU dosing does not recommend the use of 5-FU or capecitabine in patients with homozygous DPYD*2A, *13 or rs67376798 and the FDA drug labels warn to use precautions in this patient population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition DPYD DPYD*2A HOMOZYGOSITY [biomarker_term_in_review] 1203 not_mapped AN4943-1 DPYD DPYD*2A HOMOZYGOSITY DPYD NCBI:1806 gene cancer DOID:162 risk 45284-7 CIViC:718 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition DPYD DPYD*2A HOMOZYGOSITY [biomarker_term_in_review] 1203 not_mapped AN4944-1 DPYD EXON 11-19 DELETION DPYD NCBI:1806 gene head and neck squamous cell carcinoma DOID:5520 risk 45284-7 PubMed:31871216 A 69 year old patient diagnosed with HNSCC presented with an unresectable neck mass three months after surgery and adjuvant radiation therapy. A biopsy was taken for whole genome and transcriptome analysis and the patient was started on systemic therapy. After showing resistance to the systemic therapy treatment with 5-FU and leucovorin was initiated based on the discovery of a somatic exon 11-19 in frame deletion in DPYD, which was hypothesized to increase sensitivity to 5-FU in the tumour. A dramatic clinical and radiographic response was sustained for 17 weeks, but following a 3 week treatment break a new nodule appeared. This recurrence showed resistance to re-initiation of treatment with capecitabine (oral 5-FU), and analysis of an additional biopsy provided no evidence as to the mechanism of resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:11-19:deletion sequence variation in gene DPYD/NCBI:1806 1204 check_entity AN4944-1 DPYD EXON 11-19 DELETION DPYD NCBI:1806 gene head and neck squamous cell carcinoma DOID:5520 risk 45284-7 CIViC:2762 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:11-19:deletion sequence variation in gene DPYD/NCBI:1806 1204 check_entity AN4945-1 DPYD RS67376798 HOMOZYGOSITY DPYD NCBI:1806 gene cancer DOID:162 risk 45284-7 PubMed:23988873 The Clinical Pharmacogenomics Implementation Consortium Guidelines for DPYD genotype and 5-FU dosing does not recommend the use of 5-FU or capecitabine in patients with homozygous DPYD*2A, *13 or rs67376798 and the FDA drug labels warn to use precautions in this patient population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS67376798 sequence variation in gene DPYD/NCBI:1806 1205 check_entity AN4945-1 DPYD RS67376798 HOMOZYGOSITY DPYD NCBI:1806 gene cancer DOID:162 risk 45284-7 CIViC:721 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS67376798 sequence variation in gene DPYD/NCBI:1806 1205 check_entity AN4946-1 DUSP6 EXPRESSION DUSP6 NCBI:1848 gene cancer DOID:162 risk PubMed:22169769 Expression of DUSP6 was associated with sensitivity to MEK inhibitor GSK1120212 (Sensitivity: 79%; specificity: 82%: P = 0.0027) in 218 solid cancer cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene DUSP6/NCBI:1848 1206 AN4946-1 DUSP6 EXPRESSION DUSP6 NCBI:1848 gene cancer DOID:162 risk CIViC:394 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene DUSP6/NCBI:1848 1206 AN4947-1 DUX4 Fusion DUX4 NCBI:100288687 gene acute lymphoblastic leukemia DOID:9952 diagnostic;prognostic PubMed:27019113 A screen for fusion genes in Ph- AYA-ALL (Philadelphia chromosome negative acute lymphoblastic leukemia in adolescents and young adults) was performed using RNA-seq from multiple cohorts of ALL patients. DUX4, ZNF384 and MEF2D fusions were the most frequent found. DUX4 fusions were found only in AYA cases (age 15-39) and this was significant, p=0.016. DUX4 fusions clustered into groups distinct from the other fusions, and these fusions as a whole clustered with Ph- ALL cases. The authors performed extensive in vitro and in vivo experiments to demonstrate that DUX4 fusions are likely early initiating/events and that DUX4 fusion and not DUX4 wild type are tumorigenic. The authors conclude that DUX4 fusions may be a target driver resulting in AYA-ALL, and that AYA-ALL may be a distinct clinical entity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene DUX4/NCBI:100288687 1207 check_entity AN4947-1 DUX4 Fusion DUX4 NCBI:100288687 gene acute lymphoblastic leukemia DOID:9952 diagnostic;prognostic CIViC:520 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene DUX4/NCBI:100288687 1207 check_entity AN4948-1 ECSCR EXPRESSION ECSCR NCBI:641700 gene cancer DOID:162 risk PubMed:26956051 Biomarkers for response to antiangiogenic treatment were screened for in hepatocellular cancer (n = 11), renal cell cancer (n = 7) and non-small cell lung cancer (n = 2). Increased expression of tumor endothelial markers: Robo4 and ECSCR, nonsignificantly correlated with prolonged antiangiogenic time to progression (ECSCR high = 275 days vs. ECSCR low = 92.5 days; p = 0.07 and for Robo4 high = 387 days vs. Robo4 low = 90.0 days; p = 0.08). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene ECSCR/NCBI:641700 1208 AN4948-1 ECSCR EXPRESSION ECSCR NCBI:641700 gene cancer DOID:162 risk CIViC:488 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene ECSCR/NCBI:641700 1208 AN4949-1 EGF EXPRESSION EGF NCBI:1950 gene head and neck squamous cell carcinoma DOID:5520 risk 21665-5 PubMed:25677871 3 tongue cancer cell lines were used for this study. Addition of recombinant human EGF led to increased cetuximab resistance. EGF downregulation suppressed proliferation of cell lines. Results for amphiregulin and epiregulin were inconclusive. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene EGF/NCBI:1950 1209 AN4949-1 EGF EXPRESSION EGF NCBI:1950 gene head and neck squamous cell carcinoma DOID:5520 risk 21665-5 CIViC:338 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene EGF/NCBI:1950 1209 AN4950-1 EGFR A289V mutation EGFR NCBI:1956 gene high grade glioma DOID:3070 risk 21665-5 PubMed:17177598 In an in vitro study, a Ba/F3 cell line expressing EGFR A289V demonstrated increased sensitivity to erlotinib treatment, compared to Ba/F3 cells expressing EGFR wild-type. Variant function was assessed by EGFR auto-phosphorylation. Sensitivity was assessed by cell viability assay using stable transfection of each variant and increasing concentrations of erlotinib (0–10 uM). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A289V sequence variation in gene EGFR/NCBI:1956 1210 check_entity AN4950-1 EGFR A289V mutation EGFR NCBI:1956 gene high grade glioma DOID:3070 risk 21665-5 CIViC:970 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A289V sequence variation in gene EGFR/NCBI:1956 1210 check_entity AN4951-1 EGFR A763_Y764insFQEA EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:24353160 In an in vitro study, Ba/F3 and BID007 cell lines expressing EGFR A763_Y764insFQEA demonstrated increased sensitivity to erlotinib treatment (IC50=0.048�M and 0.082�M, respectively), comparable to Ba/F3 and NCI-H3255 cells expressing EGFR L858R (a known sensitizing mutation to EGFR tyrosine kinase inhibitors; IC50=0.006�M and 0.068�M, respectively). Sensitivity was determined by assessing cell proliferation, EGFR, AKT and ERK phosphorylation, levels of BIM (a marker of EGFR TKI-induced cell killing) and cell viability. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR A763_Y764insFQEA [biomarker_term_in_review] 1211 not_mapped AN4951-1 EGFR A763_Y764insFQEA EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:31208370 In a retrospective study of 2316 Chinese patients with stage IV non-small cell lung carcinoma, a 65 year old female with the EGFR exon 20 insertion A763_Y764insFQEA received osimertinib as second-line treatment. The patient achieved a partial response with greater than 50% reduction in tumour size, and progression-free survival of 5.1 months. The patient had previously achieved partial response on gefinitib, but experienced disease progression after 9.0 months at which point a rebiopsy was found to harbor a T790M mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR A763_Y764insFQEA [biomarker_term_in_review] 1211 not_mapped AN4951-1 EGFR A763_Y764insFQEA EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1423 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR A763_Y764insFQEA [biomarker_term_in_review] 1211 not_mapped AN4952-1 EGFR A767_V769dupASV mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:24353160 In a study of 19 non-small cell lung carcinoma patients with EGFR exon 20 insertion mutations and treated with erlotinib monotherapy, patients with EGFR A767_V769dupASV mutation (n=3) experienced progressive disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::a767_v769dupasv:mutation sequence variation in gene EGFR/NCBI:1956 1212 check_entity AN4952-1 EGFR A767_V769dupASV mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 CIViC:1487 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::a767_v769dupasv:mutation sequence variation in gene EGFR/NCBI:1956 1212 check_entity AN4952-2 EGFR A767_V769dupASV mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:31208370 In a retrospective study of 2316 Chinese patients with stage IV non-small cell lung carcinoma, a 63 year old female with the EGFR exon 20 insertion A767_V769dupASV received osimertinib as first-line treatment. The patient achieved a partial response with greater than 30% reduction in tumour size, and progression-free survival of 6.0 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::a767_v769dupasv:mutation sequence variation in gene EGFR/NCBI:1956 1213 check_entity AN4952-2 EGFR A767_V769dupASV mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1487 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::a767_v769dupasv:mutation sequence variation in gene EGFR/NCBI:1956 1213 check_entity AN4953-1 EGFR A864T mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:19147750 In an in vitro study, a Ba/F3 cell line expressing EGFR A864T demonstrated increased sensitivity to erlotinib treatment comparable to Ba/F3 cells expressing a known sensitizing mutation (EGFR L858R). Sensitivity was determined by assessing cell proliferation, the IC50 of erlotinib for EGFR A864T and EGFR L858R expressing cells were 49 nmol/L and 6 nmol/L, respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A864T sequence variation in gene EGFR/NCBI:1956 1214 check_entity AN4953-1 EGFR A864T mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1161 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A864T sequence variation in gene EGFR/NCBI:1956 1214 check_entity AN4954-1 EGFR Amplification EGFR NCBI:1956 gene Barrett's adenocarcinoma DOID:7941 prognostic 21665-5 PubMed:20840671 In patients with Barrett's adenocarcinoma, those with amplification of EGFR had shorter disease-specific survial. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene EGFR/NCBI:1956 1215 AN4954-1 EGFR Amplification EGFR NCBI:1956 gene Barrett's adenocarcinoma DOID:7941 prognostic 21665-5 CIViC:190 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene EGFR/NCBI:1956 1215 AN4954-2 EGFR Amplification EGFR NCBI:1956 gene cervical squamous cell carcinoma DOID:3744 prognostic 21665-5 PubMed:21730982 In patients with cervical squamous cell carcinoma, those with gene amplification of EGFR had worse overall survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene EGFR/NCBI:1956 1216 AN4954-2 EGFR Amplification EGFR NCBI:1956 gene cervical squamous cell carcinoma DOID:3744 prognostic 21665-5 CIViC:190 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene EGFR/NCBI:1956 1216 AN4954-3 EGFR Amplification EGFR NCBI:1956 gene colon adenocarcinoma DOID:234 risk 21665-5 PubMed:32162810 Case report describing a 63-year-old patient with colorectal adenocarcinoma. He started treatment with XELOX and bevacizumab. After findings of disease progression, they changed to bevacizumab and FOLFIRI. They detected EGFR::SEPT14 fusion (exon 24 & exon 10) and EGFR amplification by NGS on a paraffin sample after discontinuing the treatment due to complications. The tumor was microsatellite stable. The patient started treatment with erlotinib with signs of partial response (CT scan) 20 days later. A couple months later the patient showed signs of progressive disease, but a new variant, EGFRvIII (deletion of Exons 2-7), was detected in the mediastinal lymph nodes sample tested that likely contributed to erolotinib resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene EGFR/NCBI:1956 1217 AN4954-3 EGFR Amplification EGFR NCBI:1956 gene colon adenocarcinoma DOID:234 risk 21665-5 CIViC:4175 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene EGFR/NCBI:1956 1217 AN4954-4 EGFR Amplification EGFR NCBI:1956 gene colorectal cancer DOID:9256 risk 21665-5 PubMed:24653627 In this meta-analysis (14 studies, 1021 patients), EGFR gene copy number (GCN) was predictive of improved progression free survival (PFS) and overall survival (OS) with cetuximab or panitumumab regardless of KRAS status. For the pooled analysis, the objective response rate (ORR) was 65.2% (167/256) in patients with high EFGR GCN, while in patients with low EFGR GCN, the pooled ORR was 12.2% (44/361). The odds ratio (OR) was 6.905 (95% CI: 4.489-10.620; Z=8.79, P=0.000). In wild type KRAS patients, the pooled OR was 8.133 (95% CI: 4.316-15.326; Z=6.48, P=0.000). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene EGFR/NCBI:1956 1218 AN4954-4 EGFR Amplification EGFR NCBI:1956 gene colorectal cancer DOID:9256 risk 21665-5 PubMed:18794099 87 patients with metastatic colorectal cancer treated with cetuximab were retrospectively analyzed for EGFR amplifications by FISH. In multivariate analysis, EGFR amplification predicted response and overall survival independent of KRAS status. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene EGFR/NCBI:1956 1218 AN4954-4 EGFR Amplification EGFR NCBI:1956 gene colorectal cancer DOID:9256 risk 21665-5 CIViC:190 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene EGFR/NCBI:1956 1218 AN4954-5 EGFR Amplification EGFR NCBI:1956 gene glioblastoma DOID:3068 risk 21665-5 PubMed:26423602 Case report of a 58-year old patient with disease progression after radiotherapy and three temozolomide cycles. Afatinib and temozolomide led to disease regression. At last assessment 63 treatment cycles had been completed and the patient had survived for about 5 years since recurrence. Identified EGFR aberrations included EGFRvIII positivity, EGFR gene amplification and three somatic EGFR mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene EGFR/NCBI:1956 1219 AN4954-5 EGFR Amplification EGFR NCBI:1956 gene glioblastoma DOID:3068 risk 21665-5 CIViC:4245 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene EGFR/NCBI:1956 1219 AN4954-6 EGFR Amplification EGFR NCBI:1956 gene head and neck squamous cell carcinoma DOID:5520 prognostic;risk 21665-5 PubMed:16943533 The group of 43 out of 75 tumor samples with increased copy number or amplification of EGFR as determined by FISH (FISH-positive) had worse progression-free and overall survival than FISH-negative tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene EGFR/NCBI:1956 1220 AN4954-6 EGFR Amplification EGFR NCBI:1956 gene head and neck squamous cell carcinoma DOID:5520 prognostic;risk 21665-5 PubMed:21048039 EGFR amplification was not a predictor of response to cetuximab/5-FU/platinum in patients with recurrent or metastatic HNSSC from the EXTREME study. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene EGFR/NCBI:1956 1220 AN4954-6 EGFR Amplification EGFR NCBI:1956 gene head and neck squamous cell carcinoma DOID:5520 prognostic;risk 21665-5 CIViC:190 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene EGFR/NCBI:1956 1220 AN4954-7 EGFR Amplification EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:20826716 A meta-analysis of EGFR gene copy number as a predictive biomarker for patients receiving tyrosine kinase inhibitor treatment was performed. In total, 20 (1689 patients, 594 with increased gene copy number), 10 (822 patients, 290 with increased gene copy number) and 5 studies (294 patients, 129 with increased gene copy number) were analyzed for overall survival (OS), progression-free survival (PFS) and time-to-progression (TTP) meta-analyses respectively. EGFR amplification was associated with increased OS (HR = 0.77; 95% CI 0.66-0.89; P = 0.001), PFS (HR = 0.60; 95% CI 0.46-0.79; P<0.001) and TTP (HR = 0.50; 95% CI 0.28-0.91; P = 0.02). This effect was shown to influence survival in predominantly white patient populations but not patients of Asian descent. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene EGFR/NCBI:1956 1221 AN4954-7 EGFR Amplification EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:26722081 In 290 patients with advanced NSCLC, 177 of which were treated with EGFR TKI (erlotinib or gefitinib). EGFR amplification (Multiplex ligation-dependent probe amplification; MLPA) and Mutation (PCR) were analzed. EGFR amplification was associated with EGFR mutation but not independently with patient benefit from EGFR TKI (overall and progression-free survival). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene EGFR/NCBI:1956 1221 AN4954-7 EGFR Amplification EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:28202511 Evidence of wild-type allele-mediated resistance, a novel concept of acquired resistance in response to mutation-selective inhibitor therapy in cancer treatment. This study reports that the Src-AKT pathway contributes to acquired resistance to third generation EGFR TKIs. In addition, amplification of EGFR wild-type alleles but not mutant alleles was sufficient to confer acquired resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene EGFR/NCBI:1956 1221 AN4954-7 EGFR Amplification EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:27664271 Among TKI-treated patients, increased EGFR gene copy number appears to be associated with improved survival outcomes. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene EGFR/NCBI:1956 1221 AN4954-7 EGFR Amplification EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:190 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene EGFR/NCBI:1956 1221 AN4955-1 EGFR C797S mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:26181354 Case report of a patient with stage IV lung adenocarcinoma and a 15–base pair deletion in EGFR exon 19. Partial response with erlotinib was achieved for 15 months after initial chemotherapy. After further progression, rebiopsy additionally identified the EGFR T790M mutation and the patient received several cycles of chemotherapy and targeted therapy including afatinib, cetuximab, erlotinib, AZD9291. She was treated with AZD9291 for 9 months until disease progression. Repeat biopsy detected EGFRC797S mutation additionally to both aforementioned EGFR aberrations. In addition, PTEN Y27C and CTNNB1 S37F mutations were present in all 3 samples, and a TSC2 N486I was seen in the third biopsy sample only assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C797S sequence variation in gene EGFR/NCBI:1956 1222 check_entity AN4955-1 EGFR C797S mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 CIViC:411 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C797S sequence variation in gene EGFR/NCBI:1956 1222 check_entity AN4955-2 EGFR C797S mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:25939061 An EGFR resistance mutation, C797S, was discovered by deep sequencing of cell-free plasma DNA (cfDNA) from patients with advanced lung cancer whose tumors had developed resistance to osimertinib. Expression of this mutant EGFR construct in a cell line rendered it resistant to osimertinib. ddPCR on serial cfDNA specimens collected from 15 osimertinib-treated subjects (all positive for T790M before treatment) revealed 6 cases with acquired C797S mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C797S sequence variation in gene EGFR/NCBI:1956 1223 check_entity AN4955-2 EGFR C797S mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:411 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C797S sequence variation in gene EGFR/NCBI:1956 1223 check_entity AN4956-1 EGFR C797Y mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 PubMed:20942962 In an in vitro study performed after identification of the mutation in a malignant peritoneal mesothelioma patient, COS-7 cells expressing EGFR C797Y demonstrated increased EGFR phosphotyrosine after EGF treatment over wildtype EGFR expressing cells. Cells expressing mutant EGFR also showed increased sensitivity to erlotinib treatment compared to cells expressing EGFR wild-type. Sensitivity was determined by assessing EGFR auto-phosphorylation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C797Y sequence variation in gene EGFR/NCBI:1956 1224 check_entity AN4956-1 EGFR C797Y mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 CIViC:1482 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C797Y sequence variation in gene EGFR/NCBI:1956 1224 check_entity AN4957-1 EGFR Copy Number Variation EGFR NCBI:1956 gene head and neck squamous cell carcinoma DOID:5520 prognostic 21665-5 PubMed:17538160 In 134 patients with head and neck squamous cancer 32 had copy number variations. Tumors with variation (either increase or decrease) in copy number of EGFR had worse overall, cancer-specific, and disease-free survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR Copy Number Variation [biomarker_term_in_review] 1225 not_mapped AN4957-1 EGFR Copy Number Variation EGFR NCBI:1956 gene head and neck squamous cell carcinoma DOID:5520 prognostic 21665-5 CIViC:191 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR Copy Number Variation [biomarker_term_in_review] 1225 not_mapped AN4958-1 EGFR D761Y mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:17085664 D761Y as a secondary mutation was reported to be associated with resistance to gefitinib and erlotinib in NSCLC cells that contain the L858R-EGFR mutation. This mutation combination was observed in a single patient with lung cancer and specifically in a metastatic brain lesion following gefitinib treatment. Functional validation of its role in drug sensitivity was examined in cell lines (293T and Ba/F3 cells). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D761Y sequence variation in gene EGFR/NCBI:1956 1226 check_entity AN4958-1 EGFR D761Y mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:693 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D761Y sequence variation in gene EGFR/NCBI:1956 1226 check_entity AN4959-1 EGFR D770_N771insG EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:31208370 In a retrospective study of 2316 Chinese patients with stage IV non-small cell lung carcinoma, a 63 year old female with the EGFR exon 20 insertion D770_N771insG received osimertinib as second-line treatment. The patient had clinical improvement and achieved partial response with nearly 50% reduction in tumour size. Progression-free survival was 6.4 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR D770_N771insG [biomarker_term_in_review] 1227 not_mapped AN4959-1 EGFR D770_N771insG EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1420 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR D770_N771insG [biomarker_term_in_review] 1227 not_mapped AN4960-1 EGFR D770_N771insGL EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:24353160 2 patients with EGFR D770_N771insGL mutant lung adenocarcinoma were treated with first line erlotinib. A 45 year old male never smoker had progressive disease as best response with +24% change to target lesions, progression free survival of 3.8 months, and still alive at study end after 39.3 months. A 79 year old female never smoker had progressive disease as best response with +13% change to target lesions, progression free survival of 6 months and overall survival of 14 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR D770_N771insGL [biomarker_term_in_review] 1228 not_mapped AN4960-1 EGFR D770_N771insGL EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 CIViC:1422 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR D770_N771insGL [biomarker_term_in_review] 1228 not_mapped AN4961-1 EGFR D770_N771insGT EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:23371856 In a lung adenocarcinoma patient harboring EGFR D770_N771insGT mutation, EGFR D770_N771insGT was associated with lack of response to treatment with erlotinib monotherapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR D770_N771insGT [biomarker_term_in_review] 1229 not_mapped AN4961-1 EGFR D770_N771insGT EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 CIViC:1474 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR D770_N771insGT [biomarker_term_in_review] 1229 not_mapped AN4962-1 EGFR D770_N771insNPG EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:24353160 Ba/F3 cells transduced with EGFR D770_N771insNPG were IL3 growth independent, suggesting a driver mutation. Gefitinib growth inhibition IC50 in D770_N771insNPG transduced Ba/F3 cells was 3.356 micro molar, which was higher than cells transduced with resistance mutation T790M (IC50=2.752). Similarly, afatinib growth inhibition IC50 was 0.0724 micro molar, which was higher than cells transduced with resistance mutation T790M (IC50=0.0629). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR D770_N771insNPG [biomarker_term_in_review] 1230 not_mapped AN4962-1 EGFR D770_N771insNPG EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1477 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR D770_N771insNPG [biomarker_term_in_review] 1230 not_mapped AN4963-1 EGFR D770_N771insSVD EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:24353160 In an in vitro study, a Ba/F3 cell line expressing EGFR D770_N771insSVD demonstrated reduced sensitivity to erlotinib treatment (IC50=3.187�M), comparable to Ba/F3 cells expressing EGFR L858R and T790M co-mutation (T790M is a known resistant mutation to 1st and 2nd generation EGFR tyrosine kinase inhibitors; IC50=4.155�M). Resistance was determined by assessing cell proliferation, EGFR, AKT and ERK phosphorylation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR D770_N771insSVD [biomarker_term_in_review] 1231 not_mapped AN4963-1 EGFR D770_N771insSVD EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1353 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR D770_N771insSVD [biomarker_term_in_review] 1231 not_mapped AN4964-1 EGFR D770delinsGY EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:24353160 In a study of 19 non-small cell lung carcinoma patients with EGFR exon 20 insertion mutation and treated with erlotinib monotherapy, patients with EGFR D770delinsGY mutation (n=2) experienced progressive disease. Both patients were white females, had adenocarcinoma, and were treated with erlotinib as first line therapy. One was 76 years old with 6 former pack years, 38.1% increase in target lesion, 1 month PFS and 12 month OS. The other was 67 years old with 2 former pack years, 6.0% increase in target lesion, 1 month PFS and 1.5 month OS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR D770delinsGY [biomarker_term_in_review] 1232 not_mapped AN4964-1 EGFR D770delinsGY EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 CIViC:2090 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR D770delinsGY [biomarker_term_in_review] 1232 not_mapped AN4965-1 EGFR E734Q mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 PubMed:20942962 In an in vitro study performed after identification of the mutation in a malignant peritoneal mesothelioma patient, COS-7 cells expressing EGFR E734Q demonstrated increased EGFR phosphotyrosine after EGF treatment over wildtype EGFR expressing cells. Cells expressing mutant EGFR also showed increased sensitivity to erlotinib treatment compared to cells expressing EGFR wild-type. Sensitivity was determined by assessing EGFR auto-phosphorylation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E734Q sequence variation in gene EGFR/NCBI:1956 1233 check_entity AN4965-1 EGFR E734Q mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 CIViC:1480 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E734Q sequence variation in gene EGFR/NCBI:1956 1233 check_entity AN4966-1 EGFR E746G mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:26773740 In a meta-analysis of 7 clinical trials evaluating the efficacy of erlotinib, one patient was described with the exon 19 mutation E746G from the BeTa study. Progression-free (415 days) and overall (462 days) survival suggested sensitivity in this patient. No statistical analysis was reported for this variant and PFS or OS, citing small sample size across the studies. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E746G sequence variation in gene EGFR/NCBI:1956 1234 check_entity AN4966-1 EGFR E746G mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 CIViC:705 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E746G sequence variation in gene EGFR/NCBI:1956 1234 check_entity AN4967-1 EGFR E746_A750del EGFR NCBI:1956 gene bronchiolo-alveolar adenocarcinoma DOID:4926 risk 21665-5 PubMed:15329413 EGFR exons 18-24 were analyzed in 7 patients who had shown a partial response to erlotinib in a phase II trial for bronchioloalveolar carcinoma (BAC, or in situ pulmonary adenocarcinoma). One patient (Patient E2) had the E746_A750del mutation. The patient was a male never smoker, and demonstrated response for 8.5 months. Overall survival was 21+ months as the patient was alive at study end. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR E746_A750del [biomarker_term_in_review] 1235 not_mapped AN4967-1 EGFR E746_A750del EGFR NCBI:1956 gene bronchiolo-alveolar adenocarcinoma DOID:4926 risk 21665-5 CIViC:976 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR E746_A750del [biomarker_term_in_review] 1235 not_mapped AN4967-2 EGFR E746_A750del EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:24893891 In an in vitro study using PC9 cells (EGFR exon 19 deletion), inhibition of cell viability was used as an assay to determine sensitivity to EGFR tyrosine kinase inhibitors. PC9 cells demonstrated an increased sensitivity to gefitinib (IC50: 23.0 nmol/L vs 200.0 nmol/L) compared to NCI-H2073 cells (EGFR wild type). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR E746_A750del [biomarker_term_in_review] 1236 not_mapped AN4967-2 EGFR E746_A750del EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:15329413 Mutational profiling was performed on EGFR exons 18-24 from a group of 10 retrospectively chosen patients who had shown partial response or clinical improvement in response to gefitinib. Of 7 tumors with EGFR mutations, 4 were del E746-A750. 3 had adenocarcinoma with bronchioloalveolar carcinoma (BAC) features, with response duration and overall survival of 8 and 15 months, 5+ and 5+ months (treatment ongoing at study end) and 28 and 30+ months (alive at study end), and one former smoker with adenocarcinoma with BAC features, who had response duration of 5+ months with treatment ongoing at study end. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR E746_A750del [biomarker_term_in_review] 1236 not_mapped AN4967-2 EGFR E746_A750del EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:976 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR E746_A750del [biomarker_term_in_review] 1236 not_mapped AN4968-1 EGFR E746_T751>I mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:15329413 Mutational profiling was performed on EGFR exons 18-24 from a group of 10 retrospectively chosen lung cancer patients who had shown partial response or clinical imporvement in response to gefitinib. Of 7 tumors with EGFR mutations, 1 was del E746-T751insI. The patient was a female never smoker who had adenocarcinoma with bronchioloalveolar carcinoma features, and demonstrated response for 9 months, with overall survival 14 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::e746_t751>i:mutation sequence variation in gene EGFR/NCBI:1956 1237 check_entity AN4968-1 EGFR E746_T751>I mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 CIViC:977 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::e746_t751>i:mutation sequence variation in gene EGFR/NCBI:1956 1237 check_entity AN4969-1 EGFR E868G mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 PubMed:20942962 In an in vitro study performed after identification of the mutation in a malignant peritoneal mesothelioma patient, COS-7 cells expressing EGFR E868G demonstrated increased EGFR phosphotyrosine after EGF treatment over wildtype EGFR expressing cells. Cells expressing mutant EGFR also showed increased sensitivity to erlotinib treatment compared to cells expressing EGFR wild-type. Sensitivity was determined by assessing EGFR auto-phosphorylation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E868G sequence variation in gene EGFR/NCBI:1956 1238 check_entity AN4969-1 EGFR E868G mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 CIViC:1390 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E868G sequence variation in gene EGFR/NCBI:1956 1238 check_entity AN4970-1 EGFR EGFR::RAD51 mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:29290255 A 48-year-old Chinese man with right lung tumor and multiple brain metastases of a lung adenocarcinoma (T1N2M1, stage IV). NGS analysis indicated an EGFR-RAD51 fusion rather than the most common kind of EGFR mutations. The patient underwent oral erlotinib treatment and was considered to have a partial response (PR) (according to RECIST). Thus far, after 5 months, the disease is stable and he is continuing treatment with erlotinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EGFR::RAD51 sequence variation in gene EGFR/NCBI:1956 1239 check_entity AN4970-1 EGFR EGFR::RAD51 mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:31064887 A 26 year old non-smoker was diagnosed with lung adenocarcinoma and underwent thoracoscopic resection and treatment with cisplatin and pemetrexed. Panel NGS sequencing of the surgical sample detected an EGFR-RAD51 fusion of EGFR exons 1-24 and RAD51 exons 4-10, resulting in loss of EGFR CBL binding domain but retention of the kinase domain. Icotinib treatment resulted in tumour reduction by CT, significant improvement in chest pain, and PFS of more than 15 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EGFR::RAD51 sequence variation in gene EGFR/NCBI:1956 1239 check_entity AN4970-1 EGFR EGFR::RAD51 mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:27102076 The paper reports three patients (P1, P2 and P4) with Stage IV lung adenocarcinoma with metastasis, harboring the EGFR::RAD51 fusion detected by hybrid capture NGS (FoundationOne). Breakpoints were in intron 24 of EGFR and intron3 of RAD51. These patients were not amenable to systemic chemotherapy due to disseminated intravascular coagulation or DIC (P1 and P2) or showed disease progression following chemotherapy (P4), and were subsequently treated with the EGFR inhibitor Erlotinib. Noticeable clinical and functional improvements were seen, including regression of miliary nodules, reduction in tumor size and resolution of DIC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EGFR::RAD51 sequence variation in gene EGFR/NCBI:1956 1239 check_entity AN4970-1 EGFR EGFR::RAD51 mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:35245845 Case report of a 30- year-old male with lung adenocarcinoma , with metastasis to several organs, including several lesions in the brain. NGS assay (Foundation One CDX panel) detected the EGRF::RAD51 fusion. He was treated with platinum -based agents and palliative radiation therapy to the spine. Once the disease was stable as per RECIST guidelines, treatment was switched to Osimertinib. Marked improvement was seen within two weeks with reduction in lymph node metastases and reduction in back pain. Dramatic reductions in brain lesions were observed after 2 months of treatment (Fig 1 and Fig 2). The patient was followed up for 9 months during which significant improvement was seen in his clinical status, and he continued to remain on this therapy. The authors have also noted that osimertinib fared better in improving his CNS symptoms compared to his earlier chemotherapy treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EGFR::RAD51 sequence variation in gene EGFR/NCBI:1956 1239 check_entity AN4970-1 EGFR EGFR::RAD51 mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 CIViC:2079 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EGFR::RAD51 sequence variation in gene EGFR/NCBI:1956 1239 check_entity AN4971-1 EGFR EGFR::SEPTIN14 mutation EGFR NCBI:1956 gene colon adenocarcinoma DOID:234 risk 21665-5 PubMed:32162810 Case report describing a 63-year-old patient with colorectal adenocarcinoma. He started treatment with XELOX and bevacizumab. After findings of disease progression, they changed to bevacizumab and FOLFIRI. They detected EGFR::SEPT14 fusion (exon 24 & exon 10) and EGFR amplification by NGS on a paraffin sample after discontinuing the treatment due to complications. The tumor was microsatellite stable. The patient started treatment with erlotinib with signs of partial response (CT scan) 20 days later. A couple months later the patient showed signs of progressive disease, but a new variant, EGFRvIII (deletion of Exons 2-7), was detected in the mediastinal lymph nodes sample tested that likely contributed to erolotinib resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EGFR::SEPTIN14 sequence variation in gene EGFR/NCBI:1956 1240 check_entity AN4971-1 EGFR EGFR::SEPTIN14 mutation EGFR NCBI:1956 gene colon adenocarcinoma DOID:234 risk 21665-5 CIViC:4175 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EGFR::SEPTIN14 sequence variation in gene EGFR/NCBI:1956 1240 check_entity AN4972-1 EGFR EGFRVIII mutation EGFR NCBI:1956 gene glioblastoma DOID:3068 risk 21665-5 PubMed:26423602 Case report of a 58-year old patient with disease progression after radiotherapy and three temozolomide cycles. Afatinib and temozolomide led to disease regression. At last assessment 63 treatment cycles had been completed and the patient had survived for about 5 years since recurrence. Identified EGFR aberrations included EGFRvIII positivity, EGFR gene amplification and three somatic EGFR mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::egfrviii:mutation sequence variation in gene EGFR/NCBI:1956 1241 check_entity AN4972-1 EGFR EGFRVIII mutation EGFR NCBI:1956 gene glioblastoma DOID:3068 risk 21665-5 CIViC:4245 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::egfrviii:mutation sequence variation in gene EGFR/NCBI:1956 1241 check_entity AN4973-1 EGFR Exon 18 Overexpression EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:24039832 Overexpression of EGFR exon 18 (Affymetrix Human Exon 1.0 ST) in tumor or blood samples was associated with tumor shrinkage, independently of EGFR mutational status in NSCLC treated with bevacizumab and erlotinib. 76 patients were analyzed for this study. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of Exon 18 in gene EGFR/NCBI:1956 1242 AN4973-1 EGFR Exon 18 Overexpression EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:371 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of Exon 18 in gene EGFR/NCBI:1956 1242 AN4974-1 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:23816960 A phase III clinical trial (NCT00949650) found that median progression free survival among patients with EGFR exon 19 deletion was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). 308 patients had either exon 19 or L858 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1243 check_entity AN4974-1 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:22452895 In a phase 2 study (NCT00525148), patients with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) and EGFR mutations, treated with afatinib, were assessed by objective response. In total, 129 patients were treated with afatinib. 66% of the 106 patients with two common activating EGFR mutations (exon 19 deletion or L858R) had an objective response compared to 39% of 23 patients with less common EGFR mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1243 check_entity AN4974-1 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:24439929 Afatinib is an irreversible covalent inhibitor of EGFR (second generation). This Phase III clinical trial (LUX-Lung 6; NCT01121393) was performed in Asian patients with EGFR mutant advanced NSCLC. 364 eligible patients with EGFR mutations were assigned to afatinib (n=242) or gemcitabine and cisplatin (n=122) treatment. The trial observed significantly longer median progression-free survival with afatinib vs. gemcitabine and cisplatin treatment (11.0 vs. 5.6 months). Afatinib/Chemotherapy group compositions: 51.2/50.8 % del 19; 38/37.7 % Leu858Arg; 10.8/11.5 % Uncommon. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1243 check_entity AN4974-1 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:25589191 In analysis of LUX-Lung 3 and LUX-Lung 6 trials (NCT00949650 and NCT01121393), of EGFR mutant NSCLC, median overall survival with afatinib treatment was seen to be significantly improved over chemotherapy (33.3 vs 21.1 and 31.4 vs 18.4 months in LUX-Lung 3 and LUX-Lung 6 respectively). This effect was observed in the EGFR exon 19 deletion subgroup, but not in the L858R mutant subgroup. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1243 check_entity AN4974-1 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:22370314 In a phase 3 clinical trial of Korean, never-smoker, lung adenocarcinoma patients, a subset of patients with EGFR mutations (n=42) treated with gefitinib were associated with improved overall response rate compared to gemcitabine plus cisplatin treatment (84.6%, 22/26, vs. 37.5%, 6/16, P=0.002). By contrast, in EGFR mutation negative cases, the response rate was much lower (25.9%, 7/27). The frequency of mutation in exon 19 deletion and L858R was 64.3% (27/42) and 36.4% (16/42), respectively. Exon 19 and L858R mutations were mutually exclusive in this cohort. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1243 check_entity AN4974-1 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:27566387 In a stage IV lung adenocarcinoma patient harboring EGFR exon 19 deletion, EGFR exon 19 deletion was associated with sensitivity to erlotinib monotherapy. Prior to identification of the EGFR exon 19 deletion, the patient was underwent complex treatments with standard chemotherapy and experienced disease progression; upon identification of EGFR exon 19 deletion and treatment with erlotinib, the patient achieved a clinical response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1243 check_entity AN4974-1 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:27022112 A Japanese Phase III clinical study assessed the noninferiority of gefitinib in comparison to erlotinib in 561 patients with postoperative or recurrent stage IIIB/IV lung adenocarcinoma. Patients were pretreated with at least one chemotherapy regimen, but no tyrosine kinase inhibitors. In the subgroup of 156 patients with exon 19 deletions as their sole EGFR mutation, 83 and 78 were treated with erlotinib and gefitinib, respectively. Objective response (defined as complete + partial response) was approximately 65 percent for both erlotinib gefitinib and non significantly different (p= .965). Disease control rate (defined as complete response + partial response + stable disease) was 91.6 and 83.3 percent for erlotinib and gefitinib, respectively (p=.113). The study was unable to demonstrate statistical noninferiority via the planned end point; however, the lack of statistically significant differences between erlotinib and gefitinib responses, and the milder adverse effects experienced by gefitinib treated patients, led the authors to conclude that gefitinib is a feasible alternative to erlotinib in treating patients with ex19del EGFR positive, advanced lung adenocarcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1243 check_entity AN4974-1 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:22285168 The phase 3 (EURTAC) study consisted of of 173 non-small cell lung cancer patients who had not had prior chemotherapy for metastatic disease (although adjuvant or neoadjuvant chemotherapy was permitted) and included 160 patients with lung adenocarcinoma subtype. The patients had EGFR mutations (exon 19 deletions or L858R), and improved progression-free survival was reported in the erlotinib treated cohort as compared to the cohort that was treated with standard chemotherapy (9.7mo vs. 5.2mo, HR:0.37, 95%CI:0.25-0.54, P<0.0001, univariate analysis; HR:0.35, 95%CI:0.23-0.52, P<0.0001, multivariate analysis). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1243 check_entity AN4974-1 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 CIViC:133 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1243 check_entity AN4974-1 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 CIViC:4432 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1243 check_entity AN4974-2 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:16730237 Exon 19 deletion has been shown to be correlated with gefitinib response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1244 check_entity AN4974-2 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:16818686 NSCLC patients with exon 19 deletions in EGFR had longer overall survival than patients with an L858R mutation when treated with gefitinib or erlotinib (38 versus 17 months; P = 0.04). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1244 check_entity AN4974-2 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:25862853 Stable HEK293 cell lines expressing mutant EGFR cDNAs were created (using a pQCLIN retroviral vector) and their drug sensitivities to afatinib were examined by MTT assay. Phorphorylation of EGFR was assayed by Western blot. The 50% inhibitory concentration (IC50) of afatinib was significantly lower in cells harboring EGFR exon 19 deletion than in cells harboring EGFR L858R. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1244 check_entity AN4974-2 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:22285168 A randomized phase 3 trial involving 173 NSCLC patients with EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease. Patients were randomly allocated (1:1) to receive either erlotinib or standard chemotherapy. The primary endpoint was progression-free survival (PFS). Median PFS was 9.7 months in the erlotinib group, compared with 5.2 months in the standard chemotherapy group. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1244 check_entity AN4974-2 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:26515464 Cells harboring an exon 19 deletion were sensitive to afatinib. This study performed drug response assays using five human NSCLC cell lines with various combinations of EGFR mutations. In order to directly compare the sensitivity of multiple EGFR mutations to EGFR-TKIs the authors also generated multiple EGFR transduced Ba/F3 stable cell lines and evaluated sensitivity to EGFR-TKIs by MTS assay. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1244 check_entity AN4974-2 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:18509184 90 NSCLC patients with stage IIIB/IV chemotherapy-resistant tumors were treated with gefitinib, and exon 19 deletion of EGFR was associated with longer time to treatment failure than those with wild-type EGFR (median 8.9 versus 2.1). In multivariate analysis, exon 19 deletion was a significant predictive factor for TTF (HR = 0.0320; P < .0001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1244 check_entity AN4974-2 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:24868098 On May 14, 2013, the U.S. Food and Drug Administration approved erlotinib (Tarceva) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1244 check_entity AN4974-2 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:23982599 Afatinib, an irreversible inhibitor of the ErbB family of tyrosine kinases has been approved in the US for the first-line treatment of patients with metastatic non-small-cell lung cancer (NSCLC) who have tumours with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1244 check_entity AN4974-2 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:26768165 Non-small cell cancer patients from two studies [The ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067)] with exon 19 deletion and L858R EGFR (Exon 21) mutations were pooled to compare the efficacy of dacomitinib to erlotinib. 121 patients with any EGFR mutation were enrolled, 101 had activating mutations in exon 19 or 21. Median progression-free survival and median survival were better following dacomitinib treatment (14.6 and 26.6 months, N=53) than erlotinib (9.6 and 23.2, P = 0.146 and P = 0.265, N=48). In exon 19 mutated patients (N=32 and 36) PFS was better for dacomitinib treated patients (HR of 0.585 [95% CI 0.335–1.024], two-sided log-rank, P = 0.058) but did not reach significance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1244 check_entity AN4974-2 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:31086949 In a multicenter retrospective study, the relationship between EGFR status in 171 patients with non-small cell lung carcinoma and response to immune checkpoint blockade was examined. Immune checkpoint inhibitor included PD-1 inhibitor alone, PD-L1 inhibitor alone or PD-(L)1 inhibitor / CTLA-4 inhibitor combination. These patients were compared to 212 previously published EGFR wild type patient outcomes. The response rate in patients with EGFR wild type, EGFR L858R mutation, and EGFR exon 19 deletions were 22, 16, and 7% respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1244 check_entity AN4974-2 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:24755888 A phase 2 study of 120 stage IIIB-IV lung adenocarcinoma patients reported improved progression free survival in patients with EGFR mutation (defined as exon 19 deletion or exon 21 mutation) when treated (n=13) with gefitinib and pemetrexed/platinum combination therapy (HR: 0.20, 95% CI: 0.05-0.75, P=0.017) as compared to treatment (n=18) with pemtrexed/platinum alone. In the subgroup of patients without EGFR mutation (defined as all patients without the specific EGFR exon 19 deletion or L858R mutation) a difference in median PFS was not seen between the chemotherapy versus chemotherapy with gefitinib treatment groups. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1244 check_entity AN4974-2 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:21531810 In a study of 1261 non-small cell lung cancer patients, 49.8% of the analyzed tumors had EGFR mutations including deletions in exon 19 (n=258), L858R (n=260), T790M (n=6) and insertions or duplications in exon 20 (n=25). Patients with EGFR deletions in exon 19 or L858R mutations were associated with an improved response to erlotinib or gefitinib with partial or complete response (74.1% vs. 16.5%, P<0.001) when compared to wildtype EGFR patients. Additionally, tumors with EGFR mutations in L858R or deletions in exon 19 were associated with increased overall survival (19.6mo vs. 10.4mo) compared to wildtype (all patients were treated with either erlotinib or gefitinib). From 61 patients with uncommon EGFR mutations of unknown clinical significance, 47.5% were responders in contrast to the 74.1% responders in the exon 19 deletion/L858R group. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1244 check_entity AN4974-2 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:28958502 In the ARCHER 1050 Phase 3 Trial (NCT01774721), 452 patients with newly diagnosed stage IIIB/IV or recurrent NSCLC exon 19 deletion or the Leu858Arg mutation, (with or without the T790M) were treated with second generation tyrosine kinase inhibitor (TKI) dacomitinib (227 patients) or first generation TKI gefitinib (225 patients). Primary endpoint was progression free survival (PFS), and median PFS according to masked independent review was 14.7 months (95% CI 11.1–16.6) with dacomitinib group 9.2 months (9.1–11.0) with gefitinib (HR 0·59, 95% CI 0·47–0·74; p<0·0001). Benefit of dacomitinib over gefitinib was lower in non-Asian patient subgroup (n=106) than in Asian group (n=346) although authors note smaller sample size may explain this. Authors state that PFS was significantly improved with first line dacomitinib treatment, and that dacomitinib should be considered for EGFR mutant NSCLC treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1244 check_entity AN4974-2 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:32955177 In this phase 3, double-blind trial, 682 patients were randomly assigned 1:1 to either osimertinib (80 mg once daily) or placebo for 3 years following complete resection of EGFR mutation positive (exon 19 deletion or L858R) non-small cell lung cancer (NSCLC). At two years, 90% of the patients with stage II to IIIA disease in the osimertinib group (95% CI, 84 to 93) and 44% of those in the placebo group (95% CI, 37 to 51) were alive and disease-free (HR for disease recurrence or death, 0.17; 99.06% CI, 0.11 to 0.26; P < 0.001). Including all patients, 89% in the osimertinib group (95% CI, 85 to 92) and 52% of those in the placebo group (95% CI, 46 to 58) were alive and disease-free at two years (HR for disease recurrence or death, 0.20; 99.12% CI, 0.14 to 0.30; P < 0.001). In total, 29 patients died (9 in the osimertinib group and 20 in the placebo group), and grade 3 adverse events occurred in 20% of the osimertinib group versus 13% of the placebo group while 16% of the osimertinib group experienced serious adverse events versus 12% in the placebo group. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1244 check_entity AN4974-2 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:31591063 In this phase 3, randomized, double-blind, placebo-controlled trial, 449 patients stage IV NSCLC with EGFR exon 19 deletions or exon 21 (L858R) mutations. Patients were randomly assigned in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. The primary endpoint was investigator-assessed progression-free survival. The median duration of follow-up was 20.7 months (IQR: 15.8–27.2), and the progression-free survival was found to be significantly longer in the ramucirumab plus erlotinib group 19.4 months (95% CI: 15.4 – 21.6) than in the placebo plus erlotinib group at 12.4 months (11.0 – 13.5), with a hazard ratio of 0.59 (95% CI: 0.46 – 0·76; p < 0·0001). Lastly, grade 3/4 adverse events were reported in 159 of 221 patients in the ramucirumab plus erlotinib group versus 121 of 225 in the placebo plus erlotinib group, and one death was recorded in the ramucirumab plus erlotinib group. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1244 check_entity AN4974-2 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:24263064 In this phase-IV, open-label, single-arm study, 106 patients with NSCLC and EGFR mutations including exon 19 deletion and exon 21 L858R point mutations were administered 250 mg daily doses of gefitinib with the primary endpoint being objective response rate (ORR). The objective response rate was 69.8% (95% CI: 60.5 – 77.7), with a median progression-free survival of 9.7 months (95% CI: 8.5 – 11.0), and a median overall survival of 19.2 months (95% CI:17.0 – not calculable). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1244 check_entity AN4974-2 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:133 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1244 check_entity AN4974-2 EGFR Exon 19 Deletion EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:4432 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:19:deletion sequence variation in gene EGFR/NCBI:1956 1244 check_entity AN4975-1 EGFR Exon 20 Insertion EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:26051236 In retrospective analysis of trials, afatinib conferred limited clinical benefit to patients with EGFR exon 20 insertion mutations (N=23). Only 2 patients had objective responses. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:20:insertion sequence variation in gene EGFR/NCBI:1956 1245 check_entity AN4975-1 EGFR Exon 20 Insertion EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:22895145 In stage IV lung adenocarcinoma patients (n=2) harboring EGFR inframe exon 20 insertion mutation, EGFR exon 20 insertion was associated with progressive disease after 1 and 3 months of erlotinib monotherapy, respectively; both patients were previously treated with standard chemotherapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:20:insertion sequence variation in gene EGFR/NCBI:1956 1245 check_entity AN4975-1 EGFR Exon 20 Insertion EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 CIViC:707 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:20:insertion sequence variation in gene EGFR/NCBI:1956 1245 check_entity AN4975-2 EGFR Exon 20 Insertion EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:31208370 Retrospective study of six Chinese patients with EGFR exon 20 insertion mutant stage IV non-small cell lung carcinoma treated with osimertinib. Four of the patients experienced partial response (67.7%) and two had stable disease during treatment. Two patients had sustained disease control and remained on treatment. The median progression-free survival was 6.2 months (95% CI 5.0-12.9 months). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:20:insertion sequence variation in gene EGFR/NCBI:1956 1246 check_entity AN4975-2 EGFR Exon 20 Insertion EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:34339292 In this phase 1, open-label, dose-escalation trial, 81 patients with NSCLC involving an EGFR exon 20 insertion in phase 2 of the study were administered 1,050 mg amivantamab (1,400 mg if > 80 kg) given once weekly for the first month and then once every two weeks starting at week five based of phase 1 of the trial determining the recommended dose. The overall response rate was 40% (95% CI: 29 - 51), including three complete responses. The median duration of response of 11.1 months (95% CI: 6.9 - not reached) and the median progression-free survival was 8.3 months (95% CI: 6.5 - 10.9). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:20:insertion sequence variation in gene EGFR/NCBI:1956 1246 check_entity AN4975-2 EGFR Exon 20 Insertion EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:34647988 In this open-label phase1/2 trial, 114 patients with EGFR exon 20 insertion NSCLC who were previously treated with platinum received 160 mg mobocertinib once daily. The primary endpoint was confirmed objective response rate (ORR). The median follow-up period was 14.2 months, with a confirmed ORR of 28% (95% CI: 20% - 37%) by independent review committee (IRC) assessment and 35% (95% CI: 26% - 45%) by investigator assessment. The median duration of response was 17.5 months (95% CI: 7.4 - 20.3) by IRC assessment. Further, the median progression-free survival was 7.3 months (95% CI: 5.5 - 9.2) by IRC assessment. Lastly, the median overall survival was 24.0 months (95% CI: 14.6 - 28.8). 19 of 114 patients discontinued treatment because of adverse effects, dose reductions due to an adverse effect occurred in 29 of 114 patients, and response rates were greater in the 85 patients without dose reduction. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:20:insertion sequence variation in gene EGFR/NCBI:1956 1246 check_entity AN4975-2 EGFR Exon 20 Insertion EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:707 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:20:insertion sequence variation in gene EGFR/NCBI:1956 1246 check_entity AN4976-1 EGFR Exon 4 Deletion EGFR NCBI:1956 gene ovary epithelial cancer DOID:2152 risk 21665-5 PubMed:23764753 A variant of EGFR with exon 4 deletion (de4 EGFR) enhanced the invasiveness and cisplatin resistance of epithelial ovarian cancer cell lines (SKOV3, CAOV3, ES2) in vitro when compared with wild-type EGFR. The three cell lines were infected with lentivirus for either EGFR or de4 EGFR, and lentivirus-infected cells were used to perform transwell migration assays, invasion assays, and cisplatin sensitivity assays. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:4:deletion sequence variation in gene EGFR/NCBI:1956 1247 check_entity AN4976-1 EGFR Exon 4 Deletion EGFR NCBI:1956 gene ovary epithelial cancer DOID:2152 risk 21665-5 CIViC:248 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:4:deletion sequence variation in gene EGFR/NCBI:1956 1247 check_entity AN4977-1 EGFR Expression EGFR NCBI:1956 gene chordoma DOID:3302 risk 21665-5 PubMed:23559153 18 advanced progressing chordoma patients that were positive for EGFR by at least one technique (immunohistochemistry and/or phospho-arrays, real-time polymerase chain reaction for EGFR ligands, FISH) entered this phase 2 study investigating the efficacy of lapatinib (median age: 61 years; disease extent: metastatic 72% and locally advanced 28%). Of the 25 patients screened, three tested negative for EGFR. Six (33.3%) patients had PR and 7 (38.9%) SD, as their best Choi responses, corresponding to RECIST SD in all cases. Median PFS by Choi was 6 [interquartile (IQ) range 3-8] months. Median PFS by RECIST was 8 (IQ range 4-12) months, with a 22% CBR. This phase II study showed a modest antitumor activity of lapatinib in chordoma assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene EGFR/NCBI:1956 1248 AN4977-1 EGFR Expression EGFR NCBI:1956 gene chordoma DOID:3302 risk 21665-5 CIViC:350 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene EGFR/NCBI:1956 1248 AN4977-2 EGFR Expression EGFR NCBI:1956 gene colorectal cancer DOID:9256 risk 21665-5 PubMed:18003960 Patients with refractory colorectal cancer expressing immunohistochemically detectable EGFR were randomly assigned to receive treatment with cetuximab (n=287) or receive supportive care alone (n=285). Patients receiving cetuximab had increased overall survival (HR=0.77, 95%CI 0.64-0.92; p=0.005), increased progression-free survival (HR=0.68, 95%CI 0.57-0.80; p<0.001), and improved quality of life at 4 months measured by survey on physical deterioration (-5.9 vs -12.5; p=0.03) and global health status (-3.6 vs. -15.2; p<0.001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene EGFR/NCBI:1956 1249 AN4977-2 EGFR Expression EGFR NCBI:1956 gene colorectal cancer DOID:9256 risk 21665-5 PubMed:17470858 463 patients with 1% or more EGFR tumor cell membrane staining, with metastatic CRC progressive after standard chemotherapy were randomized to panitumumab plus best supportive care (BSC, n = 231) or BSC alone (n = 232). Panitumumab significantly prolonged PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66, [P < .0001]). Objective response rates favored panitumumab over BSC; after a 12-month minimum follow-up, response rates were 10% for panitumumab and 0% for BSC (P < .0001). No difference was observed in OS (HR, 1.00; 95% CI, 0.82 to 1.22), but 76% of BSC patients entered the cross-over study. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene EGFR/NCBI:1956 1249 AN4977-2 EGFR Expression EGFR NCBI:1956 gene colorectal cancer DOID:9256 risk 21665-5 PubMed:14993230 57 patients with chemorefractory colorectal cancer expressing EGFR (IHC staining) were treated with single-agent cetuximab in this phase 2 study. Five patients (9%; 95% CI, 3% to 19%) achieved a partial response. Twenty-one additional patients had stable disease or minor responses. The median survival in these previously treated patients with chemotherapy-refractory colorectal cancer was 6.4 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene EGFR/NCBI:1956 1249 AN4977-2 EGFR Expression EGFR NCBI:1956 gene colorectal cancer DOID:9256 risk 21665-5 CIViC:350 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene EGFR/NCBI:1956 1249 AN4977-3 EGFR Expression EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:12748244 Double blind Phase II clinical trial evaluated 208 patients for efficacy of gefitinib against non-small cell lung cancer. For individuals taking 250mg/day, they observed an objective response rate of 18.4%, a PFS of 2.7 months and a median overall survival of 7.6 months. For individuals taking 500mg/day objective response rate was 19%, PFS was 2.8 months, and median overall survival was 8.0 months. For those who responded, median duration of the response was 3 months (ranges=1-5.5 months). The disease control rate was found to be 54.4% and 51.4% for the two groups. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene EGFR/NCBI:1956 1250 AN4977-3 EGFR Expression EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:350 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene EGFR/NCBI:1956 1250 AN4978-1 EGFR G465R mutation EGFR NCBI:1956 gene colorectal cancer DOID:9256 risk 21665-5 PubMed:26888827 An EGFR G465R mutation (22% of mutant alleles) was detected in a biopsy from one patient which had been previously treated with cetuximab in the analysis of 15 patients with refractory, metastatic CRC after cetuximab/panitumumab, prior to Sym004 (Futuximab/Modotuximab mixture) treatment. Subsequent treatment of this patient with Sym004 yielded disease stabilization lasting 15 weeks. In vitro analysis in colorectal cancer cell line NIH3T3 with EGFR mutations S492R, R451C, K467T, and G465R showed that antibody mixture Sym004 effectively bound to all mutants, whereas cetuximab and panitumumab did not effectively bind to all mutants. In-vitro, Sym004 inhibited growth of S492R and G465R EGFR mutant cell lines. In-vivo analysis of S492R and G465R mutant cell lines showed regression of S492R and tumor growth delay of G465R mutant cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G465R sequence variation in gene EGFR/NCBI:1956 1251 check_entity AN4978-1 EGFR G465R mutation EGFR NCBI:1956 gene colorectal cancer DOID:9256 risk 21665-5 CIViC:439 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G465R sequence variation in gene EGFR/NCBI:1956 1251 check_entity AN4979-1 EGFR G598V mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 PubMed:17177598 In an in vitro study, a Ba/F3 cell line expressing EGFR G598V demonstrated increased sensitivity to erlotinib treatment, compared to Ba/F3 cells expressing EGFR wild-type. Variant function was assessed by EGFR auto-phosphorylation. Sensitivity was assessed by cell viability assay using stable transfection of each variant and increasing concentrations of erlotinib (0–10 uM). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G598V sequence variation in gene EGFR/NCBI:1956 1252 check_entity AN4979-1 EGFR G598V mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 CIViC:971 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G598V sequence variation in gene EGFR/NCBI:1956 1252 check_entity AN4980-1 EGFR G719 mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:26773740 In a meta-analysis of 7 clinical trials of erlotinib (some vs placebo or other treatment), 10/24 patients with Exon 18 mutations harbored a G719 variant. These variants were associated with improved progression-free and overall survival. No statistical analysis was reported for this variant and PFS or OS, citing small sample size across the studies. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G719 sequence variation in gene EGFR/NCBI:1956 1253 check_entity AN4980-1 EGFR G719 mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 CIViC:699 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G719 sequence variation in gene EGFR/NCBI:1956 1253 check_entity AN4980-2 EGFR G719 mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:21531810 EGFR G719 mutations have been associated with increased sensitivity to first generation EGFR tyrosine kinase inhibitors, including erlotinib and gefitinib. In a study of patients treated with erlotinib or gefitinib, a subset of patients with EGFR mutation at codons G719 or L861 (n=30) was associated with improved response rate (47.5% vs 16.5%, P<0.001) median progression free survival (5.0 vs 2.0 months, P<0.001), and overall survival (15.0 vs. 10.4 months, P =0.030), compared to patients with wild-type EGFR (n=272). For the subset of patients with G719, the response rate was 53.3% (8 of 15), median PFS was 8.1 months, and median overall survival was 16.4 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G719 sequence variation in gene EGFR/NCBI:1956 1254 check_entity AN4980-2 EGFR G719 mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:699 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G719 sequence variation in gene EGFR/NCBI:1956 1254 check_entity AN4981-1 EGFR G719A mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:20038723 In a study of 297 non-small cell lung cancer patients, 15% of the analyzed tumors had EGFR mutations including deletions in exon 19 (n=22), L858R (n=16) and G719A (n=2). Patients with EGFR mutations treated with gefitinib were associated with improved response rates (42.1% vs. 6.6%, P=0.04) compared to wildtype EGFR patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G719A sequence variation in gene EGFR/NCBI:1956 1255 check_entity AN4981-1 EGFR G719A mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:23749122 In a large retrospective study, EGFR exons 18-21 were assessed using direct sequencing in 753 French NSCLC cases. Clinical details and patient outcomes were taken, including whether the first generation TKIs erlotinib or gefitinib were administered. One patient was found to have a G719A mutation, was administered a TKI, and an NSCLC progression was observed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G719A sequence variation in gene EGFR/NCBI:1956 1255 check_entity AN4981-1 EGFR G719A mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:22452895 In a phase 2 trial, 129 patients with lung adenocarcinoma with EGFR mutations including mutations other than exon 19 deletions or exon 21 L858R substitutions who had no more than one previous chemotherapy regimen for advanced disease or an EGFR tyrosine-kinase inhibitor. 99 patients started with a dose of 50 mg and the other 30 patients with a starting dose of 40 mg. 79 of 129 patients had an objective response (two complete responses, 77 partial responses). 70 of the 106 patients with exon 19 deletion or exon 21 L858R EGFR mutations had an objective response, as did nine of 23 patients with the less common mutations. Median progression-free survival was 10.1 months (95% CI: 8.12 – 13.80, however, median progression-free survival was shorter for patients with the uncommon mutations. The median overall survival was 24.8 months (95% CI: 21.98 – 38.74), and the median overall survival for patients with the less common mutations was again shorter. Grade 3 adverse events were more common in patients receiving the higher 50 mg starting dose, and there was one possible drug-related death secondary to interstitial lung disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G719A sequence variation in gene EGFR/NCBI:1956 1255 check_entity AN4981-1 EGFR G719A mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:973 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G719A sequence variation in gene EGFR/NCBI:1956 1255 check_entity AN4981-1 EGFR G719A mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:4499 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G719A sequence variation in gene EGFR/NCBI:1956 1255 check_entity AN4982-1 EGFR G719D mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:21531810 In a study, 2 participants with stage IV lung adenocarcinoma were sequenced at EGFR exons 18 to 21. Both patients were found to have G719D mutation and were treated with the 1st generation TKIs gefitinib or erlotinib. The first patient (M, 81, smoker) was treated with gefitinib and had a partial response, progression free survival (PFS) of 21.7 months, overall survival (OS) of 22.5 months and was alive at study end. The second patient (M, 76, smoker) was treated with erlotinib and had stable disease as response, PFS of 2.6 months, OS of 2.6 months and was alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G719D sequence variation in gene EGFR/NCBI:1956 1256 check_entity AN4982-1 EGFR G719D mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1328 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G719D sequence variation in gene EGFR/NCBI:1956 1256 check_entity AN4983-1 EGFR G719S mutation EGFR NCBI:1956 gene colorectal cancer DOID:9256 risk 21665-5 PubMed:24894453 Whole genome sequencing of a case of colon carcinoma revealed a G724S mutation in the EGFR gene. In-vitro, this mutation was shown to be oncogenic and sensitive to Cetuximab, yet relatively insensitive towards small molecules. The same in-vitro results could be reproduced for the G719S mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G719S sequence variation in gene EGFR/NCBI:1956 1257 check_entity AN4983-1 EGFR G719S mutation EGFR NCBI:1956 gene colorectal cancer DOID:9256 risk 21665-5 CIViC:134 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G719S sequence variation in gene EGFR/NCBI:1956 1257 check_entity AN4983-2 EGFR G719S mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:15118125 Gefinitib has been shown to be effective in treating cell lines with G719S missense mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G719S sequence variation in gene EGFR/NCBI:1956 1258 check_entity AN4983-2 EGFR G719S mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:26124334 This small clinical (n=56) study suggests that patients with minor mutations of EGFR, like G719S, are likely to have a moderate response to Tyrosine kinase inhibitors like Gefitinib and Erlotinib. In this study 44 of 56 patients were treated with either gefitinib or erlotinib. 35 patients had a G719 mutation but the majority of these were G719S (20 with G719S, 9 with G719A, 3 with G719C). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G719S sequence variation in gene EGFR/NCBI:1956 1258 check_entity AN4983-2 EGFR G719S mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:19147750 In an in vitro study, a Ba/F3 cell line expressing EGFR G719S demonstrated increased sensitivity to erlotinib treatment comparable to Ba/F3 cells expressing a known sensitizing mutation (EGFR L858R). Sensitivity was determined by assessing cell proliferation, the IC50 of erlotinib for EGFR G719S and EGFR L858R expressing cells were 16 nmol/L and 6 nmol/L, respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G719S sequence variation in gene EGFR/NCBI:1956 1258 check_entity AN4983-2 EGFR G719S mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:134 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G719S sequence variation in gene EGFR/NCBI:1956 1258 check_entity AN4984-1 EGFR G724S mutation EGFR NCBI:1956 gene colorectal cancer DOID:9256 risk 21665-5 PubMed:24894453 Whole genome sequencing of a case of colon carcinoma revealed a G724S mutation in the EGFR gene. In-vitro, this mutation was shown to be oncogenic and sensitive to Cetuximab, yet relatively insensitive towards small molecules. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G724S sequence variation in gene EGFR/NCBI:1956 1259 check_entity AN4984-1 EGFR G724S mutation EGFR NCBI:1956 gene colorectal cancer DOID:9256 risk 21665-5 CIViC:313 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G724S sequence variation in gene EGFR/NCBI:1956 1259 check_entity AN4985-1 EGFR Gain-of-function EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:15118073 Study found somatic EGFR mutations localized to exons 19,21 in 8/9 patients who exhibited a response to Gefitinib treatment. Of these mutations 7/8 were localized near the ATP cleft Gefitinib targets, suggesting a specific gain-of-function mechanism. No EGFR mutations were observed in 7 patients with no response to Gefitinib. An expansion cohort independent of the Gefitinib study showed 2/25 patients harbored EGFR mutations. A second expansion independent of Gefitinib consisting of 95 tumors and 108 cell lines showed no mutations in exons 19,21. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR Gain-of-function [biomarker_term_in_review] 1260 not_mapped AN4985-1 EGFR Gain-of-function EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1641 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR Gain-of-function [biomarker_term_in_review] 1260 not_mapped AN4986-1 EGFR H773_V774insH EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:24353160 In an in vitro study, a Ba/F3 cell line expressing EGFR H773_V774insH demonstrated reduced sensitivity to erlotinib treatment (IC50=3.902�M), comparable to Ba/F3 cells expressing EGFR L858R and T790M co-mutation (T790M is a known resistant mutation to 1st and 2nd generation EGFR tyrosine kinase inhibitors; IC50=4.155�M). Resistance was determined by assessing cell proliferation, EGFR, AKT and ERK phosphorylation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR H773_V774insH [biomarker_term_in_review] 1261 not_mapped AN4986-1 EGFR H773_V774insH EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1354 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR H773_V774insH [biomarker_term_in_review] 1261 not_mapped AN4987-1 EGFR H773_V774insNPH EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:24353160 A 61 year old male never smoker with EGFR H773_V774insNPH mutant lung adenocarcinoma was treated with fourth line erlotinib and had progressive disease as best response, progression free survival of 1.6 months, and overall survival of 4.4 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR H773_V774insNPH [biomarker_term_in_review] 1262 not_mapped AN4987-1 EGFR H773_V774insNPH EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 CIViC:1421 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR H773_V774insNPH [biomarker_term_in_review] 1262 not_mapped AN4988-1 EGFR K467T mutation EGFR NCBI:1956 gene colorectal cancer DOID:9256 risk 21665-5 PubMed:26888827 In this preclinical study on the effects of cetuximab, panitumumab or sym004 on various EGFR mutations in colorectal cancer. In NIH3T3 cells expressing EGFR with a K467T mutation, Sym004 and panitumumab bound the mutated receptor and inhibited EGFR phosphorylation in the presence of ligand while cetuximab neither bound to nor inhibited EGFR phosphorylation of the mutated receptor. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K467T sequence variation in gene EGFR/NCBI:1956 1263 check_entity AN4988-1 EGFR K467T mutation EGFR NCBI:1956 gene colorectal cancer DOID:9256 risk 21665-5 CIViC:451 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K467T sequence variation in gene EGFR/NCBI:1956 1263 check_entity AN4989-1 EGFR K754E mutation EGFR NCBI:1956 gene lung cancer DOID:1324 risk 21665-5 PubMed:27478040 194 somatic mutations seen in primary lung cancers were functionally evaluated using three approaches: (1) differences in pattern or extent of changes in gene expression in A549 cells induced by transduction of lentiviral vectors containing mutant vs. wild-type genes; (2) xenograft assay based on human lung epithelial cells harbouring the variant introduced in mice and subsequent measurement of tumour size; (3) evaluation of resistance to erlotinib, afatinib, lapatinib, sofarenib and trametinib in PC9 isogenic lines expressing mutant alleles. EGFR K754E mutations showed differences in gene expression from wild-type and induced tumour formation, and were therefore classed as gain-of-function mutations, but were less sensitive to erlotinib than wild-type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K754E sequence variation in gene EGFR/NCBI:1956 1264 check_entity AN4989-1 EGFR K754E mutation EGFR NCBI:1956 gene lung cancer DOID:1324 risk 21665-5 CIViC:4337 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K754E sequence variation in gene EGFR/NCBI:1956 1264 check_entity AN4990-1 EGFR K757R mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:26773740 In a meta-analysis of 7 clinical trials evaluating the efficacy of erlotinib, one patient was described with the exon 19 mutation K757R from the MERIT study. Progression-free (250 days) and overall (435 days) survival suggested sensitivity in this patient. Literature analysis did not identify additional reports of patients harboring this mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K757R sequence variation in gene EGFR/NCBI:1956 1265 check_entity AN4990-1 EGFR K757R mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 CIViC:704 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K757R sequence variation in gene EGFR/NCBI:1956 1265 check_entity AN4991-1 EGFR K806E mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:21531810 In a study, 1 participant with stage IIIB lung adenocarcinoma was sequenced at EGFR exons 18 to 21 and was found to have K806E mutation, and was treated with the 1st generation TKI gefitinib. The patient (M, 77, nonsmoker) had progressive disease as response, progression free survival (PFS) of 1.6 months, overall survival (OS) of 28.1 months and was alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K806E sequence variation in gene EGFR/NCBI:1956 1266 check_entity AN4991-1 EGFR K806E mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1771 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K806E sequence variation in gene EGFR/NCBI:1956 1266 check_entity AN4992-1 EGFR KIF5B::EGFR mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:34163176 Case report of a 50-year-old male with Stage 1 Lung adenocarcinoma. NGS detected the presence of KIF5B::EGFR fusion (exon 15 and exon 18). The patient received two cycles of chemotherapy but experienced disease progression to lymph nodes and left rib after 13 months. The lymph nodes showed both squamous cell carcinoma and adenocarcinoma. He was then treated with afatinib and showed progression-free survival for 11 months, after which intracranial metastasis was observed, and treatment with afatinib was discontinued. Following a whole brain radiation therapy, the patient was treated with Osimertinib for 4 months due to the detection of a known resistance marker T790M, however only a limited benefit was seen and the treatment was discontinued. The authors conclude the detection of the novel KIF5B-EGFR fusion in advanced NSCLC was a good indicator of response to afatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KIF5B::EGFR sequence variation in gene EGFR/NCBI:1956 1267 check_entity AN4992-1 EGFR KIF5B::EGFR mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 CIViC:4169 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KIF5B::EGFR sequence variation in gene EGFR/NCBI:1956 1267 check_entity AN4993-1 EGFR L747P mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:21531810 In a study, 2 participants with stage IV adenocarcinoma were sequenced at EGFR exons 18 to 21. Both patients were found to have L747P mutation and were treated with the 1st generation TKIs gefitinib or erlotinib. The first patient (M, 62, nonsmoker) was treated with gefitinib and had progressive disease, progression free survival (PFS) of 1.0 months, overall survival (OS) of 7.7 months and was not alive at study end. The second patient (M, 39, nonsmoker) was treated with erlotinib and had progressive disease as response, PFS of 2.3 months, OS of 7.2 months and was alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L747P sequence variation in gene EGFR/NCBI:1956 1268 check_entity AN4993-1 EGFR L747P mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1767 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L747P sequence variation in gene EGFR/NCBI:1956 1268 check_entity AN4994-1 EGFR L747_P753delinsS EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:19147750 In an in vitro study, a Ba/F3 cell line expressing EGFR L747_P753>S demonstrated increased sensitivity to erlotinib treatment comparable to Ba/F3 cells expressing a known sensitizing mutation (EGFR L858R). Sensitivity was determined by assessing cell proliferation, the IC50 of erlotinib for EGFR L747_P753>S and EGFR L858R expressing cells were 5 nmol/L and 6 nmol/L, respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR L747_P753delinsS [biomarker_term_in_review] 1269 not_mapped AN4994-1 EGFR L747_P753delinsS EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:986 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR L747_P753delinsS [biomarker_term_in_review] 1269 not_mapped AN4994-2 EGFR L747_P753delinsS EGFR NCBI:1956 gene pancreatic adenocarcinoma DOID:4074 risk 21665-5 PubMed:28874593 Patients with recurrent pancreatic adenocarcinoma was treated with gemcitabine + nab-paclitaxel, FOLFIRINOX and docetaxel + irinotecan. After failure of these treatment, a tumor specimen from the pancreaticoduodenectomy was analyzed, which revealed an activating mutation in exon 19 (L747_P753>S) of EGFR. Mutations were also detected in CDKN2A, TP53, and amplifications of PRKCI and TERC. He began erlotinib at 150mg daily. CT imaging revealed a partial response by RECIST at 8, 24 and 32 weeks after starting erlotinib. At 40 weeks CT imaging revealed unequivocal disease progression. After disease progression to erlotinib, a repeat liver biopsy revealed an EGFR T790M mutation. He began treatment with osimertinib at 80mg daily. After 8 weeks of this treatment CT imaging revealed unequivocal disease progression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR L747_P753delinsS [biomarker_term_in_review] 1270 not_mapped AN4994-2 EGFR L747_P753delinsS EGFR NCBI:1956 gene pancreatic adenocarcinoma DOID:4074 risk 21665-5 CIViC:986 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR L747_P753delinsS [biomarker_term_in_review] 1270 not_mapped AN4995-1 EGFR L747_S752delinsQ EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:15329413 EGFR exons 18-24 were analyzed in 7 patients who had shown a partial response to erlotinib in a phase II trial for bronchioloalveolar carcinoma (BAC, or in situ pulmonary adenocarcinoma). One patient (Patient E1) had the del L747-S752 insQ mutation. The patient was a male never smoker and demonstrated response for 8 months. He continued to show response and remain on the drug when the manuscript was written. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR L747_S752delinsQ [biomarker_term_in_review] 1271 not_mapped AN4995-1 EGFR L747_S752delinsQ EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 CIViC:1488 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR L747_S752delinsQ [biomarker_term_in_review] 1271 not_mapped AN4996-1 EGFR L838P mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:21531810 In a study, 1 participant with stage IV lung adenocarcinoma was sequenced at EGFR exons 18 to 21 and was found to have L838P mutation, and was treated with the 1st generation TKI gefitinib. The patient (F, 66, nonsmoker) had a partial response, progression free survival (PFS) of 15.2 months, overall survival (OS) of 29.3 months and was not alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L838P sequence variation in gene EGFR/NCBI:1956 1272 check_entity AN4996-1 EGFR L838P mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1365 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L838P sequence variation in gene EGFR/NCBI:1956 1272 check_entity AN4997-1 EGFR L838V mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 PubMed:19147750 In an in vitro study, a Ba/F3 cell line expressing EGFR L838V demonstrated reduced sensitivity to erlotinib treatment, compared to Ba/F3 cells expressing a known sensitizing mutation (EGFR L858R). Sensitivity was determined by assessing cell proliferation, the IC50 of erlotinib for EGFR L838V and EGFR L858R expressing cells were 160 nmol/L and 6 nmol/L, respectively. Similarly, gefitinib was tested and 187 nanomolar IC50 was seen, suggesting lack of sensitivity and potential resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L838V sequence variation in gene EGFR/NCBI:1956 1273 check_entity AN4997-1 EGFR L838V mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 CIViC:992 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L838V sequence variation in gene EGFR/NCBI:1956 1273 check_entity AN4998-1 EGFR L858R mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 PubMed:19147750 EGFR L858R was expressed in Ba/F3 cells which do not contain endogenous EGFR, and conferred growth factor independance to the cells. Cells were plated and treated with 1st generation EGFR inhibitors Gefitinib, Erlotinib, or the the tool compound AEE788, and IC50 values were measured. L858R EGFR cells had very low IC50 nmol/L values for all three inhibitors in comparison to other constructs (Gefitinib=12, Erlotinib=6, AEE788=6), indicating sensitivity to all three constructs. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1274 check_entity AN4998-1 EGFR L858R mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 PubMed:17877814 MCF-7 cells were transduced with YFP tagged EGFR with E746_A750delELREA mutation, or YFP EGFR wildtype, and stained for ectopic YFP EGFR and phospho-Akt as a readout for EGFR pathway activity. Increased p-Akt stain was seen with ectopic mutant EGFR over wildtype cells. Parallel erlotinib incubations of cells with wildtype EGFR induced recompartmentalization of ectopic EGFR protien only at high concentration (10uM). Addition of erlotinib to mutant EGFR cell incubations reduced p-Akt signal and induced recompartmentalization of ectopic EGFR protien at considerably lower conecntration (100 nM) erlotinib. These results indicate the EGFR L858R variant as a growth pathway driver targetable by erlotinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1274 check_entity AN4998-1 EGFR L858R mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 PubMed:21132006 In an in vitro study, a MCF-7 cell line expressing EGFR L858R mutation demonstrated sensitivity to erlotinib treatment, compared to MCF-7 cells expressing EGFR wild-type. Sensitivity was determined by assessing YFP signal-EGFR relocation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1274 check_entity AN4998-1 EGFR L858R mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 PubMed:20942962 In an in vitro study performed after identification of the mutation in a malignant peritoneal mesothelioma patient, COS-7 cells expressing EGFR L858R demonstrated increased EGFR phosphotyrosine after EGF treatment over wildtype EGFR expressing cells. Cells expressing mutant EGFR also showed increased sensitivity to erlotinib treatment compared to cells expressing EGFR wild-type. Sensitivity was determined by assessing EGFR auto-phosphorylation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1274 check_entity AN4998-1 EGFR L858R mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 CIViC:33 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1274 check_entity AN4998-2 EGFR L858R mutation EGFR NCBI:1956 gene high grade glioma DOID:3070 risk 21665-5 PubMed:17177598 In an in vitro study, a Ba/F3 cell line expressing EGFR L858R demonstrated increased sensitivity to erlotinib treatment, compared to Ba/F3 cells expressing EGFR wild-type. Variant function was assessed by EGFR auto-phosphorylation. Sensitivity was assessed by cell viability assay using stable transfection of each variant and increasing concentrations of erlotinib (0–10 uM). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1275 check_entity AN4998-2 EGFR L858R mutation EGFR NCBI:1956 gene high grade glioma DOID:3070 risk 21665-5 CIViC:33 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1275 check_entity AN4998-3 EGFR L858R mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:23816960 A phase III clinical trial (NCT00949650) found that median progression free survival among patients with exon 19 deletions or L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = 0.001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1276 check_entity AN4998-3 EGFR L858R mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:22452895 In a phase 2 study of patients with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) and EGFR mutations, treated with afatinib were assessed by objective response. 129 patients were treated with afatinib. 66% of the 106 patients with two common activating EGFR mutations (deletion 19 or L858R) had an objective response compared to 39% of 23 patients with less common mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1276 check_entity AN4998-3 EGFR L858R mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:24439929 Afatinib is an irreversible covalent inhibitor of EGFR (second generation). This Phase III clinical trial (LUX-Lung 6; NCT01121393) was performed in Asian patients with EGFR mutant advanced NSCLC. 364 eligible patients with EGFR mutations were assigned to afatinib (n=242) or gemcitabine and cisplatin (n=122) treatment. The trial observed significantly longer median progression-free survival with afatinib vs. gemcitabine and cisplatin treatment (11.0 vs. 5.6 months). Afatinib/Chemotherapy group compositions: 51.2/50.8 % del 19; 38/37.7 % Leu858Arg; 10.8/11.5 % Uncommon. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1276 check_entity AN4998-3 EGFR L858R mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:15329413 Mutational profiling was performed on EGFR exons 18-24 from a group of 10 retrospectively chosen patients who had shown partial response or clinical improvement in response to gefitinib. Of 7 tumors with EGFR mutations, 1 was L858R. The patient was a female former smoker who had lung adenocarcinoma histology, and demonstrated response for 5 months, with overall survival 8 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1276 check_entity AN4998-3 EGFR L858R mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:22370314 In a phase 3 clinical trial of Korean, never-smoker, lung adenocarcinoma patients, a subset of patients with EGFR mutations (n=42) treated with gefitinib were associated with improved overall response rate compared to gemcitabine plus cisplatin treatment (84.6%, 22/26, vs. 37.5%, 6/16, P=0.002). By contrast, in EGFR mutation negative cases, the response rate was much lower (25.9%, 7/27). The frequency of mutation in exon 19 deletion and L858R was 64.3% (27/42) and 36.4% (16/42), respectively. Exon 19 and L858R mutations were mutually exclusive in this cohort. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1276 check_entity AN4998-3 EGFR L858R mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:27032107 In a prospective study of 46 Caucasian, advanced lung adenocarcinoma patients harboring EGFR mutations, first-line erlotinib treatment was assessed. Average PFS and OS for these 46 patients was 11 months (95% CI: 9.7-12.3 months) and 23 months (95% CI: 21.3-28.6+ months), respectively. A PFS rate of 81% at three months met the primary endpoint of presumed superiority over chemotherapy. Clinical benefit (CR+PR+SD) rate was 81%. Fifteen patients harbored EGFR L858R mutations, which was the only mutation found in exon 21. The authors note similar response profiles for exon 19 (27/46) and exon 21 mutations (15/46) to the overall population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1276 check_entity AN4998-3 EGFR L858R mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:27102076 In an in vitro study, Ba/F3 cell line expressing EGFR L858R was associated with sensitivity to erlotinib treatment (IC50 26.9 ± 12.4). Sensitivity was determined by assessing cell viability, AKT and ERK phosphorylation, and EGFR auto-phosphorylation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1276 check_entity AN4998-3 EGFR L858R mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:27022112 In a Japanese Phase III clinical trial, noninferiority of Gefitinib as compared to Erlotinib was assessed in 561 postoperative recurrent or stage IIIb/VI patients who had undergone prior chemotherapy treatment but no tyrosine kinase inhibitor therapy. In a subset of patients with sole EGFR L858R, there was an insignificant difference between the objective response and disease control rates for patients treated with erlotinib (N=67) and gefitinib (N=78). Progression free survival was also not significantly different and did not meet the noninferiority endpoint with Gefitinib and Erlotinib arms at 8.1 and 8.5 months, respectively (HR, 0.938; 95% CI, 0.675 to 1.304; P = .704). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1276 check_entity AN4998-3 EGFR L858R mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:22285168 The phase 3 (EURTAC) study consisted of of 173 non-small cell lung cancer patients who had not had prior chemotherapy for metastatic disease (although adjuvant or neoadjuvant chemotherapy was permitted) and included 160 patients with lung adenocarcinoma subtype. The patients had EGFR mutations (exon 19 deletions or L858R), and improved progression-free survival was reported in the erlotinib treated cohort as compared to the cohort that was treated with standard chemotherapy (9.7mo vs. 5.2mo, HR:0.37, 95%CI:0.25-0.54, P<0.0001, univariate analysis; HR:0.35, 95%CI:0.23-0.52, P<0.0001, multivariate analysis). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1276 check_entity AN4998-3 EGFR L858R mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 CIViC:33 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1276 check_entity AN4998-3 EGFR L858R mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 CIViC:4432 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1276 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:24736073 There is no statistical difference in progression free survival between lung cancer patients treated with gefitinib or erlotinib with EGFR L858R mutations (N=72/242; univariate: P=0.283; multivariate: P=0.250) compared to patients with Exon 19 mutations (N=170). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:24457318 In NSCLC patients treated with EGFR tyrosine kinase inhibitors, the presence of L858R mutation is prognostic for better progression free survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:15118125 Gefinitib has been shown to be effective in treating cell lines with L858R missense mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:24662454 Median survival of patients with EGFR L858R mutation is better than those with wild type EGFR. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:22285168 A randomized phase 3 trial (NCT00446225) involving 173 NSCLC patients with EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease. Patients were randomly allocated (1:1) to receive either erlotinib or standard chemotherapy. The primary endpoint was progression-free survival (PFS). Median PFS was 9.7 months in the erlotinib group, compared with 5.2 months in the standard chemotherapy group. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:26515464 Cells harboring L858R were sensitive to afatinib. This study performed drug response assays using five human NSCLC cell lines with various combinations of EGFR mutations. In order to directly compare the sensitivity of multiple EGFR mutations to EGFR-TKIs the authors also generated multiple EGFR transduced Ba/F3 stable cell lines and evaluated sensitivity to EGFR-TKIs by MTS assay. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:18509184 90 NSCLC patients with stage IIIB/IV chemotherapy-resistant tumors were treated with gefitinib, and the L858R EGFR mutation was associated with longer time to treatment failure than those with wild-type EGFR (median 9.1 versus 2.1). In multivariate analysis, L858R mutations plus adenocarcinoma was a significant predictive factor for time to treatment failure (HR = 0.1030; P = .0004). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:20038723 In a phase 3 clinical trial of non-small cell lung cancer (NSCLC) patients, a subset of patients with EGFR mutations (n=44) treated with gefitinib were associated with improved progression free survival (HR: 0.16, 95% CI: 0.05-0.49, P=0.001), and a higher objective response rate (ORR: 42.1% vs 21.1%, p=0.04) compared to patients treated with docetaxel. Of the 44 patients, 22 had an exon 19 deletion, 16 had an L858R mutation, one patient had an exon 20 T790M mutation, two had an exon G719A mutation and four had other mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:18408761 In an in vitro study using NCI-H1666 cells (wildtype EGFR) and NCI-H3255 cells (EGFR-L858R), inhibition of cell growth was used as an assay to determine sensitivity to reversible tyrosine kinase inhibitor drugs. Cells with an EGFR L858R mutation demonstrated an improved response to lapatinib (IC50: 63nM vs. 534nM) compared to wildtype EGFR cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:18089823 In an in vitro study using NCI-H322 cells (wildtype EGFR) and NCI-H3255 cells (EGFR-L858R), inhibition of cell growth was used as an assay to determine sensitivity to irreversible tyrosine kinase inhibitor (TKI) drugs. Cells with an EGFR L858R mutation demonstrated an improved response to Dacomitinib (IC50: 0.007umol/L vs. >10umol/L) compared to wildtype EGFR cells or compared to reversible TKI drug gefitinib (IC50: 0.075umol/L vs. wild-type >10umol/L). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:16818618 In an in vitro study using NCI-H3255 cells (EGFR L858R), inhibition of cell growth was used as an assay to determine sensitivity to tyrosine kinase inhibitor (TKI) drugs. Cells with an EGFR L858R mutation demonstrated sensitivity to neratinib (IC50: 0.0049 μmol/L) compared to EGFRwt A549 cells (IC50 > 1 μmol/L). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:15329413 In a phase II trial for bronchioloalveolar carcinoma (BAC, or in situ pulmonary adenocarcinoma), EGFR exons 18-24 were analyzed in 7 patients who had shown a partial response to erlotinib. Two patients had the del L858R mutation. One patient was a male former smoker who demonstrated response for 3 months with overall survival of 3.5 months, and the other patient was a female never smoker who had response for 6 months and overall survival of 17+ months as the patient was alive at study end. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:24868098 On May 14, 2013, the U.S. Food and Drug Administration approved erlotinib (Tarceva) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:23982599 Afatinib, an irreversible inhibitor of the ErbB family of tyrosine kinases has been approved in the US for the first-line treatment of patients with metastatic non-small-cell lung cancer (NSCLC) who have tumours with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:24353160 In an in vitro study, Ba/F3 and NCI-H3255 cell lines expressing EGFR L858R demonstrated increased sensitivity to erlotinib treatment (IC50=0.006 and 0.068 µM). Sensitivity was determined by assessing cell proliferation, EGFR, AKT and ERK phosphorylation, levels of BIM (a marker of EGFR TKI-induced cell killing) and cell viability. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:27612423 In an in vitro study, CHO and NCI-H3255 cells expressing EGFR L858R mutation were associated with sensitivity to erlotinib treatment. Sensitivity was determined by assessing cell density. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:22235099 This study analyzed patients with non small cell lung cancer (NSCLC) who were positive for EML4-ALK fusions (ALK+) and progressed on crizotinib monotherapy. One patient was biopsied twice following crizotinib progression and once pre-treatment. This patient was a 27 year old female with one pack year who experienced partial response on crizotinib as 4th line therapy. The patient's pre-crizotinib biopsy was ALK+ and lacked the EGFR mutation. A biopsy taken after 63 days on crizotinib showed EGFR L858R mutation and lacked ALK gene rearrangement by FISH (ALK Loss). Of note, a second post-treatment biopsy (after 113 on crizotinib) showed ALK rearrangement but lacked EGFR mutation. The authors interpreted the emergence of an ALK negative tumor (first post-critozitinib biopsy) as evidence of a separate oncogenic driver (EGFR L858R). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:24893891 In an in vitro study using NCI-H3255 cells (EGFR L858R mutation), inhibition of EGFR phosphorylation was used as an assay to determine sensitivity to EGFR tyrosine kinase inhibitors. NCI-H3255 cells demonstrated increased sensitivity to AZD9291 (IC50: 60 and 49 nM) compared to EGFRwt NCI-H2073 cells (IC50: 1865 nM; 95%CI 872-3988 nM). In vivo experiments with NCI-H3255 xenograft models showed drastic tumour volume reduction upon treatment with 5mg/kg/day AZD9291. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:26768165 The authors pooled patients with exon 19 deletion and L858R EGFR (Exon 21) mutations from both studies (The ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067)) to compare the efficacy of dacomitinib to erlotinib. 121 patients with any EGFR mutation were enrolled, 101 had activating mutations in exon 19 or 21. For those (exon19/21), the median PFS was 14.6 months with dacomitinib and 9.6 months with erlotinib The median survival was 26.6 months with dacomitinib versus 23.2 months with erlotinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:24755888 A phase 2 study of 120 stage IIIB-IV lung adenocarcinoma patients reported improved progression free survival in patients with EGFR mutation (defined as exon 19 deletion or exon 21 mutation) when treated (n=13) with gefitinib and pemetrexed/platinum combination therapy (HR: 0.20, 95% CI: 0.05-0.75, P=0.017) as compared to treatment (n=18) with pemtrexed/platinum alone. In the subgroup of patients without EGFR mutation (defined as all patients without the specific EGFR exon 19 deletion or L858R mutation) a difference in median PFS was not seen between the chemotherapy versus chemotherapy with gefitinib treatment groups. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:21531810 In a study of 1261 non-small cell lung cancer patients, 49.8% of the analyzed tumors had EGFR mutations including deletions in exon 19 (n=258), L858R (n=260), T790M (n=6) and insertions or duplications in exon 20 (n=25). Patients with EGFR deletions in exon 19 or L858R mutations were associated with an improved response to erlotinib or gefitinib with partial or complete response (74.1% vs. 16.5%, P<0.001) when compared to wildtype EGFR patients. Additionally, tumors with EGFR mutations in L858R or deletions in exon 19 were associated with increased overall survival (19.6mo vs. 10.4mo) compared to wildtype (all patients were treated with either erlotinib or gefitinib). From 61 patients with uncommon EGFR mutations of unknown clinical significance, 47.5% were responders in contrast to the 74.1% responders in the exon 19 deletion/L858R group. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:28958502 In the ARCHER 1050 Phase 3 Trial (NCT01774721), 452 patients with newly diagnosed stage IIIB/IV or recurrent NSCLC exon 19 deletion or the Leu858Arg mutation, (with or without the T790M) were treated with second generation tyrosine kinase inhibitor (TKI) dacomitinib (227 patients) or first generation TKI gefitinib (225 patients). Primary endpoint was progression free survival (PFS), and median PFS according to masked independent review was 14.7 months (95% CI 11.1–16.6) with dacomitinib group 9.2 months (9.1–11.0) with gefitinib (HR 0·59, 95% CI 0·47–0·74; p<0·0001). Benefit of dacomitinib over gefitinib was lower in non-Asian patient subgroup (n=106) than in Asian group (n=346) although authors note smaller sample size may explain this. Authors state that PFS was significantly improved with first line dacomitinib treatment, and that dacomitinib should be considered for EGFR mutant NSCLC treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:32955177 In this phase 3, double-blind trial, 682 patients were randomly assigned 1:1 to either osimertinib (80 mg once daily) or placebo for 3 years following complete resection of EGFR mutation positive (exon 19 deletion or L858R) non-small cell lung cancer (NSCLC). At two years, 90% of the patients with stage II to IIIA disease in the osimertinib group (95% CI, 84 to 93) and 44% of those in the placebo group (95% CI, 37 to 51) were alive and disease-free (HR for disease recurrence or death, 0.17; 99.06% CI, 0.11 to 0.26; P < 0.001). Including all patients, 89% in the osimertinib group (95% CI, 85 to 92) and 52% of those in the placebo group (95% CI, 46 to 58) were alive and disease-free at two years (HR for disease recurrence or death, 0.20; 99.12% CI, 0.14 to 0.30; P < 0.001). In total, 29 patients died (9 in the osimertinib group and 20 in the placebo group), and grade 3 adverse events occurred in 20% of the osimertinib group versus 13% of the placebo group while 16% of the osimertinib group experienced serious adverse events versus 12% in the placebo group. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:31591063 In this phase 3, randomized, double-blind, placebo-controlled trial, 449 patients stage IV NSCLC with EGFR exon 19 deletions or exon 21 (L858R) mutations. Patients were randomly assigned in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. The primary endpoint was investigator-assessed progression-free survival. The median duration of follow-up was 20.7 months (IQR: 15.8–27.2), and the progression-free survival was found to be significantly longer in the ramucirumab plus erlotinib group 19.4 months (95% CI: 15.4 – 21.6) than in the placebo plus erlotinib group at 12.4 months (11.0 – 13.5), with a hazard ratio of 0.59 (95% CI: 0.46 – 0·76; p < 0·0001). Lastly, grade 3/4 adverse events were reported in 159 of 221 patients in the ramucirumab plus erlotinib group versus 121 of 225 in the placebo plus erlotinib group, and one death was recorded in the ramucirumab plus erlotinib group. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:24263064 In this phase-IV, open-label, single-arm study, 106 patients with NSCLC and EGFR mutations including exon 19 deletion and exon 21 L858R point mutations were administered 250 mg daily doses of gefitinib with the primary endpoint being objective response rate (ORR). The objective response rate was 69.8% (95% CI: 60.5 – 77.7), with a median progression-free survival of 9.7 months (95% CI: 8.5 – 11.0), and a median overall survival of 19.2 months (95% CI:17.0 – not calculable). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 CIViC:33 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-4 EGFR L858R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 CIViC:4432 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1277 check_entity AN4998-5 EGFR L858R mutation EGFR NCBI:1956 gene lung small cell carcinoma DOID:5409 risk 21665-5 PubMed:24893891 In an in vitro study using NCI-H3255 cells (EGFR L858R mutation), inhibition of EGFR phosphorylation was used as an assay to determine sensitivity to EGFR tyrosine kinase inhibitors. NCI-H3255 cells demonstrated increased sensitivity to erlotinib (IC50: 8 and 11 nM) compared to EGFRwt NCI-H2073 cells (IC50: 108 nM; 95%CI 52-223 nM). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1278 check_entity AN4998-5 EGFR L858R mutation EGFR NCBI:1956 gene lung small cell carcinoma DOID:5409 risk 21665-5 CIViC:33 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L858R sequence variation in gene EGFR/NCBI:1956 1278 check_entity AN4999-1 EGFR L861 mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:21531810 EGFR L861 mutations have been associated with increased sensitivity to first generation EGFR tyrosine kinase inhibitors, including erlotinib and gefitinib. In a study of patients treated with erlotinib or gefitinib, a subset of patients with EGFR mutation at codons G719 or L861 (n=30) was associated with improved response rate (47.5% vs 16.5%, P<0.001) median progression free survival (5.0 vs 2.0 months, P<0.001), and overall survival (15.0 vs. 10.4 months, P =0.030), compared to patients with wild-type EGFR (n=272). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L861 sequence variation in gene EGFR/NCBI:1956 1279 check_entity AN4999-1 EGFR L861 mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1742 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L861 sequence variation in gene EGFR/NCBI:1956 1279 check_entity AN5000-1 EGFR L861Q mutation EGFR NCBI:1956 gene high grade glioma DOID:3070 risk 21665-5 PubMed:17177598 In an in vitro study, a Ba/F3 cell line expressing EGFR L861Q demonstrated increased sensitivity to erlotinib treatment, compared to Ba/F3 cells expressing EGFR wild-type. Variant function was assessed by EGFR auto-phosphorylation. Sensitivity was assessed by cell viability assay using stable transfection of each variant and increasing concentrations of erlotinib (0–10 uM). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L861Q sequence variation in gene EGFR/NCBI:1956 1280 check_entity AN5000-1 EGFR L861Q mutation EGFR NCBI:1956 gene high grade glioma DOID:3070 risk 21665-5 CIViC:994 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L861Q sequence variation in gene EGFR/NCBI:1956 1280 check_entity AN5000-2 EGFR L861Q mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:21531810 In a study, a group of 6 participants, 5 with stage IV and one with stage IIIB lung adenocarcinoma, were sequenced at EGFR exons 18 to 21. All patients had L861Q mutation and were treated with the 1st generation TKI gefitinib. 4 patients had partial response with progression free survival (PFS) of 4.3, 19.3, 10.0, 8.7 months; overall survival (OS) of 4.3, 34.9, 15.7, 15.7 months; and all 4 were alive at study end. One patient had stable disease, PFS 6.5 months, OS 15.2 months, and was not alive at study end. One patient had progressive disease as response, with PFS of 2.8 months, OS of 10.7 months, and was not alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L861Q sequence variation in gene EGFR/NCBI:1956 1281 check_entity AN5000-2 EGFR L861Q mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:22452895 In a phase 2 trial, 129 patients with lung adenocarcinoma with EGFR mutations including mutations other than exon 19 deletions or exon 21 L858R substitutions who had no more than one previous chemotherapy regimen for advanced disease or an EGFR tyrosine-kinase inhibitor. 99 patients started with a dose of 50 mg and the other 30 patients with a starting dose of 40 mg. 79 of 129 patients had an objective response (two complete responses, 77 partial responses). 70 of the 106 patients with exon 19 deletion or exon 21 L858R EGFR mutations had an objective response, as did nine of 23 patients with the less common mutations. Median progression-free survival was 10.1 months (95% CI: 8.12 – 13.80, however, median progression-free survival was shorter for patients with the uncommon mutations. The median overall survival was 24.8 months (95% CI: 21.98 – 38.74), and the median overall survival for patients with the less common mutations was again shorter. Grade 3 adverse events were more common in patients receiving the higher 50 mg starting dose, and there was one possible drug-related death secondary to interstitial lung disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L861Q sequence variation in gene EGFR/NCBI:1956 1281 check_entity AN5000-2 EGFR L861Q mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:994 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L861Q sequence variation in gene EGFR/NCBI:1956 1281 check_entity AN5000-2 EGFR L861Q mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:4499 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L861Q sequence variation in gene EGFR/NCBI:1956 1281 check_entity AN5001-1 EGFR L861R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:21531810 In a study, 1 participant with stage IV lung adenocarcinoma was sequenced at EGFR exons 18 to 21 and was found to have L861R mutation, and was treated with the 1st generation TKI gefitinib. The patient (M, 83, nonsmoker) had a partial response, progression free survival (PFS) of 37.5 months, overall survival (OS) of 53.3 months and was alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L861R sequence variation in gene EGFR/NCBI:1956 1282 check_entity AN5001-1 EGFR L861R mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1385 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L861R sequence variation in gene EGFR/NCBI:1956 1282 check_entity AN5002-1 EGFR M766_A767insAI EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:24353160 In an in vitro study, a Ba/F3 cell line expressing EGFR M766_A767insAI demonstrated reduced sensitivity to erlotinib treatment (IC50=3.403�M), comparable to Ba/F3 cells expressing EGFR L858R and T790M co-mutation (T790M is a known resistant mutation to 1st and 2nd generation EGFR tyrosine kinase inhibitors; IC50=4.155�M). Resistance was determined by assessing cell proliferation, EGFR, AKT and ERK phosphorylation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR M766_A767insAI [biomarker_term_in_review] 1283 not_mapped AN5002-1 EGFR M766_A767insAI EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1572 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR M766_A767insAI [biomarker_term_in_review] 1283 not_mapped AN5003-1 EGFR M766_A767insASV EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:24353160 A 43 year old female neversmoker lung adenocarcinoma patient with EGFR M766_A767insASV mutation was given erlotinib as first line treatment, and had progressive disease as best response with -3.9% change to target lesions, progression free survival of 1 month. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR M766_A767insASV [biomarker_term_in_review] 1284 not_mapped AN5003-1 EGFR M766_A767insASV EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:2089 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR M766_A767insASV [biomarker_term_in_review] 1284 not_mapped AN5004-1 EGFR Mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 prognostic 21665-5 PubMed:22810899 In a study of 1036 patients with lung adenocarcinomas, patients with EGFR mutations (n=275) showed better prognosis (OS: 34 months versus 23 months; HR=0.6; P<0.001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene EGFR/NCBI:1956 1285 check_entity AN5004-1 EGFR Mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 prognostic 21665-5 PubMed:21969500 Analysis was performed on the placebo group (n=451) of the Phase III study SATURN using erlotinib maintenance therapy for patients with advanced NSCLC who were selected for response or stable disease after first line chemotherapy. It was found that EGFR Mutant status was a significant positive prognostic factor for overall survival. (HR, 0.33; 95% CI, 0.19 to 0.59; P<0.01) assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene EGFR/NCBI:1956 1285 check_entity AN5004-1 EGFR Mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 prognostic 21665-5 CIViC:438 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene EGFR/NCBI:1956 1285 check_entity AN5004-2 EGFR Mutation EGFR NCBI:1956 gene lung cancer DOID:1324 risk 21665-5 PubMed:17409929 In a study of 52 patients with recurrent lung cancer, 27 individuals had EGFR mutation including 2 point mutations in exon 18 (G719A and G1719C), 23 deletions in exon 19, two insertions in exon 19 (I744KIPVAI), on mutation in exon 20 (S768I), and 16 point mutations in exon 21 (L858R and E709H). Patients were treated with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib, and tumors harboring an EGFR mutation had an increased frequency of partial response (PR) and a lower rate of progressive disease (PD) (PR:22, PD:2 vs. PR:2, PD:17; P<0.0001) compared to wildtype EGFR patients. Patients with KRAS mutations also had a longer overall survival compared to wildtype EGFR patients (HR:2.526, 95% CI:1.314-4.858, P=0.0055). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene EGFR/NCBI:1956 1286 check_entity AN5004-2 EGFR Mutation EGFR NCBI:1956 gene lung cancer DOID:1324 risk 21665-5 PubMed:22025157 In advanced-stage (IIIB or IV) non-small cell lung cancer patients treated with erlotinib, patients whose tumors harbored EGFR mutations (n=3) had a higher 12-week progression-free survival rate compared to wildtype EGFR patients (n=54; 100% vs. 25%, P=0.0064). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene EGFR/NCBI:1956 1286 check_entity AN5004-2 EGFR Mutation EGFR NCBI:1956 gene lung cancer DOID:1324 risk 21665-5 CIViC:438 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene EGFR/NCBI:1956 1286 check_entity AN5004-3 EGFR Mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:27083334 In the LUX-LUNG 7 trial, (NCT01466660) stage IIIB or IV NSCLC patients with EGFR exon 19 deletion, (n=186) Leu858Arg mutation, (n=132) or both (n=1) were divided into equal groups and treated with first line reversible EGFR inhibitor gefitinib or irreversible pan-ErbB family inhibitor afatinib in order to obtain a direct comparison of these two approved first line treatments. Significant difference was seen in objective response with 70% of cases with afatinib vs. 56% of cases with gefitinib. Median progression free survival was 11.0 months (10.6-12.9) with afatinib and 10.9 months (9.1-11.5) with gefitinib, HR 0.73 [0.57-0.95] p=0.017. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene EGFR/NCBI:1956 1287 check_entity AN5004-3 EGFR Mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:20022809 This open label Phase 3 Trial performed across 36 centers in Japan (WJTOG3405) assessed patients with postoperative recurrent or stage IIIB/IV NSCLC and activating EGFR mutations (Exon 19 deletion and L858R). 88 patients were treated with EGFR inhibitor gefitinib, while 89 were treated with cisplatin/docetaxel. Progression free survival was significantly longer with gefitinib treatment with a median of 9.2 months vs. 6.3 with cisplatin/docetaxel (HR 0.48; 95% CI 0.336-0.710; p<0.0001). Difference in response to gefitinib between the two EGFR mutation types was not observed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene EGFR/NCBI:1956 1287 check_entity AN5004-3 EGFR Mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:21258250 In a retrospective study, 166 non-small cell lung cancer (NSCLC) patients that tended to have selected characteristics known to be predictive for TKI sensitivity (i.e. women, never smokers, and patients with ADC) were treated with either gefitinib or erlotinib. EGFR mutations (n=42) were associated with improved objective response to drug treatment (71.4% vs. 20.1%, p<0.0001), improved but not significant overall survival (36.9 vs. 24.8 months, p=0.09), and longer median time to progression (not reached vs. 3.7 months, p<0.0001) when compared to wild-type EGFR. Through multivariate analyses, it was shown that EGFR mutations are independent predictive favorable factors of response to drug treatment (p<0.0001) and are significant predictors of longer time to progression (HR: 0.27, 95% CI: 0.14-0.52, p=0.0001) assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene EGFR/NCBI:1956 1287 check_entity AN5004-3 EGFR Mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:19692680 In a phase 3 clinical trial of East Asian advanced pulmonary adenocarcinoma patients, a subset of patients with EGFR mutations (n=261) treated with gefitinib were associated with improved response (HR:0.48, 95% CI:0.36-0.64, P<0.001), compared to carboplatin plus paclitaxel treatment. The frequency of mutation in exon 19 deletion and L858R was 53.6% (140/261) and 42.5% (111/261), respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene EGFR/NCBI:1956 1287 check_entity AN5004-3 EGFR Mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:22452896 In a phase 2b/3 study of 585 stage IIIB-IV lung adenocarcinoma patients who had a previous round of EGFR-TKI treatment, archival material was available for 141 patients. EGFR mutational analysis revealed that 96 tumors had an EGFR mutation, of which 76 (79%) were positive for either L858R or a deletion in exon 19. These mutations were associated with improved progression-free survival (median 3.3 months vs 1.0 month ; HR:0.51, 95% CI:0.31-0.85, P<0.009) compared to placebo control. No difference was reported between the treatment groups for EGFR mutation negative subgroup. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene EGFR/NCBI:1956 1287 check_entity AN5004-3 EGFR Mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:15329413 Mutational profiling was performed on EGFR exons 18-24 from a group of 10 retrospectively chosen patients who had shown partial response or clinical imporvement in response to gefitinib, and in 8 patients who had not shown gefitinib response. 7 of 10 sensitive patients had mutations in EGFR, while none of the 8 gefitinib refractory patients showed EGFR mutation in these exons (p=0.004) assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene EGFR/NCBI:1956 1287 check_entity AN5004-3 EGFR Mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:20038723 In a phase 3 clinical trial of non-small cell lung cancer (NSCLC) patients, a subset of patients with EGFR mutations (n=44) treated with gefitinib were associated with improved progression free survival (HR: 0.16, 95% CI: 0.05-0.49, P=0.001), and a higher objective response rate (ORR: 42.1% vs 21.1%, p=0.04) compared to patients treated with docetaxel. Of the 44 patients, 22 had an exon 19 deletion, 16 had an L858R mutation, one patient had an exon 20 T790M mutation, two had an exon G719A mutation and four had other mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene EGFR/NCBI:1956 1287 check_entity AN5004-3 EGFR Mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:21969500 In the placebo-controlled Phase III study SATURN, using erlotinib maintenance therapy for patients with advanced NSCLC who were selected for response or stable disease after first line chemotherapy, EGFR mutation was assessed. In patients with EGFR mutation, erlotinib maintenance reduced progression and death significantly with median progression free survival (PFS) of 44.6 vs. 13 weeks over placebo. Erlotinib also significantly improved PFS in EGFR wildtype patients, but EGFR mutant tumors treated with erlotinib had significant better PFS than EGFR wildtype. Overall, in the intent to treat population erlotinib significantly improved PFS over placebo (HR, 0.71; 95% CI, 0.62 to 0.82; P<0.001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene EGFR/NCBI:1956 1287 check_entity AN5004-3 EGFR Mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:21783417 In this open-label, randomised, phase 3 trial at 22 centres in China, patients with stage IIIB or IV NSCLC who had exon 19 deletion or exon 21 L858R point mutation, and who had not received previous systemic anticancer therapy, were administered tyrosine kinase inhibitor erlotinib (83 patients) or gemcitabine plus carboplatin (82 patients). Median progression-free survival was found to be significantly longer with erlotinib than in patients on chemotherapy (13.1 [95% CI 10.58–16.53] vs 4.6 [4.21–5.42] months; hazard ratio 0.16, 95% CI 0.10–0.26; p<0.0001). Chemotherapy was also associated with more grade 3 or 4 toxic effects. Authors conclude that in patients with advanced EGFR mutant NSCLC, erlotinib offers an improved first line treatment option. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene EGFR/NCBI:1956 1287 check_entity AN5004-3 EGFR Mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:438 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene EGFR/NCBI:1956 1287 check_entity AN5004-4 EGFR Mutation EGFR NCBI:1956 gene peritoneal mesothelioma DOID:1788 risk 21665-5 PubMed:20942962 25 patients with metastatic peritoneal mesothelioma were treated with surgical cytoreduction consolidated with intraperitoneal hyperthermic chemotherapy (CRS/IPHC). 8 of the patients carried EGFR mutations in the tyrosine kinase domain. Each mutation was not found in 100 unrelated controls. At study end 10/18 wildtype patients had died with median survival of 14 months, while 2/7 EGFR mutant patients had died and median survival was not yet reached. Median time to progression (TTP) was 12 months in the wildtype group and in the mutant group median TTP was not yet reached. 3 year progression free survival was 71% in the mutant group and 28% in the wildtype group. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene EGFR/NCBI:1956 1288 check_entity AN5004-4 EGFR Mutation EGFR NCBI:1956 gene peritoneal mesothelioma DOID:1788 risk 21665-5 CIViC:438 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene EGFR/NCBI:1956 1288 check_entity AN5005-1 EGFR N771_P772insL EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:31208370 In a retrospective study of 2316 Chinese patients with stage IV non-small cell lung carcinoma, a 69 year old male with the novel EGFR exon 20 insertion N771_P772insL received osimertinib as first-line treatment. The patient achieved stable disease as best response with greater than 10% reduction in tumour size, and progression-free survival of 4.9 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR N771_P772insL [biomarker_term_in_review] 1289 not_mapped AN5005-1 EGFR N771_P772insL EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:3172 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR N771_P772insL [biomarker_term_in_review] 1289 not_mapped AN5006-1 EGFR N826S mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:19147750 In an in vitro study, a Ba/F3 cell line expressing EGFR N826S demonstrated reduced sensitivity to erlotinib treatment, compared to Ba/F3 cells expressing a known sensitizing mutation (EGFR L858R). Sensitivity was determined by assessing cell proliferation, the IC50 of erlotinib for EGFR N826S and EGFR L858R expressing cells were 505 nmol/L and 6 nmol/L, respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N826S sequence variation in gene EGFR/NCBI:1956 1290 check_entity AN5006-1 EGFR N826S mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1162 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N826S sequence variation in gene EGFR/NCBI:1956 1290 check_entity AN5007-1 EGFR N826Y mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:21531810 In a study, 1 participant with stage IV lung adenocarcinoma was sequenced at EGFR exons 18 to 21 and was found to have N826Y mutation, and was treated with the 1st generation TKI gefitinib. The patient (F, 46, nonsmoker) had progressive disease as response, progression free survival (PFS) of 3.3 months, overall survival (OS) of 13.9 months and was not alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N826Y sequence variation in gene EGFR/NCBI:1956 1291 check_entity AN5007-1 EGFR N826Y mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1772 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N826Y sequence variation in gene EGFR/NCBI:1956 1291 check_entity AN5008-1 EGFR N842S mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:21531810 In a study, 1 participant with stage IV lung adenocarcinoma was sequenced at EGFR exons 18 to 21 and was found to have N842S mutation, and was treated with the 1st generation TKI gefitinib. The patient (F, 73, nonsmoker) progressive disease as response, progression free survival (PFS) of 0.9 months, overall survival (OS) of 9.7 months and was not alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N842S sequence variation in gene EGFR/NCBI:1956 1292 check_entity AN5008-1 EGFR N842S mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1775 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N842S sequence variation in gene EGFR/NCBI:1956 1292 check_entity AN5009-1 EGFR Overexpression EGFR NCBI:1956 gene brain glioblastoma multiforme DOID:3073 prognostic 21665-5 PubMed:14583498 In patients with glioblastoma multiforme, those with overespression of wild-type EGFR had shorter overall survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene EGFR/NCBI:1956 1293 AN5009-1 EGFR Overexpression EGFR NCBI:1956 gene brain glioblastoma multiforme DOID:3073 prognostic 21665-5 CIViC:193 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene EGFR/NCBI:1956 1293 AN5009-2 EGFR Overexpression EGFR NCBI:1956 gene esophagus squamous cell carcinoma DOID:3748 prognostic;risk 21665-5 PubMed:26459251 55 tumor samples were analyzed for EGFR expression using IHC. The objective response rate to anti-EGFR antibody nimotuzumab did not differ significantly between EGFR high- (18 pts) and EGFR low to moderate groups (37 pts). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene EGFR/NCBI:1956 1294 AN5009-2 EGFR Overexpression EGFR NCBI:1956 gene esophagus squamous cell carcinoma DOID:3748 prognostic;risk 21665-5 CIViC:193 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene EGFR/NCBI:1956 1294 AN5009-3 EGFR Overexpression EGFR NCBI:1956 gene head and neck squamous cell carcinoma DOID:5520 prognostic;risk 21665-5 PubMed:23265711 EGFR expression level was not predicitive of response to cetuximab-containing first line regimens in recurrent or metastatic head and neck squamous cell carcinoma and KRAS-wild type colorectal carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene EGFR/NCBI:1956 1295 AN5009-3 EGFR Overexpression EGFR NCBI:1956 gene head and neck squamous cell carcinoma DOID:5520 prognostic;risk 21665-5 PubMed:9625170 Primary tumors of 91 patients with head and neck squamous cell carcinoma were analyzed for expression of EGFR and TGF-alpha using IHC. Expression of EGFR or TGF-alpha were associated with reduced disease-free and cause-specific survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene EGFR/NCBI:1956 1295 AN5009-3 EGFR Overexpression EGFR NCBI:1956 gene head and neck squamous cell carcinoma DOID:5520 prognostic;risk 21665-5 PubMed:21653686 47 HNSCC patients treated with cetuximab/docetaxel were retrospectively analyzed for EGFRvIII, EGFR and AREG expression with IHC. 73 % of cases expressed high level of EGFR. EGFR expression had no impact on PFS (P=0.73) or OS (P=0.75). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene EGFR/NCBI:1956 1295 AN5009-3 EGFR Overexpression EGFR NCBI:1956 gene head and neck squamous cell carcinoma DOID:5520 prognostic;risk 21665-5 CIViC:193 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene EGFR/NCBI:1956 1295 AN5009-4 EGFR Overexpression EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:22056021 EGFR overexpression was correlated with longer overall survival in patients with advanced NSCLC treated with first line chemotherapy and cetuximab than those treated with first line chemotherapy alone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene EGFR/NCBI:1956 1296 AN5009-4 EGFR Overexpression EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:26439803 In this prospective study in 37 patients of whom 34 were treated with different EGFR inhibitors (gefitinib, erlotinib, afatinib), EGFR mutations and a higher relative expression of EGFR in comparison to MET expression were correlated with longer PFS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene EGFR/NCBI:1956 1296 AN5009-4 EGFR Overexpression EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:16707605 82 patients treated with gefitinib were retrospectively analyzed for EGFR mRNA expression (rt-PCR in 64 patients). Patients with high EGFR mRNA expression (>5.01) had 43% response probability, whereas patients with low EGFR mRNA expression had 8% response probability (P = 0.006). PFS but not OS was also longer in patients with high EGFR mRNA expression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene EGFR/NCBI:1956 1296 AN5009-4 EGFR Overexpression EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:193 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene EGFR/NCBI:1956 1296 AN5010-1 EGFR P753S mutation EGFR NCBI:1956 gene skin squamous cell carcinoma DOID:3151 risk 21665-5 PubMed:24934779 72-year old male patient presents with SCC with a mutation profile consistent with UV exposure. Sequencing revealed a number of abnormalities including P753S mutation in EGFR. Patient began therapy with cetuximab and sirolimus and continued for 9 months. Disease burden was not measurable by Response Evaluation Criteria in Solid Tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P753S sequence variation in gene EGFR/NCBI:1956 1297 check_entity AN5010-1 EGFR P753S mutation EGFR NCBI:1956 gene skin squamous cell carcinoma DOID:3151 risk 21665-5 CIViC:456 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P753S sequence variation in gene EGFR/NCBI:1956 1297 check_entity AN5011-1 EGFR P772_H773insYNP EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:24353160 A 79 year old Asian male never smoker with not otherwise specified NSCLC harboring EGFR P772_H773insYNP mutation was given erlotinib as first line treatment, and had progressive disease as best response with +2.3% change to target lesions, progression free survival of 2.1 months and overall survival of 16.5 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR P772_H773insYNP [biomarker_term_in_review] 1298 not_mapped AN5011-1 EGFR P772_H773insYNP EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1575 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR P772_H773insYNP [biomarker_term_in_review] 1298 not_mapped AN5012-1 EGFR P772_V774insPHV EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:24353160 A 57 year old male 10 packyear former smoker with lung adenocarcinoma with EGFR P772_V774insPHV mutation was given erlotinib as first line treatment, and had progressive disease as best response with progression free survival of 2 months and overall survival of 16 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR P772_V774insPHV [biomarker_term_in_review] 1299 not_mapped AN5012-1 EGFR P772_V774insPHV EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 CIViC:1576 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR P772_V774insPHV [biomarker_term_in_review] 1299 not_mapped AN5013-1 EGFR R108K mutation EGFR NCBI:1956 gene high grade glioma DOID:3070 risk 21665-5 PubMed:17177598 In an in vitro study, a Ba/F3 cell line expressing EGFR R108K demonstrated increased sensitivity to erlotinib treatment, compared to Ba/F3 cells expressing EGFR wild-type. Variant function was assessed by EGFR auto-phosphorylation. Sensitivity was assessed by cell viability assay using stable transfection of each variant and increasing concentrations of erlotinib (0–10 uM). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R108K sequence variation in gene EGFR/NCBI:1956 1300 check_entity AN5013-1 EGFR R108K mutation EGFR NCBI:1956 gene high grade glioma DOID:3070 risk 21665-5 CIViC:968 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R108K sequence variation in gene EGFR/NCBI:1956 1300 check_entity AN5014-1 EGFR R451C mutation EGFR NCBI:1956 gene colorectal cancer DOID:9256 risk 21665-5 PubMed:26888827 In this preclinical study on the effects of cetuximab, panitumumab or sym004 on various EGFR mutations in colorectal cancer. The R451C mutation showed moderate drug-receptor binding with sym004, cetuximab and panitumumab treatment and inhibition of EGFR phosphorylation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R451C sequence variation in gene EGFR/NCBI:1956 1301 check_entity AN5014-1 EGFR R451C mutation EGFR NCBI:1956 gene colorectal cancer DOID:9256 risk 21665-5 CIViC:450 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R451C sequence variation in gene EGFR/NCBI:1956 1301 check_entity AN5015-1 EGFR R705K mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:23749122 In a large retrospective study, EGFR exons 18-21 were assessed using direct sequencing in 753 French NSCLC cases. Clinical details and patient outcomes were taken, including whether the first generation TKIs erlotinib or gefitinib were administered. One patient was found to have a R705K mutation, was administered a TKI, and an NSCLC progression was observed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R705K sequence variation in gene EGFR/NCBI:1956 1302 check_entity AN5015-1 EGFR R705K mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:2206 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R705K sequence variation in gene EGFR/NCBI:1956 1302 check_entity AN5016-1 EGFR R776C mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:19147750 In an in vitro study, a Ba/F3 cell line expressing EGFR R776C demonstrated increased sensitivity to erlotinib treatment comparable to Ba/F3 cells expressing a known sensitizing mutation (EGFR L858R). Sensitivity was determined by assessing cell proliferation, the IC50 of erlotinib for EGFR V742A and EGFR L858R expressing cells were 47 nmol/L and 6 nmol/L, respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R776C sequence variation in gene EGFR/NCBI:1956 1303 check_entity AN5016-1 EGFR R776C mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1155 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R776C sequence variation in gene EGFR/NCBI:1956 1303 check_entity AN5017-1 EGFR R831H mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 PubMed:20942962 In an in vitro study performed after identification of the mutation in a malignant peritoneal mesothelioma patient, COS-7 cells expressing EGFR R831H demonstrated increased EGFR phosphotyrosine after EGF treatment over wildtype EGFR expressing cells. Cells expressing mutant EGFR also showed increased sensitivity to erlotinib treatment compared to cells expressing EGFR wild-type. Sensitivity was determined by assessing EGFR auto-phosphorylation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R831H sequence variation in gene EGFR/NCBI:1956 1304 check_entity AN5017-1 EGFR R831H mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 CIViC:991 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R831H sequence variation in gene EGFR/NCBI:1956 1304 check_entity AN5018-1 EGFR Rare Exon 18-21 Mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:21531810 In a cohort of NSCLC patients treated with tyrosine kinase inhibitors erlotinib or gefitinib, 61 patients with uncommon mutations of unknown clinical significance (UMUCS) in EGFR exons 18-21 responded at a rate of 47.5% (primarily G719 and L861, N=30/61). This was significantly greater (p<0.001) than a response rate of 16.5% in EGFR wild type patients but significantly smaller (p<0.001) than a 74.1% response in EGFR mutant patients with canonical exon 19 deletion or L858R mutation. Uncommon mutations also had greater median PFS (5.0 vs. 2.0 months, P < 0.001) and median overall survival (15.0 vs. 10.4 months, P = 0.030) than in patients with the wild-type EGFR. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rare:exon:18-21:mutation sequence variation in gene EGFR/NCBI:1956 1305 check_entity AN5018-1 EGFR Rare Exon 18-21 Mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1739 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rare:exon:18-21:mutation sequence variation in gene EGFR/NCBI:1956 1305 check_entity AN5019-1 EGFR Rare Mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:27022112 A Japanese Phase III clinical study assessed the noninferiority of gefitinib as compared to erlotinib in 561 advanced stage (IIIB and IV) postoperative lung adenocarcinoma patients. All patients had prior chemotherapy but no treatment with TKIs. 19 patients had unspecified uncommon EGFR mutations, including single mutations other than ex19del and L858R and double mutations. Of those 19 patients, 7 were treated with erlotinib and 12 were treated with gefitinib. Objective response (42.9% for erlotinib and 25% for gefitinib) and disease control rate (71.4% with eflotinib and 66.7% with gefitinib) between were not significantly different between the treatments. The study failed to satisfy the primary endpoint of demonstrating statistical noninferiority in PFS of gefitinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rare:mutation sequence variation in gene EGFR/NCBI:1956 1306 check_entity AN5019-1 EGFR Rare Mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 CIViC:2207 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rare:mutation sequence variation in gene EGFR/NCBI:1956 1306 check_entity AN5020-1 EGFR S492R mutation EGFR NCBI:1956 gene colorectal cancer DOID:9256 risk 21665-5 PubMed:22270724 In-vitro studies found this mutation to confer resistance to cetuximab. 2 of 10 patients studied also harbored EGFR S492R and were resistant to cetuximab therapy. Panitumumab was still active in-vitro and in one patient. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S492R sequence variation in gene EGFR/NCBI:1956 1307 check_entity AN5020-1 EGFR S492R mutation EGFR NCBI:1956 gene colorectal cancer DOID:9256 risk 21665-5 PubMed:26888827 In this preclinical study of cetuximab, panitumumab or sym004 on various EGFR mutations in colorectal cancer. The S492R mutation was sensitive to Sym004 and panitumumab treatment but resistant to cetuximab. Experiments include flow cytometry binding assay, kinase phosphorylation, cell viability, downstream signalling. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S492R sequence variation in gene EGFR/NCBI:1956 1307 check_entity AN5020-1 EGFR S492R mutation EGFR NCBI:1956 gene colorectal cancer DOID:9256 risk 21665-5 CIViC:449 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S492R sequence variation in gene EGFR/NCBI:1956 1307 check_entity AN5021-1 EGFR S645C mutation EGFR NCBI:1956 gene lung cancer DOID:1324 risk 21665-5 PubMed:27478040 194 somatic mutations seen in primary lung cancers were functionally evaluated using three approaches: (1) differences in pattern or extent of changes in gene expression in A549 cells induced by transduction of lentiviral vectors containing mutant vs. wild-type genes; (2) xenograft assay based on human lung epithelial cells harbouring the variant introduced in mice and subsequent measurement of tumour size; (3) evaluation of resistance to erlotinib, afatinib, lapatinib, sorafenib and trametinib in PC9 isogenic lines expressing mutant alleles. EGFR S645C mutations showed differences in gene expression from wild-type and induced tumour formation, and were therefore classed as gain-of-function mutations, but were less sensitive to erlotinib than wild-type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S645C sequence variation in gene EGFR/NCBI:1956 1308 check_entity AN5021-1 EGFR S645C mutation EGFR NCBI:1956 gene lung cancer DOID:1324 risk 21665-5 CIViC:4336 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S645C sequence variation in gene EGFR/NCBI:1956 1308 check_entity AN5022-1 EGFR S720 mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:26773740 Efficacy of erlotinib treatment was evaluated by meta-analysis of results from seven trials and literature review. Two patients with p.S270P, and one patient with p.S720F were observed to have poor survival outcomes. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S720 sequence variation in gene EGFR/NCBI:1956 1309 check_entity AN5022-1 EGFR S720 mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 CIViC:701 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S720 sequence variation in gene EGFR/NCBI:1956 1309 check_entity AN5023-1 EGFR S768I mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 PubMed:19147750 In an in vitro study, a Ba/F3 cell line expressing EGFR S768I demonstrated reduced sensitivity to erlotinib treatment, compared to Ba/F3 cells expressing a known sensitizing mutation (EGFR L858R). Sensitivity was determined by assessing cell proliferation, the IC50 of erlotinib for EGFR S768I and EGFR L858R expressing cells were 250 nmol/L and 6 nmol/L, respectively. Gefitinib was similarly tested and IC50 of 315 nanomolar was obtained, indicating non-response and potential resistance assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S768I sequence variation in gene EGFR/NCBI:1956 1310 check_entity AN5023-1 EGFR S768I mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 CIViC:558 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S768I sequence variation in gene EGFR/NCBI:1956 1310 check_entity AN5023-2 EGFR S768I mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:25521405 A patient with metastatic lung adenocarcinoma was found to harbor EGFR T790M and S768I mutations when acquired resistance developed after 8 years of erlotinib treatment. Analysis of original tumor samples from 2001 and 2003 were found to also harbor the S768I (but not T790M) mutation. Three-dimensional visualization showed the 768 position to be outside of the erlotinib binding position. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S768I sequence variation in gene EGFR/NCBI:1956 1311 check_entity AN5023-2 EGFR S768I mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:20522446 Case report of an 81-year old man with lung adenocarcinoma and EGFR S768I mutation. The patient then received chemotheraoy (vinorelbine) and showed stable disease. Gefitinib was administered when disease progression was noted 4 months later and the patient was followed-up without signs of disease progression for 461 days. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S768I sequence variation in gene EGFR/NCBI:1956 1311 check_entity AN5023-2 EGFR S768I mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:22895145 In stage IV lung adenocarcinoma patients (n=2) harboring EGFR S768I mutation, EGFR S768I was associated with progressive disease after 1 month of erlotinib monotherapy; the patient was previously treated with standard chemotherapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S768I sequence variation in gene EGFR/NCBI:1956 1311 check_entity AN5023-2 EGFR S768I mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 CIViC:558 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S768I sequence variation in gene EGFR/NCBI:1956 1311 check_entity AN5023-3 EGFR S768I mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:27211795 S768I mutations in exon 20 of the EGFR gene are rare and are typically seen in conjunction with sensitizing EGFR mutations. Because of this mutation's rarity and the variability of responses of treated cases, its exact prognostic and predictive role is not fully understood. In our experience, S768I mutations in isolation do not necessarily confer sensitivity to erlotinib, but in conjunction with sensitizing EGFR mutations, S768I mutations do not restrict efficacy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S768I sequence variation in gene EGFR/NCBI:1956 1312 check_entity AN5023-3 EGFR S768I mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:22452895 In a phase 2 trial, 129 patients with lung adenocarcinoma with EGFR mutations including mutations other than exon 19 deletions or exon 21 L858R substitutions who had no more than one previous chemotherapy regimen for advanced disease or an EGFR tyrosine-kinase inhibitor. 99 patients started with a dose of 50 mg and the other 30 patients with a starting dose of 40 mg. 79 of 129 patients had an objective response (two complete responses, 77 partial responses). 70 of the 106 patients with exon 19 deletion or exon 21 L858R EGFR mutations had an objective response, as did nine of 23 patients with the less common mutations. Median progression-free survival was 10.1 months (95% CI: 8.12 – 13.80, however, median progression-free survival was shorter for patients with the uncommon mutations. The median overall survival was 24.8 months (95% CI: 21.98 – 38.74), and the median overall survival for patients with the less common mutations was again shorter. Grade 3 adverse events were more common in patients receiving the higher 50 mg starting dose, and there was one possible drug-related death secondary to interstitial lung disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S768I sequence variation in gene EGFR/NCBI:1956 1312 check_entity AN5023-3 EGFR S768I mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:558 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S768I sequence variation in gene EGFR/NCBI:1956 1312 check_entity AN5023-3 EGFR S768I mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:4499 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S768I sequence variation in gene EGFR/NCBI:1956 1312 check_entity AN5024-1 EGFR S768_D770dup mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:31208370 In a retrospective study of 2316 Chinese patients with stage IV non-small cell lung carcinoma, two patients with the EGFR exon 20 insertion S768_D770dup received osimertinib treatment. A 59 year old female with previous systemic treatment had a partial response and progression-free survival (PFS) of 14.6+ months, remaining on osimertinib at data cut-off. The second patient, a 70 year old female, had previous systemic therapy and treatment with the EGFR inhibitor afatinib. This patient also remained on treatment at data cut-off with stable disease and PFS of 11.2+ months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::s768_d770dup:mutation sequence variation in gene EGFR/NCBI:1956 1313 check_entity AN5024-1 EGFR S768_D770dup mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1419 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::s768_d770dup:mutation sequence variation in gene EGFR/NCBI:1956 1313 check_entity AN5025-1 EGFR T263P mutation EGFR NCBI:1956 gene high grade glioma DOID:3070 risk 21665-5 PubMed:17177598 In an in vitro study, a Ba/F3 cell line expressing EGFR T263P demonstrated increased sensitivity to erlotinib treatment, compared to Ba/F3 cells expressing EGFR wild-type. Variant function was assessed by EGFR auto-phosphorylation. Sensitivity was assessed by cell viability assay using stable transfection of each variant and increasing concentrations of erlotinib (0–10 uM). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T263P sequence variation in gene EGFR/NCBI:1956 1314 check_entity AN5025-1 EGFR T263P mutation EGFR NCBI:1956 gene high grade glioma DOID:3070 risk 21665-5 CIViC:969 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T263P sequence variation in gene EGFR/NCBI:1956 1314 check_entity AN5026-1 EGFR T785A mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 PubMed:20942962 In an in vitro study performed after identification of the mutation in a malignant peritoneal mesothelioma patient, COS-7 cells expressing EGFR T785A demonstrated increased EGFR phosphotyrosine after EGF treatment over wildtype EGFR expressing cells. Cells expressing mutant EGFR also showed increased sensitivity to erlotinib treatment compared to cells expressing EGFR wild-type. Sensitivity was determined by assessing EGFR auto-phosphorylation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T785A sequence variation in gene EGFR/NCBI:1956 1315 check_entity AN5026-1 EGFR T785A mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 CIViC:1481 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T785A sequence variation in gene EGFR/NCBI:1956 1315 check_entity AN5027-1 EGFR T790M mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 PubMed:19147750 Experimental - EGFR T790M mutation has been associated with resistance to first generation EGFR tyrosine kinase inhibitors, including erlotinib and gefitinib. In an in vitro study, Ba/F3 cells stably expressing EGFR T790M demonstrated resistance to gefitinib and erlotinib and the tool construct AEE788. These cells had very high IC50 nmol/L values for all three inhibitors in comparison to other constructs (Gefitinib>2000, Erlotinib>2000, AEE788>2000), indicating resitance to all three inhibitors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1316 check_entity AN5027-1 EGFR T790M mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 CIViC:34 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1316 check_entity AN5027-2 EGFR T790M mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:23470965 155 patients with lung adenocarcinomas underwent rebiopsy and genotyping (EGFR, AKT1, BRAF, ERBB2, KRAS, MEK1, NRAS, PIK3CA and FISH for MET and HER2) after the development of acquired resistance to EGFR inhibitors (gefitinib or erlotinib). 98 patients were found to have developed EGFR T790M mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1317 check_entity AN5027-2 EGFR T790M mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:26181354 Case report of a patient with stage IV lung adenocarcinoma and a 15–base pair deletion in EGFR exon 19. Partial response with erlotinib was achieved for 15 months after initial chemotherapy. After further progression, rebiopsy additionally identified the EGFR T790M mutation and the patient received several cycles of chemotherapy and targeted therapy including afatinib, cetuximab, erlotinib, AZD9291. She was treated with AZD9291 for 9 months until disease progression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1317 check_entity AN5027-2 EGFR T790M mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:26269204 In a lung adenocarcinoma patient harboring an EGFR E746_A750 mutation and an acquired EGFR T790M co-mutation, EGFR T790M was associated with sensitivity to osimertinib monotherapy. Prior to the development of the EGFR T790M mutation, the patient was treated with gefitinib and achieved a partial response, but subsequently tumor progression occurred; however, osimertinib treatment resulted a favorable tumor response with the extinguishment of the EGFR T790M mutation. In a stage IV lung adenocarcinoma patient harboring an EGFR L858R mutation and an acquired EGFR T790M co-mutation, EGFR T790M was associated with sensitivity to osimertinib monotherapy. Prior to the development of the EGFR T790M mutation, the patient was treated with erlotinib, followed by gefitinib for 12 months and achieved stable disease, but subsequently metastasis occurred; the EGFR T790M was then identified and subsequent 10 month treatment with osimertinib monotherapy resulted in a 45% disease regression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1317 check_entity AN5027-2 EGFR T790M mutation EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 CIViC:34 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1317 check_entity AN5027-3 EGFR T790M mutation EGFR NCBI:1956 gene lung cancer DOID:1324 risk 21665-5 PubMed:18227510 Lung cancers can accumulate activating mutations in oncogenes such as EGFR. The common L858R EGFR mutation has been shown previously to be sensitive to small molecular tyrosine kinase inhibitors (ie. erlotinib). In response, tumors may accumulate an additional 'gatekeeper' mutation in EGFR, T790M. Authors show that T790M retain low affinity for gefitinib and that introduction of T790M in the presence of L858R mutant increases the ATP affinity of L858R and activates wild-type EGFR, thus showing that increased ATP affinity is the primary mode of resistance in tumors with T790M, though irreversible ATP inhibitors (ie. HKI-272) are able to overcome this resistance via covalent bonding. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1318 check_entity AN5027-3 EGFR T790M mutation EGFR NCBI:1956 gene lung cancer DOID:1324 risk 21665-5 CIViC:34 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1318 check_entity AN5027-4 EGFR T790M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:25668228 The T790M mutation in EGFR has been shown to confer resistance to the tyrosine kinase inhibitor erlotinib, and patients harboring this mutation that are placed on the drug are likely to relapse. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1319 check_entity AN5027-4 EGFR T790M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:15728811 In non-small cell lung cancer, the appearance of T790M mutation leads to resistance to gefitinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1319 check_entity AN5027-4 EGFR T790M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:21430269 In Lung Cancer patients with acquired resistance to Dacomitinib (PF00299804), MET amplification and EGFR T790M were found to be the primary drivers of resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1319 check_entity AN5027-4 EGFR T790M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:24636847 In an NSCLC patient initially with L858R mutation, pemetrexed and cisplatin combination treatment was followed by erlotinib treatment. A slow progression developed which was found to be positive for L858R as well as T790M mutation which confers resistance to tyrosine kinase inhibitors. Due to slow tumor growth erlotinib was continued despite T790M, with re-addition of premetrexed, and this reduced tumor size and resulted in stable disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1319 check_entity AN5027-4 EGFR T790M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:24658966 In NSCLC containing a T790M mutation, staurosporine may be inhibitive of EGFR, especially when an L858R mutation is also present. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1319 check_entity AN5027-4 EGFR T790M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:24623981 In NSCLC patients with T790M and another activating mutations, their progression free survival is shorter compared to those who do not possess T790M mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1319 check_entity AN5027-4 EGFR T790M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:24729716 Patients with NSCLC harboring EGFR T790M mutation have statistically worse overall survival compared to patients with L858R or other exon 19 activating mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1319 check_entity AN5027-4 EGFR T790M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:25923550 In a phase1-2 study, patients with the T790M mutation were more sensitive to rocelitinib in comparison to patients with T790M-negative NSCLC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1319 check_entity AN5027-4 EGFR T790M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:24065731 CO-1686 (Rociletinib) more effectively induced apoptosis in EGFR mutated (T790M and others) NSCLC cell lines than those harboring wildtype EGFR. CO-1686 also more effectively reduced tumor volume of mouse xenografts harboring the T790M than those with wildtype EGFR. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1319 check_entity AN5027-4 EGFR T790M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:24893891 Cell line, xenograft, and transgenic models were used to establish Osimertinib as an inhibitor of both EGFR mutation sensitizing (L858M, del exon 19) and T790M resistance mutants. Preclinically, the drug inhibits signaling pathways and cellular growth in both EGFRm(+) and EGFRm(+)/T790M(+) mutant cell lines in vitro, with lower activity against wild-type EGFR lines. Sustained tumor regression was observed in EGFR-mutant tumor xenograft and transgenic models. Treatment of 2 patients with advanced EGFRm(+) T790M(+) NSCLC was reported as proof of principle. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1319 check_entity AN5027-4 EGFR T790M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:25923549 This phase I/II trial (NCT01802632) involved 253 non-small cell lung cancer patients with activating EGFR mutations, who had progressed on first generation tyrosine kinase inhibitor treatment, and were subsequently treated with Osimertinib (AZD9291). The overall objective tumor response rate was 51%. Among 127 patients with EGFR T790M who could be evaluated for response, the response rate was 61% (95% CI, 52 to 70). In contrast, among 61 patients without EGFR T790M, the response rate was 21% (95% CI, 12 to 34). The median progression-free survival was 9.6 months in EGFR T790M-positive patients and 2.8 months in EGFR T790M-negative patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1319 check_entity AN5027-4 EGFR T790M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:26720284 This study summarized 9 EGFR-mutant patients from two clinical trials involving rociletinib (NCT01526928) and subsequent osimertinib (NCT01802632). 8 were T790M-positive prior to treatment with osimertinib. 6 transitioned directly from rociletinib to osimertinib. 3 patients achieved PR and 4 achieved SD. The median PFS was 208 days (95% CI, 41-208 days). Among 6 patients who transitioned directly from rociletinib to osimertinib all derived clinical benefit from osimertinib with either prolonged SD or PR. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1319 check_entity AN5027-4 EGFR T790M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:26515464 For cell harboring EGFR T790M mutation, osimertinib and rociletinib showed potent inhibition compared to erlotinib or afatinib. This study performed drug response assays using five human NSCLC cell lines with various combinations of EGFR mutations. In order to directly compare the sensitivity of multiple EGFR mutations to EGFR-TKIs the authors also generated multiple EGFR transduced Ba/F3 stable cell lines and evaluated sensitivity to EGFR-TKIs by MTS assay. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1319 check_entity AN5027-4 EGFR T790M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:26729184 Osimertinib has been approved for the treatment of EGFR T790M mutant NSCLC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1319 check_entity AN5027-4 EGFR T790M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:27304188 48 tumor samples from 41 patients with EGFR mutant lung adenocarcinoma that were resistant to tyrosine kinase inhibition by gefitinib (n=1) or erlotinib (n=40) underwent next generation sequencing (NGS failed in 5 samples leading to a remaining 43 specimens from 39 patients). The prevalence of various mutations post-treatment was analyzed. 79%, or 31 out of the 39 patients, had the T790M EGFR mutation present, indicating its importance in the development of resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1319 check_entity AN5027-4 EGFR T790M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:24035188 Patients with advanced NSCLC and acquired resistance to EGFR TKI (gefitinib or erlotinib) were analyzed for T790M mutations. Of the 70 patients analyzed, 36 (51%) had the T790M mutation and 34 (49%) were T790M-negative. There was no significant difference in the median post-progression or overall survival between patients with T790M mutation and without T790M mutation for initial TKI treatment. However, subsequent treatment with afatinib showed partial response in six patients where 1/21(5%) were in the T790M-positive group and 5/13 (38%) were in the T790M-negative group (P=0.01). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1319 check_entity AN5027-4 EGFR T790M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:27959700 Randomized, international, open-label, phase 3 trial (NCT02151981) in 419 patients with T790M-positive advanced NSCLC and disease progression after first-line EGFR-TKI therapy. Patients were randomized, in a 2:1 ratio, to oral osimertinib or chemotherapy (pemetrexed plus either carboplatin or cisplatin every 3 weeks for up to six cycles, maintenance pemetrexed was allowed). Primary end point was PFS, which was significantly longer with osimertinib than with chemotherapy (10.1 months vs. 4.4 months; HR 0.30; 95% CI: 0.23 to 0.41; P<0.001). Objective response rate was significantly better with osimertinib (71%; 95% CI, 65 to 76) than with chemotherapy (31%; 95% CI, 24 to 40) (odds ratio for objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1319 check_entity AN5027-4 EGFR T790M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:15737014 In a study of 6 patients with progressive non-small cell lung cancer during gefitinib or erlotinib therapy, comparison of DNA sequences from the original diagnostic biopsy specimen and a post-treatment biopsy specimen demonstrated that 3 patients acquired a new EGFR-T790M mutation. Analysis of EGFR sequence from 155 NSCLC samples prior to treatment with an EGFR inhibitor showed no T790M mutations, suggesting that T790M is associated with progression on gefitinib or erlotinib. In vitro experiments showed that the addition of T790M drastically reduced sensitivity to gefitinib or erlotinib in cells containing the sensitizing EGFR mutation L858R. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1319 check_entity AN5027-4 EGFR T790M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:17020982 In a study of 14 patients with progressive non-small cell lung cancer during gefitinib treatment, comparison of DNA sequences from the original diagnostic biopsy specimen and the post-treatment biopsy specimen demonstrated that 7 patients acquired a new EGFR-T790M mutation. In addition, 52 pre-treatment tumours were examined with a sensitive real-time PCR assay and found no evidence of low frequency T790M mutation prior to gefitinib treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1319 check_entity AN5027-4 EGFR T790M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:18408761 In an in vitro study using NCI-H1666 cells (wildtype EGFR) and NCI-H1975 cells (EGFR-L858R/T790M), inhibition of cell growth was used as an assay to determine sensitivity to reversible tyrosine kinase inhibitor drugs. Cells with an EGFR L858R/T790M mutation demonstrated a reduced response to lapatinib (IC50: >4000nM vs. 534nM) compared to wildtype EGFR cells. Similarly, NIH-3T3 ectopically expression EGFR-L858R/T790M showed reduced sensistivity to lapatinib compared to EGFR wt or L585R mutant cells. These results were further confirmed in a Ba/F3 cell line model assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1319 check_entity AN5027-4 EGFR T790M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:18089823 In an in vitro study using NCI-H322 cells (wildtype EGFR) and NCI-H1975 cells (EGFR-L858R/T790M), inhibition of cell growth was used as an assay to determine sensitivity to irreversible tyrosine kinase inhibitor (TKI) drugs. PF00299804 inhibited the growth of Ba/F3 cell lines containing the EFGR T790M resistance mutation as well as H1975 and H3255 cell lines that contain both EGFR L858R and T790M mutations and H820 containing an EGFR exon 19 deletion (Del 747_L751, Ins S) and a T790M mutation. All three cell lines were resistant to gefitinib in vitro, but sensitive to PF00299804 (IC50 <1 μmol/L for all three cell lines). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1319 check_entity AN5027-4 EGFR T790M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:16818618 The NSCLC cell line NCI-H1975 carrying the EGFR T790M mutation was resistant to erlotinib but showed increased sensitivity to HKI-272 (neratinib, IC50: 0.29 μmol/L). In an in vitro study Ba/F3 cells transfected with either EGFR-L858R or EGFR-L858R/T790M were used to assay cell growth. Ba/F3 cells require IL-3 in order to proliferate, but cells transfected with an activated oncogene are IL-3 independent. Cells with an EGFR L858R/T790M mutation demonstrated an improved response to neratinib (IC50: 0.185umol/L vs. >10umol/L) compared to the same cells treated with erlotinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1319 check_entity AN5027-4 EGFR T790M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 PubMed:21732342 In an in vitro study using purified EGFR protein, kinase activity was assayed and compared for wildtype EGFR, EGFR-T790M and EGFR-T790M/L858R using both reversible and irreversible TKI drugs. EFGR proteins with T790M or T790M/L858R mutations were more sensitive to afatinib treatment (IC50: 9.8nM and 24nM, respectively vs. IC50: >1000nM and >1000nM, respectively) compared to treatment with erlotinib or lapatinib treatment. In an in vitro study using NCI-H358 cells (wildtype EGFR) and NCI-H1975 cells (EGFR-L858R/T790M), inhibition of cell growth was used as an assay to determine sensitivity to tyrosine kinase inhibitor drugs. Cells with an EGFR L858R/T790M mutation demonstrated an improved response to afatinib (GI50: 42.0nM vs. >1000nM) compared to the same cells treated with erlotinib. However, IC50s were intermediate compared to a more potent pan-HER inhibitor. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1319 check_entity AN5027-4 EGFR T790M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21665-5 CIViC:34 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1319 check_entity AN5027-5 EGFR T790M mutation EGFR NCBI:1956 gene pancreatic adenocarcinoma DOID:4074 risk 21665-5 PubMed:28874593 Patients with recurrent pancreatic adenocarcinoma was treated with gemcitabine + nab-paclitaxel, FOLFIRINOX and docetaxel + irinotecan. After failure of these treatment, a tumor specimen from the pancreaticoduodenectomy was analysed, which revealed an activating mutation in exon 19 (L747_P753>S) of EGFR. Mutations were also detected in CDKN2A, TP53, and amplifications of PRKCI and TERC. He began erlotinib at 150mg daily. CT imaging revealed a partial response by RECIST at 8, 24 and 32 weeks after starting erlotinib. At 40 weeks CT imaging revealed unequivocal disease progression. After disease progression to erlotinib, a repeat liver biopsy revealed an EGFR T790M mutation. He began treatment with osimertinib at 80mg daily. After 8 weeks of this treatment CT imaging revealed unequivocal disease progression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1320 check_entity AN5027-5 EGFR T790M mutation EGFR NCBI:1956 gene pancreatic adenocarcinoma DOID:4074 risk 21665-5 CIViC:34 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T790M sequence variation in gene EGFR/NCBI:1956 1320 check_entity AN5028-1 EGFR T847I mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:21531810 In a study, 1 participant with stage IIIB lung adenocarcinoma was sequenced at EGFR exons 18 to 21 and was found to have T847I mutation, and was treated with the 1st generation TKI gefitinib. The patient (M, 77, smoker) progressive disease as response, progression free survival (PFS) of 1.1 months, overall survival (OS) of 1.1 months and was not alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T847I sequence variation in gene EGFR/NCBI:1956 1321 check_entity AN5028-1 EGFR T847I mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1371 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T847I sequence variation in gene EGFR/NCBI:1956 1321 check_entity AN5029-1 EGFR V441F mutation EGFR NCBI:1956 gene colorectal cancer DOID:9256 risk 21665-5 PubMed:29196463 Next-generation sequencing data of cfDNA from 1,397 patients with colorectal cancer identified a novel cluster of extracellular domain (ECD). EGFR V441G/D/F mutations were found in 19% (n=8) of patients with EGFR ECD domain III (location of cetuximab and panitumumab binding epitope) mutations. V441D and V441G were more common than V441F. Resistance of V441G to cetuximab was modeled in silico, and authors predicted that it destroys a critical hydrophobic node. In vitro, V441G/D transduced NIH3T3 cells had significantly reduced binding to panitumumab and cetuximab compared to EGFR wt NH3T3 cells (p<0.01 for all comparisons to wt). Authors inferred that EGFR domain III (ECD) mutations, including V441F, may be responsible for secondary resistance to EGFR blockade. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V441F sequence variation in gene EGFR/NCBI:1956 1322 check_entity AN5029-1 EGFR V441F mutation EGFR NCBI:1956 gene colorectal cancer DOID:9256 risk 21665-5 CIViC:2486 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V441F sequence variation in gene EGFR/NCBI:1956 1322 check_entity AN5030-1 EGFR V742A mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:19147750 In an in vitro study, a Ba/F3 cell line expressing EGFR V742A demonstrated increased sensitivity to erlotinib treatment comparable to Ba/F3 cells expressing a known sensitizing mutation (EGFR L858R). Sensitivity was determined by assessing cell proliferation, the IC50 of erlotinib for EGFR V742A and EGFR L858R expressing cells were 21 nmol/L and 6 nmol/L, respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V742A sequence variation in gene EGFR/NCBI:1956 1323 check_entity AN5030-1 EGFR V742A mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:975 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V742A sequence variation in gene EGFR/NCBI:1956 1323 check_entity AN5031-1 EGFR V769_D770insASV EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 PubMed:26773740 In this meta-analysis of 7 clinical trials evaluating the efficacy of erlotinib, 1 patient with V769_770insASV had overall and progression-free survival of 642 days. From this and literature review it was concluded that although EGFR exon 20 insertions may confer reduced sensitivity to erlotinib, patients with this particular mutation appeared to benefit from therapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR V769_D770insASV [biomarker_term_in_review] 1324 not_mapped AN5031-1 EGFR V769_D770insASV EGFR NCBI:1956 gene lung adenocarcinoma DOID:3910 risk 21665-5 CIViC:717 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR V769_D770insASV [biomarker_term_in_review] 1324 not_mapped AN5032-1 EGFR V774A mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:21531810 In a study, 1 participant with stage IV adenocarcinoma was sequenced at EGFR exons 18 to 21 and was found to have V774A mutation, and was treated with the 1st generation TKI gefitinib. The patient (F, 51, nonsmoker) had a partial response, progression free survival (PFS) of 6.9 months, overall survival (OS) of 29.7 months and was alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V774A sequence variation in gene EGFR/NCBI:1956 1325 check_entity AN5032-1 EGFR V774A mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1768 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V774A sequence variation in gene EGFR/NCBI:1956 1325 check_entity AN5033-1 EGFR V774M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:21531810 In a study, 1 participant with stage IV squamous cell lung carcinoma was sequenced at EGFR exons 18 to 21 and was found to have V774M mutation, and was treated with the 1st generation TKI erlotinib. The patient (M, 80, smoker) had progressive disease as response, progression free survival (PFS) of 1.6 months, overall survival (OS) of 6.7 months and was not alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V774M sequence variation in gene EGFR/NCBI:1956 1326 check_entity AN5033-1 EGFR V774M mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1770 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V774M sequence variation in gene EGFR/NCBI:1956 1326 check_entity AN5034-1 EGFR V834I mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:21531810 In a study, 1 participant with stage IIIB lung adenocarcinoma was sequenced at EGFR exons 18 to 21 and was found to have V834I mutation, and was treated with the 1st generation TKI gefitinib. The patient (F, 79, nonsmoker) had a partial response, progression free survival (PFS) of 5.0 months, overall survival (OS) of 15.0 months and was not alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V834I sequence variation in gene EGFR/NCBI:1956 1327 check_entity AN5034-1 EGFR V834I mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1773 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V834I sequence variation in gene EGFR/NCBI:1956 1327 check_entity AN5035-1 EGFR V851I mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:21531810 In a study, 1 participant with stage IV lung adenocarcinoma was sequenced at EGFR exons 18 to 21 and was found to have V851I mutation, and was treated with the 1st generation TKI gefitinib. The patient (F, 69, nonsmoker) progressive disease as response, progression free survival (PFS) of 0.7 months, overall survival (OS) of 1.6 months and was not alive at study end. As a whole, patients with uncommon EGFR mutations had a response rate of 47.5%, which was between common mutations (del19 and L858R) at 74.1%, and wild type EGFR at 16.5%. Median PFS and OS (months) for the three groups: 5.0 and 15.0 uncommon, 8.5 and 19.6 common, 2.0 and 10.4 wild type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V851I sequence variation in gene EGFR/NCBI:1956 1328 check_entity AN5035-1 EGFR V851I mutation EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1374 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V851I sequence variation in gene EGFR/NCBI:1956 1328 check_entity AN5036-1 EGFR VIII mutation EGFR NCBI:1956 gene brain glioma DOID:0060108 risk 21665-5 PubMed:26778701 Two human glioma cell lines (U87MG or LNZ308) overexpressing either wild-type (wt) EGFR or EGFRvIII were treated with nimotuzumab, temozolomide, or both in vitro. Anti-tumor effects of nimotuzumab were greater in EGFRvIII in comparison to EGFRwt (as measured by antitumor effects, growth suppression, survival elongation and EGFR and Akt phosphorylation). Combination of nimotuzumab and temozolomide further increased efficacy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::viii:mutation sequence variation in gene EGFR/NCBI:1956 1329 check_entity AN5036-1 EGFR VIII mutation EGFR NCBI:1956 gene brain glioma DOID:0060108 risk 21665-5 CIViC:308 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::viii:mutation sequence variation in gene EGFR/NCBI:1956 1329 check_entity AN5036-2 EGFR VIII mutation EGFR NCBI:1956 gene glioblastoma DOID:3068 risk 21665-5 PubMed:16282176 49 patients (26 pretreatment tissues available for analysis) with recurrent glioblastomas who were treated with EGFR TKIs were analyzed in this study. Results were confirmed in an independent cohort of 33 patients. EGFRvIII and PTEN coexpression were associated with responsiveness to EGFR TKI. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::viii:mutation sequence variation in gene EGFR/NCBI:1956 1330 check_entity AN5036-2 EGFR VIII mutation EGFR NCBI:1956 gene glioblastoma DOID:3068 risk 21665-5 PubMed:25586468 In a Phase II clinical trial, patients with Glioblastoma Multiforme (GBM), positive for EGFR VIII deletion mutation (N=65), were treated with the Rindopepimut cancer vaccine, and standard adjuvant temozolomide chemotherapy. Median progression free survival (PFS) was 9.2 months, and median overall survival (OS) was 21.8 months. A pivotal, randomized Phase III trial is currently underway. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::viii:mutation sequence variation in gene EGFR/NCBI:1956 1330 check_entity AN5036-2 EGFR VIII mutation EGFR NCBI:1956 gene glioblastoma DOID:3068 risk 21665-5 CIViC:308 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::viii:mutation sequence variation in gene EGFR/NCBI:1956 1330 check_entity AN5036-3 EGFR VIII mutation EGFR NCBI:1956 gene head and neck squamous cell carcinoma DOID:5520 risk 21665-5 PubMed:21653686 47 HNSCC patients treated with cetuximab/docetaxel were retrospectively analyzed for EGFRvIII, EGFR, and AREG expression by IHC. 17% of cases expressed high levels of EGFRvIII. High vIII expression was associated with reduced disease control rate (DCR) and shortened progression free survival (PFS) (HR: 3.3, P = 0.005) but not with OS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::viii:mutation sequence variation in gene EGFR/NCBI:1956 1331 check_entity AN5036-3 EGFR VIII mutation EGFR NCBI:1956 gene head and neck squamous cell carcinoma DOID:5520 risk 21665-5 CIViC:308 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::viii:mutation sequence variation in gene EGFR/NCBI:1956 1331 check_entity AN5036-4 EGFR VIII mutation EGFR NCBI:1956 gene high grade glioma DOID:3070 risk 21665-5 PubMed:17177598 In an in vitro study, a Ba/F3 cell line expressing EGFR vIII demonstrated increased sensitivity to erlotinib treatment, compared to Ba/F3 cells expressing EGFR wild-type. Variant function was assessed by EGFR auto-phosphorylation. Sensitivity was assessed by cell viability assay using stable transfection of each variant and increasing concentrations of erlotinib (0–10 uM). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::viii:mutation sequence variation in gene EGFR/NCBI:1956 1332 check_entity AN5036-4 EGFR VIII mutation EGFR NCBI:1956 gene high grade glioma DOID:3070 risk 21665-5 CIViC:308 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::viii:mutation sequence variation in gene EGFR/NCBI:1956 1332 check_entity AN5037-1 EGFR W731L mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 PubMed:20942962 In an in vitro study performed after identification of the mutation in a malignant peritoneal mesothelioma patient, COS-7 cells expressing EGFR W731L demonstrated increased EGFR phosphotyrosine after EGF treatment over wildtype EGFR expressing cells. Cells expressing mutant EGFR also showed increased sensitivity to erlotinib treatment compared to cells expressing EGFR wild-type. Sensitivity was determined by assessing EGFR auto-phosphorylation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::W731L sequence variation in gene EGFR/NCBI:1956 1333 check_entity AN5037-1 EGFR W731L mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 CIViC:1479 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::W731L sequence variation in gene EGFR/NCBI:1956 1333 check_entity AN5038-1 EGFR Wildtype EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:19692680 In a phase 3 clinical trial of East Asian pulmonary adenocarcinoma patients, a subset of patients with EGFR mutations (n=261) treated with gefitinib were associated with improved response compared to carboplatin plus paclitaxel treatment, but in patients shown to be negative for EGFR mutation (n=176), patients given gefitinib fared worse than those given carboplatin and paclitaxel: Hazard ratio 2.85 (85% CI 2.05-3.98) p<0.001 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR Wildtype [biomarker_term_in_review] 1334 not_mapped AN5038-1 EGFR Wildtype EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:2050 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR Wildtype [biomarker_term_in_review] 1334 not_mapped AN5039-1 EGFR Y1092 PHOSPHORYLATION EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:22901364 While EGFR mutation is a strong predictive factor for EGFR inhibition, some patients with EGFR wild-type also respond. The authors investigated whether phosphorylated EGFR could be a potential predictive biomarker in patients with wild-type EGFR. Phosphorylation of Y1068 (assessed by IHC) was associated with improved progression free survival (PFS) in 205 patients with stage IIb and IV NSCLC treated with EGFR tyrosine kinase inhibitors (gefitinib or erlotinib) compared to phospho-Y1068 negative patients (median PFS 7.0 months vs. 1.2 months, P < 0.001). In this group, 92 (44.9%) were EGFR mutant. In a subgroup of patients with wild-type EGFR, phospho-Y1068 expression positive patients had a significantly prolonged PFS (4.2 months vs.1.2 months P < 0.001) compared with those without phospho-Y1068 expression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR Y1092 PHOSPHORYLATION [biomarker_term_in_review] 1335 not_mapped AN5039-1 EGFR Y1092 PHOSPHORYLATION EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:386 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR Y1092 PHOSPHORYLATION [biomarker_term_in_review] 1335 not_mapped AN5040-1 EGFR Y764_V765insHH EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 PubMed:24353160 In an in vitro study, a Ba/F3 cell line expressing EGFR Y764_V765insHH demonstrated reduced sensitivity to erlotinib treatment (IC50=3.845�M), comparable to Ba/F3 cells expressing EGFR L858R and T790M co-mutation (T790M is a known resistant mutation to 1st and 2nd generations EGFR tyrosine kinase inhibitors; IC50=4.155�M). Resistance was determined by assessing cell proliferation, EGFR, AKT and ERK phosphorylation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR Y764_V765insHH [biomarker_term_in_review] 1336 not_mapped AN5040-1 EGFR Y764_V765insHH EGFR NCBI:1956 gene lung non-small cell carcinoma DOID:3908 risk 21665-5 CIViC:1573 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EGFR Y764_V765insHH [biomarker_term_in_review] 1336 not_mapped AN5041-1 EGFR Y801H mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 PubMed:20942962 In an in vitro study performed after identification of the mutation in a malignant peritoneal mesothelioma patient, COS-7 cells expressing EGFR Y801H demonstrated increased EGFR phosphotyrosine after EGF treatment over wildtype EGFR expressing cells. Cells expressing mutant EGFR also showed increased sensitivity to erlotinib treatment compared to cells expressing EGFR wild-type. Sensitivity was determined by assessing EGFR auto-phosphorylation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y801H sequence variation in gene EGFR/NCBI:1956 1337 check_entity AN5041-1 EGFR Y801H mutation EGFR NCBI:1956 gene cancer DOID:162 risk 21665-5 CIViC:1483 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y801H sequence variation in gene EGFR/NCBI:1956 1337 check_entity AN5042-1 EIF1AX MUTATION EIF1AX NCBI:1964 gene uveal melanoma DOID:6039 prognostic PubMed:23793026 EIF1AX was identified as a uveal melanoma (UM) driver gene by whole-exome sequencing. Approximately 14%–20% of UM carry a mutation in EIF1AX, with most mutations found in exons 1 and 2. EIF1AX mutations are associated with a good prognosis, and are inversely associated with metastasis. This assertion is based on observed survival for 19 EIF1AX mutant UM cases compared to 69 EIF1AX wildtype cases. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene EIF1AX/NCBI:1964 1338 check_entity AN5042-1 EIF1AX MUTATION EIF1AX NCBI:1964 gene uveal melanoma DOID:6039 prognostic CIViC:670 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene EIF1AX/NCBI:1964 1338 check_entity AN5043-1 EIF4EBP1 PHOSPHORYLATION EIF4EBP1 NCBI:1978 gene colorectal cancer DOID:9256 risk PubMed:22262166 12 CRC cell lines were evaluated. 40% of these were intrinsically resistant to mTOR inhibition with BEZ235, PP242 or WYE354. mTOR independent phosphorylation of EIF4EBP1 (T37/46) was associated with resistance to mTOR inhibitors in one analyzed cell line (SW620). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EIF4EBP1 PHOSPHORYLATION [biomarker_term_in_review] 1339 not_mapped AN5043-1 EIF4EBP1 PHOSPHORYLATION EIF4EBP1 NCBI:1978 gene colorectal cancer DOID:9256 risk CIViC:383 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EIF4EBP1 PHOSPHORYLATION [biomarker_term_in_review] 1339 not_mapped AN5043-2 EIF4EBP1 PHOSPHORYLATION EIF4EBP1 NCBI:1978 gene gastric adenocarcinoma DOID:3717 risk PubMed:23340172 8 gastric cancer cell lines were treated with the MTOR inhibitor everolimus. Cell proliferation was effectively inhibited in 3 cell lines by everolimus. Phosphorylated EIF4EBP1 (T37/46, T70) levels were higher in cell lines and xenografts sensitive to everolimus. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EIF4EBP1 PHOSPHORYLATION [biomarker_term_in_review] 1340 not_mapped AN5043-2 EIF4EBP1 PHOSPHORYLATION EIF4EBP1 NCBI:1978 gene gastric adenocarcinoma DOID:3717 risk CIViC:383 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition EIF4EBP1 PHOSPHORYLATION [biomarker_term_in_review] 1340 not_mapped AN5044-1 EPAS1 Overexpression EPAS1 NCBI:2034 gene colorectal cancer DOID:9256 prognostic PubMed:20363910 Expression of EPAS1 (HIF-2alpha) was assessed in 731 colorectal cancers from two prospective cohort studies. EPAS1 overexpression was found in 322 (46%) cancers by immunohistochemistry and not significantly associated with patient survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene EPAS1/NCBI:2034 1341 AN5044-1 EPAS1 Overexpression EPAS1 NCBI:2034 gene colorectal cancer DOID:9256 prognostic CIViC:431 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene EPAS1/NCBI:2034 1341 AN5044-2 EPAS1 Overexpression EPAS1 NCBI:2034 gene renal cell carcinoma DOID:4450 risk PubMed:23881929 HIF2A (EPAS1) staining was conducted on tumors from 66 patients, of which 27 were classified as low expression and 39 were classified as high expression. The response rates of patients with low and high HIF2A expression to pazopanib were 44% and 33% (p=0.36) respectively and no significant difference in PFS between the two groups (p=0.76) was observed. The authors concluded that HIF2A expression levels are not associated with clinical response to pazopanib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene EPAS1/NCBI:2034 1342 AN5044-2 EPAS1 Overexpression EPAS1 NCBI:2034 gene renal cell carcinoma DOID:4450 risk CIViC:431 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene EPAS1/NCBI:2034 1342 AN5045-1 EPCAM 3' Exon Deletion EPCAM NCBI:4072 gene Lynch syndrome DOID:3883 diagnostic 89039-2 PubMed:21309036 Rare but recurring germline truncating mutations of the 3’ end of EPCAM, were reported for 27 independent families, shown to lead to epigenetic silencing of a neighbouring gene, MSH2, and suggested to cause Lynch syndrome. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::3':exon:deletion sequence variation in gene EPCAM/NCBI:4072 1343 check_entity AN5045-1 EPCAM 3' Exon Deletion EPCAM NCBI:4072 gene Lynch syndrome DOID:3883 diagnostic 89039-2 CIViC:801 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::3':exon:deletion sequence variation in gene EPCAM/NCBI:4072 1343 check_entity AN5046-1 EPHB4 EXPRESSION EPHB4 NCBI:2050 gene colorectal cancer DOID:9256 risk PubMed:23579861 EPHB4 expression, as assessed by quantitative RT-PCR in 13 colorectal cancer patients treated with bevacizumab, was higher in non-responders (p = 0.048). No difference was observed in a control group without bevacizumab treatment. qRT-PCR results were also shown to correlate with protein expression measured by IHC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene EPHB4/NCBI:2050 1344 AN5046-1 EPHB4 EXPRESSION EPHB4 NCBI:2050 gene colorectal cancer DOID:9256 risk CIViC:377 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene EPHB4/NCBI:2050 1344 AN5047-1 ERBB2 Activating Mutation ERBB2 NCBI:2064 gene cancer DOID:162 risk 42783-1 PubMed:35939768 In this phase II NCI-MATCH trial, 40 patients with ERBB2 SNVs or ERBB2 insertions/deletions were treated with afatinib. The ORR was 2.7% (90% CI, 0.14-12.2). 37.8% of the patients had SD as the best response, and 54.1% of patients had progression as the best response. A median six-month PFS rate of 12.0% (90% CI; 5.6-25.8) was reported. The median PFS was 1.7 months (90% CI;1.6-4.2) and the median OS was 6.5 months (90% CI; 4.9-8.9). Overall, no promising antitumor activity was observed, however, the antitumor activity in the rare tumour type, EMPD was considered significant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::activating:mutation sequence variation in gene ERBB2/NCBI:2064 1345 check_entity AN5047-1 ERBB2 Activating Mutation ERBB2 NCBI:2064 gene cancer DOID:162 risk 42783-1 CIViC:2526 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::activating:mutation sequence variation in gene ERBB2/NCBI:2064 1345 check_entity AN5048-1 ERBB2 Amplification ERBB2 NCBI:2064 gene biliary tract cancer DOID:4607 risk 42783-1 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Two of seven patients (29%; 95% CI, 4% to 71%) with biliary cancer and HER2 amplification/overexpression had PR, and three had SD > 120 days assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1346 AN5048-1 ERBB2 Amplification ERBB2 NCBI:2064 gene biliary tract cancer DOID:4607 risk 42783-1 CIViC:302 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1346 AN5048-2 ERBB2 Amplification ERBB2 NCBI:2064 gene bladder carcinoma DOID:4007 risk 42783-1 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Three of nine patients (33%; 95% CI, 8% to 70%) with advanced bladder cancer and HER2 amplification/overexpression had responses (one CR ongoing at 15 months; two PR lasting 1 and 6 months), and two patients had SD > 120 days. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1347 AN5048-2 ERBB2 Amplification ERBB2 NCBI:2064 gene bladder carcinoma DOID:4007 risk 42783-1 CIViC:302 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1347 AN5048-3 ERBB2 Amplification ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 PubMed:18725974 Xenografts established from breast cancer cell lines with ERBB2 amplification and PIK3CA mutation (BT474) or PIK3CA mutation alone (MCF7) were effectively inhibited in-vivo with an AKT1/2-inhibitor (AKTi-1/2; naphthyridinone). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1348 AN5048-3 ERBB2 Amplification ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 PubMed:16091755 In-vitro studies using ERBB2 over-expressing breast cancer cell lines BT474 and SKBR3 (with ERBB2 amplification) showed apoptosis under either labatinib or trastuzumab treatment. A marked synergistic apoptotic effect under lapatinib and trastuzumab co-treatment was observed in BT474 cells, and a milder synergistic effect was observed in SKBR3 cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1348 AN5048-3 ERBB2 Amplification ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 PubMed:21358673 In a panel of 31 breast cancer cell lines with varied mutation backgrounds, 10 cell lines harbored HER2 (ERBB2) amplification. Sensitivity to the mTORC1/2 inhibitor PP242 was assessed, and 8/10 HER2 positive cell lines were reported to be sensitive (IC50 < 1 micro molar PP242). 8/21 without HER2 amplification were reported as resistant (IC50 > 1 micro molar PP242). This pattern of HER2 positive cell sensitivity was not reported with the rapamycin analog mTORC1 inhibitor everolimus. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1348 AN5048-3 ERBB2 Amplification ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 PubMed:20453058 This preclinical study tested the efficacy of GDC-0941, a selective inhibitor of class I PI3K, on several cell lines of breast cancer. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. Authors tested six HER2 amplified breast cancer cell lines for sensitivity to GDC-0941. Their IC50s ranged from 0.19uM to 1.29uM (5/6 cell lines had IC50s below 1umol/L). Authors further note that HER2 amplified breast cancer cell lines are generally more sensitive to GDC-0941 than basal-type cell lines (p = 0.002). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1348 AN5048-3 ERBB2 Amplification ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 PubMed:33480963 In this phase III, randomized, open-label trial, 536 patients with HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, with at least one being for metastatic disease. The patients were randomized 1:1 to margetuximab 15 mg/kg or trastuzumab 6 mg/kg (loading dose of 8 mg/kg), each in 3-week cycles. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The study found that margetuximab improved primary PFS over trastuzumab (HR, 0.76; 95% CI: 0.59 - 0.98; p = .03; median, 5.8 [95% CI: 5.5 - 7.0] months versus 4.9 [95% CI: 4.2 - 5.6] months). At the second interim analysis of 270 deaths, the median OS was 21.6 months for margetuximab versus 19.8 months with trastuzumab (HR, 0.89; 95% CI: 0.69 - 1.13; p = .33, and PFS showed relative risk reduction favouring margetuximab (HR, 0.71; 95% CI: 0.58 - 0.86; p < .001; median, 5.7 versus 4.4 months). Margetuximab improved ORR over trastuzumab at both times of analysis on October 10th, 2018, and September 10th, 2019: 22% vs 16% (p = .06;) and 25% vs 14% (p < .001) respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1348 AN5048-3 ERBB2 Amplification ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 CIViC:302 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1348 AN5048-4 ERBB2 Amplification ERBB2 NCBI:2064 gene childhood ependymoma DOID:5509 risk 42783-1 PubMed:20713864 From a phase one clinical trial, pediatric patients with refractory CNS malignancies were administered 300-1150 mg/m2 twice daily of ERBB2 and EGFR inhibitor lapatinib. The maximum-tolerated dose was established at 900 mg/m2 twice daily, regardless of steroid use. From the 59 patients, 12 patients, including 5 diagnosed with ependymoma, demonstrated a prolonged stable disease in response to lapatinib. In comparison to other CNS tumors, pretrial samples from patients with ependymoma tumors displayed high expression of ERBB2 and activation of ERBB2 signaling. Due to the high expression of ERBB2 receptors, targeting ERBB2 may be a viable treatment for patients with ependymoma tumors and other high expressing ERBB2 brain tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1349 AN5048-4 ERBB2 Amplification ERBB2 NCBI:2064 gene childhood ependymoma DOID:5509 risk 42783-1 CIViC:302 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1349 AN5048-5 ERBB2 Amplification ERBB2 NCBI:2064 gene cholangiocarcinoma DOID:4947 risk 42783-1 PubMed:31453370 A patient with cholangiocarcinoma harboring with ERBB2 amplification (3+) detected by circulating tumor DNA testing and confirmed by tissue-based testing was treated with trastuzumab and pertuzumab. This treatment showed a tumor response and continued over 12 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1350 AN5048-5 ERBB2 Amplification ERBB2 NCBI:2064 gene cholangiocarcinoma DOID:4947 risk 42783-1 CIViC:302 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1350 AN5048-6 ERBB2 Amplification ERBB2 NCBI:2064 gene colorectal cancer DOID:9256 risk 42783-1 PubMed:24146218 141 patients were analyzed for ERBB2 (HER2) positivity by FISH and/or IHC. Only 6 (4.3%) were ERBB2 positive. These patients did not show a difference in outcome after capecitabine, oxaliplatin and chemoradiotherapy, with or without cetuximab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1351 AN5048-6 ERBB2 Amplification ERBB2 NCBI:2064 gene colorectal cancer DOID:9256 risk 42783-1 PubMed:22586653 A cohort of patient-derived xenografts (PDX) from 85 patients with metastatic colorectal cancer was created. PDX were treated with cetuximab and mechanisms of resistance investigated. None of the xenografts harboring KRAS (N=18), NRAS (N=7) or BRAF (N=3) mutations showed a response to cetuximab whereas 1 out of 4 xenografts with a PIK3CA mutation responded to cetuximab. Among 11 quadruple-negative samples with resistance to cetuximab, HER2 overexpression and amplification (N=3) and amplification (N=1) were identified. In an independent second retrospective patient cohort, 3 out of 17 patients with KRAS wt, cetuximab resitant CRC were found to harbor HER2 overexpression and amplification. In this cohort no HER2 overexpression or amplification was identified in 14 KRAS wt patients with response to cetuximab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1351 AN5048-6 ERBB2 Amplification ERBB2 NCBI:2064 gene colorectal cancer DOID:9256 risk 42783-1 PubMed:23348520 HER2 amplification (FISH) was assessed in 170 KRAS wt mCRC patients treated with cetuximab or panitumumab. HER2 copy number status was significantly correlated with response rate, PFS and OS. Patients with amplification in all neoplastic cells (4%) had worse outcome compared to patients without amplification (35%, intermediate outcome) or amplification in minor clones (61%, highest survival probability). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1351 AN5048-6 ERBB2 Amplification ERBB2 NCBI:2064 gene colorectal cancer DOID:9256 risk 42783-1 PubMed:27108243 Phase 2 study in 27 patients with HER2 positive (IHC, FISH), KRAS wt metastatic colorectal cancer refractory to standard of care received trastuzumab and lapatinib. After a median follow-up of 94 weeks, eight (30%, 95% CI 14-50) of 27 patients had achieved an objective response, with one patient (4%, 95% CI -3 to 11) achieving a complete response, and seven (26%, 95% CI 9-43) achieving partial responses; 12 (44%, 95% CI 25-63) patients had stable disease. A total of 914 patients with KRAS wt were screened for this study, 48 patients (5%) were identified to have HER2-positive tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1351 AN5048-6 ERBB2 Amplification ERBB2 NCBI:2064 gene colorectal cancer DOID:9256 risk 42783-1 PubMed:28223103 We identified 142 patients with metastatic colorectal cancer whose tumors harbored both wild-type exons 2, 3, and 4 in KRAS and NRAS, and wild-type exon 15 in BRAF. All patients received cetuximab after oxaliplatin, irinotecan, and fluoropyrimidine failure. HER2 status was determined using immunohistochemistry and silver in situ hybridization and correlated with cetuximab efficacy. Of 142 RAS and BRAF wild-type tumors, we observed 7 cases (4.9%) of HER2 amplification by SISH. After a median follow-up of 13.2 months (range, 1.4-78.1 months), median progression-free survival (PFS) was significantly different according to HER2 status: 3.1 months in patients with HER2 amplification compared with 5.6 months in those with non-amplified HER2 (HR = 2.73; 95% CI = 1.18-6.31; P = 0.019). Overall survival (OS) was not significantly different between groups, although there was a tendency towards shorter OS in patients with HER2-amplified tumors (HR = 0.31; 95% CI = 0.61-2.82; 10.1 vs. 13.5 months; P = 0.488). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1351 AN5048-6 ERBB2 Amplification ERBB2 NCBI:2064 gene colorectal cancer DOID:9256 risk 42783-1 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Thirty of 114 patients (26%; 95% CI, 19% to 35%) with HER2 amplification/overexpression had objective responses to treatment with trastuzumab plus pertuzumab (two CR, 28 PR). Patients with HER2-amplified/overexpressing metastatic colorectal cancer composed the largest tumor-pathway cohort. In this group of 37 patients with refractory disease (median, four previous lines of therapy), treatment with trastuzumab plus pertuzumab produced PRs in 14 patients (38%; 95% CI, 23% to 55%; Fig 2A). An additional four patients had SD > 120 days. The median DOR was 11 months (range, < 1 to 16+ months; 95% CI, 2.8 months to not estimable). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1351 AN5048-6 ERBB2 Amplification ERBB2 NCBI:2064 gene colorectal cancer DOID:9256 risk 42783-1 PubMed:30857956 In an updated report of a part of the phase 2a MyPathway trial, 57 patients with treatment-refractory, metastatic colorectal cancer with HER2 amplification received pertuzumab and trastuzumab. Objective response rate was 32% (n=18/57). One patient had a complete response, and 17 experienced a partial response. Patients were determined to have HER2 amplification by NGS and/or FISH/CISH. In addition, the authors note that 27/35 patients had HER2 overexpression as determined by IHC, 3 of 47 tested had HER2 mutations, 8 had PIK3CA mutations, and 13 had mutated KRAS. Exploratory analysis found that KRAS wild-type patients had better ORR as compared to KRAS mutated patients (40% vs 8%). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1351 AN5048-6 ERBB2 Amplification ERBB2 NCBI:2064 gene colorectal cancer DOID:9256 risk 42783-1 PubMed:26296355 Afatinib monotherapy was tested in patient-derived colorectal cancer (M051) mouse xenografts and gastric cancer cell-line (NCI-N87) mouse xenografts. Tumor shrinkage was observed and tumor volume was significantly decreased compared to treatment with vehicle or lapatinib monotherapy (p<0.0001 (M051 Afatinib vs. Lapatinib) and p=0.0003 (NCI-N87 Afatinib vs. Lapatinib). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1351 AN5048-6 ERBB2 Amplification ERBB2 NCBI:2064 gene colorectal cancer DOID:9256 risk 42783-1 PubMed:36315917 In this clinical study of 38 patients with colorectal cancer (CRC), 28 had CRC with ERBB2 amplification, and were treated with a combination of Pertuzumab and Trastuzumab. The DC rate in the patients was 54% (95% CI; 37-67) and the OR rate was 25% (95% CI, 11-45). Seven patients had partial response and seven patients had stable disease of at least 16 weeks. The reported PFS and OS were 17.2 weeks (11.1-27.4) and 60 weeks (32.1-102.3) respectively. Out of the 38 patients in the study, 4 experienced adverse or serious adverse events. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1351 AN5048-6 ERBB2 Amplification ERBB2 NCBI:2064 gene colorectal cancer DOID:9256 risk 42783-1 CIViC:302 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1351 AN5048-7 ERBB2 Amplification ERBB2 NCBI:2064 gene endometrial cancer DOID:1380 risk 42783-1 PubMed:19840887 This phase II single arm study assessed trastuzumab monotherapy in HER2 positive endometrial cancers with tumor response as primary endpoint. Participants had stage III, IV or recurrent HER2 positive endometrial cancer. During the trial's initial phase, 23 of 132 patients screened met the criteria of IHC2+ or 3+ or FISH positivity for HER2 status. In the absence of results, the trial entered phase B, where only patients with HER2 amplification by FISH were admitted. The trial ended early due to poor accrual with 11 of 154 screened meeting the phase B criteria. No major objective tumor responses were observed in the study. 28% of the cancers were of the serous type that had shown trastuzumab response in case studies. The investigators note that in other HER2 cancers, such as breast and gastrointestinal, trastuzumab in combination with chemotherapy has been found most effective, and could warrant more study. Currently a clinical trial (NCT01367002) is evaluating carboplatin/paclitaxel with or without trastuzumab in uterine serous cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1352 AN5048-7 ERBB2 Amplification ERBB2 NCBI:2064 gene endometrial cancer DOID:1380 risk 42783-1 CIViC:302 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1352 AN5048-8 ERBB2 Amplification ERBB2 NCBI:2064 gene endometrial serous adenocarcinoma DOID:5750 prognostic;risk 42783-1 PubMed:15746676 In a study of 27 African American and caucasian patients, endometrial adenocarcinoma samples were assessed for HER2 via IHC staining, and association studies were performed using corresponding patient information. Earlier deaths were seen with heavier HER2 expression. Multivariate Cox regression indicated that shorter survival was associated with higher HER2 expression, and not with age or ethnicity, and that observed differences in survival rates between ethnicities can be ascribed to higher rates of HER2 overexpression in African American patients. The authors conclude that high HER2 expression in USPC is associated with poor outcome and explains observed differences in outcome between ethnicities. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1353 AN5048-8 ERBB2 Amplification ERBB2 NCBI:2064 gene endometrial serous adenocarcinoma DOID:5750 prognostic;risk 42783-1 PubMed:18555254 HER2 expression in uterine serous papillary carcinoma (USPC) is thought to be associated with poor prognosis and may act as a targetable driver mutation in this cancer. HER2 overexpression in USPC is more common in African American women. This report covered 2 African American patients, the first of which presented high-grade endometrial adenocarcinoma with IHC3+ HER2-positivity as well as positivity by FISH. Prior treatment involved surgery and chemotherapy. Treatment with pacitaxel/carboplatin with trastuzumab showed clear clinical improvement assessed by CT scan and drop in CA-125 levels from 988 to 7.9 U/mL. The second patient had USPC, and was treated with surgery and radiation. Trastuzumab monotheraby was then administered. After 7 months of treatment, the patient showed no sign of disease progression and CA-125 had dropped from 144 to 41 U/mL. The investigators conclude there is promise in trastuzumab-based therapies in advanced endometrial cancers, including USPC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1353 AN5048-8 ERBB2 Amplification ERBB2 NCBI:2064 gene endometrial serous adenocarcinoma DOID:5750 prognostic;risk 42783-1 CIViC:302 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1353 AN5048-9 ERBB2 Amplification ERBB2 NCBI:2064 gene gastric adenocarcinoma DOID:3717 risk 42783-1 PubMed:20728210 ToGA, a Phase III study (NCT01041404) addressed use of trastuzumab in HER2 positive advanced gastric cancer, where chemotherapy using fluoropyrimidine-based and platinum-based combinations had been common practice. Patients were given a chemotherapy regime containing capecitabine, flourouracil and cisplatin with (n=298) or without (n=296) trastuzumab, and had not been previously treated for metastatic cancer. Study endpoint was overall survival, which was significantly different in the two populations (13.8 months with chemotherapy + trastuzumab and 11.1 months for chemotherapy alone). The authors conclude that trastuzumab should be a standard option for HER2 positive advanced gastric cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1354 AN5048-9 ERBB2 Amplification ERBB2 NCBI:2064 gene gastric adenocarcinoma DOID:3717 risk 42783-1 PubMed:24868024 TyTAN, a Phase III study in Asian patients, looked at addition of tyrosine kinase inhibitor lapatinib to chemptherapy in advanced HER2 positive gastric cancer. Primary endpoint was Overall Survival (OS). Participants had progressed under previous treatment and only a small percentage had seen first line trastuzumab. Patients were a mix of those having undergone gastrectomy and not. OS was not significantly different in the ITT population, but certain subpopulations showed significant differences. In the subset of patients showing a stronger immunohistochemistry result for HER2 (IHC3+), progression free survival was significantly different at 5.6 months for lapatinib + pacitaxel vs. 4.2 months for pacitaxel alone. The authors conclude that proof of concept for lapatanib addition to chemotherapy for certain subgroups is provided in this study. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1354 AN5048-9 ERBB2 Amplification ERBB2 NCBI:2064 gene gastric adenocarcinoma DOID:3717 risk 42783-1 CIViC:302 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1354 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:11248153 A randomized clinical trial of 469 patients with previously untreated, HER2-positive, metastatic breast cancer demonstrated improved time to disease progression, objective response rate, and duration of response for patients who received trastuzumab in addition to chemotherapy compared to chemotherapy alone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:15911866 A randomized clinical trial of 186 patients with previously untreated, HER2-positive, metastatic breast cancer demonstrated improved overall survival, response rate, response duration, time to progression, and time to treatment failure for patients who received trastuzumab in addition to chemotherapy (docetaxel) compared to chemotherapy alone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:20142587 Oral neratinib showed objective response rates of 24 and 56% respectively in prior-trastuzumab (n=63) and trastuzumab-naive (n=64) cohorts in a Phase II trial. As for the primary endpoint, the 16-week progression free survival was 59% in the prior-trastuzumab + neratibin patients and 78% in the trastuzumab-naive + neratinib patients. Overall, neratinib treatment results in substantial clinical activity and is well tolerated by patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:25537159 In this phase 2 trial, treatment-naive, ERBB2-positive (by IHC) breast cancer patients with stage IIIA, B, C or inflammatory disease were randomized 1:1:1 to afatinib (n = 10), lapatinib (n = 8), or trastuzumab (n = 11). The primary end point was objective response rate. Objective response was seen in 8 afatinib-, 6 lapatinib-, and 4 trastuzumab-treated patients. Afatinib demonstrated clinical activity that compared favorably to trastuzumab and lapatinib for neoadjuvant treatment of HER2-positive breast cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:22418700 A phase II study involving adult female patients, >=18 years, with stage IIIB or IV HER2-positive (by IHC and/or in situ fluorescence) metastatic breast cancer. All patients were previously treated with trastuzumab and a median of three chemotherapy lines. 41 patients received 50 mg afatinib once-daily until disease progression and the primary endpoint was objective response rate. 4 patients (10% of 41 treated; 11% of evaluable patients) had partial response and 15 patients (37% of 41) had stable disease as best response. Thus a total of 19 (46% of 41) achieved clinical benefit. Median progression-free survival was 15.1 weeks. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:22493419 In light of results showing increased PFS using mAB plus TKI in heavily pretreated patients, the efficacy of trastuzumab plus lapatinib in a neoadjuvant setting with untreated stage II or IIIA HER2 positive breast cancer was assessed. In this randomized 3 arm phase II study (CHER-LOB), patients received (A) chemotherapy plus trastuzumab, (B) chemotherapy plus lapatinib, or (C) chemotherapy plus trastuzumab and lapatinib, with pathologic complete response (pCR) as endpoint. From 121 patients, pCR rates were 25% in arm A, 26.3% in arm B, and 46.7% in arm C. The authors conclude these results support the superiority of dual-HER2 inhibition in the neoadjuvant context of HER2 positive BC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:26255196 This Phase III trial compared the activity of lapatinib vs. trastuzumab vs. sequential trastuzumab followed by lapatinib vs. lapatinib plus trastuzumab in an adjuvant treatment setting. 8381 women were randomized to one of four treatment arms. Patients had HER2 positive non-metastatic operable BC. The primary endpoint was disease free survival. First results report that after median 4.5 year follow up, a non significant 16% improvement in DFS was seen in trastuzumab + lapatinib vs. trastuzumab alone. The results are interpreted as showing no added benefit for labatinib addition to trastuzumab in the adjuvant treatment context. This trial is ongoing but not recruiting patients (NCT00490139). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:20124187 This Phase III study (EGF104900) was motivated by preclinical and other data demonstrating synergistic activity between lapatinib and trastuzumab against HER2 positive breast cancer (BC) cells. In this study of HER2 positive metastatic BC which had progressed on trastuzumab, two arms were compared: lapatinib vs. lapatinib + trastuzumab. Progression free survival (PFS) was the primary endpoint. For 296 patients, 148 in each arm, median PFS of 8.1 weeks for lapatinib and 12.0 for combination therapy was observed (P=0.008). The authors conclude that in the context of metastatic trastuzumab-progressed HER2 positive BC, trastuzumab with lapatinib TKI addition is a favorable treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:26596672 This Phase II trial (LUX-Breast 3 - NCT01441596) compared afatinib, afatinib plus vinorelbine, or investigator's choice of treatment. 121 patients with HER2 overexpressing breast cancer with CNS recurrence or regression who had previously progressed on trastuzumab or lapatinib were assigned to 3 arms, with endpoint in the intention-to-treat population being patient benefit at 12 weeks defined as absence of CNS or extra CNS progression, no tumor related worsening of neurological symptoms and no increase in corticosteroid dose. Benefit was seen in 30% of 40 patients assigned to afatinib alone, 34.2% of 38 assigned to afatinib plus vinorelbine, and 41.9% of 43 assigned to investigator's treatment choice. Differences were not statistically significant, and afatanib patients experienced more adverse effects. While Afatanib did show response in HER2 breast cancer patients, it was not better than investigator's treatment choice and the investigators state that no further development of afatinib for HER2 breast cancer will be planned. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:26822398 LUX-Breast 1 is a phase 3 trial (NCT01125566) which enrolled 508 patients with metastatic HER2 positive BC who had progressed after adjuvant or first-line trastuzumab. It was thought that the wider range of ErbB family blocking and irreversible properties of afatinib could be beneficial in trastuzumab resistant cancer cells, since ErbB family members are thought to play a role in trastuzumab resistance. Primary endpoint was intention-to-treat group PFS. 339 patients were assigned to afatanib + vinorelbine and 169 to trastuzumab + vinorelbine. Recruitment was stopped prematurely when it was deemed unlikely that the increased PFS would be seen in the afatinib group. Median PFS was 5.5 months in the afatinib group and 5.6 months in the trastuzumab group. Afatanib plus vinorelbine was less well tolerated than trastuzumab plus vinorelbine, and the authors conclude that trastuzumab remains the best choice for treatment of trastuzumab-progressed HER2 positive metastatic BC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:25370464 Trastuzumab resistance is thought to consist of multiple compensatory mechanisms involving ErbB family members such as increased signaling through ErbB family heterodimers. The irreversible TKI afatinib blocks EGFR, HER2, ErbB3 and ErbB4. Thus afatinib was studied in this Phase I trial of trastuzumab-progressed HER2 positive metastatic BC (MBC) in combination with continued trastuzumab treatment, where trastuzumab is still the perferred treatment for trastuzumab-progressed MBC. Objective response and disease control rates were 11% and 39%. The authors conclude that the clinical activity observed in this trial warrants further work with afatinib and trastuzumab combination therapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:25693012 CLEOPATRA (NCT00567190) was a Phase III, randomized and double-blind, placebo-controlled study of 808 patients with HER2-positive metastatic breast cancer. Patients were HER2-positive by IHC3+ or FISH, and patients who had received prior hormonal treatment or adjuvant/neo-adjuvant therapy with or without trastuzumab for longer than 12 months before randomization were also eligible. The two arms of the study were trastuzumab and docetaxel with either placebo or pertuzumab. Median PFS in the placebo arm was 12.4 months while in the petuzumab arm 18.5 months was achieved. Median OS in the control arm was 40.8 months and 56.5 months with pertuzumab. These strong results make a case for dual antibody blockade in first line treatments of HER2-positive metastatic breast cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:26874901 In this two arm, Phase III study (NCT00878709) of the efficacy of a 12 month course of the TKI neratinib after trastuzumab-based adjuvant therapy of early stage HER2-positive breast cancer was assessed using invasive disease-free survival as primary endpoint. HER2 positivity was assessed via FISH. At 2 year follow-up, 70 vs. 109 disease-free survival events had occurred and disease-free survival rates were 93.9% vs. 91.6% (significant) in neratinib vs. placebo groups respectively. Distant disease-free survival and time to distant recurrence were similar in both groups. These results are an interesting contrast to results of long-term adjuvant therapy with trastuzumab (HERA) which did not show significant benefit. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:16236737 HERA was a Phase III trial assessing application of trastuzumab in an extended adjuvant setting. Patients were HER2 positive with completely excised invasive BC, node positive or negative, and having undergone prior adjuvant or neo-adjuvant chemotherapy. In the 3 arm study patients were given trastuzumab courses of 1 year, 2 years, or untreated. At the first planned interim analysis, trastuzumab treatment for one year was compared with observation alone. A significant difference in disease-free survival was seen with 220 DFS events out of 1693 in the observation arm versus 127 DFS events out of 1694 in the 1 year trastuzumab arm. 1 year adjuvant trastuzumab is currently the standard of care. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:17192538 This Phase III trial took patients with locally advanced or metastatic HER2 (ERBB2) positive breast cancer that had progressed on prior trastuzumab treatment. Patients were given capecitabine (n=161) or lapatinib plus capecitabine (n=163). The primary endpoint of the study was time to progression. Median time to progression was 4.4 months in the capecitabine group and 8.4 months in capecitabine plus lapatinib group (hazard ratio was 0.49 ; 95% confidence interval, 0.34 to 0.71; P<0.001). The results indicated that lapatinib may be useful in addressing the problem of trastuzumab progression in HER2 breast cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:19289619 In this Phase III trial, trastuzumab-based treatment was assessed in women with locally advanced or metastatic HER2 positive breast cancer who had progressed on trastuzumab. Patients had 12 weeks or greater previous trastuzumab treatment with time since end of last cycle less than 6 weeks. Primary endpoint was time to progression. 78 patients were assigned to each group, with median time to progression of 5.6 months in capecitabine group and 8.2 months in trastuzumab plus capecitabine group. The results are in contrast to the principle of change of treatment on disease progression, and authors suggest that chemotherapy-sensitizing mechanisms of trastuzumab remain intact in HER2 breast cancer cells with trastuzumab progression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:24793816 The Phase III trial, TH3RESA (NCT01419197), was performed in patients with advanced HER2 breast cancer that was heavily pretreated. Patients were required to have prior exposure to trastuzumab and lapatinib as well as a taxane. This patient population has not seen many studies, responds poorly to late-line treatment with trastuzumab, and in this study was treated with trastuzumab emtansine (T-DM1, n=404) vs. physician's choice (usually trastuzumab plus chemotherapy, n=198). Results showed progression free survival was 6.2 months in T-DM1 treatment vs. 3.3 months under physician's choice, along with lower incidence of grade 3 or worse events with T-DM1. The authors conclude that their findings in this heavily pretreated population, along with findings in the EMILIA trial, indicate promise for antibody-drug conjugates. The NCI-MATCH trial with further study T-DM1 in the context of HER2 amplification. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:23020162 The EMILIA study (NCT00829166) was a Phase II trial to assess the efficacy of trastuzumab emtansine (T-DM1, n=495) in comparison to lapatinib plus capecitabine (n=496), in treatment of advanced HER2 positive breast cancer. Patients were required to have progressed on or after treatments involving trastuzumab and a taxane, and no prior exposure to lapatinib or T-DM1. Primary endpoints included independently assessed progression free survival (PFS) and safety. PFS was 9.6 months in T-DM1 group vs. 6.4 months in lapatinib plus capecitabine. Rates of adverse events of grade 3 or higher were greater with lapatinib plus capecitabine. These results, together with other trials such as TH3RESA indicate promise for T-DM1 therapy in HER2 amplification, and this will be further studied in an arm of the NCI-MATCH trial. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:22802530 The HER2/Neu mammary tumor mouse model MMTV-NeuT was employed to demonstrate dependence of HER2 tumor formation on PIK3 p110alpha isoform. MMTV-NeuT mice were crossed with floxed p110alpha mice. Diassacociated tumors cells from these mice were treated with Cre adenovirus to delete p110alpha, or GFP adenovirus, and cells were transplanted into athymic mice. GFP treated cells formed new tumors, while p110alpha deletion blocked tumor formation indicating tumor dependence on PI3KA. Next, MMTV-NeuT tumors were dissociated and treated with pan-PI3K inhibitor GDC-0941. Reduced lipid kinase activity and reduced phospho-Akt levels were seen in these cells. Administration of 125 mg/kg GDC-0941 to athymic mice with transplantation of tumor cells caused marked reduction of tumor cell volume in comparison to control treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:23382472 In a randomized phase II study, first line treatment of HER2-positive metastatic breast cancer with trastuzumab emtansine (T-DM1) resulted in improved progression free survival and fewer serious adverse effects when compared to treatment with combination trastuzumab plus docetaxel (HT) (median follow up 14 months, median PFS with T-DM1 14.2 vs 9.2 with HT). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:22149875 In a randomized phase 3 trial, HER2 positive metastatic breast cancer patients given first-line treatment of pertuzumab plus trastuzumb plus docetaxel experienced improved progression free survival (18.5 vs 12.4 months, P<0.001) and increased objective response rate (80.2% vs 69.3%, P=0.001) than the control group given placebo plus trastuzumab plus docetaxel. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:22257673 In a randomized open label phase 3 study (NCT00553358), women with HER2 positive primary breast cancer treated with lapatinib plus trasuzumab had higher rates of pathological complete responses than seen in control groups receiving either IV trastuzumab or oral lapatinib alone (combination treatment pCR rate of 51% vs 29.5% and 24.7% for trastuzumab and lapatinib alone, respectively). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:23204226 In 5 trastuzumab resistant HER2 overexpressing breast cancer cell lines, combination of the pan-PI3K inhibitor XL147 (pilaralisib) and trastuzumab treatment induced cell death to similar or greater levels than XL147 alone. In three trastuzumab resistant cell lines tested, colony formation in matrigel was markedly inhibited by combination treatment. Apoptotic markers were apparent with combination treatment. In athymic mice, trastuzumab resistant cell line HR6 was used in tumor xenografts and tumors were allowed to form. Mice subsequently treated with trastuzumab or XL147 showed continued tumor growth without marked difference from control, while combination treatment essentially halted tumor growth rate. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:19874578 In a panel of 47 breast cancer cell lines, HER2 overexpressing cells were among those more sensitive to CDK4/6 inhibitor Palbociclib (PD0332991). In the trastuzumab sensitive cell line Bt474, palbociclib synergized with trastuzumab in growth inhibition, while in 2 trastuzumab resistant cell lines, addition of trastuzumab to palbociclib treatment resulted in increased growth inhibition over palbociclib alone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:21172893 In the single arm Phase II study (TDM4258g) breast cancer patients who had progressed on previous anti-HER2 therapy were given transtuzumab emtansine (T-DM1), a HER2 monoclonal antibody and antimicrotubule drug conjugate. 95 trial participants with archival primary tumor were reassessed for HER2 status (positivity defined by FISH or IHC 3+), and 74 patients were confirmed for HER2 positivity and 21 were normal. Overall response rate was 33.8% (95% CI, 23.2% to 44.9%) in patients with confirmed HER2-positive tumors and 4.8% (95% CI, 1.0% to 21.8%) in HER2 normal patients. Median PFS was 8.2 months (95% CI, 4.4 months to not estimable) in patients with confirmed HER2-positive tumors and 2.6 months (95% CI, 1.4 to 3.9 months) in HER2 normal patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-10 ERBB2 Amplification ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 CIViC:302 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1355 AN5048-11 ERBB2 Amplification ERBB2 NCBI:2064 gene lung adenocarcinoma DOID:3910 risk 42783-1 PubMed:23470965 155 patients with lung adenocarcinomas underwent rebiopsy and genotyping (EGFR, AKT1, BRAF, ERBB2, KRAS, MEK1, NRAS, PIK3CA and FISH for MET and HER2) after the development of acquired resistance to EGFR inhibitors (gefitinib or erlotinib). 2 of 24 patients tested were found to have HER2 amplification (but no baseline samples available for analysis). One patient of which had a metastasis sample which was reported to have only HER2 amplification whereas another autopsy specimen from the same patient was HER2 negative but EGFR T790M positive. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1356 AN5048-11 ERBB2 Amplification ERBB2 NCBI:2064 gene lung adenocarcinoma DOID:3910 risk 42783-1 CIViC:302 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1356 AN5048-12 ERBB2 Amplification ERBB2 NCBI:2064 gene lung non-small cell carcinoma DOID:3908 risk 42783-1 PubMed:14679114 In this phase II trial with 2 arms, 103 patients with untreated stage IIIB/IV HER2 positive NSCLC were given gemcitabine-cisplatin with or without trastuzumab. HER2 positivity was broadly defined as IHC2+/3+, positive by FISH, or increased circulating HER2 extracellular domain. Significant differences between the treatment arms were not observed, but in a small subset of IHC3+/FISH positive patients, 5 of 6 responded to trastuzumab and had increased PFS of 8.5 months in comparison to 6.1 months in the IHC2+ group. Although from 2004, this study remains cited in 2016 literature when discussing the unclear efficacy of trastuzumab in wild-type HER2 overexpressing NSCLC. The authors conclude that future studies of trastuzumab in HER2 positive NSCLC should focus on high expressing subjects. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1357 AN5048-12 ERBB2 Amplification ERBB2 NCBI:2064 gene lung non-small cell carcinoma DOID:3908 risk 42783-1 PubMed:14967075 In this phase II trial a small group of patients with IHC2+ or IHC3+ HER2 NSCLC, in which primary platinum-based therapy had failed, were given either docetaxel or trastuzumab after which both groups were given docetaxel and trastuzumab together. there was one partial response in the docetaxel group and none in the trastuzumab group. The authors report that due to the limited clinical activity of trastuzumab-based therapy in this cohort, as well as similar results in other trastuzumab studies, that targets other than HER2 in NSCLC should be considered for future study. This 2004 study remains cited in 2016 literature in discussing the unclear efficacy of trastuzumab in wild-type HER2 overexpressing NSCLC, but mutant HER2 in NSCLC has been further studied and a picture of different HER2 mutations being potentially responsive to specific targeted therapies is emerging. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1357 AN5048-12 ERBB2 Amplification ERBB2 NCBI:2064 gene lung non-small cell carcinoma DOID:3908 risk 42783-1 PubMed:24898067 Efficacy of trastuzumab in HER2 overexpressing NSCLC remains unclear. In this study using a panel of NSCLC HER2 overexpressing cell lines, antiproliferative effects of trastuzumab emtansine (T-DM1) were observed in a HER2-expression dependant manner, with strongest effects in Calu-3 (high expressing) and no effects in Calu-6 (low expressing). Trastuzumab did not show notable effects on cell growth in any tested cells. HER2 positivity in NSCLC is fairly common at 2-20%. A clinical trial (NCT02289833) is currently underway to asses TDM-1 in HER2 overexpressing lung cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1357 AN5048-12 ERBB2 Amplification ERBB2 NCBI:2064 gene lung non-small cell carcinoma DOID:3908 risk 42783-1 PubMed:25899785 Phase 2 trial of ERBB-inhibitor dacomitinib in stage IIIB/IV lung cancers with HER2 mutations or amplification. 4 patients with HER2 amplified NSCLC were enrolled in the trial, no one among them had a response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1357 AN5048-12 ERBB2 Amplification ERBB2 NCBI:2064 gene lung non-small cell carcinoma DOID:3908 risk 42783-1 CIViC:302 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1357 AN5048-13 ERBB2 Amplification ERBB2 NCBI:2064 gene lung small cell carcinoma DOID:5409 risk 42783-1 PubMed:25601188 This report details 2 case studies in relapsed HER2 positive SCLC. In the first case, a 50 pack-year patient showed intense non-mutant HER2 expression by IHC without DNA amplification, and had undergone multiple prior lines of treatment. With induction of trastuzumab and irinotecan treatment, tumor regression was observed with progression free survival of 4.5 months. Case 2 involved a 68 year old never-smoker with relapsed SCLC. Tumor showed HER2 positive SCLC cells with no amplification or mutation. Third line trastuzumab plus irinotecan brought about some symptom improvement and PFS of 3.5 months. While the efficacy of trastuzumab against NSCLC with elevated levels of wild-type HER2 expression remains unclear, the authors conclude that trastuzumab based therapy is a promising strategy for chemo-resistant SCLC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1358 AN5048-13 ERBB2 Amplification ERBB2 NCBI:2064 gene lung small cell carcinoma DOID:5409 risk 42783-1 CIViC:302 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1358 AN5048-14 ERBB2 Amplification ERBB2 NCBI:2064 gene pancreatic adenocarcinoma DOID:4074 risk 42783-1 PubMed:26668065 Afatinib was growth-inhibitory for three pancreatic cancer cell lines but cytotoxic only toward BxPC3 (KRAS wt) and Capan-2 (KRAS mut) cells, both of which express high levels of EGFR, ERBB2, and ERBB3 receptors. Afatinib increased the radiosensitivity of BxPC3 and Capan-2 cells. In comparison, Panc-1 cells (KRAS mut) expressing low levels of EGFR family receptors were resistant to afatinib-induced radiosensitization. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1359 AN5048-14 ERBB2 Amplification ERBB2 NCBI:2064 gene pancreatic adenocarcinoma DOID:4074 risk 42783-1 CIViC:302 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1359 AN5048-15 ERBB2 Amplification ERBB2 NCBI:2064 gene pancreatic cancer DOID:1793 risk 42783-1 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Two of nine patients (22%) with HER2 amplified/overexpressing pancreatic cancer had a PR with trastuzumab/pertuzumab combination. Another patient had SD > 120days. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1360 AN5048-15 ERBB2 Amplification ERBB2 NCBI:2064 gene pancreatic cancer DOID:1793 risk 42783-1 CIViC:302 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1360 AN5048-16 ERBB2 Amplification ERBB2 NCBI:2064 gene salivary gland carcinoma DOID:0050904 risk 42783-1 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Four of five patients with HER2 amplified/overexpressing salivary gland carcinoma (80%; 95% CI, 28% to > 99%) had responses (all PR). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1361 AN5048-16 ERBB2 Amplification ERBB2 NCBI:2064 gene salivary gland carcinoma DOID:0050904 risk 42783-1 CIViC:302 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1361 AN5048-17 ERBB2 Amplification ERBB2 NCBI:2064 gene scrotum Paget's disease DOID:3444 risk 42783-1 PubMed:25692060 A 71-year old male with metastatic extramammary Paget’s disease of the scrotum overexpressing Her2/neu was treated with trastuzumab, achieving a complete response. At 12 months, he maintains stable disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1362 AN5048-17 ERBB2 Amplification ERBB2 NCBI:2064 gene scrotum Paget's disease DOID:3444 risk 42783-1 CIViC:302 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1362 AN5048-18 ERBB2 Amplification ERBB2 NCBI:2064 gene stomach cancer DOID:10534 risk 42783-1 PubMed:31047804 In a phase 1 trial, 44 patients with HER2-positive gastric or gastroesophageal junction cancer previously treated with trastuzumab were treated with Trastuzumab Deruxtecan (DS-8201a). The response rate was 43.2% (19/44). All patients had at least one treatment-emergent adverse event (AE). A serious AE was recorded in 11 patients but without a drug-related death. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1363 AN5048-18 ERBB2 Amplification ERBB2 NCBI:2064 gene stomach cancer DOID:10534 risk 42783-1 CIViC:302 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1363 AN5048-19 ERBB2 Amplification ERBB2 NCBI:2064 gene uterine cancer DOID:363 risk 42783-1 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. None of the 7 patients with HER2 amplified/overexpressing uterus cancer responded to pertuzumab/trastuzumab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1364 AN5048-19 ERBB2 Amplification ERBB2 NCBI:2064 gene uterine cancer DOID:363 risk 42783-1 CIViC:302 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1364 AN5048-20 ERBB2 Amplification ERBB2 NCBI:2064 gene uterine corpus endometrial carcinoma DOID:0050939 risk 42783-1 PubMed:25268372 Eight uterine cancer cell lines (four with ERBB2 amplification and four without) were treated with scalar concentrations of afatinib. Primary chemotherapy-resistant USC cell lines harbouring ERBB2 gene amplification were sensitive to afatinib exposure and significantly more sensitive than non-amplified cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1365 AN5048-20 ERBB2 Amplification ERBB2 NCBI:2064 gene uterine corpus endometrial carcinoma DOID:0050939 risk 42783-1 CIViC:302 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene ERBB2/NCBI:2064 1365 AN5049-1 ERBB2 D769H mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 PubMed:23220880 In MCF10A cell lines, the D769H mutation was shown to be sensitive to neratinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D769H sequence variation in gene ERBB2/NCBI:2064 1366 check_entity AN5049-1 ERBB2 D769H mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 CIViC:35 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D769H sequence variation in gene ERBB2/NCBI:2064 1366 check_entity AN5050-1 ERBB2 D769Y mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 PubMed:23220880 In MCF10A cell lines, the D769Y mutation was shown to be sensitive to neratinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D769Y sequence variation in gene ERBB2/NCBI:2064 1367 check_entity AN5050-1 ERBB2 D769Y mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 CIViC:36 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D769Y sequence variation in gene ERBB2/NCBI:2064 1367 check_entity AN5050-2 ERBB2 D769Y mutation ERBB2 NCBI:2064 gene mammary Paget's disease DOID:3443 risk 42783-1 PubMed:35939768 In this phase II NCI-MATCH trial, a patient with extra-mammary Paget disease of the skin with ERBB2 D769Y mutation was treated with afatinib. A confirmed RECIST response was reported in the patient who progressed after cycle 6. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D769Y sequence variation in gene ERBB2/NCBI:2064 1368 check_entity AN5050-2 ERBB2 D769Y mutation ERBB2 NCBI:2064 gene mammary Paget's disease DOID:3443 risk 42783-1 CIViC:36 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D769Y sequence variation in gene ERBB2/NCBI:2064 1368 check_entity AN5050-3 ERBB2 D769Y mutation ERBB2 NCBI:2064 gene peritoneal carcinoma DOID:1791 risk 42783-1 PubMed:35939768 In this phase II NCI-MATCH trial, a patient with primary peritoneal carcinoma with ERBB2 D769Y mutation was treated with afatinib. A RECIST response was reported in the patient, however, it wasn't confirmed on follow-up radiological assessment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D769Y sequence variation in gene ERBB2/NCBI:2064 1369 check_entity AN5050-3 ERBB2 D769Y mutation ERBB2 NCBI:2064 gene peritoneal carcinoma DOID:1791 risk 42783-1 CIViC:36 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D769Y sequence variation in gene ERBB2/NCBI:2064 1369 check_entity AN5051-1 ERBB2 Exon 20 Insertion ERBB2 NCBI:2064 gene lung non-small cell carcinoma DOID:3908 risk 42783-1 PubMed:34534430 In a phase 2 trial, 91 patients with ERBB2-mutant metastatic non-small-cell lung cancer, refractory to standard treatment, were treated with trastuzumab deruxtecan. The objective response was 55% (95% CI, 44 to 65), the median duration of response was 9.3 months (95% CI 5.7 to 14.7), the median PFS was 8.2 months (95% CI 6.0 to 11.9), and the median OS was 17.8 months (95% CI 13.8 to 22.1). 81 of 91 patients had an Exon 20 Insertion mutation and 46 of 78 evaluable patients with this mutation type had a partial response (PR). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:20:insertion sequence variation in gene ERBB2/NCBI:2064 1370 check_entity AN5051-1 ERBB2 Exon 20 Insertion ERBB2 NCBI:2064 gene lung non-small cell carcinoma DOID:3908 risk 42783-1 CIViC:2723 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:20:insertion sequence variation in gene ERBB2/NCBI:2064 1370 check_entity AN5052-1 ERBB2 G309A mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 PubMed:23220880 In MCF10A cell lines, the G309A mutation was shown to be sensitive to neratinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G309A sequence variation in gene ERBB2/NCBI:2064 1371 check_entity AN5052-1 ERBB2 G309A mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 CIViC:38 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G309A sequence variation in gene ERBB2/NCBI:2064 1371 check_entity AN5053-1 ERBB2 G776L mutation ERBB2 NCBI:2064 gene lung adenocarcinoma DOID:3910 risk 42783-1 PubMed:22325357 A Phase II study for use of Afatinib in non- or light smokers with lung adenocarcinoma. Three patients with metastatic lung adenocarcinomas bearing mutations in the kinase domain of HER2 gene were identified (Y772_A775dup, G776L, and G778_P780dup). Objective response was observed in all three of these patients. The patient with G776L (Case 2 in the paper) achieved a partial response after two months of afatinib (50 mg/day). The time to progression of this single agent was four months. The patient was also noted to have a EGFR kinase domain (exon 21: p.Ala859Thr) mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G776L sequence variation in gene ERBB2/NCBI:2064 1372 check_entity AN5053-1 ERBB2 G776L mutation ERBB2 NCBI:2064 gene lung adenocarcinoma DOID:3910 risk 42783-1 CIViC:794 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G776L sequence variation in gene ERBB2/NCBI:2064 1372 check_entity AN5054-1 ERBB2 G778_P780DUP mutation ERBB2 NCBI:2064 gene lung adenocarcinoma DOID:3910 risk 42783-1 PubMed:22325357 A Phase II study for use of Afatinib in non- or light smokers with lung adenocarcinoma. Three patients with metastatic lung adenocarcinomas bearing mutations in the kinase domain of HER2 gene were identified (Y772_A775dup, G776L, and G778_P780dup). Objective response was observed in all three of these patients. The patient with G778_P780dup (Case 3 in the paper), had a rapid clinical and symptomatic response to Afatinib and stable disease which lasted for 3 months. Progressive disease at 4 months led to the addition of paclitaxel, resulting in partial response. Total Afatinib treatment was 15 months (11 in combination) at which time the patient developed a brain metastasis but no other progressive disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::g778_p780dup:mutation sequence variation in gene ERBB2/NCBI:2064 1373 check_entity AN5054-1 ERBB2 G778_P780DUP mutation ERBB2 NCBI:2064 gene lung adenocarcinoma DOID:3910 risk 42783-1 CIViC:795 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::g778_p780dup:mutation sequence variation in gene ERBB2/NCBI:2064 1373 check_entity AN5054-2 ERBB2 G778_P780DUP mutation ERBB2 NCBI:2064 gene lung non-small cell carcinoma DOID:3908 risk 42783-1 PubMed:25899785 Phase 2 trial of ERBB-inhibitor dacomitinib in stage IIIB/IV lung cancers with HER2 mutations or amplification. Two patients were identified with identical HER2 p.G778_P780dup mutations (p. P780_Y781insGSP, c. 2339_2340ins GGCTCCCCA) and no amplification. Both had a confirmed partial response lasting 11 and 14 months. Only 3/30 patients on this trial had a partial response (no complete responses). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::g778_p780dup:mutation sequence variation in gene ERBB2/NCBI:2064 1374 check_entity AN5054-2 ERBB2 G778_P780DUP mutation ERBB2 NCBI:2064 gene lung non-small cell carcinoma DOID:3908 risk 42783-1 CIViC:795 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::g778_p780dup:mutation sequence variation in gene ERBB2/NCBI:2064 1374 check_entity AN5055-1 ERBB2 H878Y mutation ERBB2 NCBI:2064 gene cancer DOID:162 risk 42783-1 PubMed:22046346 Cell proliferation analysis of ERBB2 mutant expressing cell lines showed that the ERBB2-H878Y mutant, which is observed in 11% of hepatocellular carcinoma patients, had the highest sensitivity against lapatinib. The IC50 for H878Y mutant cells was 14nM, compared to 30nM for wild-type ERBB2 expressing cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H878Y sequence variation in gene ERBB2/NCBI:2064 1375 check_entity AN5055-1 ERBB2 H878Y mutation ERBB2 NCBI:2064 gene cancer DOID:162 risk 42783-1 CIViC:848 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H878Y sequence variation in gene ERBB2/NCBI:2064 1375 check_entity AN5056-1 ERBB2 Kinase Domain Mutation ERBB2 NCBI:2064 gene lung adenocarcinoma DOID:3910 risk 42783-1 PubMed:22325357 A Phase II study for use of Afatinib in non- or light smokers with lung adenocarcinoma. Three patients with metastatic lung adenocarcinomas bearing mutations in the kinase domain of HER2 gene were identified (Y772_A775dup, G776L, and G778_P780dup). Objective response was observed in all three of these patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::kinase:domain:mutation sequence variation in gene ERBB2/NCBI:2064 1376 check_entity AN5056-1 ERBB2 Kinase Domain Mutation ERBB2 NCBI:2064 gene lung adenocarcinoma DOID:3910 risk 42783-1 PubMed:26598547 This was a retrospective study of patients with advanced HER2-mutant NSCLC who had undergone varied courses of treatment. All tumors were adenocarcinoma with in-frame HER2 exon 20 insertions. In patients (n=57) that had been treated with trastuzumab plus chemotherapy, an overall response rate of 75% and progression free survival of 5.1 months were observed. No standard of care currently exists for HER2-mutant NSCLC. While trastuzumab has not shown clear benefit yet in wild-type HER2 overexpressed NSCLC, the authors conclude that further prospective studies should be done with trastuzumab plus chemotherapy in advanced HER2 mutant NSCLC, and that trastuzumab plus chemotherapy should be considered in current treatment courses of this cancer type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::kinase:domain:mutation sequence variation in gene ERBB2/NCBI:2064 1376 check_entity AN5056-1 ERBB2 Kinase Domain Mutation ERBB2 NCBI:2064 gene lung adenocarcinoma DOID:3910 risk 42783-1 CIViC:409 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::kinase:domain:mutation sequence variation in gene ERBB2/NCBI:2064 1376 check_entity AN5057-1 ERBB2 L755P mutation ERBB2 NCBI:2064 gene cancer DOID:162 risk 42783-1 PubMed:22046346 Cell proliferation analysis of Ba/F3 cells expressing ERBB2-L755P showed IC50 value of 1545nM, and was considered as lapatinib-resistant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L755P sequence variation in gene ERBB2/NCBI:2064 1377 check_entity AN5057-1 ERBB2 L755P mutation ERBB2 NCBI:2064 gene cancer DOID:162 risk 42783-1 CIViC:1278 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L755P sequence variation in gene ERBB2/NCBI:2064 1377 check_entity AN5058-1 ERBB2 L755S mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 PubMed:23220880 The L755S mutation was shown to confer resistance to lapatinib in MCF10A cell lines retrovirally transduced with wildtype or mutant ERBB2. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L755S sequence variation in gene ERBB2/NCBI:2064 1378 check_entity AN5058-1 ERBB2 L755S mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 CIViC:39 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L755S sequence variation in gene ERBB2/NCBI:2064 1378 check_entity AN5058-2 ERBB2 L755S mutation ERBB2 NCBI:2064 gene cancer DOID:162 risk 42783-1 PubMed:22046346 Cell proliferation analysis of Ba/F3 cells expressing ERBB2-L755S showed IC50 value of >2000nM, and was considered as lapatinib-resistant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L755S sequence variation in gene ERBB2/NCBI:2064 1379 check_entity AN5058-2 ERBB2 L755S mutation ERBB2 NCBI:2064 gene cancer DOID:162 risk 42783-1 CIViC:39 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L755S sequence variation in gene ERBB2/NCBI:2064 1379 check_entity AN5058-3 ERBB2 L755S mutation ERBB2 NCBI:2064 gene colon cancer DOID:219 risk 42783-1 PubMed:26243863 Colon cancer patient derived xenografts with HER2 mutations are sensitive to HER2 targeted drugs and the greatest tumor reduction was seen with the combination of a tyrosine kinase inhibitor with trastuzumab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L755S sequence variation in gene ERBB2/NCBI:2064 1380 check_entity AN5058-3 ERBB2 L755S mutation ERBB2 NCBI:2064 gene colon cancer DOID:219 risk 42783-1 CIViC:39 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L755S sequence variation in gene ERBB2/NCBI:2064 1380 check_entity AN5058-4 ERBB2 L755S mutation ERBB2 NCBI:2064 gene colorectal adenocarcinoma DOID:0050861 risk 42783-1 PubMed:27626067 Patient was a 35 year old male who was treated with pseudoadjuvant FOLFOX chemotherapy. Patient relapsed and was found to have an ERBB2 L755S kinase domain mutation along with mutations in APC and BRAF. He was then treated with trastuzumab combined with infusional 5-Fu and leucovorin but exhibited no response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L755S sequence variation in gene ERBB2/NCBI:2064 1381 check_entity AN5058-4 ERBB2 L755S mutation ERBB2 NCBI:2064 gene colorectal adenocarcinoma DOID:0050861 risk 42783-1 CIViC:39 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L755S sequence variation in gene ERBB2/NCBI:2064 1381 check_entity AN5059-1 ERBB2 L755W mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 PubMed:23220880 MCF10A cells transduced with ERBB2 harboring an L755W mutation were sensitive to the irreversible kinase inhibitor neratinib in an matrigel colony forming assay. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L755W sequence variation in gene ERBB2/NCBI:2064 1382 check_entity AN5059-1 ERBB2 L755W mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 CIViC:40 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L755W sequence variation in gene ERBB2/NCBI:2064 1382 check_entity AN5060-1 ERBB2 L755_T759del ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 PubMed:23220880 In MCF10A cell lines retrovirally transduced with wildtype or mutant ERBB2, cells expressing the in-frame deletion of amino acids 755-759 were shown to be sensitive to neratinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ERBB2 L755_T759del [biomarker_term_in_review] 1383 not_mapped AN5060-1 ERBB2 L755_T759del ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 CIViC:37 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ERBB2 L755_T759del [biomarker_term_in_review] 1383 not_mapped AN5061-1 ERBB2 L866M mutation ERBB2 NCBI:2064 gene colon cancer DOID:219 risk 42783-1 PubMed:26243863 Colon cancer patient derived xenografts with HER2 mutations are sensitive to HER2 targeted drugs and the greatest tumor reduction was seen with the combination of a tyrosine kinase inhibitor with trastuzumab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L866M sequence variation in gene ERBB2/NCBI:2064 1384 check_entity AN5061-1 ERBB2 L866M mutation ERBB2 NCBI:2064 gene colon cancer DOID:219 risk 42783-1 CIViC:492 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L866M sequence variation in gene ERBB2/NCBI:2064 1384 check_entity AN5062-1 ERBB2 M774DELINSWLV ERBB2 NCBI:2064 gene lung non-small cell carcinoma DOID:3908 risk 42783-1 PubMed:25899785 Phase 2 trial of ERBB-inhibitor dacomitinib in stage IIIB/IV lung cancers with HER2 mutations or amplification (N=30). One patient was found to harbor a unique Exon 20 indel (p. M774delinsWLV, c.2320A>TGGCT GG; p. M774delinsWLV, c.2320delins TGGCTGG) and was among the three patients that had a partial response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ERBB2 M774DELINSWLV [biomarker_term_in_review] 1385 not_mapped AN5062-1 ERBB2 M774DELINSWLV ERBB2 NCBI:2064 gene lung non-small cell carcinoma DOID:3908 risk 42783-1 CIViC:796 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ERBB2 M774DELINSWLV [biomarker_term_in_review] 1385 not_mapped AN5063-1 ERBB2 Mutation ERBB2 NCBI:2064 gene bladder carcinoma DOID:4007 risk 42783-1 PubMed:25636205 In patients with muscle-invasive bladder chancer, a cohort of complete responders to platinum chemotherapy (n=38) and non-responders to platinum chemotherapy (n=33) were evaluated for 178 cancer-associated genes. Of the complete responders, 24% had an ERBB2 missense mutations and no non-responders had ERBB2 mutations (p=0.003). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ERBB2/NCBI:2064 1386 check_entity AN5063-1 ERBB2 Mutation ERBB2 NCBI:2064 gene bladder carcinoma DOID:4007 risk 42783-1 CIViC:662 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ERBB2/NCBI:2064 1386 check_entity AN5063-2 ERBB2 Mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 PubMed:28679771 16 patients with HER2-mutated metastatic breast cancer were treated with neratinib monotherapy. Of these 16 patients, 14 had known-activating mutations and 2 had mutations of unknown significance. Five of the 16 patients achieved clinical benefit including 1 complete response (6%), 1 partial response (6%) and 3 with stable disease >24 weeks (19%). Clinical benefit was observed across different HER2 mutations including L755S, V777_G778 insGSP, P780_Y781 insGSP, V842I, S310F, and L869R. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ERBB2/NCBI:2064 1387 check_entity AN5063-2 ERBB2 Mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 CIViC:662 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ERBB2/NCBI:2064 1387 check_entity AN5063-3 ERBB2 Mutation ERBB2 NCBI:2064 gene colorectal cancer DOID:9256 risk 42783-1 PubMed:36315917 In this clinical study of 38 patients with colorectal cancer (CRC), 10 had CRC with ERBB2/ERBB3 mutation, and were treated with a combination of Pertuzumab and Trastuzumab. A DC of 10% and OR of 0% were reported. A PFS of 9.6 weeks (95% CI; 5.1 - 16.0) and OS of 28.8 weeks (95% CI; 7.6 -146.3) were noted. Overall, no antitumor activity was observed in the cohort with this combination. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ERBB2/NCBI:2064 1388 check_entity AN5063-3 ERBB2 Mutation ERBB2 NCBI:2064 gene colorectal cancer DOID:9256 risk 42783-1 CIViC:4706 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ERBB2/NCBI:2064 1388 check_entity AN5063-4 ERBB2 Mutation ERBB2 NCBI:2064 gene lung non-small cell carcinoma DOID:3908 risk 42783-1 PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Among thirty-six patients that received treatment with trastuzumab plus pertuzumab because of a HER2 mutation (without amplification/overexpression) four patients (11%; 95% CI, 3% to 26%) had objective responses. Fourteen of the 36 patients with HER2-mutated tumors had NSCLC (adenocarcinoma, n = 13; adenosquamous, n = 1); in this group, three patients (21%; 95% CI, 5% to 51%) had PR and three had SD > 120 days. Only one of the other 22 patients with HER2-mutated tumors responded to treatment with pertuzumab plus trastuzumab (biliary cancer). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ERBB2/NCBI:2064 1389 check_entity AN5063-4 ERBB2 Mutation ERBB2 NCBI:2064 gene lung non-small cell carcinoma DOID:3908 risk 42783-1 CIViC:662 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ERBB2/NCBI:2064 1389 check_entity AN5064-1 ERBB2 N857S mutation ERBB2 NCBI:2064 gene cancer DOID:162 risk 42783-1 PubMed:22046346 Cell proliferation analysis of Ba/F3 cells expressing ERBB2-N857S showed IC50 value of 75nM and IC90 of approximately 0.5 µM, and was considered as lapatinib-sensitive. Since levels of up to 1 µM of lapatinib may be achieved in patients, ERBB2-N857S might respond to higher doses of lapatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N857S sequence variation in gene ERBB2/NCBI:2064 1390 check_entity AN5064-1 ERBB2 N857S mutation ERBB2 NCBI:2064 gene cancer DOID:162 risk 42783-1 CIViC:847 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N857S sequence variation in gene ERBB2/NCBI:2064 1390 check_entity AN5065-1 ERBB2 Overexpression ERBB2 NCBI:2064 gene head and neck squamous cell carcinoma DOID:5520 risk 42783-1 PubMed:28061634 Case report of a 60-year old patient with p16 positive tumor of the tonsil with lung metastases after primary radiochemotherapy. The metastases were analyzed using a commercial molecular analysis and overexpression of HER2 was identified (IHC, 95% of cells, with high intensity 3+ staining) which was confirmed on RNA-level. The patient was treated with single-agent lapatinib. A locally recurrent tumor was excised (and found HER2-negative) and the patient continued on lapatinib (for 2 years) as well as 5 cycles 5-FU and irinotecan. All lung metastases decreased in size within 3 months of lapatinib mono therapy initiation. The patient remains free of local or distant disease 5 years after starting lapatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ERBB2/NCBI:2064 1391 AN5065-1 ERBB2 Overexpression ERBB2 NCBI:2064 gene head and neck squamous cell carcinoma DOID:5520 risk 42783-1 CIViC:849 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ERBB2/NCBI:2064 1391 AN5065-2 ERBB2 Overexpression ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 PubMed:28526536 Trastuzumab emtansine has its indication for patients with HER2-positive metastatic breast cancer after therapy with Trastuzumab and Taxane, approval based on PFS and preliminary OS data. EMILIA was a randomised open-label, phase III study for patients with HER2-positive, unresectable, locally advanced, or metastatic breast cancer previously treated with Trastuzumab and a Taxane, randomized 1:1 to Trastuzumab-emtansine or Capecitabine plus Lapatinib. 991 patients were enrolled. Median OS was 29.9m vs. 25.9m. Fewer grade 3 or worse AE occurred with trastuzumab emtansine than with capecitabine plus lapatinib control treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ERBB2/NCBI:2064 1392 AN5065-2 ERBB2 Overexpression ERBB2 NCBI:2064 gene Her2-receptor positive breast cancer DOID:0060079 risk 42783-1 CIViC:849 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ERBB2/NCBI:2064 1392 AN5065-3 ERBB2 Overexpression ERBB2 NCBI:2064 gene pancreatic cancer DOID:1793 risk 42783-1 PubMed:22374460 This is Phase II trial of Trastuzumab and capecitabine as first line treatment in patients with IHC 3+ HER2 expressing advanced pancreatic cancer or cancer with HER2 gene amplification of stage IVB. Total 207 patients could be assessed for HER2 expression. From the 23 patient with IHC 3+ HER2 expression or IHC 2+ and HER2 gene amplification, 17 patients were included in the study and could be assessed for response to the treatment. Contrary to breast and gastric cancer, only 7 out of 11 (64%) patients with IHC 3+ HER2 expression showed gene amplification. PFS rate at 12 weeks was estimated as 23.5%. Median PFS was 65 days. Median OS was 6.9 months. Authors concluded not to recommend further evaluation of anti-HER2 treatment in patients with metastatic pancreatic cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ERBB2/NCBI:2064 1393 AN5065-3 ERBB2 Overexpression ERBB2 NCBI:2064 gene pancreatic cancer DOID:1793 risk 42783-1 PubMed:15581051 Patients with metastatic pancreatic cancer with IHC 2+/3+ HER2 received gemcitabine and Trastuzumab combination. Screening logs demonstrated the rate of HER2 overexpression was 16%. Thirty-four patients were enrolled. Thirty patients (88%) had pancreatic cancers with 2+ overexpression and 4 patients (12%) had 3+ overexpression. Confirmed partial responses were observed in 2 of 32 patients (6%). The median survival for all 34 patients was 7 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ERBB2/NCBI:2064 1393 AN5065-3 ERBB2 Overexpression ERBB2 NCBI:2064 gene pancreatic cancer DOID:1793 risk 42783-1 CIViC:849 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ERBB2/NCBI:2064 1393 AN5065-4 ERBB2 Overexpression ERBB2 NCBI:2064 gene salivary gland cancer DOID:8850 risk 42783-1 PubMed:23826550 Case report of a 61-year-old caucasian male with a renal mass and subsequent liver metastases. Histopathological examination of the liver led to the diagnosis of metastastic adenocarcinoma of the salivary Gland, which had been diagnosed and treated in the Patient 20 years earlier. IHC revealed Her2/neu, 3+. The patient was treated successfully with trastuzumab/paclitaxel with near-complete response as measured by PET-CT scans for more than a year. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ERBB2/NCBI:2064 1394 AN5065-4 ERBB2 Overexpression ERBB2 NCBI:2064 gene salivary gland cancer DOID:8850 risk 42783-1 PubMed:20504363 Case report of a a 58 year old man with multiple bone metastases after local therapy of a carcinoma ex pleomorphic adenoma one year earlier. The original tumor tested strongly positive for HER2/neu by immunohistochemistry. The patient was treated with trastuzumab, capecitabine, and zoledronic acid. He experienced total resolution of symptoms and repeat FDG-PET scan after three cycles revealed interval disease resolution. Continued treatment resulted in maintenance of disease control for over 2 years. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ERBB2/NCBI:2064 1394 AN5065-4 ERBB2 Overexpression ERBB2 NCBI:2064 gene salivary gland cancer DOID:8850 risk 42783-1 CIViC:849 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ERBB2/NCBI:2064 1394 AN5066-1 ERBB2 P780INS ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 PubMed:23220880 In MCF10A cell lines, the in-frame insertion of a single amino acid at position 780 was shown to be sensitive to neratinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ERBB2 P780INS [biomarker_term_in_review] 1395 not_mapped AN5066-1 ERBB2 P780INS ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 CIViC:41 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ERBB2 P780INS [biomarker_term_in_review] 1395 not_mapped AN5066-2 ERBB2 P780INS ERBB2 NCBI:2064 gene lung adenocarcinoma DOID:3910 risk 42783-1 PubMed:25899785 'In this phase II study (NCT00818441) of dacomitinib in HER2 amplified or mutant NSCLC tumors, three of 26 patients with HER2 p.P780_Y781insGSP or p.M774delinsWLV showed partial responses of duration between 3 and 14 months, while 13 patients with the more common HER2 p. A775_G776insYVMA showed no partial responses. The authors conclude that in the set of activating HER2 mutations, benefits of an individual agent may be specific to certain mutations, and that ''HER2-positive lung cancers'' is not an adequate term to describe this group of distinguishable illnesses.' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ERBB2 P780INS [biomarker_term_in_review] 1396 not_mapped AN5066-2 ERBB2 P780INS ERBB2 NCBI:2064 gene lung adenocarcinoma DOID:3910 risk 42783-1 CIViC:41 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ERBB2 P780INS [biomarker_term_in_review] 1396 not_mapped AN5067-1 ERBB2 R678Q mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 PubMed:23220880 MCF10A cells transduced with ERBB2 harboring an R678Q mutation were sensitive to lapatinib and the irreversible kinase inhibitor neratinib in an matrigel colony forming assay. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R678Q sequence variation in gene ERBB2/NCBI:2064 1397 check_entity AN5067-1 ERBB2 R678Q mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 CIViC:42 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R678Q sequence variation in gene ERBB2/NCBI:2064 1397 check_entity AN5068-1 ERBB2 R896C mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 PubMed:23220880 In MCF10A cell lines, the R896C mutation was shown to be sensitive to neratinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R896C sequence variation in gene ERBB2/NCBI:2064 1398 check_entity AN5068-1 ERBB2 R896C mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 CIViC:43 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R896C sequence variation in gene ERBB2/NCBI:2064 1398 check_entity AN5069-1 ERBB2 S310F mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 PubMed:35939768 In this phase II NCI-MATCH trial, a patient with ER+ lobular breast cancer with ERBB2 S310F mutation was treated with afatinib. A 51% reduction of RECIST target lesions was reported after six cycles, however, the disease progressed because of a new nontarget lesion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S310F sequence variation in gene ERBB2/NCBI:2064 1399 check_entity AN5069-1 ERBB2 S310F mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 CIViC:4470 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S310F sequence variation in gene ERBB2/NCBI:2064 1399 check_entity AN5070-1 ERBB2 S310F/Y mutation ERBB2 NCBI:2064 gene colon cancer DOID:219 risk 42783-1 PubMed:26243863 Colon cancer patient derived xenografts with HER2 mutations are sensitive to HER2 targeted drugs and the greatest tumor reduction was seen with the combination of a tyrosine kinase inhibitor with trastuzumab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::s310f/y:mutation sequence variation in gene ERBB2/NCBI:2064 1400 check_entity AN5070-1 ERBB2 S310F/Y mutation ERBB2 NCBI:2064 gene colon cancer DOID:219 risk 42783-1 CIViC:493 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::s310f/y:mutation sequence variation in gene ERBB2/NCBI:2064 1400 check_entity AN5071-1 ERBB2 SERUM LEVELS ERBB2 NCBI:2064 gene breast cancer DOID:1612 prognostic;risk 42783-1 PubMed:26811533 Serum and tissue levels of HER2 (ERBB2) were analyzed in 1,902 breast cancer patients treated with lapatinib or control. Serum HER2 (sHER2) levels measured by ELISA were higher in patients with HER2 amplification (median sHER2 levels were 25.1 ng/mL in patients with HER2-positive tumors). Serum HER2 levels were Independent predictors of lapatinib progression free survival benefit (HR per 10-ng/mL increase in serum HER2: lapatinib-containing therapies, 1.009 v nonlapatinib-containing therapies, 1.044; P interaction < .001). Tissue HER2 levels were also predictive, but within this subgroup, serum HER2 still independently predicted lapatinib PFS benefit. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ERBB2 SERUM LEVELS [biomarker_term_in_review] 1401 not_mapped AN5071-1 ERBB2 SERUM LEVELS ERBB2 NCBI:2064 gene breast cancer DOID:1612 prognostic;risk 42783-1 CIViC:412 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ERBB2 SERUM LEVELS [biomarker_term_in_review] 1401 not_mapped AN5072-1 ERBB2 T798I mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 PubMed:28274957 Efficacy of osimertinib and its metabolite, AZ5104, at reducing phosphorylation of key proteins was evaluated by western blot. Osimertinib failed to induce substantial reductions in phosphorylated ERBB2 in NR6 mouse fibroblast cells transduced to co-express ERBB2 L869R and T798I or ERBB2 wt. AZ5104 blocked phosphorylation to a greater extent in the mutant and wildtype cells. MCF10A cells transduced with ERBB2 wt, ERBB2 T798I alone or ERBB2 L869R and T798I co-expressed did not show substantial reductions in phosphorylated ERBB2, AKT, ERK or S6. AZ5104 induced greater reductions. Authors note that AZ5104 is not being developed independently of osimertinib and only 10% of osimertinib is metabolized into AZ5104 in humans. Authors concluded that ERBB2 T798I is not sensitive to osimertinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T798I sequence variation in gene ERBB2/NCBI:2064 1402 check_entity AN5072-1 ERBB2 T798I mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 CIViC:2204 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T798I sequence variation in gene ERBB2/NCBI:2064 1402 check_entity AN5073-1 ERBB2 T798M mutation ERBB2 NCBI:2064 gene cancer DOID:162 risk 42783-1 PubMed:22046346 Cell proliferation analysis of Ba/F3 cells expressing ERBB2-T798M showed IC50 value of 1433nM, and was considered as lapatinib-resistant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T798M sequence variation in gene ERBB2/NCBI:2064 1403 check_entity AN5073-1 ERBB2 T798M mutation ERBB2 NCBI:2064 gene cancer DOID:162 risk 42783-1 CIViC:1279 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T798M sequence variation in gene ERBB2/NCBI:2064 1403 check_entity AN5074-1 ERBB2 T862A mutation ERBB2 NCBI:2064 gene cancer DOID:162 risk 42783-1 PubMed:22046346 Cell proliferation analysis of Ba/F3 cells expressing ERBB2-T862A showed IC50 value of 125nM and IC90 of approximately 0.5 µM, and was considered as lapatinib-sensitive. Since levels of up to 1 µM of lapatinib may be achieved in patients, ERBB2-T862A might respond to higher doses of lapatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T862A sequence variation in gene ERBB2/NCBI:2064 1404 check_entity AN5074-1 ERBB2 T862A mutation ERBB2 NCBI:2064 gene cancer DOID:162 risk 42783-1 CIViC:845 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T862A sequence variation in gene ERBB2/NCBI:2064 1404 check_entity AN5075-1 ERBB2 V773A mutation ERBB2 NCBI:2064 gene cancer DOID:162 risk 42783-1 PubMed:22046346 Cell proliferation analysis of Ba/F3 cells expressing ERBB2-V773A showed IC50 value of 146nM and IC90 of approximately 0.5 µM, and was considered as lapatinib-sensitive. Since levels of up to 1 µM of lapatinib may be achieved in patients, ERBB2-V773A might respond to higher doses of lapatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V773A sequence variation in gene ERBB2/NCBI:2064 1405 check_entity AN5075-1 ERBB2 V773A mutation ERBB2 NCBI:2064 gene cancer DOID:162 risk 42783-1 CIViC:846 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V773A sequence variation in gene ERBB2/NCBI:2064 1405 check_entity AN5076-1 ERBB2 V777L mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 PubMed:23220880 In MCF10A cell lines, the V777L mutation was shown to be sensitive to neratinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V777L sequence variation in gene ERBB2/NCBI:2064 1406 check_entity AN5076-1 ERBB2 V777L mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 PubMed:35939768 In this phase II NCI-MATCH trial, a patient with ER+ invasive ductal breast cancer with ERBB2 V777L mutation was treated with afatinib. A RECIST response was reported in the patient, however, it wasn't confirmed on follow-up radiological assessment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V777L sequence variation in gene ERBB2/NCBI:2064 1406 check_entity AN5076-1 ERBB2 V777L mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 CIViC:44 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V777L sequence variation in gene ERBB2/NCBI:2064 1406 check_entity AN5076-2 ERBB2 V777L mutation ERBB2 NCBI:2064 gene cancer DOID:162 risk 42783-1 PubMed:22046346 Ba/F3 cells expressing ERBB2 V777L were treated with lapatinib and showed an IC50 value of 27nM, compared to 30nM for wild-type ERBB2 cells. The authors considered V777L as lapatinib-sensitive. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V777L sequence variation in gene ERBB2/NCBI:2064 1407 check_entity AN5076-2 ERBB2 V777L mutation ERBB2 NCBI:2064 gene cancer DOID:162 risk 42783-1 CIViC:44 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V777L sequence variation in gene ERBB2/NCBI:2064 1407 check_entity AN5076-3 ERBB2 V777L mutation ERBB2 NCBI:2064 gene colon cancer DOID:219 risk 42783-1 PubMed:26243863 Colon cancer patient derived xenografts with HER2 mutations are sensitive to HER2 targeted drugs and the greatest tumor reduction was seen with the combination of a tyrosine kinase inhibitor with trastuzumab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V777L sequence variation in gene ERBB2/NCBI:2064 1408 check_entity AN5076-3 ERBB2 V777L mutation ERBB2 NCBI:2064 gene colon cancer DOID:219 risk 42783-1 CIViC:44 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V777L sequence variation in gene ERBB2/NCBI:2064 1408 check_entity AN5077-1 ERBB2 V842I mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 PubMed:23220880 In MCF10A cell lines, the V842I mutation was shown to be sensitive to neratinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V842I sequence variation in gene ERBB2/NCBI:2064 1409 check_entity AN5077-1 ERBB2 V842I mutation ERBB2 NCBI:2064 gene breast cancer DOID:1612 risk 42783-1 CIViC:45 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V842I sequence variation in gene ERBB2/NCBI:2064 1409 check_entity AN5077-2 ERBB2 V842I mutation ERBB2 NCBI:2064 gene colon cancer DOID:219 risk 42783-1 PubMed:26243863 Colon cancer patient derived xenografts with HER2 mutations are sensitive to HER2 targeted drugs and the greatest tumor reduction was seen with the combination of a tyrosine kinase inhibitor with trastuzumab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V842I sequence variation in gene ERBB2/NCBI:2064 1410 check_entity AN5077-2 ERBB2 V842I mutation ERBB2 NCBI:2064 gene colon cancer DOID:219 risk 42783-1 CIViC:45 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V842I sequence variation in gene ERBB2/NCBI:2064 1410 check_entity AN5078-1 ERBB2 Y772_A775DUP mutation ERBB2 NCBI:2064 gene lung adenocarcinoma DOID:3910 risk 42783-1 PubMed:26559459 A 55 year old heavily pretreated patient with equivocal HER2 overexpression (IHC2+ and no amplification in FISH) was found to have the HER2 YMVA kinase domain insertion. Afatinib monotherapy resulted in resolution of symptoms and 10 months before progressive disease. The patient was subsequently given trastuzumab with no response. The observed efficacy of afatinib against M774insAYVM, and studies reporting afatinib activity against other variants in the HER2 kinase domain, are cited by the authors as motivation for the arm of NCI-MATCH focusing on afatinib and activating HER2 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::y772_a775dup:mutation sequence variation in gene ERBB2/NCBI:2064 1411 check_entity AN5078-1 ERBB2 Y772_A775DUP mutation ERBB2 NCBI:2064 gene lung adenocarcinoma DOID:3910 risk 42783-1 PubMed:25789838 A 51-year old female never smoker with stage IV lung adenocarcinoma carrying a HER2 insertion in exon 20 (p.A775_G776insYVMA) by sequencing archived material, HER2 overexpression by IHC (2+) and HER2 amplification by in situ hybridization was treated with T-DM1 (trastuzumab emtansine). Patient received two cycles off-label at 3.6mg/kg and was found to have morphologic response of lung and bone lesions by PET and CT. TDM-1 therapy was ongoing as of publication April 2015. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::y772_a775dup:mutation sequence variation in gene ERBB2/NCBI:2064 1411 check_entity AN5078-1 ERBB2 Y772_A775DUP mutation ERBB2 NCBI:2064 gene lung adenocarcinoma DOID:3910 risk 42783-1 PubMed:22325357 A Phase II study for use of Afatinib in non- or light smokers with lung adenocarcinoma. Three patients with metastatic lung adenocarcinomas bearing mutations in the kinase domain of HER2 gene were identified (Y772_A775dup, G776L, and G778_P780dup). Objective response was observed in all three of these patients. The patient with Y772_A775dup (Case 1 in the paper), maintained a metabolic complete response for 3 months, ultimately received a total of 9 months of Afatinib, and survived one year from study entry. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::y772_a775dup:mutation sequence variation in gene ERBB2/NCBI:2064 1411 check_entity AN5078-1 ERBB2 Y772_A775DUP mutation ERBB2 NCBI:2064 gene lung adenocarcinoma DOID:3910 risk 42783-1 CIViC:410 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::y772_a775dup:mutation sequence variation in gene ERBB2/NCBI:2064 1411 check_entity AN5078-2 ERBB2 Y772_A775DUP mutation ERBB2 NCBI:2064 gene lung carcinoma DOID:3905 risk 42783-1 PubMed:19122144 Human HER2 with YVMA insertion was put under a clara cell specific, rtTA promoter system inducible via doxycycline. Induction of mutant HER2 in these mice drove rapid development of adenosquamous lung tumors, where tumor maintenance was dependent on continued YMVA HER2 induction by doxycycline. Administration of afatinib had a stronger effect than erlotinib or trastuzumab, as measured by histology and tumor volume regression. Authors state that in the case of afatinib vs. trastuzumab, intracellular HER2 signaling may be blocked by afatanib but remain unaltered by trastuzumab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::y772_a775dup:mutation sequence variation in gene ERBB2/NCBI:2064 1412 check_entity AN5078-2 ERBB2 Y772_A775DUP mutation ERBB2 NCBI:2064 gene lung carcinoma DOID:3905 risk 42783-1 CIViC:410 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::y772_a775dup:mutation sequence variation in gene ERBB2/NCBI:2064 1412 check_entity AN5078-3 ERBB2 Y772_A775DUP mutation ERBB2 NCBI:2064 gene lung non-small cell carcinoma DOID:3908 risk 42783-1 PubMed:19122144 In preclinical studies of transgenic mice and xenografts, continuous expression of mutant ERBB2 (M774insAYVM or the equivalent A775insYVMA) was found to be essential for tumor maintenance. Furthermore, preclinical in vivo studies assessing erlotinib, trastuzumab, afatinib (aka BIBW2992), and/or sirolimus (aka rapamycin) revealed that the combination of afatinib and sirolimus was most effective in shrinking tumors harboring this insertion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::y772_a775dup:mutation sequence variation in gene ERBB2/NCBI:2064 1413 check_entity AN5078-3 ERBB2 Y772_A775DUP mutation ERBB2 NCBI:2064 gene lung non-small cell carcinoma DOID:3908 risk 42783-1 PubMed:25899785 Phase 2 trial of ERBB-inhibitor dacomitinib in stage IIIB/IV lung cancers with HER2 mutations or amplification (N=30). Thirteen tumors harbored identical 12 base pair exon 20 insertions [A775_G776insYVMA, alternative nomenclature p.Y772_A775dup(c.2313_2324dup)]. No partial responses were found in this subgroup even though some were on study treatment for >2 years and 3 patients with other HER2 mutations achieved PRs. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::y772_a775dup:mutation sequence variation in gene ERBB2/NCBI:2064 1413 check_entity AN5078-3 ERBB2 Y772_A775DUP mutation ERBB2 NCBI:2064 gene lung non-small cell carcinoma DOID:3908 risk 42783-1 CIViC:410 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::y772_a775dup:mutation sequence variation in gene ERBB2/NCBI:2064 1413 check_entity AN5079-1 ERBB3 EXPRESSION ERBB3 NCBI:2065 gene cancer DOID:162 risk PubMed:25542901 The authors conducted an in vivo efficacy study of AV-203 (ERBB3 inhibitory antibody) using a panel of 32 xenograft models representing 12 human cancer types. To identify biomarkers that can predict response to AV-203, the relationship between tumor growth inhibition (TGI) by AV-203 and the expression levels of ERBB3 and NRG1 were evaluated in these tumor models. ERBB3 expression was not predictive of response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene ERBB3/NCBI:2065 1414 AN5079-1 ERBB3 EXPRESSION ERBB3 NCBI:2065 gene cancer DOID:162 risk CIViC:357 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene ERBB3/NCBI:2065 1414 AN5079-2 ERBB3 EXPRESSION ERBB3 NCBI:2065 gene pancreatic ductal adenocarcinoma DOID:3498 risk PubMed:25216528 In mice xenografts expressing ERBB3 (HER3) the combination of ERBB2 (HER2) and ERBB3 inhibitors pertuzumab and 9F7-F11enhanced tumor inhibition and the median survival time. Sensitivity to single-agent pertuzumab might also be increased through ERBB3 expression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene ERBB3/NCBI:2065 1415 AN5079-2 ERBB3 EXPRESSION ERBB3 NCBI:2065 gene pancreatic ductal adenocarcinoma DOID:3498 risk CIViC:357 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene ERBB3/NCBI:2065 1415 AN5080-1 ERBB3 G284R mutation ERBB3 NCBI:2065 gene transitional cell carcinoma DOID:2671 risk PubMed:27044931 In this phase II trial, patients with metastatic platinum-refractory urothelial carcinoma (UC) received afatinib (40 mg/day). Among the 21 tumors, five of six patients (83.3%) with ERBB2 (HER2) and/or ERBB3 alterations achieved 3-month progression-free survival (PFS3) versus none of 15 patients without alterations (P < .001). Three of three patients with ERBB3 somatic mutations (G284R, V104M, and R103G) achieved PFS3. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G284R sequence variation in gene ERBB3/NCBI:2065 1416 check_entity AN5080-1 ERBB3 G284R mutation ERBB3 NCBI:2065 gene transitional cell carcinoma DOID:2671 risk CIViC:684 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G284R sequence variation in gene ERBB3/NCBI:2065 1416 check_entity AN5081-1 ERBB3 Mutation ERBB3 NCBI:2065 gene colorectal cancer DOID:9256 risk PubMed:36315917 In this clinical study of 38 patients with colorectal cancer (CRC), 10 had CRC with ERBB2/ERBB3 mutation, and were treated with a combination of Pertuzumab and Trastuzumab. A DC of 10% and OR of 0% were reported. A PFS of 9.6 weeks (95% CI; 5.1 - 16.0) and OS of 28.8 weeks (95% CI; 7.6 -146.3) were noted. Overall, no antitumor activity was observed in the cohort with this combination. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ERBB3/NCBI:2065 1417 check_entity AN5081-1 ERBB3 Mutation ERBB3 NCBI:2065 gene colorectal cancer DOID:9256 risk CIViC:4706 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ERBB3/NCBI:2065 1417 check_entity AN5082-1 ERBB3 Overexpression ERBB3 NCBI:2065 gene cancer DOID:162 risk PubMed:24685132 Preclinical study in KRAS mutant lung and colon cancer models. A synthetic lethal screen using a total of 3,530 shRNAs to target 518 human kinases identified ERBB3 knockdown to confer sensitivity of selumetinib-resistant H358 cells (NSCLC cell line) to the MEK inhibitor selumetinib. The dual EGFR-ERBB2 inhibitors afatinib and dacomitinib each showed synergy with MEK Inhibition via selumetinib in 4 KRAS mutant cell lines. Western blot evaluation of 9 NSCLC and 12 CRC cell lines showed ERBB3 expression correlated with the synergy score for combination afatinib and trametinib treatment. I.e. the synergy score was low in cells having low basal levels of ERBB3 protein and high for cells having high basal ERBB3 expression. Using selumetinib in patient-derived CRC xenografts or trametinib in NSCLC xenografts, MEK inhibition by selumetinib or trametinib in combination with afatinib more effectively inhibited increases in tumor volume than either monotherapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ERBB3/NCBI:2065 1418 AN5082-1 ERBB3 Overexpression ERBB3 NCBI:2065 gene cancer DOID:162 risk CIViC:285 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ERBB3/NCBI:2065 1418 AN5082-2 ERBB3 Overexpression ERBB3 NCBI:2065 gene colorectal cancer DOID:9256 risk PubMed:25520391 High expression of ERBB3 (her3) was associated with shorter overall survival (OS) from Cetuximab treatment in patients with metastatic colorectal cancer. Gene expression measures (qRT-PCR) were available for 103 patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ERBB3/NCBI:2065 1419 AN5082-2 ERBB3 Overexpression ERBB3 NCBI:2065 gene colorectal cancer DOID:9256 risk CIViC:285 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ERBB3/NCBI:2065 1419 AN5082-3 ERBB3 Overexpression ERBB3 NCBI:2065 gene Her2-receptor positive breast cancer DOID:0060079 risk PubMed:26920887 In a phase 3 clinical trial (NCT00829166), metastatic HER-2 amplified breast cancer patients whose tumors harbored higher than median levels of ERBB3 mRNA treated with ado-trastuzumab emtansine (T-DM1; n=210) were associated with similar median progression free survival (PFS) compared to patients whose tumors harbored the median or lower levels of ERBB3 mRNA (n=214; PFS: 9.8 vs. 9.3 months). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ERBB3/NCBI:2065 1420 AN5082-3 ERBB3 Overexpression ERBB3 NCBI:2065 gene Her2-receptor positive breast cancer DOID:0060079 risk CIViC:285 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ERBB3/NCBI:2065 1420 AN5083-1 ERBB3 R103G mutation ERBB3 NCBI:2065 gene transitional cell carcinoma DOID:2671 risk PubMed:27044931 In this phase II trial, patients with metastatic platinum-refractory urothelial carcinoma (UC) received afatinib (40 mg/day). Among the 21 tumors, five of six patients (83.3%) with ERBB2 (HER2) and/or ERBB3 alterations achieved 3-month progression-free survival (PFS3) versus none of 15 patients without alterations (P < .001). Three of three patients with ERBB3 somatic mutations (G284R, V104M, and R103G) achieved PFS3. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R103G sequence variation in gene ERBB3/NCBI:2065 1421 check_entity AN5083-1 ERBB3 R103G mutation ERBB3 NCBI:2065 gene transitional cell carcinoma DOID:2671 risk CIViC:683 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R103G sequence variation in gene ERBB3/NCBI:2065 1421 check_entity AN5084-1 ERBB3 V104M mutation ERBB3 NCBI:2065 gene transitional cell carcinoma DOID:2671 risk PubMed:27044931 In this phase II trial, patients with metastatic platinum-refractory urothelial carcinoma (UC) received afatinib (40 mg/day). Among the 21 tumors, five of six patients (83.3%) with ERBB2 (HER2) and/or ERBB3 alterations achieved 3-month progression-free survival (PFS3) versus none of 15 patients without alterations (P < .001). Three of three patients with ERBB3 somatic mutations (G284R, V104M, and R103G) achieved PFS3. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V104M sequence variation in gene ERBB3/NCBI:2065 1422 check_entity AN5084-1 ERBB3 V104M mutation ERBB3 NCBI:2065 gene transitional cell carcinoma DOID:2671 risk CIViC:682 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V104M sequence variation in gene ERBB3/NCBI:2065 1422 check_entity AN5085-1 ERBB3 V855A mutation ERBB3 NCBI:2065 gene lung non-small cell carcinoma DOID:3908 risk PubMed:26689995 Case report on a novel V855A mutation located in exon 21 of the HER3 tyrosine kinase domain and found in the tumor specimen of an adolescent patient with a chemotherapy-resistant advanced NSCLC. Protein alignments indicated this mutation was analogous to EGFR-L858R and BRAF-L597V. Co-expression of wildtype HER2 and HER3-V855A in Ba/F3 cells led to sensitivity to afatinib and pertuzumab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V855A sequence variation in gene ERBB3/NCBI:2065 1423 check_entity AN5085-1 ERBB3 V855A mutation ERBB3 NCBI:2065 gene lung non-small cell carcinoma DOID:3908 risk CIViC:762 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V855A sequence variation in gene ERBB3/NCBI:2065 1423 check_entity AN5086-1 ERBB4 EXPRESSION ERBB4 NCBI:2066 gene breast cancer DOID:1612 risk PubMed:25153719 siRNA knockdown of HER4 or inhibition with neratinib enhanced trastuzumab response in breast cancer cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene ERBB4/NCBI:2066 1424 AN5086-1 ERBB4 EXPRESSION ERBB4 NCBI:2066 gene breast cancer DOID:1612 risk PubMed:25590338 ERBB4 protein expression was identified in breast cancer cell lines with acquired lapatinib resistance. Genetic ablation of ERBB4 (not ERBB1-3) led to apoptosis in trastuzumab- and lapatinib resistant cells, probably through a decrease in the PI3K/Akt pathway. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene ERBB4/NCBI:2066 1424 AN5086-1 ERBB4 EXPRESSION ERBB4 NCBI:2066 gene breast cancer DOID:1612 risk CIViC:361 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene ERBB4/NCBI:2066 1424 AN5087-1 ERBB4 Mutation ERBB4 NCBI:2066 gene melanoma DOID:1909 risk PubMed:19718025 ERBB4 was the most commonly mutated protein tyrosine kinase in this study in melanoma (19% in 79 patients). Seven of the identified mutations in ERBB4 (E317K, E452K, E542K, R544W, E563K, E836K and E872K) were transforming and activating in-vitro. ERBB4 inhibition with shRNA or lapatinib led to reduced cell growth. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ERBB4/NCBI:2066 1425 check_entity AN5087-1 ERBB4 Mutation ERBB4 NCBI:2066 gene melanoma DOID:1909 risk CIViC:306 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ERBB4/NCBI:2066 1425 check_entity AN5088-1 ERBB4 NUCLEAR TRANSLOCATION ERBB4 NCBI:2066 gene breast cancer DOID:1612 risk PubMed:25153719 HER4 nuclear translocation was identified as a mediator of trastuzumab resistance in HER2 positive breast cancer cell lines. Increased nuclear staining was also identified in xenograft and patient samples after trastuzumab treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ERBB4 NUCLEAR TRANSLOCATION [biomarker_term_in_review] 1426 not_mapped AN5088-1 ERBB4 NUCLEAR TRANSLOCATION ERBB4 NCBI:2066 gene breast cancer DOID:1612 risk CIViC:360 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ERBB4 NUCLEAR TRANSLOCATION [biomarker_term_in_review] 1426 not_mapped AN5089-1 ERCC1 Expression ERCC1 NCBI:2067 gene bladder carcinoma DOID:4007 prognostic;risk PubMed:26162296 Immunhistochemistry of ERCC1 expression in 432 patients revealed no correlation to response to cisplatin based chemotherapy. In-vitro studies also did not show any effects. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene ERCC1/NCBI:2067 1427 AN5089-1 ERCC1 Expression ERCC1 NCBI:2067 gene bladder carcinoma DOID:4007 prognostic;risk CIViC:325 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene ERCC1/NCBI:2067 1427 AN5090-1 ERCC1 Underexpression ERCC1 NCBI:2067 gene lung non-small cell carcinoma DOID:3908 risk PubMed:19884554 As part of a randomized phase III trial (USO-03012) in advanced NSCLC of gemcitabine vs. combination gemcitabine and carboplatin, protein expression levels for RRM1 (n=69) and ERCC1 (n=65) were evaluated using fluorescence-based IHC. RRM1 levels were significantly inversely correlated with response (r = −0.41; P = .001, n=58), as were ERCC1 levels (r = −0.39; P = .003, n=55). RRM1 and ERCC1 levels were correlated with each other (r = 0.36; P = .003, n=65). There was no significant interaction with treatment arm (P = .64 for RRM1; P = .79 for ERCC1). The authors conclude that RRM1 and ERCC1 expression levels are predictive of response to gemcitabine, and gemcitabine and carboplatin. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ERCC1/NCBI:2067 1428 AN5090-1 ERCC1 Underexpression ERCC1 NCBI:2067 gene lung non-small cell carcinoma DOID:3908 risk CIViC:2282 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ERCC1/NCBI:2067 1428 AN5090-2 ERCC1 Underexpression ERCC1 NCBI:2067 gene ovary epithelial cancer DOID:2152 risk PubMed:30797591 Ovarian epithelial tumours (n=235) were used to create TMAs and IHC results were scored for ERCC1 (n=114 low, n=121 high). For platinum sensitive patients (n=250 in supplementary table, but not all have ERCC1 levels available), low ERCC1 was associated with better PFS (p = 0.034, HR 1.9, 95% CI 1.1-3.6). For platinum resistant patients (n=26 in supplementary table, but not all have ERCC1 levels available), there was no significant association (p = 0.550, HR 0.5, 95% CI 0.1-4.3). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ERCC1/NCBI:2067 1429 AN5090-2 ERCC1 Underexpression ERCC1 NCBI:2067 gene ovary epithelial cancer DOID:2152 risk CIViC:2282 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene ERCC1/NCBI:2067 1429 AN5091-1 ERCC2 K751Q mutation ERCC2 NCBI:2068 gene lung non-small cell carcinoma DOID:3908 risk PubMed:19470925 The ERCC2 K751Q variant is significantly correlated with increased response to paclitaxel and carboplatin therapies in non small cell lung cancer (NSCLC). The researchers utilized data from three previous clinical trials in Japan and the United States with a total of 526 NSCLC patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K751Q sequence variation in gene ERCC2/NCBI:2068 1430 check_entity AN5091-1 ERCC2 K751Q mutation ERCC2 NCBI:2068 gene lung non-small cell carcinoma DOID:3908 risk CIViC:260 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K751Q sequence variation in gene ERCC2/NCBI:2068 1430 check_entity AN5091-2 ERCC2 K751Q mutation ERCC2 NCBI:2068 gene osteosarcoma DOID:3347 risk PubMed:19434073 The ERCC2 K751Q variant was significantly correlated with a lower response to cisplatin chemotherapy in osteosarcoma patients and shorter event-free survival. 91 osteosarcoma patients with a median age of 15 years were followed in this study. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K751Q sequence variation in gene ERCC2/NCBI:2068 1431 check_entity AN5091-2 ERCC2 K751Q mutation ERCC2 NCBI:2068 gene osteosarcoma DOID:3347 risk CIViC:260 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K751Q sequence variation in gene ERCC2/NCBI:2068 1431 check_entity AN5092-1 ERCC5 RS751402 mutation ERCC5 NCBI:2073 gene parietal lobe ependymoma DOID:0050903 prognostic PubMed:26338418 The rs751402 polymorphism in the 5' UTR of ERCC5 was correlated with reduced progression free-survival in children with ependymoma that had been treated with platinum-based therapies. 55 post-operative frozen samples were used in this study. The results were also confirmed in vitro by treating neuroblastoma and B-cell lines expressing the wild-type or rs751402 polymorphism and finding that the rs751402 polymorphism was correlated with higher survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS751402 sequence variation in gene ERCC5/NCBI:2073 1432 check_entity AN5092-1 ERCC5 RS751402 mutation ERCC5 NCBI:2073 gene parietal lobe ependymoma DOID:0050903 prognostic CIViC:251 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS751402 sequence variation in gene ERCC5/NCBI:2073 1432 check_entity AN5093-1 EREG EXPRESSION EREG NCBI:2069 gene colorectal cancer DOID:9256 risk PubMed:23374602 226 cetuximab-treated patients with CRC were analyzed for mRNA expression of EGFR and its ligands. Favorable predictors in a multivariate analysis were high AREG mRNA in KRAS wild type tumours, high EREG mRNA and low Ephrin A2 receptor mRNA. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene EREG/NCBI:2069 1433 AN5093-1 EREG EXPRESSION EREG NCBI:2069 gene colorectal cancer DOID:9256 risk PubMed:26867820 'Prospectively planned retrospective biomarker study in archived tumor tissue from 323 patients from the PICCOLO trial (panitumumab plus irinotecan in CRC patients with KRAS wt). Tumors were classified as ''high expressor'' (either EREG or AREG mRNA level) or ''low expressor'' (neither EREG nor AREG in top tertile). For RAS wild-type patients with high ligand expression, median PFS was 8.3 [4.0-11.0] months (irinotecan with panitumumab) vs 4.4 [2.8-6.7] months (irinotecan alone); HR, 0.38 [95% CI, 0.24-0.61]; P < .001. In RAS wild-type patients with low ligand expression, median PFS was 3.2 [2.7-8.1] months (irinotecan with panitumumab) vs 4.0 [2.7-7.5] months (irinotecan); HR, 0.93 [95% CI, 0.64-1.37]; P = .73; interaction test results were significant [P = .01]). Results were less clear for response rate (interaction P = .17) and OS (interaction P = .11).' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene EREG/NCBI:2069 1433 AN5093-1 EREG EXPRESSION EREG NCBI:2069 gene colorectal cancer DOID:9256 risk CIViC:314 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene EREG/NCBI:2069 1433 AN5093-2 EREG EXPRESSION EREG NCBI:2069 gene lung adenocarcinoma DOID:3910 prognostic PubMed:26894620 Study reporting an in-vivo two-stage initiation/promotion model, testing the hypothesis that Ereg deficiency would reduce lung tumor promotion in mice. Cancerogenesis with chemical initiators/promoters (3-methylcholanthrene or control, butylated hydroxytoluene) was assessed in mice lacking Ereg (Ereg-/-) and wildtype controls (BALB/ByJ; Ereg+/+) at multiple time points and endpoints (bronchoalveolar lavage analysis, tumor analysis, mRNA expression, ELISA, wound assay). Initially a significantly reduced amount of inflammation (macrophages, PMNs) was observed in the Ereg-/- mice. At 20 wk, tumor multiplicity was also significantly decreased in the Ereg-/- mice. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene EREG/NCBI:2069 1434 AN5093-2 EREG EXPRESSION EREG NCBI:2069 gene lung adenocarcinoma DOID:3910 prognostic CIViC:314 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene EREG/NCBI:2069 1434 AN5094-1 ERG TMPRSS2::ERG mutation ERG NCBI:2078 gene prostate carcinoma DOID:10286 diagnostic PubMed:16254181 TMPRSS2/ERG gene fusion was observed in 23 of 29 (79%) of prostate carcinoma samples, and 90% of ERG expression positive prostate carcinoma samples. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::TMPRSS2::ERG sequence variation in gene ERG/NCBI:2078 1435 check_entity AN5094-1 ERG TMPRSS2::ERG mutation ERG NCBI:2078 gene prostate carcinoma DOID:10286 diagnostic CIViC:195 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::TMPRSS2::ERG sequence variation in gene ERG/NCBI:2078 1435 check_entity AN5095-1 ERRFI1 E384* mutation ERRFI1 NCBI:54206 gene cholangiocarcinoma DOID:4947 risk PubMed:24550739 An ERRFI1 (E384X) was detected in a patient with metastatic, recurrent/refractory cholangiocarcinoma (allelic fraction 11%) without any mutations or amplifications in other EGFR signaling members such as EGFR and BRAF. The patient was treated with erlotinib 150 mg orally/daily. After 3 months, RECIST v1.1 partial response evidenced by a decrease of 58% in the sum of largest diameters was observed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E384* sequence variation in gene ERRFI1/NCBI:54206 1436 check_entity AN5095-1 ERRFI1 E384* mutation ERRFI1 NCBI:54206 gene cholangiocarcinoma DOID:4947 risk CIViC:672 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E384* sequence variation in gene ERRFI1/NCBI:54206 1436 check_entity AN5096-1 ESR1 D538G mutation ESR1 NCBI:2099 gene breast cancer DOID:1612 risk PubMed:24185512 MCF7 cell lines harboring the D538G mutation in the ligand-binding domain of ESR1 have shown resistance to hormone therapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D538G sequence variation in gene ESR1/NCBI:2099 1437 check_entity AN5096-1 ESR1 D538G mutation ESR1 NCBI:2099 gene breast cancer DOID:1612 risk PubMed:24185510 Using an estrogen response element (ERE)-luciferase reporter system co-transfected with one of five ESR1 mutants, the N538G ligand binding domain mutation was shown to result in constitutive activity (response in the absence of beta-estradiol ligand) and continued responsiveness (inhibition of downstream target activation) to anti-estrogen therapies (tamoxifen or fulvestrant) in HEK293T cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D538G sequence variation in gene ESR1/NCBI:2099 1437 check_entity AN5096-1 ESR1 D538G mutation ESR1 NCBI:2099 gene breast cancer DOID:1612 risk CIViC:47 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D538G sequence variation in gene ESR1/NCBI:2099 1437 check_entity AN5097-1 ESR1 L536Q mutation ESR1 NCBI:2099 gene breast cancer DOID:1612 risk PubMed:24185512 MCF7 cell lines harboring the L536Q mutation in the ligand-binding domain of ESR1 have shown resistance to hormone therapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L536Q sequence variation in gene ESR1/NCBI:2099 1438 check_entity AN5097-1 ESR1 L536Q mutation ESR1 NCBI:2099 gene breast cancer DOID:1612 risk PubMed:24185510 Using an estrogen response element (ERE)-luciferase reporter system co-transfected with one of five ESR1 mutants, the L536Q ligand binding domain mutation was shown to result in constitutive activity (response in the absence of beta-estradiol ligand) and continued responsiveness (inhibition of downstream target activation) to anti-estrogen therapies (tamoxifen or fulvestrant) in HEK293T cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L536Q sequence variation in gene ESR1/NCBI:2099 1438 check_entity AN5097-1 ESR1 L536Q mutation ESR1 NCBI:2099 gene breast cancer DOID:1612 risk CIViC:46 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L536Q sequence variation in gene ESR1/NCBI:2099 1438 check_entity AN5098-1 ESR1 MUTATION ESR1 NCBI:2099 gene breast cancer DOID:1612 risk PubMed:35584336 In a phase 3 trial (NCT03778931), the selective ER-degrader elacestrant was shown to increase progression free survival (PFS) in both ESR1 mutant and ESR1 wild type, ER-positive, HER2-negative breast cancer patients, previously treated with endocrine and CDK4/6 inhibitor therapy. Of 477 patients, 239 received elacestrant and 238 received SOC (fulvestrant or aromatase inhibitors) with almost half of all patients (228 of 477) having ESR1 mutations. Elacestrant significantly reduced the risk of progression or death compared with SOC by 30% in the overall cohort and by 45% in patients with ESR1 mutation. This led to the FDA-approval of elacestrant in 2023. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ESR1/NCBI:2099 1439 check_entity AN5098-1 ESR1 MUTATION ESR1 NCBI:2099 gene breast cancer DOID:1612 risk CIViC:3778 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene ESR1/NCBI:2099 1439 check_entity AN5099-1 ESR1 Overexpression ESR1 NCBI:2099 gene breast cancer DOID:1612 risk PubMed:25524798 A phase 2 clinical trial evaluated 165 patients with oestrogen receptor positive and HER2-negative breast cancer such that 84 patients received combination therapy of palbociclib plus letrozole and 81 patients received letrozole alone. The combination therapy arm had higher median duration of progression-free survival when compared to the letrozole only group (20.2 months vs. 10.2 months; p<0.0004). A subcategory of patients taking combination therapy, who lacked mutations in p16 or CCND1 (n=34), had an even higher median free survival of 26.1 months. Noticeable side effects in the combination therapy group included neutropenia (54%) leucopenia (19%), fatigue (4%) back pain (2%), diarrhea (2%) and pulmonary embolism (4%). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ESR1/NCBI:2099 1440 AN5099-1 ESR1 Overexpression ESR1 NCBI:2099 gene breast cancer DOID:1612 risk CIViC:603 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ESR1/NCBI:2099 1440 AN5100-1 ESR1 S463P mutation ESR1 NCBI:2099 gene estrogen-receptor positive breast cancer DOID:0060075 risk PubMed:24185512 ESR1 S463P variants were observed after extensive treatment with hormonal therapy (aromatase inhibition). Expression of the S463P mutant was found to induce modest activity in the absence of hormone. This mutation displayed elevated levels of Ser118 phosphorylation compared to wild-type ERα and appeared to possess estrogen-independent activity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S463P sequence variation in gene ESR1/NCBI:2099 1441 check_entity AN5100-1 ESR1 S463P mutation ESR1 NCBI:2099 gene estrogen-receptor positive breast cancer DOID:0060075 risk CIViC:673 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S463P sequence variation in gene ESR1/NCBI:2099 1441 check_entity AN5101-1 ESR1 Y537C mutation ESR1 NCBI:2099 gene breast cancer DOID:1612 risk PubMed:24185512 MCF7 cell lines harboring the Y537C mutation in the ligand-binding domain of ESR1 have shown resistance to hormone therapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y537C sequence variation in gene ESR1/NCBI:2099 1442 check_entity AN5101-1 ESR1 Y537C mutation ESR1 NCBI:2099 gene breast cancer DOID:1612 risk PubMed:24185510 Using an estrogen response element (ERE)-luciferase reporter system co-transfected with one of five ESR1 mutants, the Y537C ligand binding domain mutation was shown to result in constitutive activity (response in the absence of beta-estradiol ligand) and continued responsiveness (inhibition of downstream target activation) to anti-estrogen therapies (tamoxifen or fulvestrant) in HEK293T cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y537C sequence variation in gene ESR1/NCBI:2099 1442 check_entity AN5101-1 ESR1 Y537C mutation ESR1 NCBI:2099 gene breast cancer DOID:1612 risk CIViC:48 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y537C sequence variation in gene ESR1/NCBI:2099 1442 check_entity AN5102-1 ESR1 Y537N mutation ESR1 NCBI:2099 gene breast cancer DOID:1612 risk PubMed:24185512 MCF7 cell lines harboring the Y537N mutation in the ligand-binding domain of ESR1 have shown resistance to hormone therapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y537N sequence variation in gene ESR1/NCBI:2099 1443 check_entity AN5102-1 ESR1 Y537N mutation ESR1 NCBI:2099 gene breast cancer DOID:1612 risk PubMed:24185510 Using an estrogen response element (ERE)-luciferase reporter system co-transfected with one of five ESR1 mutants, the Y537N ligand binding domain mutation was shown to result in constitutive activity (response in the absence of beta-estradiol ligand) and continued responsiveness (inhibition of downstream target activation) to anti-estrogen therapies (tamoxifen or fulvestrant) in HEK293T cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y537N sequence variation in gene ESR1/NCBI:2099 1443 check_entity AN5102-1 ESR1 Y537N mutation ESR1 NCBI:2099 gene breast cancer DOID:1612 risk CIViC:49 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y537N sequence variation in gene ESR1/NCBI:2099 1443 check_entity AN5103-1 ESR1 Y537S mutation ESR1 NCBI:2099 gene breast cancer DOID:1612 risk PubMed:24185512 MCF7 cell lines harboring the L537S mutation in the ligand-binding domain of ESR1 have shown resistance to hormone therapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y537S sequence variation in gene ESR1/NCBI:2099 1444 check_entity AN5103-1 ESR1 Y537S mutation ESR1 NCBI:2099 gene breast cancer DOID:1612 risk PubMed:24185510 Using an estrogen response element (ERE)-luciferase reporter system co-transfected with one of five ESR1 mutants, the Y537S ligand binding domain mutation was shown to result in constitutive activity (response in the absence of beta-estradiol ligand) and continued responsiveness (inhibition of downstream target activation) to anti-estrogen therapies (tamoxifen or fulvestrant) in HEK293T cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y537S sequence variation in gene ESR1/NCBI:2099 1444 check_entity AN5103-1 ESR1 Y537S mutation ESR1 NCBI:2099 gene breast cancer DOID:1612 risk CIViC:50 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y537S sequence variation in gene ESR1/NCBI:2099 1444 check_entity AN5104-1 ETS2 RS461155 mutation ETS2 NCBI:2114 gene lung non-small cell carcinoma DOID:3908 risk PubMed:26893365 Eighty SNPs in miRNA binding sites of cancer related genes selected from 18,500 miRNA:target bindings in crosslinking, ligation, and sequencing of hybrids (CLASH) data were investigated in 379 advanced NSCLC patients using a sequenom mass spectrometry-based genotype assay. 16 SNPs were significantly associated with the clinical outcomes after chemotherapy with paclitaxel-cisplatin: ETS2 SNP: OR = 1.34, 95% CI = 1.00–1.81, P = 0.05; aHR = 0.80, 95% CI = 0.69–0.94, P = 0.006, under additive model. ETS2 rs461155A>G was significantly associated with decreased ETS2 mRNA expression in both tumor and paired normal lung tissues (Ptrend = 4 × 10-7, and 3 × 10-4, respectively). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS461155 sequence variation in gene ETS2/NCBI:2114 1445 check_entity AN5104-1 ETS2 RS461155 mutation ETS2 NCBI:2114 gene lung non-small cell carcinoma DOID:3908 risk CIViC:441 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS461155 sequence variation in gene ETS2/NCBI:2114 1445 check_entity BB1475-1 ETV4 Overexpression ETV4 NCBI:2118 gene prostate cancer DOID:10283 prognostic PubMed:25544710 Immunohistochemical methods were used to evaluate the expression levels of ETV4 in prostate cancer (PCa) tumor samples. Increased expression of ETV4 was associated with greater Gleason score (P = 0.045) , pathological tumor stage (P = 0.041), and an unfavorable prognosis (P = 0.040). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ETV4/NCBI:2118 1446 BB1475-1 ETV4 Overexpression ETV4 NCBI:2118 gene prostate cancer DOID:10283 prognostic CIViC:649 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene ETV4/NCBI:2118 1446 AN5106-1 ETV6 ETV6::RUNX1 mutation ETV6 NCBI:2120 gene B-lymphoblastic leukemia/lymphoma with ETV6-RUNX1 DOID:0080645 diagnostic PubMed:27069254 ETV6-RUNX1 rearranged leukemia is a well established diagnostic entity in the WHO classification of leukemia. It is designated as B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::RUNX1 sequence variation in gene ETV6/NCBI:2120 1447 check_entity AN5106-1 ETV6 ETV6::RUNX1 mutation ETV6 NCBI:2120 gene B-lymphoblastic leukemia/lymphoma with ETV6-RUNX1 DOID:0080645 diagnostic CIViC:3009 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::RUNX1 sequence variation in gene ETV6/NCBI:2120 1447 check_entity AN5107-1 EWSR1 EWSR1::ERG mutation EWSR1 NCBI:2130 gene Ewing sarcoma DOID:3369 diagnostic PubMed:23706910 The t(21;22) rearrangement resulting in the EWSR1::ERG fusion is associated with the diagnosis of Ewing sarcoma. EWSR1::ERG is the second most common gene fusion reported in this disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EWSR1::ERG sequence variation in gene EWSR1/NCBI:2130 1448 check_entity AN5107-1 EWSR1 EWSR1::ERG mutation EWSR1 NCBI:2130 gene Ewing sarcoma DOID:3369 diagnostic PubMed:7524604 Molecular analysis of 30 Ewing tumors (designated as Ewing's sarcomas and primitive neuroectodermal tumors (PNET) in this 1994 paper) from patients with well-documented clinical course was performed. RT-PCR revealed fusion transcripts in 28 of 30 cases (93%) with EWSR1::FLI1 found in 93% (26 of 28) and EWSR1::ERG in 7% (2 of 28). Of note, these fusions were not identified in 7 tumors of other diagnoses. The two tumors with EWSR1::ERG had breakpoints between exon 7 of EWSR1 and exon 6 of ERG with a t(2;22) rearrangement detected in 1 of these 2 cases by karyotyping. Authors conclude RT-PCR is a sensitive method for identifying these EWSR1 rearranged tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EWSR1::ERG sequence variation in gene EWSR1/NCBI:2130 1448 check_entity AN5107-1 EWSR1 EWSR1::ERG mutation EWSR1 NCBI:2130 gene Ewing sarcoma DOID:3369 diagnostic PubMed:26690869 An analysis of 85 small blue round cell tumors (SBRCTs) that were negative for EWSR1, CIC, or BCOR by FISH identified 6 FUS::ERG and 1 FUS::FEV fusions. Clinicopathologic characterization of these 7 cases with FUS fusions and 8 FUS-rearranged SBRCTs reported in the literature described the morphology as monomorphic round cell cytomorphology (keeping with a classic Ewing sarcoma phenotype) with diffuse membranous CD99 reactivity in all except one case with patchy staining. Of note, there were 4 patients in this group who had scored negative for EWSR1 FISH that were positive for EWSR1::ERG by other means (FusionSeq, RT-PCR, etc.) and the authors caution of the false negatives with EWSR1 FISH due to the complexity of the the EWSR1::ERG rearrangement. The authors conclude that these rarer alternative fusions also lead to classic Ewing sarcoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EWSR1::ERG sequence variation in gene EWSR1/NCBI:2130 1448 check_entity AN5107-1 EWSR1 EWSR1::ERG mutation EWSR1 NCBI:2130 gene Ewing sarcoma DOID:3369 diagnostic CIViC:4668 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EWSR1::ERG sequence variation in gene EWSR1/NCBI:2130 1448 check_entity AN5108-1 EWSR1 EWSR1::FLI1 mutation EWSR1 NCBI:2130 gene Ewing sarcoma DOID:3369 diagnostic PubMed:23706910 t(11;22) rearrangements of EWSR1-FLI1 are diagnostic of ewing sarcoma, and are observed in 90% of cytogenetic samples. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EWSR1::FLI1 sequence variation in gene EWSR1/NCBI:2130 1449 check_entity AN5108-1 EWSR1 EWSR1::FLI1 mutation EWSR1 NCBI:2130 gene Ewing sarcoma DOID:3369 diagnostic PubMed:7524604 Molecular analysis of 30 Ewing tumors (designated as Ewing's sarcomas and primitive neuroectodermal tumors (PNET) in this 1994 paper) from patients with well-documented clinical course was performed. RT-PCR revealed fusion transcripts in 28 of 30 cases (93%) with EWSR1::FLI1 found in 93% (26 of 28) and EWSR1::ERG in 7% (2 of 28). Of note, these fusions were not identified in 7 tumors of other diagnoses. 19 of 28 (67%) were EWSR1 ex7::FLI1 ex6 (type I), 4 of 28 (14%) were EWSR1 ex7::FLI1 ex5 (type II) and there was 1 each of EWSR1 ex7:: FLI1 ex7, EWSR1 ex 10::FLI1 ex 5, and EWSR1 ex 9::FLI1 ex4. This last tumor (EWSR1 ex 9::FLI1 ex4) had evidence of an additional 4 splicing variants corresponding to EWSR1 exon 7 to FLI1 exons 4, 6, 8 and 9. Two tumors had EWSR1::ERG with breakpoints between exon 7 of EWSR1 and exon 6 of ERG. Of note, karyotyping only revealed a chromosome 22 rearrangement in 18 out of 27 cases tested (67%), however this was thought to be due to failure to obtain mitotic figures (5 of 9) and insufficient material (4 of 9). Authors conclude RT-PCR is better than karyotyping for identifying these EWSR1 rearranged tumors. In this small study, EWSR::FLI1 type I fusion predominated over type II in localized Ewing's and were more abundant in tumors affecting the long bones (9 versus 0), however no correlations between different EWSR1 transcripts and any other clinical parameters could be identified. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EWSR1::FLI1 sequence variation in gene EWSR1/NCBI:2130 1449 check_entity AN5108-1 EWSR1 EWSR1::FLI1 mutation EWSR1 NCBI:2130 gene Ewing sarcoma DOID:3369 diagnostic CIViC:687 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EWSR1::FLI1 sequence variation in gene EWSR1/NCBI:2130 1449 check_entity AN5108-2 EWSR1 EWSR1::FLI1 mutation EWSR1 NCBI:2130 gene Ewing sarcoma of bone DOID:3368 diagnostic PubMed:3163261 A total of 85 unrelated cases of Ewing's sarcoma were examined and 83% were found to harbor the t(11;22)(q24;q12) chromosomal abnormality knwon to result in the EWSR1::FLI1 fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EWSR1::FLI1 sequence variation in gene EWSR1/NCBI:2130 1450 check_entity AN5108-2 EWSR1 EWSR1::FLI1 mutation EWSR1 NCBI:2130 gene Ewing sarcoma of bone DOID:3368 diagnostic PubMed:9741544 The authors propose RT-PCR as a diagnostic test for Ewing sarcoma using FFPE materials. Starting with 40 cases, intact RNA could be isolated from 6, and of these the EWSR1-FLI1 fusion was detected in 2 by nested PCR. Alternative diagnostic assays for this event are also considered. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EWSR1::FLI1 sequence variation in gene EWSR1/NCBI:2130 1450 check_entity AN5108-2 EWSR1 EWSR1::FLI1 mutation EWSR1 NCBI:2130 gene Ewing sarcoma of bone DOID:3368 diagnostic PubMed:16258512 An evaluation of alternative strategies for detection of EWS-FLI (FISH break apart, FISH fusion, and RT-PCR). Of the 22 informative EWS/PNETs, 20 cases (91%) were positive by FISH break apart, FISH fusion, or both. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EWSR1::FLI1 sequence variation in gene EWSR1/NCBI:2130 1450 check_entity AN5108-2 EWSR1 EWSR1::FLI1 mutation EWSR1 NCBI:2130 gene Ewing sarcoma of bone DOID:3368 diagnostic CIViC:687 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EWSR1::FLI1 sequence variation in gene EWSR1/NCBI:2130 1450 check_entity AN5109-1 EWSR1 EWSR1::WT1 mutation EWSR1 NCBI:2130 gene desmoplastic small round cell tumor DOID:6785 diagnostic PubMed:9738572 In an analysis of a cohort of desmoplastic small round cell tumor, evidence of a functional EWSR1::WT1 fusion was detected in 25 of 26 cases. In these cases, the genomic breakpoints in WT1 was in intron 7 and for EWSR1 the breakpoints occurred in introns 7, 8, and 9. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EWSR1::WT1 sequence variation in gene EWSR1/NCBI:2130 1451 check_entity AN5109-1 EWSR1 EWSR1::WT1 mutation EWSR1 NCBI:2130 gene desmoplastic small round cell tumor DOID:6785 diagnostic PubMed:7862627 In an analysis of 6 desmoplastic small round cell tumors, chimeric EWSR1::WT1 transcripts were detected in 4. The translocation resulted in an in-frame fusion of the N terminus (first 7 exons) of EWSR1 to the last three zinc fingers of the DNA-binding domain of WT1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EWSR1::WT1 sequence variation in gene EWSR1/NCBI:2130 1451 check_entity AN5109-1 EWSR1 EWSR1::WT1 mutation EWSR1 NCBI:2130 gene desmoplastic small round cell tumor DOID:6785 diagnostic PubMed:8187063 Molecular analysis of desmoplastic small round cell tumors with recurrent translocation, t(11;22) (p13;q12) identified EWSR1 on 22q12 and WT1 on 11p13 as the genes involved in the rearrangement. Further analysis confirmed a EWSR1::WT1 fusion joining exon 7 of EWSR1 to exon 8 of WT1. This is one of the first studies identifying the underlying molecular fusion driving desmoplastic small round cell tumor. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EWSR1::WT1 sequence variation in gene EWSR1/NCBI:2130 1451 check_entity AN5109-1 EWSR1 EWSR1::WT1 mutation EWSR1 NCBI:2130 gene desmoplastic small round cell tumor DOID:6785 diagnostic CIViC:2810 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EWSR1::WT1 sequence variation in gene EWSR1/NCBI:2130 1451 check_entity AN5110-1 EZH2 A682G mutation EZH2 NCBI:2146 gene follicular lymphoma DOID:0050873 risk 96964-2 PubMed:34159682 This phase II study involved 17 Japanese adult patients with relapsed/refractory follicular lymphoma (FL), previously treated with chemotherapy without an available standard therapy. The patients harbored EZH2 activating mutations and were recruited to test the efficacy and safety of the EZH2 inhibitor- Tazemetostat. Tazemetostat was given at 800 mg dose twice a day for 28-days cycle. The objective response rate in this cohort was 76.5%, including six patients who had a complete response and seven who had partial response. The remaining three patients had stable disease status. Finally, the median progression‐free survival was not reached at the median follow‐up of 12.9 months. The authors highlight the efficacy and manageable safety profile of Tazemetostat in refractory/relapsed FL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A682G sequence variation in gene EZH2/NCBI:2146 1452 check_entity AN5110-1 EZH2 A682G mutation EZH2 NCBI:2146 gene follicular lymphoma DOID:0050873 risk 96964-2 CIViC:4344 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A682G sequence variation in gene EZH2/NCBI:2146 1452 check_entity AN5111-1 EZH2 A692V mutation EZH2 NCBI:2146 gene follicular lymphoma DOID:0050873 risk 96964-2 PubMed:34159682 This phase II study involved 17 Japanese adult patients with relapsed/refractory follicular lymphoma (FL), previously treated with chemotherapy without an available standard therapy. The patients harbored EZH2 activating mutations and were recruited to test the efficacy and safety of the EZH2 inhibitor- Tazemetostat. Tazemetostat was given at 800 mg dose twice a day for 28-days cycle. The objective response rate in this cohort was 76.5%, including six patients who had a complete response and seven who had partial response. The remaining three patients had stable disease status. Finally, the median progression‐free survival was not reached at the median follow‐up of 12.9 months. The authors highlight the efficacy and manageable safety profile of Tazemetostat in refractory/relapsed FL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A692V sequence variation in gene EZH2/NCBI:2146 1453 check_entity AN5111-1 EZH2 A692V mutation EZH2 NCBI:2146 gene follicular lymphoma DOID:0050873 risk 96964-2 CIViC:4344 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A692V sequence variation in gene EZH2/NCBI:2146 1453 check_entity AN5112-1 EZH2 Activating Mutation EZH2 NCBI:2146 gene follicular lymphoma DOID:0050873 risk 96964-2 PubMed:33035457 Tazemetostat was found to have increased anti-tumor activity in patients with relapsed/refractory follicular lymphoma with gain-of-function EZH2 mutations (cobas EZH2 Mutation Test; objective response rate of 69%) versus patients with wild-type EZH2 (objective response rate of 35%). Treatment shows good tolerability and durability of response in both groups of patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::activating:mutation sequence variation in gene EZH2/NCBI:2146 1454 check_entity AN5112-1 EZH2 Activating Mutation EZH2 NCBI:2146 gene follicular lymphoma DOID:0050873 risk 96964-2 PubMed:33492746 In this phase I study, four Japanese patients with follicular lymphoma were recruited to test the efficacy of EZH2 inhibitor-Tazemetostat. Patients were screened for presence of EZH2 mutations and only one patient had an activating mutation in EZH2. The patients were treated with Tazemetostat at a dose of 800 mg twice a day. Three of the four patients had partial response (including the one with the activating mutation), while one had a stable disease status after the treatment cycle. The authors highlight the treatment's acceptable safety profile and promising antitumor activity in relapsed or refractory B-cell lymphomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::activating:mutation sequence variation in gene EZH2/NCBI:2146 1454 check_entity AN5112-1 EZH2 Activating Mutation EZH2 NCBI:2146 gene follicular lymphoma DOID:0050873 risk 96964-2 CIViC:3605 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::activating:mutation sequence variation in gene EZH2/NCBI:2146 1454 check_entity AN5113-1 EZH2 Intron 6 Mutation EZH2 NCBI:2146 gene colorectal cancer DOID:9256 prognostic 96964-2 PubMed:21926398 The rs3757441 variant in Intron 6 of EZH2 (C/C versus C/T or T/T) was significantly correlated with lower progression free survival and overall survival in patients with metastatic Colorectal Cancer (mCRC). Blood samples from 106 patients with mCRC before and after treatment were used for this study. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::intron:6:mutation sequence variation in gene EZH2/NCBI:2146 1455 check_entity AN5113-1 EZH2 Intron 6 Mutation EZH2 NCBI:2146 gene colorectal cancer DOID:9256 prognostic 96964-2 CIViC:253 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::intron:6:mutation sequence variation in gene EZH2/NCBI:2146 1455 check_entity AN5114-1 EZH2 Mutation EZH2 NCBI:2146 gene follicular lymphoma DOID:0050873 prognostic 96964-2 PubMed:26256760 In advanced stage follicular lymphoma patients receiving rituximab + chemotherapy (R-CHOP or R-CVP), EZH2 mutations were associated with better failure free survival in patients with high-risk FLIPI scores compared to patients that were EZH2 wildtype with high-risk FLIPI scores. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene EZH2/NCBI:2146 1456 check_entity AN5114-1 EZH2 Mutation EZH2 NCBI:2146 gene follicular lymphoma DOID:0050873 prognostic 96964-2 CIViC:163 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene EZH2/NCBI:2146 1456 check_entity AN5114-2 EZH2 Mutation EZH2 NCBI:2146 gene myelodysplastic syndrome DOID:0050908 prognostic 96964-2 PubMed:20601954 In myelodysplastic syndrome, patients with point mutations in EZH2 have worse overall survival that their wild-type counterparts. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene EZH2/NCBI:2146 1457 check_entity AN5114-2 EZH2 Mutation EZH2 NCBI:2146 gene myelodysplastic syndrome DOID:0050908 prognostic 96964-2 CIViC:163 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene EZH2/NCBI:2146 1457 check_entity AN5115-1 EZH2 Overexpression EZH2 NCBI:2146 gene cancer DOID:162 prognostic 96964-2 PubMed:26683709 High expression of EZH2 was associated with poorer outcome in a meta-analysis encompassing 51 studies and 9444 patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene EZH2/NCBI:2146 1458 AN5115-1 EZH2 Overexpression EZH2 NCBI:2146 gene cancer DOID:162 prognostic 96964-2 CIViC:287 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene EZH2/NCBI:2146 1458 AN5116-1 EZH2 Y646 mutation EZH2 NCBI:2146 gene diffuse large B-cell lymphoma DOID:0050745 diagnostic 96964-2 PubMed:20081860 Heterozygous mutations in EZH2 at Y641 were the second most frequent genetic event (after BCL2 t(14;18)) associated with a diagnosis of GCB-DLBCL in 35 / 320 patient samples. In contrast, mutations in EZH2 Y641 are not observed in centroblast samples from healthy controls. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y646 sequence variation in gene EZH2/NCBI:2146 1459 check_entity AN5116-1 EZH2 Y646 mutation EZH2 NCBI:2146 gene diffuse large B-cell lymphoma DOID:0050745 diagnostic 96964-2 CIViC:165 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y646 sequence variation in gene EZH2/NCBI:2146 1459 check_entity AN5116-2 EZH2 Y646 mutation EZH2 NCBI:2146 gene follicular lymphoma DOID:0050873 diagnostic 96964-2 PubMed:20081860 Heterozygous mutations in EZH2 at Y641 were the second most frequent genetic event (after BCL2 t(14;18)) associated with a diagnosis of Follicular non-Hodgkin Lymphoma in 18 / 251 patient samples. In contrast, mutations in EZH2 Y641 are not observed in centroblast samples from healthy controls. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y646 sequence variation in gene EZH2/NCBI:2146 1460 check_entity AN5116-2 EZH2 Y646 mutation EZH2 NCBI:2146 gene follicular lymphoma DOID:0050873 diagnostic 96964-2 CIViC:165 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y646 sequence variation in gene EZH2/NCBI:2146 1460 check_entity AN5116-3 EZH2 Y646 mutation EZH2 NCBI:2146 gene skin melanoma DOID:8923 risk 96964-2 PubMed:26304929 Preclinical study in melanoma cell lines. EZH2 expression was higher in EZH2 mutant (N=3) and wild-type melanoma cell lines (N=12) than untransformed cells (human epithelial melanocytes and human dermal fibroblasts). EZH2 mutant cell lines were the most sensitive to GSK126 compared to wild-type and untransformed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y646 sequence variation in gene EZH2/NCBI:2146 1461 check_entity AN5116-3 EZH2 Y646 mutation EZH2 NCBI:2146 gene skin melanoma DOID:8923 risk 96964-2 CIViC:165 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y646 sequence variation in gene EZH2/NCBI:2146 1461 check_entity AN5117-1 EZH2 Y646C mutation EZH2 NCBI:2146 gene follicular lymphoma DOID:0050873 risk 96964-2 PubMed:34159682 This phase II study involved 17 Japanese adult patients with relapsed/refractory follicular lymphoma (FL), previously treated with chemotherapy without an available standard therapy. The patients harbored EZH2 activating mutations and were recruited to test the efficacy and safety of the EZH2 inhibitor- Tazemetostat. Tazemetostat was given at 800 mg dose twice a day for 28-days cycle. The objective response rate in this cohort was 76.5%, including six patients who had a complete response and seven who had partial response. The remaining three patients had stable disease status. Finally, the median progression‐free survival was not reached at the median follow‐up of 12.9 months. The authors highlight the efficacy and manageable safety profile of Tazemetostat in refractory/relapsed FL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y646C sequence variation in gene EZH2/NCBI:2146 1462 check_entity AN5117-1 EZH2 Y646C mutation EZH2 NCBI:2146 gene follicular lymphoma DOID:0050873 risk 96964-2 CIViC:4344 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y646C sequence variation in gene EZH2/NCBI:2146 1462 check_entity AN5118-1 EZH2 Y646F mutation EZH2 NCBI:2146 gene B-cell lymphoma DOID:707 risk 96964-2 PubMed:27135738 Ezh2 Y641F (EZH2 Y641F) was conditionally expressed in mouse B-cells and caused high-penetrance lymphoma that was further accelerated by Bcl2 overexpression or p53 loss (but not c-Myc overexpression). Expression of Ezh2 Y641F increased global abundance of H3K27 trimethylation (H3K27me3) and also caused widespread redistribution of H3K27me3 leading to widespread transciptional changes. Overall, these results suggest that Ezh2 Y641F induces B-cell lymphoma through widespread reorganization of chromatin structure. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y646F sequence variation in gene EZH2/NCBI:2146 1463 check_entity AN5118-1 EZH2 Y646F mutation EZH2 NCBI:2146 gene B-cell lymphoma DOID:707 risk 96964-2 CIViC:2858 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y646F sequence variation in gene EZH2/NCBI:2146 1463 check_entity AN5118-2 EZH2 Y646F mutation EZH2 NCBI:2146 gene follicular lymphoma DOID:0050873 risk 96964-2 PubMed:34159682 This phase II study involved 17 Japanese adult patients with relapsed/refractory follicular lymphoma (FL), previously treated with chemotherapy without an available standard therapy. The patients harbored EZH2 activating mutations and were recruited to test the efficacy and safety of the EZH2 inhibitor- Tazemetostat. Tazemetostat was given at 800 mg dose twice a day for 28-days cycle. The objective response rate in this cohort was 76.5%, including six patients who had a complete response and seven who had partial response. The remaining three patients had stable disease status. Finally, the median progression‐free survival was not reached at the median follow‐up of 12.9 months. The authors highlight the efficacy and manageable safety profile of Tazemetostat in refractory/relapsed FL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y646F sequence variation in gene EZH2/NCBI:2146 1464 check_entity AN5118-2 EZH2 Y646F mutation EZH2 NCBI:2146 gene follicular lymphoma DOID:0050873 risk 96964-2 CIViC:4344 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y646F sequence variation in gene EZH2/NCBI:2146 1464 check_entity AN5118-3 EZH2 Y646F mutation EZH2 NCBI:2146 gene skin melanoma DOID:8923 risk 96964-2 PubMed:27135738 Experiment with immunodeficient mice transplanted with melanoma cell lines indicates EZH2 inhibitor JQEZ5 might be effective in combination with a B-RAF inhibitor in RAF-mutant melanoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y646F sequence variation in gene EZH2/NCBI:2146 1465 check_entity AN5118-3 EZH2 Y646F mutation EZH2 NCBI:2146 gene skin melanoma DOID:8923 risk 96964-2 CIViC:4241 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y646F sequence variation in gene EZH2/NCBI:2146 1465 check_entity AN5119-1 EZH2 Y646H mutation EZH2 NCBI:2146 gene diffuse large B-cell lymphoma DOID:0050745 risk 96964-2 PubMed:29650362 A phase I safety and dose-escalation study (NCT01897571) was completed for tazemetostat in relapsed or refractory B-cell non-Hodgkin lymphoma or advanced solid tumors. Durable objective responses, including complete responses, were observed in eight (38%) of 21 patients with B-cell non-Hodgkin lymphoma and two (5%) of 43 patients with solid tumours. EZH2 mutation status was assessed retrospectively. Two DLBCL patients had mutations. One of these (with a Y646H mutation) had a durable partial response before disease progression after 16 months on study. The variant in the second patient was not reported and the duration of therapy for this patient that did not respond was among the shortest in the trial. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y646H sequence variation in gene EZH2/NCBI:2146 1466 check_entity AN5119-1 EZH2 Y646H mutation EZH2 NCBI:2146 gene diffuse large B-cell lymphoma DOID:0050745 risk 96964-2 CIViC:3232 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y646H sequence variation in gene EZH2/NCBI:2146 1466 check_entity AN5119-2 EZH2 Y646H mutation EZH2 NCBI:2146 gene follicular lymphoma DOID:0050873 risk 96964-2 PubMed:34159682 This phase II study involved 17 Japanese adult patients with relapsed/refractory follicular lymphoma (FL), previously treated with chemotherapy without an available standard therapy. The patients harbored EZH2 activating mutations and were recruited to test the efficacy and safety of the EZH2 inhibitor- Tazemetostat. Tazemetostat was given at 800 mg dose twice a day for 28-days cycle. The objective response rate in this cohort was 76.5%, including six patients who had a complete response and seven who had partial response. The remaining three patients had stable disease status. Finally, the median progression‐free survival was not reached at the median follow‐up of 12.9 months. The authors highlight the efficacy and manageable safety profile of Tazemetostat in refractory/relapsed FL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y646H sequence variation in gene EZH2/NCBI:2146 1467 check_entity AN5119-2 EZH2 Y646H mutation EZH2 NCBI:2146 gene follicular lymphoma DOID:0050873 risk 96964-2 CIViC:4344 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y646H sequence variation in gene EZH2/NCBI:2146 1467 check_entity AN5120-1 EZH2 Y646N mutation EZH2 NCBI:2146 gene follicular lymphoma DOID:0050873 risk 96964-2 PubMed:34159682 This phase II study involved 17 Japanese adult patients with relapsed/refractory follicular lymphoma (FL), previously treated with chemotherapy without an available standard therapy. The patients harbored EZH2 activating mutations and were recruited to test the efficacy and safety of the EZH2 inhibitor- Tazemetostat. Tazemetostat was given at 800 mg dose twice a day for 28-days cycle. The objective response rate in this cohort was 76.5%, including six patients who had a complete response and seven who had partial response. The remaining three patients had stable disease status. Finally, the median progression‐free survival was not reached at the median follow‐up of 12.9 months. The authors highlight the efficacy and manageable safety profile of Tazemetostat in refractory/relapsed FL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y646N sequence variation in gene EZH2/NCBI:2146 1468 check_entity AN5120-1 EZH2 Y646N mutation EZH2 NCBI:2146 gene follicular lymphoma DOID:0050873 risk 96964-2 CIViC:4344 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y646N sequence variation in gene EZH2/NCBI:2146 1468 check_entity AN5121-1 EZH2 Y646S mutation EZH2 NCBI:2146 gene follicular lymphoma DOID:0050873 risk 96964-2 PubMed:34159682 This phase II study involved 17 Japanese adult patients with relapsed/refractory follicular lymphoma (FL), previously treated with chemotherapy without an available standard therapy. The patients harbored EZH2 activating mutations and were recruited to test the efficacy and safety of the EZH2 inhibitor- Tazemetostat. Tazemetostat was given at 800 mg dose twice a day for 28-days cycle. The objective response rate in this cohort was 76.5%, including six patients who had a complete response and seven who had partial response. The remaining three patients had stable disease status. Finally, the median progression‐free survival was not reached at the median follow‐up of 12.9 months. The authors highlight the efficacy and manageable safety profile of Tazemetostat in refractory/relapsed FL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y646S sequence variation in gene EZH2/NCBI:2146 1469 check_entity AN5121-1 EZH2 Y646S mutation EZH2 NCBI:2146 gene follicular lymphoma DOID:0050873 risk 96964-2 CIViC:4344 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y646S sequence variation in gene EZH2/NCBI:2146 1469 check_entity AN5122-1 EZH2 expression EZH2 NCBI:2146 gene diffuse large B-cell lymphoma germinal center B-cell type DOID:0080997 risk 96964-2 PubMed:33492746 In this phase I study, one patient with germinal center B‐cell‐like (GCB) DLBCL and two with non-GCB DLBCL types were recruited to test the efficacy of EZH2 inhibitor-Tazemetostat in Japanese patients with refractory/relapsed B-cell lymphomas. The patients were treated with a dose of 800 mg twice a day and an objective response was reached only in the patient with the GCB-DLBCL type (complete response), while the other two had progressive disease status. Since EZH2 is known to be expressed in GC and have a role in cellular proliferation and differentiation, the authors speculate that the the cellular origin of DLBCL might be a key in predicting the efficacy of Tazemetostat. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene EZH2/NCBI:2146 1470 AN5122-1 EZH2 expression EZH2 NCBI:2146 gene diffuse large B-cell lymphoma germinal center B-cell type DOID:0080997 risk 96964-2 CIViC:4347 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene EZH2/NCBI:2146 1470 AN5123-1 FANCC Loss-of-function FANCC NCBI:2176 gene pancreatic cancer DOID:1793 risk 32639-7 PubMed:16243825 In the pancreatic cell lines PL11 (FANCC homozygous deletion) and Hs766T (FANCG-mutated), sensitivity to DNA cross-linking agents was observed. PL11 cells (empty vector transduced) were more sensitive to mitomycin C (MMC), cisplatin, chlorambucil, and melphalan than PL11 cells transduced with a vector wildtype FANCC. Similarly, mouse xenografts of PL11 cells (empty vector) were more sensitive to MMC or gemcitabine than PL11 cells expressing a wildtype FANCC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition FANCC Loss-of-function [biomarker_term_in_review] 1471 not_mapped AN5123-1 FANCC Loss-of-function FANCC NCBI:2176 gene pancreatic cancer DOID:1793 risk 32639-7 CIViC:530 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition FANCC Loss-of-function [biomarker_term_in_review] 1471 not_mapped AN5124-1 FBXW7 Loss-of-function FBXW7 NCBI:55294 gene cancer DOID:162 risk 100028-0 PubMed:18787170 FBXW7 was shown to target mTOR for ubiquitination and degradation. A reciprocal relationship between FBXW7 or PTEN loss was identified in breast cancer tumors and cell lines (mutual exclusivity of these two events). In total only 4 out of 450 tumor and cell line samples had concomitant loss of both genes (p=4.9x10^-7). Cell lines (n=5) with FBXW7 mutations or deletions were significantly sensitive to rapamycin and downregulation of FBXW7 (shRNA) increased the sensitivity to rapamycin. In summary, this evidence suggests that FBXW7 may be a biomarker for cancers sensitivity to inhibitors of the mTOR pathway. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition FBXW7 Loss-of-function [biomarker_term_in_review] 1472 not_mapped AN5124-1 FBXW7 Loss-of-function FBXW7 NCBI:55294 gene cancer DOID:162 risk 100028-0 CIViC:633 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition FBXW7 Loss-of-function [biomarker_term_in_review] 1472 not_mapped AN5124-2 FBXW7 Loss-of-function FBXW7 NCBI:55294 gene renal cell carcinoma DOID:4450 risk 100028-0 PubMed:24253377 mTOR protein levels were found to underly a circadian 24-hour rhythm regulated by time-dependent Fbxw7-mediated ubiquitination. Survival rates of tumor-bearing mice with everolimus showed time-dependency consistent with mTOR protein levels. It could be hypothesized that FBXW7 loss leads to an increase in mTOR protein levels independent of circadian regulation and higher sensitivity to mTOR inhibitors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition FBXW7 Loss-of-function [biomarker_term_in_review] 1473 not_mapped AN5124-2 FBXW7 Loss-of-function FBXW7 NCBI:55294 gene renal cell carcinoma DOID:4450 risk 100028-0 CIViC:633 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition FBXW7 Loss-of-function [biomarker_term_in_review] 1473 not_mapped AN5125-1 FBXW7 Mutation FBXW7 NCBI:55294 gene cancer DOID:162 risk 100028-0 PubMed:24586741 418 patients with advanced cancer were screened for FBXW7 mutations using a multiplex gene panel. 17 FBXW7 mutations were detected (isolated mutation in 2 patients). Ten patients were treated with an mTOR inhibitor with 7 patients having stable disease as best responses and a median time to treatment failure of 2.8 months, two patients had prolonged stable disease of >16 weeks. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene FBXW7/NCBI:55294 1474 check_entity AN5125-1 FBXW7 Mutation FBXW7 NCBI:55294 gene cancer DOID:162 risk 100028-0 CIViC:277 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene FBXW7/NCBI:55294 1474 check_entity AN5125-2 FBXW7 Mutation FBXW7 NCBI:55294 gene colorectal cancer DOID:9256 risk 100028-0 PubMed:26508446 65 patients were retrospectively analyzed for mutational profiles predictive of response to EGFR-inhibitors (cetuximab or panitumumab). FBXW7 mutation was found to be more prevalent in non-responders (5 mutations) than responders (1 mutation). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene FBXW7/NCBI:55294 1475 check_entity AN5125-2 FBXW7 Mutation FBXW7 NCBI:55294 gene colorectal cancer DOID:9256 risk 100028-0 CIViC:277 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene FBXW7/NCBI:55294 1475 check_entity AN5126-1 FCGR2A H167R mutation FCGR2A NCBI:2212 gene breast cancer DOID:1612 prognostic PubMed:22906996 A total of 57 women with HER2-positive metastatic breast cancer were analyzed after taxane plus trastuzumab chemotherapy. FCGR2A H131R carriers did not have a significantly different response rate, progression-free survival, or overall survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H167R sequence variation in gene FCGR2A/NCBI:2212 1476 check_entity AN5126-1 FCGR2A H167R mutation FCGR2A NCBI:2212 gene breast cancer DOID:1612 prognostic CIViC:452 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H167R sequence variation in gene FCGR2A/NCBI:2212 1476 check_entity AN5126-2 FCGR2A H167R mutation FCGR2A NCBI:2212 gene Her2-receptor positive breast cancer DOID:0060079 risk PubMed:24989892 1325 HER2-positive breast cancer patients treated with trastuzumab and chemotherapy from the N9831 clinical trial were analyzed. There was no statistical difference in disease-free survival between trastuzumab-treated patients who had the FCGR2A 131 H/H high-affinity genotype and patients without that genotype. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H167R sequence variation in gene FCGR2A/NCBI:2212 1477 check_entity AN5126-2 FCGR2A H167R mutation FCGR2A NCBI:2212 gene Her2-receptor positive breast cancer DOID:0060079 risk CIViC:452 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H167R sequence variation in gene FCGR2A/NCBI:2212 1477 check_entity AN5127-1 FCGR2B I232T mutation FCGR2B NCBI:2213 gene breast cancer DOID:1612 prognostic PubMed:24989892 1325 HER2-positive breast cancer patients treated with trastuzumab and chemotherapy from the N9831 clinical trial were analyzed. There was a difference in disease-free survival for FCGR2B I232T, with I/I patients deriving benefit from trastuzumab (p<0.001) compared to the T carriers who did not (p=0.81). The interaction between FCGR2B genotype and treatment was statistically significant (p=0.03). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I232T sequence variation in gene FCGR2B/NCBI:2213 1478 check_entity AN5127-1 FCGR2B I232T mutation FCGR2B NCBI:2213 gene breast cancer DOID:1612 prognostic CIViC:454 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I232T sequence variation in gene FCGR2B/NCBI:2213 1478 check_entity AN5128-1 FCGR3A F212V mutation FCGR3A NCBI:2214 gene breast cancer DOID:1612 prognostic PubMed:22906996 A total of 57 women with HER2-positive metastatic breast cancer were analyzed after taxane plus trastuzumab chemotherapy. FCGR3A V158F carriers did not have a significantly different response rate, progression-free survival, or overall survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F212V sequence variation in gene FCGR3A/NCBI:2214 1479 check_entity AN5128-1 FCGR3A F212V mutation FCGR3A NCBI:2214 gene breast cancer DOID:1612 prognostic CIViC:453 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F212V sequence variation in gene FCGR3A/NCBI:2214 1479 check_entity AN5128-2 FCGR3A F212V mutation FCGR3A NCBI:2214 gene Her2-receptor positive breast cancer DOID:0060079 risk PubMed:24989892 1325 HER2-positive breast cancer patients treated with trastuzumab and chemotherapy from the N9831 clinical trial were analyzed. There was no statistically significant difference in disease-free survival between trastuzumab-treated patients who had the FCGR3A 158 V/V high-affinity genotype and patients without that genotype (V/F and F/F). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F212V sequence variation in gene FCGR3A/NCBI:2214 1480 check_entity AN5128-2 FCGR3A F212V mutation FCGR3A NCBI:2214 gene Her2-receptor positive breast cancer DOID:0060079 risk CIViC:453 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F212V sequence variation in gene FCGR3A/NCBI:2214 1480 check_entity AN5129-1 FGF13 CYTOPLASMIC EXPRESSION FGF13 NCBI:2258 gene prostate cancer DOID:10283 prognostic PubMed:26891277 243 primary PCa, 37 metastatic PCa, and 20 castration-resistant PCa (CRPC) specimens underwent IHC and microarray analysis. Immunohistochemistry (IHC) showed that FGF13 was detectable in the majority of human PCa samples, and FGF13 IHC scores were higher in high-grade prostatic intraepithelial neoplasia, in primary PCa, and in metastatic PCa than in benign prostatic tissue. There was a significant association between high cytoplasmic FGF13 staining and a risk of biochemical recurrence (BCR) after radical prostatectomy. Multivariate regression analysis indicated that high cytoplasmic FGF13 staining was associated with BCR. Results were recapitulated in cell lines and public databases. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene FGF13/NCBI:2258 1481 AN5129-1 FGF13 CYTOPLASMIC EXPRESSION FGF13 NCBI:2258 gene prostate cancer DOID:10283 prognostic CIViC:443 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene FGF13/NCBI:2258 1481 AN5130-1 FGF19 Overexpression FGF19 NCBI:9965 gene hepatocellular carcinoma DOID:684 risk PubMed:31575541 In a phase 1 trial, patients with hepatocellular carcinoma were treated with selective FGFR4 inhibitor, fisogatinib (BLU-554). For dose escalation, 25 patients received 140 to 900 mg fisogatinib once daily. FGF19 expression was evaluated by immunohistochemistry. Across doses, the overall response rate was 17% (11/66) in FGF19 positive patients and 0% (0/32) in FGF19 negative patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene FGF19/NCBI:9965 1482 AN5130-1 FGF19 Overexpression FGF19 NCBI:9965 gene hepatocellular carcinoma DOID:684 risk CIViC:2653 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene FGF19/NCBI:9965 1482 AN5131-1 FGF2 EXPRESSION FGF2 NCBI:2247 gene acute myeloid leukemia DOID:9119 risk 40427-7 PubMed:27671675 AML MOLM14 cells were cocultured with FLT3 inhibitor AC220 (10 nM) and selected proteins expressed in the bone marrow microenvironment. FL and FGF2 were the only proteins that increased viability >2 standard deviations. FGFR inhibitor PD173074 (and FGFR1 siRNA) was able to attenuate the protective effect of FGF2. Removing FL or FGF2 from ligand-dependent resistant cultures transiently restored sensitivity to AC220, but accelerated acquisition of secondary resistance mutations. 10 FLT3-ITD AML patients treated with AC220 developed increased FGF2 expression (IHC) in marrow stromal cells, which peaked prior to overt clinical relapse and detection of resistance mutations assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene FGF2/NCBI:2247 1483 AN5131-1 FGF2 EXPRESSION FGF2 NCBI:2247 gene acute myeloid leukemia DOID:9119 risk 40427-7 CIViC:669 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene FGF2/NCBI:2247 1483 AN5132-1 FGF3 Amplification FGF3 NCBI:2248 gene breast cancer DOID:1612 risk PubMed:23658459 81 patients were enrolled in a clinical trial with the FGFR inhibitor dovitinib. Four of these patients had FGF3 amplifications (qPCR) and showed tumor reductions of 100%, 30.8%, 23.0%, and 7.5%, respectively. 3 of these 4 patients also had FGFR1 amplifications (≥6 copies by qPCR) and the fourth presented with FGFR1-gene gain (3.4 copies of FGFR1 by qPCR and SISH negative). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGF3/NCBI:2248 1484 AN5132-1 FGF3 Amplification FGF3 NCBI:2248 gene breast cancer DOID:1612 risk CIViC:626 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGF3/NCBI:2248 1484 AN5133-1 FGFR1 Amplification FGFR1 NCBI:2260 gene adenosquamous lung carcinoma DOID:4829 risk 42785-6 PubMed:24302556 Patient diagnosed with metastatic squamous cell lung cancer had high-level amplification of FGFR1 and high expression of MYC. Patient was treated with 400 mg pazopanib twice a day. CT taken four and eight weeks after start of pazopanib showed tumor regression and cavitation. Due to side effects, patient stopped taking pazopanib after 6 months. No clinical or radiologic signs of tumor progression were present at that time. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1485 AN5133-1 FGFR1 Amplification FGFR1 NCBI:2260 gene adenosquamous lung carcinoma DOID:4829 risk 42785-6 CIViC:263 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1485 AN5133-2 FGFR1 Amplification FGFR1 NCBI:2260 gene bladder carcinoma DOID:4007 risk 42785-6 PubMed:27870574 Phase 1 study of FGFR-inhibitor BGJ398 in advanced cancer with FGFR-aberrations. Of the eight patients with FGFR3-mutated bladder/urothelial cancer, one patient with FGFR1 amplification was treated with 125 mg and progressed rapidly in cycle 1 after 11 days of treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1486 AN5133-2 FGFR1 Amplification FGFR1 NCBI:2260 gene bladder carcinoma DOID:4007 risk 42785-6 CIViC:263 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1486 AN5133-3 FGFR1 Amplification FGFR1 NCBI:2260 gene breast cancer DOID:1612 risk 42785-6 PubMed:20179196 FGFR1-amplified breast cancer cell lines show resistance to 4-hydroxytamoxifen, which is reversed by small interfering RNA silencing of FGFR1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1487 AN5133-3 FGFR1 Amplification FGFR1 NCBI:2260 gene breast cancer DOID:1612 risk 42785-6 PubMed:23658459 Dovitinib was evaluated in-vitro, in xenograft and in a phase 2 study. Dovitinib inhibited proliferation in one FGFR1- and one FGFR2-amplified breast cancer cell lines at higher IC50 values than in 11 nonamplified cell lines. Dovitinib inhibited tumor growth and caused regression in both a FGFR1- and FGFR2-amplified xenograft model. 81 patients were enrolled in the trial and treated with dovitinib. Unconfirmed response or stable disease >6 months was observed in 25% of FGFR1-amplified/HR-positive vs. 3% FGFR1-nonamplified/HR-positive breast cancer patientes. When FGF3 and FGFR2 amplifications were also assessed, a combined FGF-pathway amplified patient group had a higher mean reduction in target lesion size than patients with FGF-non-amplified tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1487 AN5133-3 FGFR1 Amplification FGFR1 NCBI:2260 gene breast cancer DOID:1612 risk 42785-6 PubMed:27870574 Phase 1 study of FGFR-inhibitor BGJ398 (infigratinib) in advanced cancer with FGFR-aberrations (n=132). Among the 21 continuously treated (>100mg) patients with breast cancer and FGFR1 amplification (as classified by FISH), 9 had a best response of SD, three of which experienced reductions in tumor burden. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1487 AN5133-3 FGFR1 Amplification FGFR1 NCBI:2260 gene breast cancer DOID:1612 risk 42785-6 PubMed:27179038 Activity of the FGFR-selective inhibitor AZD4547 in FGFR1-amplified breast cancer and FGFR2-amplified gastroesophageal cancer was analyzed in this study. 341 patients with advanced cancer were screened by FISH, identifying FGFR1 amplification in 18% of advanced HER2-negative breast cancers and FGFR2 amplification in 9% of advanced gastroesophageal cancer. 1 patient had a confirmed response among 8 patients treated with FGFR1-amplified breast cancer. In a preclinical model, FGFR1 amplification in breast cancer cell lines was less pronounced than FGFR2-amplifications in gastroesophageal cancers, which also had a higher response rate in the trial, indicating that high level amplification is associated with response and less common in FGFR1-amplified breast cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1487 AN5133-3 FGFR1 Amplification FGFR1 NCBI:2260 gene breast cancer DOID:1612 risk 42785-6 PubMed:29223982 Case report in a HR positive, Her2/neu negative breast cancer patient harboring an FGFR1 amplification. The patient responded to treatment to Pazopanib - including a near CR of brain metastases. Duration of Treatment or median PFS was not reported at the time of publication. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1487 AN5133-3 FGFR1 Amplification FGFR1 NCBI:2260 gene breast cancer DOID:1612 risk 42785-6 PubMed:25193991 In a phase 1 trial, patients with advanced solid tumors were treated with FGFR1/2, VEGFR1/2/3, and PDGFR inhibitor lucitanib. Among 12 patients with breast cancer harboring FGFR alterations (8 FGFR1 amplification, 4 11q amplification), 6 patients showed tumor response. The response rate was 50% and the duration of response was 48.7 weeks. Among the 8 patients with FGFR1 amplification, 4 showed a partial response and 4 achieved stable disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1487 AN5133-3 FGFR1 Amplification FGFR1 NCBI:2260 gene breast cancer DOID:1612 risk 42785-6 CIViC:263 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1487 AN5133-4 FGFR1 Amplification FGFR1 NCBI:2260 gene cancer DOID:162 prognostic 42785-6 PubMed:25171497 Meta-Analysis on prognostic value of FGFR1 amplification in different types of cancer shows significantly worse overall survival for patients with FGFR1 and FGFR2 amplification. However, larger studies are warranted for confirmation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1488 AN5133-4 FGFR1 Amplification FGFR1 NCBI:2260 gene cancer DOID:162 prognostic 42785-6 CIViC:263 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1488 AN5133-5 FGFR1 Amplification FGFR1 NCBI:2260 gene estrogen-receptor positive breast cancer DOID:0060075 risk 42785-6 PubMed:22238366 In MDA-MB-134 cells (ER-positive breast cancer cells with amplified FGFR1) ponatinib potently inhibited cell growth with a GI50 value of 23 nmol/L and inhibited FGFR1 phosphorylation with an IC50 value of 7 nmol/L. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1489 AN5133-5 FGFR1 Amplification FGFR1 NCBI:2260 gene estrogen-receptor positive breast cancer DOID:0060075 risk 42785-6 CIViC:263 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1489 AN5133-6 FGFR1 Amplification FGFR1 NCBI:2260 gene Ewing sarcoma of bone DOID:3368 risk 42785-6 PubMed:26179511 116 Ewing's sarcoma tumor samples were analyzed in this study. 2 patient's samples underwent whole genome sequencing, tumor samples from 51 patients underwent exome sequencing and expression analysis, 63 samples underwent FGFR1 copy number analysis, mRNA analysis and IHC. A FGFR1 N546K mutation was detected in one patient. Gain of the FGFR1 locus (qPCR) was observed in 13 of 41 patients (31.7%) and Ewing sarcoma cell lines (A673, CADO, SK-NMC, SK-ES, and VH-64). FGFR1 was also highly expressed in Ewing sarcoma (mRNA and IHC) and correlated with copy number. Retroviral transduction of FGFR1 wild-type or the FGFR1 N546K mutant into NIH3T3 cells led to enhanced proliferation especially for cells harboring the FGFR1 mutation. ShRNA mediated knockdown of FGFR1 inhibited growth of Ewing sarcoma and other cancer cells (A549 lung carcinoma cell line or leukemia cell lines HL60 and Kasumi) with almost complete growth suppression only in the Ewing sarcoma cell lines and knockdown of FGFR1 abrogated growth of cell lines in xenograft. Ponatinib treatment inhibited growth of Ewing sarcoma cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1490 AN5133-6 FGFR1 Amplification FGFR1 NCBI:2260 gene Ewing sarcoma of bone DOID:3368 risk 42785-6 CIViC:263 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1490 AN5133-7 FGFR1 Amplification FGFR1 NCBI:2260 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 42785-6 PubMed:23806793 This study shows a reduction in the risk of death for patients with FGFR1 copy-number between 4 and 6. No difference in survival is seen between amplified and non-amplified patients in general. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1491 AN5133-7 FGFR1 Amplification FGFR1 NCBI:2260 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 42785-6 PubMed:21666749 Preclinical study showing FGFR1 amplification in NSCLC and efficacy of FGFR-1 inhibition in one amplified cell line. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1491 AN5133-7 FGFR1 Amplification FGFR1 NCBI:2260 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 42785-6 PubMed:27315356 Clinical trial studied the efficacy of Dovitinib on 26 patients with FGFR1 amplifications. Objective response for the cohort was 11.5%, disease control rate was 50%. 11.5% of patients exhibited partial response, 38.5% exhibited stable disease. Median PFS was 2.9 months, median OS was 5 months, this trend was worse with increases in FGFR1 amplification above average. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1491 AN5133-7 FGFR1 Amplification FGFR1 NCBI:2260 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 42785-6 CIViC:263 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1491 AN5133-8 FGFR1 Amplification FGFR1 NCBI:2260 gene lung squamous cell carcinoma DOID:3907 prognostic;risk 42785-6 PubMed:21160078 Preclinical (in-vitro, in-vivo) evidence suggests predictive value of FGFR1 amplification for treatment with FGFR1-inhibitors. 4 of 83 cell lines exhibited FGFR1 amplification, and 3 of these were highly sensitive to PD173074. This sensitivity was confirmed in a mouse xenograft. Clinical trials are currently ongoing. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1492 AN5133-8 FGFR1 Amplification FGFR1 NCBI:2260 gene lung squamous cell carcinoma DOID:3907 prognostic;risk 42785-6 PubMed:23182986 In this study in surgically resected squamous cell lung cancer, FGFR1 amplification has been shown as an independent negative prognostic factor in Asian patients. FGFR1 amplification also correlates with cigarette smoking. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1492 AN5133-8 FGFR1 Amplification FGFR1 NCBI:2260 gene lung squamous cell carcinoma DOID:3907 prognostic;risk 42785-6 PubMed:25086725 This study shows an association of FGFR1 amplification with shorter overall and disease-free survival. However, no statistically significant association is seen on multivariate analysis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1492 AN5133-8 FGFR1 Amplification FGFR1 NCBI:2260 gene lung squamous cell carcinoma DOID:3907 prognostic;risk 42785-6 PubMed:25433983 Effect of FGFR1 amplification on survival unclear, no significant correlation with PFS and OS seen in this meta-analysis. However, FGFR1 amplification is significantly correlated with lymph node metastasis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1492 AN5133-8 FGFR1 Amplification FGFR1 NCBI:2260 gene lung squamous cell carcinoma DOID:3907 prognostic;risk 42785-6 PubMed:27870574 Phase 1 study of FGFR-inhibitor BGJ398 (infigratinib) in advanced cancer with FGFR-aberrations (n=132). In the subgroup of FGFR1-amplified squamous NSCLC (as classified by FISH), 36 patients were treated at doses >100mg continuously and disease control was achieved in 50% of patients (4 PR and 14 SD) with 6 patients receiving treatment after 16 weeks. Of the 27 patients who had evaluable pre- and post- treatment target lesion assessments, 11 had reduced tumor burden. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1492 AN5133-8 FGFR1 Amplification FGFR1 NCBI:2260 gene lung squamous cell carcinoma DOID:3907 prognostic;risk 42785-6 CIViC:263 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR1/NCBI:2260 1492 AN5134-1 FGFR1 Expression FGFR1 NCBI:2260 gene bladder carcinoma DOID:4007 risk 42785-6 PubMed:21119661 One urothelial cell line (JMSU1) with high expression of FGFR1 was sensitive to treatment with FGFR inhibitors (SU5402, TKI258 or PD173074). IC50 values for PD173074 and TKI-258 (Dovitinib) were in nanomolar range compared with micromolar concentration for SU5402. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene FGFR1/NCBI:2260 1493 AN5134-1 FGFR1 Expression FGFR1 NCBI:2260 gene bladder carcinoma DOID:4007 risk 42785-6 CIViC:264 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene FGFR1/NCBI:2260 1493 AN5134-2 FGFR1 Expression FGFR1 NCBI:2260 gene breast cancer DOID:1612 prognostic 42785-6 PubMed:26673008 FGFR1 expression, was assessed by IHC in 1,086 invasive breast cancers. FGFR1 expression was mainly associated with luminal cancer subtypes. Multivariate Cox regression analysis showed FGFR1 to be an independent poor prognostic marker in luminal A cancers for disease free survival (hazard ratio = 3.341, p = 0.008). In luminal A cancers, FGFR1 expression was also significantly associated with higher pN (lymph node metastases; p = 0.023) and pT (unfavorable tumor characteristics; p = 0.003) stages and lymphovascular invasion (p = 0.010). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene FGFR1/NCBI:2260 1494 AN5134-2 FGFR1 Expression FGFR1 NCBI:2260 gene breast cancer DOID:1612 prognostic 42785-6 CIViC:264 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene FGFR1/NCBI:2260 1494 AN5134-3 FGFR1 Expression FGFR1 NCBI:2260 gene colorectal cancer DOID:9256 risk 42785-6 PubMed:24135816 In vitro studies showed efficacy of FGFR inhibitor NVP-BGJ398 in cell lines exhibiting high FGFR1 protein. Three cell lines (SNU-C1, HDC9, HCT116) were analyzed. FGFR1 amplification (24/454, assessed by FISH) and/or activated pFGFR1 protein (18/99, assessed by mRNA in situ hybridization) was identified in primary CRC tissue samples. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene FGFR1/NCBI:2260 1495 AN5134-3 FGFR1 Expression FGFR1 NCBI:2260 gene colorectal cancer DOID:9256 risk 42785-6 CIViC:264 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene FGFR1/NCBI:2260 1495 AN5134-4 FGFR1 Expression FGFR1 NCBI:2260 gene gastric adenocarcinoma DOID:3717 risk 42785-6 PubMed:26637881 FGFR inhibitor BGJ398 was most effective in a gastric cancer cell line model with high expression of FGFR1 and FGFR2IIIc. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene FGFR1/NCBI:2260 1496 AN5134-4 FGFR1 Expression FGFR1 NCBI:2260 gene gastric adenocarcinoma DOID:3717 risk 42785-6 CIViC:264 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene FGFR1/NCBI:2260 1496 AN5134-5 FGFR1 Expression FGFR1 NCBI:2260 gene head and neck squamous cell carcinoma DOID:5520 prognostic;risk 42785-6 PubMed:26115874 This review identified 12 studies that addressed the prognostic role of FGFRs in HNSSC. Evidence was found for the expression of FGFR1 in cancer-associated fibroblasts, other results were conflicting. Significant risk of bias was reported for the included studies. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene FGFR1/NCBI:2260 1497 AN5134-5 FGFR1 Expression FGFR1 NCBI:2260 gene head and neck squamous cell carcinoma DOID:5520 prognostic;risk 42785-6 PubMed:26015511 FGFR1 mRNA expression, rather than copy number alterations, were predictive of response to FGFR inhibitor BGJ398 in cell lines and patient derived xenografts. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene FGFR1/NCBI:2260 1497 AN5134-5 FGFR1 Expression FGFR1 NCBI:2260 gene head and neck squamous cell carcinoma DOID:5520 prognostic;risk 42785-6 PubMed:16454808 Expression of bFGF and FGFR1 were evaluated in 61 biopsy specimens of primary OSCC (IHC). Expression was evaluated in both the cancer cells and fibroblasts at the invasive front of each tumor. bFGF and FGFR1 were expressed in all tumor specimens, whereas expression of these proteins in cancer-associated fibroblasts was associated with lymph node metastasis (P < 0.05) and worse patient survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene FGFR1/NCBI:2260 1497 AN5134-5 FGFR1 Expression FGFR1 NCBI:2260 gene head and neck squamous cell carcinoma DOID:5520 prognostic;risk 42785-6 CIViC:264 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene FGFR1/NCBI:2260 1497 AN5134-6 FGFR1 Expression FGFR1 NCBI:2260 gene lung cancer DOID:1324 risk 42785-6 PubMed:24771645 Preclinical evidence (in-vitro) for predictive value of FGFR1 mRNA and protein expression as well as mRNA expression of FGF2 and FGF9 for sensitivity to FGFR1 inhibition. The authors suggested that FGFR1 expression is a better predictive marker than FGFR1 amplification and proposes a connection between KRAS and PIK3CA mutations. This study used 58 cell lines, of which 14 exhibited ponatinib sensitivity. This sensitivity was correlated with FGFR1 mRNA and protein expression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene FGFR1/NCBI:2260 1498 AN5134-6 FGFR1 Expression FGFR1 NCBI:2260 gene lung cancer DOID:1324 risk 42785-6 CIViC:264 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene FGFR1/NCBI:2260 1498 AN5134-7 FGFR1 Expression FGFR1 NCBI:2260 gene sarcoma DOID:1115 risk 42785-6 PubMed:27535980 Targeting of FGFR1 by RNA interference and small-molecule inhibitors (PD173074, AZD4547, BGJ398) revealed that the requirement for FGFR1 signaling in STS cells is dictated by FGFR1 expression levels, and identified the MAPK-ERK1/2 axis as critical FGFR1 effector pathway. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene FGFR1/NCBI:2260 1499 AN5134-7 FGFR1 Expression FGFR1 NCBI:2260 gene sarcoma DOID:1115 risk 42785-6 CIViC:264 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene FGFR1/NCBI:2260 1499 AN5135-1 FGFR1 FGFR1OP2::FGFR1 mutation FGFR1 NCBI:2260 gene acute myeloid leukemia DOID:9119 risk 42785-6 PubMed:21482694 In this preclinial trial, the AML cell line KG1 with FGFR1OP2-FGFR1 mutation was treated with Ponatinib. This drug effectively inhibits both FGFR phosphorylation and viability for KG1 cells at IC50 values 3 nmol/L and 17 nmol/L respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FGFR1OP2::FGFR1 sequence variation in gene FGFR1/NCBI:2260 1500 check_entity AN5135-1 FGFR1 FGFR1OP2::FGFR1 mutation FGFR1 NCBI:2260 gene acute myeloid leukemia DOID:9119 risk 42785-6 CIViC:2612 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FGFR1OP2::FGFR1 sequence variation in gene FGFR1/NCBI:2260 1500 check_entity AN5136-1 FGFR1 Fusion FGFR1 NCBI:2260 gene acute myeloid leukemia DOID:9119 risk 42785-6 PubMed:21482694 In a preclinical trial, the AML cell line KG1 with the FGFR1OP2-FGFR1 fusion mutation was treated with the tyrosine kinase inhibitors (TKI) ponatinib, sorafenib, and sunitinib. Ponatinib was much more effective in the growth inhibition of cells harboring the fusion mutation (IC50=17 nmol/L) compared to sorafenib (IC50>100 nmol/L) and sunitinib (IC50>100 nmol/L). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene FGFR1/NCBI:2260 1501 check_entity AN5136-1 FGFR1 Fusion FGFR1 NCBI:2260 gene acute myeloid leukemia DOID:9119 risk 42785-6 CIViC:565 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene FGFR1/NCBI:2260 1501 check_entity AN5136-2 FGFR1 Fusion FGFR1 NCBI:2260 gene chronic myelomonocytic leukemia DOID:0080188 diagnostic 42785-6 PubMed:27069254 The 2016 World Health Organization guidelines for the classification of myeloid malignancies uses the detection of PCM1-JAK2 or rearrangements involving PDGFRA, PDGFRB, or FGFR1 as recommended exclusion criteria for a diagnosis of chronic myelomonocytic leukemia, particularly in patients with evidence of eosinophilia. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene FGFR1/NCBI:2260 1502 check_entity AN5136-2 FGFR1 Fusion FGFR1 NCBI:2260 gene chronic myelomonocytic leukemia DOID:0080188 diagnostic 42785-6 CIViC:565 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene FGFR1/NCBI:2260 1502 check_entity AN5136-3 FGFR1 Fusion FGFR1 NCBI:2260 gene hematologic cancer DOID:2531 diagnostic 42785-6 PubMed:27069254 The 2016 World Health Organization guidelines for the classification of myeloid malignancies and acute leukemia describes a new class of disease defined by myeloid or lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene FGFR1/NCBI:2260 1503 check_entity AN5136-3 FGFR1 Fusion FGFR1 NCBI:2260 gene hematologic cancer DOID:2531 diagnostic 42785-6 CIViC:565 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene FGFR1/NCBI:2260 1503 check_entity AN5137-1 FGFR1 Internal Duplication FGFR1 NCBI:2260 gene childhood low-grade glioma DOID:0080830 diagnostic 42785-6 PubMed:23583981 This GWAS study identified a structural variant of FGFR1. Duplication of the tyrosine kinase domain (TKD) of FGFR1 was found in 11 of 149 patients (13/151 tumor samples, including 2 recurrent tumors) with pediatric low-grade gliomas (PLGGs) and related low-grade glioneuronal tumors (LGGNTs). This alteration resulted in autophosphorylation of FGFR1 and subsequent activation of downstream PI3K and MAPK/ERK pathways. Also, transfection of Tp53-null astrocytes with TDK duplicated FGFR1 and implantation into the brains of nude mice results in high-grade astrocytic tumours with short latency and complete penetrance. Of note, this variant was present in 24% (8 of 34) of grade II diffuse cerebral gliomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition FGFR1 Internal Duplication [biomarker_term_in_review] 1504 not_mapped AN5137-1 FGFR1 Internal Duplication FGFR1 NCBI:2260 gene childhood low-grade glioma DOID:0080830 diagnostic 42785-6 CIViC:2528 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition FGFR1 Internal Duplication [biomarker_term_in_review] 1504 not_mapped AN5138-1 FGFR1 N546K mutation FGFR1 NCBI:2260 gene Ewing sarcoma of bone DOID:3368 risk 42785-6 PubMed:26179511 116 Ewing's sarcoma tumor samples were analyzed in this study. 2 patient's samples underwent whole genome sequencing, tumor samples from 51 patients underwent exome sequencing and expression analysis, 63 samples underwent FGFR1 copy number analysis, mRNA analysis and IHC. A FGFR1 N546K mutation was detected in one patient. Gain of the FGFR1 locus (qPCR) was observed in 13 of 41 patients (31.7%) and Ewing sarcoma cell lines (A673, CADO, SK-NMC, SK-ES, and VH-64). FGFR1 was also highly expressed in Ewing sarcoma (mRNA and IHC) and correlated with copy number. Retroviral transduction of FGFR1 wild-type or the FGFR1 N546K mutant into NIH3T3 cells led to enhanced proliferation especially for cells harboring the FGFR1 mutation. ShRNA mediated knockdown of FGFR1 inhibited growth of Ewing sarcoma and other cancer cells (A549 lung carcinoma cell line or leukemia cell lines HL60 and Kasumi) with almost complete growth suppression only in the Ewing sarcoma cell lines and knockdown of FGFR1 abrogated growth of cell lines in xenograft. Ponatinib treatment inhibited growth of Ewing sarcoma cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N546K sequence variation in gene FGFR1/NCBI:2260 1505 check_entity AN5138-1 FGFR1 N546K mutation FGFR1 NCBI:2260 gene Ewing sarcoma of bone DOID:3368 risk 42785-6 CIViC:511 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N546K sequence variation in gene FGFR1/NCBI:2260 1505 check_entity AN5138-2 FGFR1 N546K mutation FGFR1 NCBI:2260 gene pilocytic astrocytoma DOID:4851 risk 42785-6 PubMed:35507888 Case report of a 32-year old male patient with pilocytic astrocytoma. Genomic profiling (FoundationOne) revealed a FGFR1 N546K mutation. The patient was enrolled in a phase I/II trial of pemigatinib and achieved a partial response lasting 18 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N546K sequence variation in gene FGFR1/NCBI:2260 1506 check_entity AN5138-2 FGFR1 N546K mutation FGFR1 NCBI:2260 gene pilocytic astrocytoma DOID:4851 risk 42785-6 CIViC:511 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N546K sequence variation in gene FGFR1/NCBI:2260 1506 check_entity AN5139-1 FGFR1 ZNF198::FGFR1 mutation FGFR1 NCBI:2260 gene myeloproliferative neoplasm DOID:2226 risk 42785-6 PubMed:15448205 A t(8;13)(p11;q12) patient with ZNF198-FGFR1-induced progressive myeloproliferative disorder was treated with PKC412. Radiographic studies performed 3 months after initiation of therapy revealed marked improvement of her cervical, mediastinal, and retroperitoneal lymphadenopathy, and marked regression of splenomegaly to normal size. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ZNF198::FGFR1 sequence variation in gene FGFR1/NCBI:2260 1507 check_entity AN5139-1 FGFR1 ZNF198::FGFR1 mutation FGFR1 NCBI:2260 gene myeloproliferative neoplasm DOID:2226 risk 42785-6 CIViC:462 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ZNF198::FGFR1 sequence variation in gene FGFR1/NCBI:2260 1507 check_entity AN5140-1 FGFR2 Amplification FGFR2 NCBI:2263 gene breast cancer DOID:1612 risk 21674-7 PubMed:23658459 Dovitinib was evaluated in-vitro, in xenograft and in a phase 2 study. Dovitinib inhibited proliferation in one FGFR1- and one FGFR2-amplified breast cancer cell lines at higher IC50 values than in 11 nonamplified cell lines. Dovitinib inhibited tumor growth and caused regression in both a FGFR1- and FGFR2-amplified xenograft model. 81 patients were enrolled in the trial and treated with dovitinib. 2 patients were reported to harbor FGFR2 amplifications and both had a reduction in tumor size of 18.5 and 28.2%, respectively. When FGFR1, FGF3 and FGFR2 amplifications were combined, a combined FGF-pathway amplified patient group had a higher mean reduction in target lesion size than patients with FGF-non-amplified tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR2/NCBI:2263 1508 AN5140-1 FGFR2 Amplification FGFR2 NCBI:2263 gene breast cancer DOID:1612 risk 21674-7 CIViC:625 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR2/NCBI:2263 1508 AN5140-2 FGFR2 Amplification FGFR2 NCBI:2263 gene stomach carcinoma DOID:5517 risk 21674-7 PubMed:27179038 Nine patients with FGFR2-amplified gastroesophageal cancer were treated with AZD4547. Of these 9 patients, 3 showed confirmed responses to AZD4547. Median progression-free survival was 6.6 months (range=6.2-10.5). Two additional patients had a response in day 15 using FDG-PET but were not considered complete responders by RECIST criteria. High-level FGFR2-amplified (arbitrarily defined as FISH-ratio > 5) cancers had a higher likelihood of response and were associated with a substantially higher expression of both FGFR2 mRNA and FGFR2 protein (IHC). In vitro and in PDX models, FGFR2-amplified cell lines were sensitive to FGFR inhibition. Further preclinical analyses suggested, that FGFR2 amplification mainly signals via the PI3K pathway. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR2/NCBI:2263 1509 AN5140-2 FGFR2 Amplification FGFR2 NCBI:2263 gene stomach carcinoma DOID:5517 risk 21674-7 CIViC:625 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FGFR2/NCBI:2263 1509 AN5141-1 FGFR2 FGFR2::AHCYL1 mutation FGFR2 NCBI:2263 gene cholangiocarcinoma DOID:4947 diagnostic;risk 21674-7 PubMed:24122810 Massively parallel whole transcriptome sequencing in eight specimens from cholangiocarcinoma patients identified two fusion kinase genes, FGFR2-AHCYL1 and FGFR2-BICC1. In RT-PCR screening, the FGFR2 fusion was detected in nine patients with cholangiocarcinoma (9/102), exclusively in the intrahepatic subtype (9/66, 13.6%). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FGFR2::AHCYL1 sequence variation in gene FGFR2/NCBI:2263 1510 check_entity AN5141-1 FGFR2 FGFR2::AHCYL1 mutation FGFR2 NCBI:2263 gene cholangiocarcinoma DOID:4947 diagnostic;risk 21674-7 CIViC:764 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FGFR2::AHCYL1 sequence variation in gene FGFR2/NCBI:2263 1510 check_entity AN5142-1 FGFR2 FGFR2::BICC1 mutation FGFR2 NCBI:2263 gene cholangiocarcinoma DOID:4947 diagnostic;risk 21674-7 PubMed:24122810 Massively parallel whole transcriptome sequencing in eight specimens from cholangiocarcinoma patients identified two fusion kinase genes, FGFR2-AHCYL1 and FGFR2-BICC1. In RT-PCR screening, the FGFR2 fusion was detected in nine patients with cholangiocarcinoma (9/102), exclusively in the intrahepatic subtype (9/66, 13.6%). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FGFR2::BICC1 sequence variation in gene FGFR2/NCBI:2263 1511 check_entity AN5142-1 FGFR2 FGFR2::BICC1 mutation FGFR2 NCBI:2263 gene cholangiocarcinoma DOID:4947 diagnostic;risk 21674-7 CIViC:763 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FGFR2::BICC1 sequence variation in gene FGFR2/NCBI:2263 1511 check_entity AN5142-2 FGFR2 FGFR2::BICC1 mutation FGFR2 NCBI:2263 gene endometrial cancer DOID:1380 risk 21674-7 PubMed:26324363 Phase 1 study of pan-FGFR inhibitor JNJ-42756493 in patients with solid tumors. No responses were seen 36 patients without FGFR pathway aberrations. Among 23 patients with FGFR pathway aberrations, 4 partial responses as well as 16 with stable disease were seen. A patient with endometrial cancer with synchronous FGFR3-TACC3 and FGFR2-BICC1/FGFR2-OFD1 fusions had a PR. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FGFR2::BICC1 sequence variation in gene FGFR2/NCBI:2263 1512 check_entity AN5142-2 FGFR2 FGFR2::BICC1 mutation FGFR2 NCBI:2263 gene endometrial cancer DOID:1380 risk 21674-7 CIViC:763 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FGFR2::BICC1 sequence variation in gene FGFR2/NCBI:2263 1512 check_entity AN5142-3 FGFR2 FGFR2::BICC1 mutation FGFR2 NCBI:2263 gene transitional cell carcinoma DOID:2671 risk 21674-7 PubMed:26324363 Phase 1 study of pan-FGFR inhibitor JNJ-42756493 in patients with solid tumors. No responses were seen 36 patients without known FGFR pathway aberrations. Among 23 patients with FGFR pathway aberrations, 4 partial responses as well as 16 with stable disease were seen. In patients with FGFR2-BICC1 fusions, 1 patient with urothelial cancer harboring FGFR2-BICC1/FGFR2-CASP7 fusions had a PR. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FGFR2::BICC1 sequence variation in gene FGFR2/NCBI:2263 1513 check_entity AN5142-3 FGFR2 FGFR2::BICC1 mutation FGFR2 NCBI:2263 gene transitional cell carcinoma DOID:2671 risk 21674-7 CIViC:763 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FGFR2::BICC1 sequence variation in gene FGFR2/NCBI:2263 1513 check_entity AN5143-1 FGFR2 FGFR2::MGEA5 mutation FGFR2 NCBI:2263 gene cholangiocarcinoma DOID:4947 risk 21674-7 PubMed:24550739 In a single patient with this fusion in intrahepatic cholangiocarcinoma. Ponatinib treatment resulted in necrosis and shrinkage of the primary and metastatic sites and overall stable disease. However, this response did not meet criteria for RECIST partial response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FGFR2::MGEA5 sequence variation in gene FGFR2/NCBI:2263 1514 check_entity AN5143-1 FGFR2 FGFR2::MGEA5 mutation FGFR2 NCBI:2263 gene cholangiocarcinoma DOID:4947 risk 21674-7 CIViC:52 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FGFR2::MGEA5 sequence variation in gene FGFR2/NCBI:2263 1514 check_entity AN5144-1 FGFR2 FGFR2::TACC3 mutation FGFR2 NCBI:2263 gene cholangiocarcinoma DOID:4947 risk 21674-7 PubMed:24550739 In a 43 year old female patient with this fusion in intrahepatic cholangiocarcinoma. Both pazopanib and ponatinib separately resulted in minor tumor shrinkage. This fusion is also shown to be recurrent in multiple other cancer types. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FGFR2::TACC3 sequence variation in gene FGFR2/NCBI:2263 1515 check_entity AN5144-1 FGFR2 FGFR2::TACC3 mutation FGFR2 NCBI:2263 gene cholangiocarcinoma DOID:4947 risk 21674-7 CIViC:54 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FGFR2::TACC3 sequence variation in gene FGFR2/NCBI:2263 1515 check_entity AN5145-1 FGFR2 Fusion FGFR2 NCBI:2263 gene cancer DOID:162 risk 21674-7 PubMed:26324363 Phase 1 study of pan-FGFR inhibitor JNJ-42756493 in patients with solid tumors. No responses were seen 36 patients without FGFR pathway aberrations. Among 23 patients with FGFR pathway aberrations, 4 partial responses as well as 16 with stable disease were seen. In patients with FGFR2 fusions, 1 patient with urothelial cancer had a PR harbored FGFR2-BICC1/FGFR2-CASP7 fusions, a patient with endometrial cancer and synchronous FGFR3-TACC3 and FGFR2-BICC1/FGFR2-OFD1 fusions had a PR, and tumor shrinkage was observed in a patient with adrenal carcinoma and FGFR3-TACC3/FGFR2-CCDC6 fusions. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene FGFR2/NCBI:2263 1516 check_entity AN5145-1 FGFR2 Fusion FGFR2 NCBI:2263 gene cancer DOID:162 risk 21674-7 CIViC:2078 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene FGFR2/NCBI:2263 1516 check_entity AN5145-2 FGFR2 Fusion FGFR2 NCBI:2263 gene cholangiocarcinoma DOID:4947 risk 21674-7 PubMed:27870574 Phase 1 study of FGFR-inhibitor BGJ398 (infigratinib) in advanced cancer with FGFR-aberrations (n=132). Two cholangiocarcinoma patients harbored FGFR2 fusions. Both were treated at BGJ398 doses >100mg and saw stable disease. One patient had an unknown FGFR2 fusion partner and saw 20.2% reduction in target lesion size. The other patient harbored FGFR2 BICC1 fusion, and saw a 9.8% reduction in target lesion size. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene FGFR2/NCBI:2263 1517 check_entity AN5145-2 FGFR2 Fusion FGFR2 NCBI:2263 gene cholangiocarcinoma DOID:4947 risk 21674-7 PubMed:29182496 This Phase II trial of BGJ398 for FGFR2 aberant cholangiocarcinoma included 48 patients with FGFR2 fusions. Among these patients with FGFR2 fusions, eight showed tumor response (18.8%) and thirty-six showed tumor shrinkage (75%). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene FGFR2/NCBI:2263 1517 check_entity AN5145-2 FGFR2 Fusion FGFR2 NCBI:2263 gene cholangiocarcinoma DOID:4947 risk 21674-7 PubMed:34358484 In this open-label, phase 2 trial, 122 patients with histologically or cytologically confirmed, locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or rearrangement. Each patient received 125 mg of oral infigratinib once daily for 21 days of 28-day cycles and this was continued until there was disease progression, intolerance, withdrawal of consent, or death. Median follow-up of 10.6 months (IQR: 6.2 – 15.6) and the objective response rate was 23.1% (95% CI: 15.6 – 32.2), with one confirmed complete response and 24 partial responses. The median progression-free survival was 7.3 months (95% CI: 5.6 – 7.6) and the median overall survival was 12.2 months (95% CI: 10.7 – 14.9). There were 61 grade 3 adverse events, and 9 grade 4 adverse events, however, there were no treatment-related deaths. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene FGFR2/NCBI:2263 1517 check_entity AN5145-2 FGFR2 Fusion FGFR2 NCBI:2263 gene cholangiocarcinoma DOID:4947 risk 21674-7 CIViC:2078 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene FGFR2/NCBI:2263 1517 check_entity AN5145-3 FGFR2 Fusion FGFR2 NCBI:2263 gene intrahepatic cholangiocarcinoma DOID:4928 risk 21674-7 PubMed:30420614 Actionable fibroblast growth factor receptor 2 (FGFR2) fusions have been identified in intrahepatic cholangiocarcinomas (iCCA). Derazantinib, a multi-kinase inhibitor with potent pan-FGFR activity showed anti-tumour activity and a manageable safety profile in patients with advanced, unresectable iCCA with FGFR2 fusion who progressed after chemotherapy. In twenty-nine patients, overall response rate was 20.7%, disease control rate was 82.8%, and median PFS was 5.7 months (95% CI: 4.0–9.2). Similar to other pan-FGFR inhibitors, common AEs included asthenia/fatigue, hyperphosphatemia, eye toxicity and increase in ALT/AST. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene FGFR2/NCBI:2263 1518 check_entity AN5145-3 FGFR2 Fusion FGFR2 NCBI:2263 gene intrahepatic cholangiocarcinoma DOID:4928 risk 21674-7 CIViC:2078 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene FGFR2/NCBI:2263 1518 check_entity AN5146-1 FGFR2 Mutation FGFR2 NCBI:2263 gene cholangiocarcinoma DOID:4947 risk 21674-7 PubMed:27870574 Phase 1 study of FGFR-inhibitor BGJ398 in advanced cancer with FGFR-aberrations. Among three patients with cholangiocarcinoma and FGFR2 aberrations (2 fusions, 1 mutation), all three had stable disease with a reduced tumor burden. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene FGFR2/NCBI:2263 1519 check_entity AN5146-1 FGFR2 Mutation FGFR2 NCBI:2263 gene cholangiocarcinoma DOID:4947 risk 21674-7 PubMed:29182496 Eight patients with cholangiocarcinoma haboring FGFR2 mutations received BGJ398. No response was observed, but one tumor showed a 23% reduction in size. Water fall plot of this article showed 5 patients with stable disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene FGFR2/NCBI:2263 1519 check_entity AN5146-1 FGFR2 Mutation FGFR2 NCBI:2263 gene cholangiocarcinoma DOID:4947 risk 21674-7 CIViC:507 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene FGFR2/NCBI:2263 1519 check_entity AN5146-2 FGFR2 Mutation FGFR2 NCBI:2263 gene endometrial cancer DOID:1380 risk 21674-7 PubMed:26574622 Preclinical study in endometrial cancer cell lines (MFE-296, AN3CA, MFE-280 and Ishikawa). In cell proliferation assays, the three FGFR2 mutant cell lines were more sensitive to the pan-FGFR inhibitor ponatinib (AP24534) than the FGFR2 wild type cell line (Ishikawa) and human embryonic kidney cell line (HEK293). Ponatinib also inhibited FGFR2 kinase activity and phosphorylation (MFE-296 and MFE-280) as well as cell migration and invasion (MFE-296 and AN3CA) of FGFR2 mutated cancer cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene FGFR2/NCBI:2263 1520 check_entity AN5146-2 FGFR2 Mutation FGFR2 NCBI:2263 gene endometrial cancer DOID:1380 risk 21674-7 CIViC:507 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene FGFR2/NCBI:2263 1520 check_entity AN5147-1 FGFR2 N550K mutation FGFR2 NCBI:2263 gene endometrial cancer DOID:1380 risk 21674-7 PubMed:18757403 The endometrial cancer cell lines, AN3CA and MFE296, which carry the N550K FGFR2 mutation, were found to be sensitive to FGFR inhibition with PD174074 (10 to 40x more sensitive than cell lines with wild type FGFR2.). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N550K sequence variation in gene FGFR2/NCBI:2263 1521 check_entity AN5147-1 FGFR2 N550K mutation FGFR2 NCBI:2263 gene endometrial cancer DOID:1380 risk 21674-7 CIViC:541 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N550K sequence variation in gene FGFR2/NCBI:2263 1521 check_entity AN5148-1 FGFR2 P253R mutation FGFR2 NCBI:2263 gene head and neck squamous cell carcinoma DOID:5520 risk 21674-7 PubMed:23786770 FGFR2 p.P253R mutation detected in patient with head and neck SCC. Mutation initially detected by RNA-Seq and confirmed by Sanger sequencing. Patient is 52 y/o male with initial diagnosis of SCC of right tongue in 2008. Recurrences treated with surgery, radiotherapy and chemotherapy including carboplatin, paclitaxel, cisplatin, and cetuximab. In 2012, progression was detected in right neck and left axilla. Patient was treated with 800 mg of pazopanib daily. At 12 day follow up patient had marked reduction in tumor size. Patient continued treatment for 2 months until he presented with right carotid hemorrhage. Last follow up shows patient is alive 11 months after beginning pazopanib treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P253R sequence variation in gene FGFR2/NCBI:2263 1522 check_entity AN5148-1 FGFR2 P253R mutation FGFR2 NCBI:2263 gene head and neck squamous cell carcinoma DOID:5520 risk 21674-7 CIViC:2774 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P253R sequence variation in gene FGFR2/NCBI:2263 1522 check_entity AN5149-1 FGFR3 FGFR3::BAIAP2L1 mutation FGFR3 NCBI:2261 gene bladder carcinoma DOID:4007 risk 21676-2 PubMed:23558953 Following identification of this fusion in a patient, this fusion was expressed in HEK 293T cells leading to oligomerization in the absence of ligand, induced morphologic changes in the cell and increased cellular proliferation consistent with FGFR activation. Mouse xenografts using the bladder cell line SW780 which harbors an FGFR3-BAIAP2L1 fusion showed reduced tumor burden when treated with the FGFR inhibitor PD173074. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FGFR3::BAIAP2L1 sequence variation in gene FGFR3/NCBI:2261 1523 check_entity AN5149-1 FGFR3 FGFR3::BAIAP2L1 mutation FGFR3 NCBI:2261 gene bladder carcinoma DOID:4007 risk 21676-2 CIViC:53 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FGFR3::BAIAP2L1 sequence variation in gene FGFR3/NCBI:2261 1523 check_entity AN5150-1 FGFR3 FGFR3::TACC3 mutation FGFR3 NCBI:2261 gene cancer DOID:162 risk 21676-2 PubMed:26324363 Phase 1 study of pan-FGFR inhibitor JNJ-42756493 in patients with solid tumors. No responses were seen 36 patients without FGFR pathway aberrations. Among 23 patients with FGFR pathway aberrations, 5 partial responses (PR) and 16 with stable disease were seen. In patients harboring FGFR3-TACC3, there were 2 urothelial cancer patients with PRs, 1 endometrial cancer patient with PR (also had FGFR2-BICC1/FGFR2-OFD1 fusions), and tumor shrinkage in a patient with adrenal carcinoma (also had FGFR2-CCDC6 fusion). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FGFR3::TACC3 sequence variation in gene FGFR3/NCBI:2261 1524 check_entity AN5150-1 FGFR3 FGFR3::TACC3 mutation FGFR3 NCBI:2261 gene cancer DOID:162 risk 21676-2 CIViC:808 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FGFR3::TACC3 sequence variation in gene FGFR3/NCBI:2261 1524 check_entity AN5150-2 FGFR3 FGFR3::TACC3 mutation FGFR3 NCBI:2261 gene transitional cell carcinoma DOID:2671 risk 21676-2 PubMed:29848605 In this one-arm study, 67 patients with metastastic urothelial carcinoma and diverse FGFR3 alterations were treated with pan-FGFR Inhibitor BGJ398. The majority of patients (70.1%) had received two or more prior antineoplastic therapies. An overall response rate of 25.4% was observed and an additional 38.8% of patients had disease stabilization. No clear differences between type of FGFR3 aberration and response could be seen. Four of five patients with FGFR3-TACC3 fusions had response data, with three achieving stable disease and one having a complete response. The authors conclude that BGJ398 appears to have moderate anticancer activity in patients with metastatic urothelial carcinoma, that response rates and disease control rate exceed outcomes with most agents in this setting, and that enriching for patients with activating FGFR3 mutations together with the high specificity of BGJ398 for FGFR3 likely explains this improved response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FGFR3::TACC3 sequence variation in gene FGFR3/NCBI:2261 1525 check_entity AN5150-2 FGFR3 FGFR3::TACC3 mutation FGFR3 NCBI:2261 gene transitional cell carcinoma DOID:2671 risk 21676-2 CIViC:808 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FGFR3::TACC3 sequence variation in gene FGFR3/NCBI:2261 1525 check_entity AN5151-1 FGFR3 Fusion FGFR3 NCBI:2261 gene adrenal carcinoma DOID:3950 risk 21676-2 PubMed:26324363 Phase 1 study of pan-FGFR inhibitor JNJ-42756493 in patients with solid tumors. No responses were seen 36 patients without FGFR pathway aberrations. Among 23 patients with FGFR pathway aberrations, 4 partial responses as well as 16 with stable disease were seen. Tumor shrinkage was observed in a patient with adrenal carcinoma and FGFR3-TACC3/FGFR2-CCDC6 fusions. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene FGFR3/NCBI:2261 1526 check_entity AN5151-1 FGFR3 Fusion FGFR3 NCBI:2261 gene adrenal carcinoma DOID:3950 risk 21676-2 CIViC:1599 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene FGFR3/NCBI:2261 1526 check_entity AN5152-1 FGFR3 G370C mutation FGFR3 NCBI:2261 gene cancer DOID:162 risk 21676-2 PubMed:19381019 Ba/F3 cells transfected with wild type FGFR3 or common bladder carcinoma variant FGFR3 G372C both resulted in IL-3 independence with FGF1 dependence for growth. Monoclonal antibody R3Mab treatment with FGF1 suppressed proliferation of Ba/F3 FGFR3 G372C cells. Wildtype FGFR3 overexpression in Ba/F3 cells as well as bladder cancer cell lines RT112 and RT4 (who both have normal levels of endogenously expressed wildtype FGFR3), were similarly sensitive to R3Mab treatment, therefore mutation G372C did not change that responsiveness. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G370C sequence variation in gene FGFR3/NCBI:2261 1527 check_entity AN5152-1 FGFR3 G370C mutation FGFR3 NCBI:2261 gene cancer DOID:162 risk 21676-2 CIViC:2279 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G370C sequence variation in gene FGFR3/NCBI:2261 1527 check_entity AN5153-1 FGFR3 K650E mutation FGFR3 NCBI:2261 gene cancer DOID:162 risk 21676-2 PubMed:19381019 Ba/F3 cells transfected with wildtype FGFR3 resulted in IL-3 independence with FGF1 dependence for growth, whereas cells transfected with common bladder carcinoma variant FGFR3 K652E resulted in IL-3 independence, weak ligand-independent proliferation and a strong growth response to FGF1. Monoclonal antibody R3Mab treatment with FGF1 suppressed proliferation of Ba/F3 FGFR3 K652E cells. Wildtype FGFR3 overexpression in Ba/F3 cells as well as bladder cancer cell lines RT112 and RT4 (who both have normal levels of endogenously expressed wildtype FGFR3), were similarly sensitive to R3Mab treatment, therefore mutation K652E did not change that responsiveness. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K650E sequence variation in gene FGFR3/NCBI:2261 1528 check_entity AN5153-1 FGFR3 K650E mutation FGFR3 NCBI:2261 gene cancer DOID:162 risk 21676-2 CIViC:1308 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K650E sequence variation in gene FGFR3/NCBI:2261 1528 check_entity AN5154-1 FGFR3 Mutation FGFR3 NCBI:2261 gene bladder carcinoma DOID:4007 risk 21676-2 PubMed:27870574 Phase 1 study evaluated 132 patients who had advanced cancer with FGFR-aberrations treated with FGFR-inhibitor BGJ398. In the subgroup of eight patients with FGFR3-mutated bladder/urothelial cancer treated at doses ≥ 100 mg, the disease control rate (SD + PR) was 75%. Three patients achieved partial response and 3 patients had stable disease. Of the six patients with disease control, the time on treatment ranged from 15.1 to ≥ 101 weeks, with one ongoing at data cutoff. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene FGFR3/NCBI:2261 1529 check_entity AN5154-1 FGFR3 Mutation FGFR3 NCBI:2261 gene bladder carcinoma DOID:4007 risk 21676-2 CIViC:805 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene FGFR3/NCBI:2261 1529 check_entity AN5154-2 FGFR3 Mutation FGFR3 NCBI:2261 gene transitional cell carcinoma DOID:2671 risk 21676-2 PubMed:31340094 In a phase 2 trial, patients with locally advanced and unresectable or metastatic urothelial carcinoma harboring FGFR3 mutation or FGFR2/3 fusion were treated with Erdafitinib. All the patients had a history of disease progression during or after at least one course of chemotherapy. The response rate in patients receiving continuous daily 8 or 9mg Erdafitinib treatment was 40% (40/99). Within this treatment group, the response rate of patients with FGFR3 mutation was 49% (36/74), and an additional 26 patients (35%) had stable disease. FGFR3 mutations included G370C (4), R248C (13), S249C (45), and Y373C (12). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene FGFR3/NCBI:2261 1530 check_entity AN5154-2 FGFR3 Mutation FGFR3 NCBI:2261 gene transitional cell carcinoma DOID:2671 risk 21676-2 CIViC:805 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene FGFR3/NCBI:2261 1530 check_entity AN5154-3 FGFR3 Mutation FGFR3 NCBI:2261 gene urinary bladder cancer DOID:11054 risk 21676-2 PubMed:29941343 In this study, 52 patients with Muscle Invasive Bladder Cancer (MIBC) were randomly selected and administered neoadjuvant cisplatin and gemcitabine chemotherapy. 39 out of 52 patients showed pathological response (partial & complete) and 13 patients were resistant to neoadjuvant chemotherapy.35.9% (14/39) patients that responded to neoadjuvant chemotherapy had the following FGFR3 somatic mutations - p.S249C,p.V372C, p.G299S, p.V411M. FGFR3 somatic mutations exclusively occurred in the responder group.The somatic FGFR3 mutation frequency in the responder group was also compared with three unselected bladder cancer populations from TCGA, Kim et al.study and Guo et al. studies.This analysis revealed that FGFR3 somatic mutations were significantly enriched in the responder cohort compared with the unselected bladder cancer cohorts. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene FGFR3/NCBI:2261 1531 check_entity AN5154-3 FGFR3 Mutation FGFR3 NCBI:2261 gene urinary bladder cancer DOID:11054 risk 21676-2 CIViC:805 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene FGFR3/NCBI:2261 1531 check_entity AN5155-1 FGFR3 Overexpression FGFR3 NCBI:2261 gene bladder carcinoma DOID:4007 risk 21676-2 PubMed:21119661 The effects of FGFR inhibitors (PD173074, TKI-258 and SU5402) in bladder carcinoma cell lines were related to FGFR3 (and/or FGFR1) expression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene FGFR3/NCBI:2261 1532 AN5155-1 FGFR3 Overexpression FGFR3 NCBI:2261 gene bladder carcinoma DOID:4007 risk 21676-2 CIViC:321 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene FGFR3/NCBI:2261 1532 AN5155-2 FGFR3 Overexpression FGFR3 NCBI:2261 gene cancer DOID:162 risk 21676-2 PubMed:19381019 Pro-B Ba/F3 cells transfected with wild type FGFR3 resulted in Il-3 independence with FGF1 dependence for growth. Monoclonal antibody R3Mab treatment in addition to FGF1 resulted in suppression of proliferation of Ba/F3 cells with wild type FGFR3. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene FGFR3/NCBI:2261 1533 AN5155-2 FGFR3 Overexpression FGFR3 NCBI:2261 gene cancer DOID:162 risk 21676-2 CIViC:321 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene FGFR3/NCBI:2261 1533 AN5156-1 FGFR3 R248C mutation FGFR3 NCBI:2261 gene cancer DOID:162 risk 21676-2 PubMed:19381019 In this preclinical study, R3Mab (a monoclonal antibody specific to FGFR3) inhibited ligand-independent proliferation in Ba/F3 cells expressing common bladder carcinoma variant: FGFR3 R248C. Authors note that R3Mab similarly inhibited proliferation of FGF1 stimulated Ba/F3 cells expressing wildtype FGFR3 and bladder carcinoma cell lines expressing wildtype FGFR3 (RT112 and RT4). They conclude that R3Mab inhibits wildtype and mutant FGFR3 by inhibiting receptor dimerization. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R248C sequence variation in gene FGFR3/NCBI:2261 1534 check_entity AN5156-1 FGFR3 R248C mutation FGFR3 NCBI:2261 gene cancer DOID:162 risk 21676-2 CIViC:2276 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R248C sequence variation in gene FGFR3/NCBI:2261 1534 check_entity AN5157-1 FGFR3 S249C mutation FGFR3 NCBI:2261 gene bladder urothelial carcinoma DOID:4006 risk 21676-2 PubMed:16338952 In contrast to controls (empty vector and FGFR3 wildtype overexpression NIH-3T3 cell lines), the stable transfection of NIH-3T3 cells with FGFR3b-S249C led to ligand-independent phosphorylation of FGFR3 and the acquisition of elongated, refractile spindle-shaped morphology like transformed cells. Using a thymidine incorporation assay, S249C expressing cells were shown to lose contact inhibition and grew 3x to 4x more rapidly than controls. Soft agar assays demonstrated increased colony formation and anchorage independent growth in S249C expressing cells versus controls. All nude mice subcutaneously injected with S249C cells rapidly formed tumors, but no tumors were observed in empty vector injected mice. The authors conclude mutated FGFR3b-S249C has transforming properties attributed to oncogenes. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S249C sequence variation in gene FGFR3/NCBI:2261 1535 check_entity AN5157-1 FGFR3 S249C mutation FGFR3 NCBI:2261 gene bladder urothelial carcinoma DOID:4006 risk 21676-2 CIViC:624 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S249C sequence variation in gene FGFR3/NCBI:2261 1535 check_entity AN5157-2 FGFR3 S249C mutation FGFR3 NCBI:2261 gene lung squamous cell carcinoma DOID:3907 risk 21676-2 PubMed:23786770 NIH-3T3 cells with the FGFR3 S249C extracellular domain mutation demonstrated an increase in colony formation compared to wild-type in an anchorage-independence assay, which was counteracted by the treatment with AP24534 or BGJ398. Xenograft assays showed similar results with all transforming FGFR3 mutations leading to increased tumor growth compared to wild-type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S249C sequence variation in gene FGFR3/NCBI:2261 1536 check_entity AN5157-2 FGFR3 S249C mutation FGFR3 NCBI:2261 gene lung squamous cell carcinoma DOID:3907 risk 21676-2 CIViC:624 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S249C sequence variation in gene FGFR3/NCBI:2261 1536 check_entity AN5157-3 FGFR3 S249C mutation FGFR3 NCBI:2261 gene transitional cell carcinoma DOID:2671 risk 21676-2 PubMed:25766722 Case report of a 67 year old woman with high-grade papillary urothelial carcinoma. The patient underwent chemotherapy and palliative cystectomy followed by tumor progression and pulmonary lesion enlargement. Genomic profiling of the cystectomy specimen identified FGFR3, CCND1 and FGF19 amplification as well as an FGFR3 S249C mutation (allele frequency 58%). Pazopanib was initiated on the basis of these findings and a partial response was achieved for >6 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S249C sequence variation in gene FGFR3/NCBI:2261 1537 check_entity AN5157-3 FGFR3 S249C mutation FGFR3 NCBI:2261 gene transitional cell carcinoma DOID:2671 risk 21676-2 PubMed:31316618 Bladder cancer cell line 97-7 expressing endogenous FGFR3 S249C (IC50 44.6ug/ml) was resistant to cisplatin compared to two FGFR3 wild-type cell lines, 5637 (IC50 2.07ug/ml) and T24 (IC50 1.58ug/ml) as shown by a CCK-8 colorimetric cytotoxicity. Western blot revealed the ratio of phosphorylated-Akt/total Akt was higher in the 97-7 cells than in the wild-type cells, which was reversed by siRNA knockdown of FGFR3. Inhibition of Akt signaling by treatment with GDC0068 or LY294002 increased the cisplatin sensitivity of 97-7 cells (IC50 4.17ug/ml & 8.91ug/ml respectively). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S249C sequence variation in gene FGFR3/NCBI:2261 1537 check_entity AN5157-3 FGFR3 S249C mutation FGFR3 NCBI:2261 gene transitional cell carcinoma DOID:2671 risk 21676-2 CIViC:624 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S249C sequence variation in gene FGFR3/NCBI:2261 1537 check_entity AN5158-1 FGFR3 V555M mutation FGFR3 NCBI:2261 gene myeloid neoplasm DOID:0070004 risk 21676-2 PubMed:22869148 Preclinical study of FGFR Inhibitors AZ12908010, PD173074 and AZD4547 in cancer cell lines. Cell lines with aberrant FGFR signalling were more sensitive to FGFR Inhibition. Sequencing of a myeloma cell line KMS-11R with acquired resistance to FGFR inhibition revealed a FGFR3 V555M Mutation. These cells were cross-resistant to AZD4547 and PD173074. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V555M sequence variation in gene FGFR3/NCBI:2261 1538 check_entity AN5158-1 FGFR3 V555M mutation FGFR3 NCBI:2261 gene myeloid neoplasm DOID:0070004 risk 21676-2 CIViC:2273 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V555M sequence variation in gene FGFR3/NCBI:2261 1538 check_entity AN5159-1 FGFR3 Y373C mutation FGFR3 NCBI:2261 gene bladder carcinoma DOID:4007 diagnostic 21676-2 PubMed:20542753 Y375C mutation results in activation of FGFR3 and is associated with bladder carcinoma. Patients with low-grade tumors were more likely to have FGFR3 mutations than those with high-grade tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y373C sequence variation in gene FGFR3/NCBI:2261 1539 check_entity AN5159-1 FGFR3 Y373C mutation FGFR3 NCBI:2261 gene bladder carcinoma DOID:4007 diagnostic 21676-2 CIViC:2277 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y373C sequence variation in gene FGFR3/NCBI:2261 1539 check_entity AN5159-2 FGFR3 Y373C mutation FGFR3 NCBI:2261 gene cancer DOID:162 risk 21676-2 PubMed:19381019 Pro-B Ba/F3 cells transfected with wild type FGFR3 resulted in IL-3 independence with FGF1 dependence for growth. Cell transfected FGFR3 with mutation Y375C also resulted in IL-3 independence and FGF1 dependence. Monoclonal antibody R3Mab treatment along with FGF1 resulted in suppression of proliferation of Ba/F3 cells with FGFR3 Y375C. Wild type FGFR3 overexpression in Ba/F3 cells with FGF1 was sensitive to monoclonal antibody R3Mab treatment, and mutation Y375C did not change that responsiveness. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y373C sequence variation in gene FGFR3/NCBI:2261 1540 check_entity AN5159-2 FGFR3 Y373C mutation FGFR3 NCBI:2261 gene cancer DOID:162 risk 21676-2 CIViC:2277 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y373C sequence variation in gene FGFR3/NCBI:2261 1540 check_entity AN5159-3 FGFR3 Y373C mutation FGFR3 NCBI:2261 gene urinary bladder cancer DOID:11054 risk 21676-2 PubMed:16338952 The authors identified a bladder cancer cell line (MGH-U3) with a homozygous Y373C mutation. With immunoprecipitation (IP), and immunoblotting (IB) experiments, they demonstrated constitutional phosphorylation of FGFR3 Y373C protein. Then with SU5492 (an FGFR3 TKI) and FGFR3 siRNA, they also demonstrate that constitutional phosphorylation of the FGFR3 Y373C can be inhibited. Furthermore, cells treated with SU5492 (for inhibition) and FGFR3 siRNA (for depletion) of the mutant FGFR3 Y373C protein show inhibition of cell proliferation and anchorage independent growth. These studies suggest potentially oncogenic properties for the Y373C mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y373C sequence variation in gene FGFR3/NCBI:2261 1541 check_entity AN5159-3 FGFR3 Y373C mutation FGFR3 NCBI:2261 gene urinary bladder cancer DOID:11054 risk 21676-2 CIViC:2277 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y373C sequence variation in gene FGFR3/NCBI:2261 1541 check_entity AN5160-1 FLCN c.1285dupC mutation FLCN NCBI:201163 gene renal cell carcinoma DOID:4450 risk 57963-1 PubMed:23995526 A case study showed that the mTOR inhibitor everolimus exhibited a relatively long-term effect in a patient with renal cell carcinoma and a FLCN germline mutation (c. 1285dupC, likely loss of function). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.1285dupc:mutation sequence variation in gene FLCN/NCBI:201163 1542 check_entity AN5160-1 FLCN c.1285dupC mutation FLCN NCBI:201163 gene renal cell carcinoma DOID:4450 risk 57963-1 CIViC:3595 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.1285dupc:mutation sequence variation in gene FLCN/NCBI:201163 1542 check_entity AN5161-1 FLI1 EWSR1::FLI1 e7-e6 FLI1 NCBI:2313 gene Ewing sarcoma DOID:3369 prognostic PubMed:9552022 In patients with Ewing's sarcoma, those with type 1 EWS-FLI1 fusions had longer overall survival than those with other types of EWS-FLI1 fusions. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition FLI1 EWSR1::FLI1 e7-e6 [biomarker_term_in_review] 1543 not_mapped AN5161-1 FLI1 EWSR1::FLI1 e7-e6 FLI1 NCBI:2313 gene Ewing sarcoma DOID:3369 prognostic CIViC:164 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition FLI1 EWSR1::FLI1 e7-e6 [biomarker_term_in_review] 1543 not_mapped AN5162-1 FLT3 Amplification FLT3 NCBI:2322 gene colorectal cancer DOID:9256 risk 47958-4 PubMed:33068284 A clinical study in 10 patients with Colorectal Cancer with FLT-3 amplification treated with Sunitinib. Two patients achieved SD, however one of the patients died due to disease progression. A PFS of 10.1 weeks (95% CI; 6.0-15.9) and OS of 38 weeks (95% CI; 7.0 - 47.6) were reported. Overall, no meaningful anti-tumor activity was observed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FLT3/NCBI:2322 1544 AN5162-1 FLT3 Amplification FLT3 NCBI:2322 gene colorectal cancer DOID:9256 risk 47958-4 CIViC:2492 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FLT3/NCBI:2322 1544 AN5163-1 FLT3 D835 mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 PubMed:23430109 An in-vitro saturation mutagenesis screen of 50 independently derived FLT3-ITD clones was performed to identify mutations that confer resistance to ponatinib. Mutations at 3 AL residues (D835 [n = 31], D839 [n = 3], and Y842 [n = 16]), with varying degrees of resistance to ponatinib were identified. FLT3 D835 mutations were shown to confer resistance to the tyrosine kinase inhibitor AC220 and ponatinib. This was especially found for D835Y and D835V mutations, whereas D835H mutations were found to confer moderate resistance to ponatinib but relatively minimal resistance to AC220. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D835 sequence variation in gene FLT3/NCBI:2322 1545 check_entity AN5163-1 FLT3 D835 mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 PubMed:19318574 An in-vitro cell-based screening approach generated FLT3-ITD-expressing cell lines resistant to the FLT3 inhibitors SU5614, PKC412, and sorafenib. SU5614 resistance mutations were limited to exchanges in the second part of the kinase domain (TK2), with exchanges of D835 predominating (D835E were most common). In clones that emerged at 1,500 nmol/L SU5614 after ENU (mutagen) treatment, 127 of 179 clones (71%) displayed mutations, generating 9 different exchanges affecting 6 positions in the activation loop of FLT3. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D835 sequence variation in gene FLT3/NCBI:2322 1545 check_entity AN5163-1 FLT3 D835 mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 PubMed:22504184 In an in-vitro study using an in vitro saturation mutagenesis assay, 4 residues with AC220 (quizartinib) resistance-conferring mutations in the kinase domain of FLT3-ITD were identified. Mutations at three of these amino acid positions conferred high degrees of in vitro AC220 resistance (based on proliferation and cell-based biochemical assays). Among these residues, two within the activation loop were found (D835, Y842). Pre-treatment and relapse samples of 8 patients (treated with AC220) with FLT3-ITD+ acute myeloid leukemia were analyzed. The activation loop mutation D835Y was detected in three cases, D835V in two, and D835F was identified in a single patient. Cross-resistance to sorafenib was identified in-vitro. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D835 sequence variation in gene FLT3/NCBI:2322 1545 check_entity AN5163-1 FLT3 D835 mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 PubMed:22368270 13 patients with relapsed or chemo-refractory FLT3-ITD+ AML were treated with sorafenib (200-400 mg twice daily). 12 patients responded, but sorafenib response was lost in most patients after 72 (range 54-287) days. Leukemia initiating cells bearing the D835 mutation expanded during sorafenib treatment and dominated during the subsequent clinical resistance. Results were recapitulated in-vivo. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D835 sequence variation in gene FLT3/NCBI:2322 1545 check_entity AN5163-1 FLT3 D835 mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 CIViC:433 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D835 sequence variation in gene FLT3/NCBI:2322 1545 check_entity AN5164-1 FLT3 D835H mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 PubMed:23969938 Three children with relapsed or refractory FLT3-ITD-positive AML were treated with sorafenib. FLT3 mutations were assessed before treatment and at the time of resistance. During the initiation of the treatment, all three patients had undetectable levels of FLT3 (D835H) mutations, however, after resistance developed, the mutation frequency rose to 33.1%, 35.7%, and 11.0% in the three patients. Ba/F3 cells expressing FLT3 mutants were resistant to sorafenib-dependent inhibition of cell viability assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D835H sequence variation in gene FLT3/NCBI:2322 1546 check_entity AN5164-1 FLT3 D835H mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 PubMed:27908881 Ba/F3 cells were transfected to express FLT3-ITD or FLT3 tyrosine kinase domain mutations. Immunoblots revealed gilteritinib IC50s of 2nM, 1.6nM, and 5nM for D835H, FLT3-ITD, and wildtype (cell line: SEMK2) cells, respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D835H sequence variation in gene FLT3/NCBI:2322 1546 check_entity AN5164-1 FLT3 D835H mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 CIViC:608 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D835H sequence variation in gene FLT3/NCBI:2322 1546 check_entity AN5165-1 FLT3 D835H/Y mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 PubMed:23969938 Mouse Ba/F3 cells with FLT3 mutations were evaluated for sorafenib resistance. Cells with single FLT3 (D835H/Y) mutants were resistant to sorafenib (IC50 81 nm/210 nM) whereas cells with FLT3 (ITD) mutants were not resistant to sorafenib (IC50 1.1 nM). Cells with double mutants (ITD-D835H/Y or ITD F691L) were highly resistant to sorafenib (IC50 460-3300 nM). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::d835h/y:mutation sequence variation in gene FLT3/NCBI:2322 1547 check_entity AN5165-1 FLT3 D835H/Y mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 CIViC:609 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::d835h/y:mutation sequence variation in gene FLT3/NCBI:2322 1547 check_entity AN5166-1 FLT3 D835I mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 PubMed:27908881 A 62-year-old female patient (AML5) was refractory to conventional chemotherapy and developed disease progression to quizartinib due to a D835I mutation. Using MTT to measure cytotoxicity, gilteritinib inhibited this patient’s relapse sample. Additionally, immunoblot demonstrated gilteritinib inhibited FLT3 phosphoryaltion at a concentration of 20 nM in the patient dereivd relapse cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D835I sequence variation in gene FLT3/NCBI:2322 1548 check_entity AN5166-1 FLT3 D835I mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 CIViC:2944 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D835I sequence variation in gene FLT3/NCBI:2322 1548 check_entity AN5167-1 FLT3 D835V mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 PubMed:15256420 Murine Ba/F3 cells with FLT3-D835V mutations were evaluated as non-responsive to MLN518 (Tandutinib). Cells with single FLT3 (D835V) mutants were resistant to MLN518(IC50 > 10uM) whereas cells with FLT3 (ITD) mutants were not resistant to MLN518 (IC50 0.55uM). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D835V sequence variation in gene FLT3/NCBI:2322 1549 check_entity AN5167-1 FLT3 D835V mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 PubMed:15304385 Murine Ba/F3 cells with FLT3 D835V mutation were assessed as not sensitive to SU11248 (Sunitinib) with dose required to inhibit proliferation of cells to 50% of untreated controls ED50 = 110nM. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D835V sequence variation in gene FLT3/NCBI:2322 1549 check_entity AN5167-1 FLT3 D835V mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 PubMed:23497317 Murine Ba/F3 cell line has a restrictive sensitivity to Quizartinib (AC220), a second generation class II tyrosine kinase inhibitor (IC50 for proliferation = 172nM, IC50 for induction of apoptosis = 888nM). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D835V sequence variation in gene FLT3/NCBI:2322 1549 check_entity AN5167-1 FLT3 D835V mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 PubMed:17330097 Murine Ba/F3 cells with FLT3 D835V mutation were assessed as sensitive to both AS602868 and AG1296.(IC50 = 1.85uM and IC50 = 4.55uM, respectively) assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D835V sequence variation in gene FLT3/NCBI:2322 1549 check_entity AN5167-1 FLT3 D835V mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 PubMed:15459012 In a retrospective study of 15 acute myeloid leukemia patients, the patients with FLT3 D835 mutation (n=2) were associated with improved response to sunitinib treatment (2/2 vs. 2/7) compared to FLT3 wild-type patients. The FLT3 D835 mutation positive patients were treated with sunitinib after failure of standard chemotherapy. After 4wk of sunitinib therapy, one patient showed morphological response and the other patient showed partial response to sunitinib therapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D835V sequence variation in gene FLT3/NCBI:2322 1549 check_entity AN5167-1 FLT3 D835V mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 PubMed:27908881 Ba/F3 cells were transfected to express FLT3-ITD or FLT3 tyrosine kinase domain mutations. Immunoblots revealed gilteritinib IC50s of 0.7nM, 1.6nM, and 5nM for D835H, FLT3-ITD, and wildtype (cell line: SEMK2) cells, respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D835V sequence variation in gene FLT3/NCBI:2322 1549 check_entity AN5167-1 FLT3 D835V mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 CIViC:1276 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D835V sequence variation in gene FLT3/NCBI:2322 1549 check_entity AN5168-1 FLT3 D835Y mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 PubMed:27908881 A 35 year-old male patient (AML4) presented with a FLT3-ITD mutation at diagnosis and was refractory to induction and salvage chemotherapy. He then received quizartinib and underwent allogenic transplant, but relapsed after 6 months. He then responded to sorafenib, but had disease progression with a FLT3-D835Y mutation. The patient derived relapse sample containing ITD and D835Y mutations was sensitive to gilteritinib based on cytotoxicity assays using MTT. Additionally, immunoblot demonstrated gilteritinib reduced FLT3 phosphorylation in Ba/F3 cells expressing only D835Y with an IC50 of 1.4 nM. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D835Y sequence variation in gene FLT3/NCBI:2322 1550 check_entity AN5168-1 FLT3 D835Y mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 PubMed:22368270 Thirteen relapsed FLT3 internal tandem duplication positive AML patients were treated with sorafenib. Emergence of D835Y mutation occurred in 3 patients following exposure to sorafenib, suggesting that D835Y leads to resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D835Y sequence variation in gene FLT3/NCBI:2322 1550 check_entity AN5168-1 FLT3 D835Y mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 CIViC:2880 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D835Y sequence variation in gene FLT3/NCBI:2322 1550 check_entity AN5168-1 FLT3 D835Y mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 CIViC:4616 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D835Y sequence variation in gene FLT3/NCBI:2322 1550 check_entity AN5168-2 FLT3 D835Y mutation FLT3 NCBI:2322 gene cancer DOID:162 risk 47958-4 PubMed:28516360 Gilteritinib inhibited the cell growth of Ba/F3 cells expressing D835Y (IC50 1.6 nM; 95% CI: 1.1–2.4 nM) compared to controls (IC50 420nM; 95% CI: 350–500 nM). Additionally, immunoblots showed gliteritinib reduced phosphorylation of FLT3 and downstream targets in Ba/F3 D835Y cells in a dose dependent manner. Furthermore, in nude mice xenografted with Ba/F3 cells expressing D835Y, gilteritinib showed antitumor efficacy at 10 mg/kg and 30 mg/kg, and induced tumor regression at 30 mg/k. Computational modelling demonstrated that gilteritinib interacts with activated FLT3 at the ATP-binding site, which is distant from the D835 containing activation loop. This inhibitory mechanism allows for kinase inhibition to occur in the face of D835 mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D835Y sequence variation in gene FLT3/NCBI:2322 1551 check_entity AN5168-2 FLT3 D835Y mutation FLT3 NCBI:2322 gene cancer DOID:162 risk 47958-4 CIViC:2880 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D835Y sequence variation in gene FLT3/NCBI:2322 1551 check_entity AN5169-1 FLT3 F691L mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 PubMed:22858906 A screen using saturation mutagenesis of FLT3/ITD followed by selection of transfected TF1 cells in FLT3 TKIs identified F691L. Cytotoxicity assessed by MTT demonstrated Ba/F3 cells expressing FLT3/ITD F691L conferred moderate resistance to lestaurtinib (IC50: 8nM) compared to FLT3/ITD control cells (IC50: 2nM). Immunoblotting showed lestaurtinib was able to partially inhibit FLT3 autophosphorylation and the activation of downstream pathways in Ba/F3 FLT3/ITD F691L cells. Structural modeling revealed F691 to be located in the ATP binding cleft. The authors hypothesize this amino acid change weakens inhibitor affinity as this residue likely makes direct contact with FLT3 TKIs. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F691L sequence variation in gene FLT3/NCBI:2322 1552 check_entity AN5169-1 FLT3 F691L mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 CIViC:2940 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F691L sequence variation in gene FLT3/NCBI:2322 1552 check_entity AN5170-1 FLT3 ITD mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:22490330 In young AML patients (<60 years old), DNMT3A mutation status was not predictive of overall and relapse free survival in patients with NPM1 mutations and wildtype FLT3 or wildtype NPM1 and FLT3-ITD. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1553 check_entity AN5170-1 FLT3 ITD mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:21067377 In AML patients with FLT3-ITD mutations, concurrent DNMT3A mutations were associated with worse overall survival compared to those without DNMT3A mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1553 check_entity AN5170-1 FLT3 ITD mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:19965647 ATRA treatment did not effect overall survival in patients <60 years old with FLT3-ITD mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1553 check_entity AN5170-1 FLT3 ITD mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:17957027 FLT3-ITD mutation without NPM1 was associated with increased relapse risk and reduced overall survival in young adult AML patients (median age 43). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1553 check_entity AN5170-1 FLT3 ITD mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:15626738 Ba/F3 cells with both FLT3-ITD and TKD mutations on the same allele have more resistance to daunorubicin than cells with FLT3-ITD alone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1553 check_entity AN5170-1 FLT3 ITD mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:21537333 FLT3-ITD duplication length did not effect prognosis in patients with an NPM1 mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1553 check_entity AN5170-1 FLT3 ITD mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:24801015 Meta-analysis of studies involving cytogentically normal younger (<60) patients showed reduced overall and relapse-free survival for patients with FLT3-ITD. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1553 check_entity AN5170-1 FLT3 ITD mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:16455956 Coocurrence of FLT3-ITD mutations significantly reduced overall (N=74 vs 95, P=0.003) and disease-free survival (N=43 vs 67, P=0.02) of normal karyotype AML patients (<60 years old) compared to patients with NPM1 mutations alone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1553 check_entity AN5170-1 FLT3 ITD mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:24855211 Patients with NPM1 mutations and low (<25%, N=63), intermediate (25-50%, N=156) or high (>50%, N=66) levels of FLT3-ITD have worse overall survival (P<0.0001 for trend) and cumulative incidence of relapse (P<0.001) than those with NPM1 mutations alone (N=387) in young adult, intermediate risk AML patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1553 check_entity AN5170-1 FLT3 ITD mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:11290608 WBC counts were higher in AML patients with internal tandem repeat of Flt3 compared to wild type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1553 check_entity AN5170-1 FLT3 ITD mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:14726387 CEP701 was effective in reducing blast counts of 5/14 heavily pre-treated AML patients with FLT3 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1553 check_entity AN5170-1 FLT3 ITD mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:18230792 Sorafenib is effective in patients with FLT3 internal tandem repeats, but not in wild type or D835 mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1553 check_entity AN5170-1 FLT3 ITD mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:12357354 AG1296 is effective in triggering apoptosis in Ba/F3 and primary AML cells with FLT3 internal tandem repeat. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1553 check_entity AN5170-1 FLT3 ITD mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:11585760 Simultaneous tandem repeat of FLT3 with loss of wild type FLT3 leads to poor survival and inferior disease free survival in patients with AML. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1553 check_entity AN5170-1 FLT3 ITD mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:22368270 13 patients with relapsed or chemo-refractory FLT3-ITD+ AML were treated with sorafenib (200-400 mg twice daily). 12 patients showed clearance or near clearance of bone marrow myeloblasts after 27 (range 21-84) days with evidence of differentiation of leukemia cells. Sorafenib response was lost in most patients after 72 (range 54-287) days. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1553 check_entity AN5170-1 FLT3 ITD mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:24178622 Forty-seven patients with relapsed/refractory AML or 60+ years old with untreated AML were enrolled on a phase II study. In FLT3 wild-type patients, six out of 36 (17%) had a response (1 PR, 3 MR, 2 uMR) that lasted a median of 58 days (range, 33–273 days). No patient with FLT3-ITD (n = 10) responded. One patient with unknown FLT3 status also had no response. Of note, this study did not meet its primary endpoint of 6 responses (CR, CRi, PR or MR) in the first 35 patients enrolled. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1553 check_entity AN5170-1 FLT3 ITD mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:27276561 In the absence of a FLT3 (ITD) mutation, a co-mutation of NPM1 and DNMT3A had a 50% 10-year survival rate, whereas triple-mutation of NPM1, DNMT3A, and FLT3 (ITD) had a 20% 10-year survival rate. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1553 check_entity AN5170-1 FLT3 ITD mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:23969938 Six children with relapsed or refractory FLT3-ITD-positive AML received initial therapy with sorafenib (alone or in combination with clofarabine and cytarabine). Four of the patients initially achieved morphological complete remission (bone marrow blasts <5%), however, 3 patients developed resistance within 14-37 weeks and and 1 required a bone marrow transplant. Two patients did not have any clinical response to sorafenib upon initial treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1553 check_entity AN5170-1 FLT3 ITD mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:21482694 In a preclinical trial, multiple experiments testing the effectiveness of ponatinib on the mutation FLT3-ITD in acute myeloid leukemia (AML) were conducted. Ponatinib was very effective in targeting the FLT3-ITD mutation in MV4-11 cell lines (growth inhibition: IC50=2 nmol/L) compared to native FLT3 in RS4;11 cell lines (IC50>100 nmol/L). Additionally, MV4-11 cell lines incubated for 1 hour were shown to have reduced phosphorylation of tyrosine kinases beginning at a ponatinib concentration of 0.3 nmol/L. Ponatinib was shown to induce apoptotic mechanisms measured by caspase-3/7 activity in MV4-cell lines. In mice with the MV4-11 xenograft, ponatinib was very effective in targeting the FLT3-ITD mutation, as dosages of 1-5 mg/kg led to tumor growth inhibition and regression, while dosages of 10 and 25 mg/kg led to complete tumor regression. In primary blast cells from AML patients, Ponatinib was selectively effective in growth inhibition of the FLT3-ITD patient cells (n=1, IC50=4nmol/L) when compared to the native FLT3 patient cells (n=3, IC50>100nmol/L). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1553 check_entity AN5170-1 FLT3 ITD mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:27908881 This study was designed to test the efficacy of FLT3 inhibitors in vitro against FLT3-ITD and other TKD variants clinically observed. IC50s were determined from immunoblots quantifying FLT3 phosphorylation in endogenous (Molm14) or ectopic expression FLT3-ITD cell lines (TF-1, Ba/F3) and the endogenous wildtype FLT3 SEMK2 cell line after gilteritinib treatment. IC50 values ranged from 1.4 to 1.8 nM in the three FLT3-ITD lines compared to 5nM in wildtype cells, suggesting increased sensitivity to the inhibitor. As measured by MTT assay, primary cultures from two AML patients with high allelic FLT3-ITD showed cytotoxic response to gilteritinib. Additionally, plasma taken from 3 patients receiving 120mg of gilteritinib daily was able to inhibit FLT3 phosphorylation in Molm14 cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1553 check_entity AN5170-1 FLT3 ITD mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:28516360 In vitro gilteritinib treatment of MV4-11 and MOLM-13 cells, which endogenously express FLT3-ITD, showed growth suppression based on CellTiter GLO cytotoxicity assays with IC50 values of 0.92 nM (95% CI: 0.23–3.6 nM) and 2.9 nM (95% CI: 1.4–5.8 nM), respectively. Phosphorylation of FLT3 and its downstream targets were rapidly inhibited in MV4-11 cells relative to control treatment (DMSO). In a mouse xenograft model using MV4-11 cells, increasing doses of gilteritinib further reduced tumor size and growth and inhibited phosphorylation of both FLT3 and STAT5 (N=6, p<0.05 at lowest dose). Gilteritinib inhibited growth in vitro of Ba/F3 cells expressing FLT3-ITD (IC50 1.8nM; 95% CI: 1.0-3.0 nM) and in vivo as tumor maintenance or shrinkage was also significant in mice xenografted with Ba/F3 FLT3-ITD cells (N=5, p<0.001). Mice receiving an intra-bone marrow injection of MV4-11 cells labelled with luciferase began gilteritinib treatment on day 15. Gilteritinib treated mice showed significantly less widespread disease at day 42 than control counterparts (N=10, p<0.001) and significantly improved survival (log-rank, p<0.001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1553 check_entity AN5170-1 FLT3 ITD mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 CIViC:55 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1553 check_entity AN5170-1 FLT3 ITD mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 CIViC:4616 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1553 check_entity AN5170-2 FLT3 ITD mutation FLT3 NCBI:2322 gene acute promyelocytic leukemia DOID:0060318 prognostic;risk 47958-4 PubMed:21461300 In a study of 53 APL patients treated with combination ATRA/anthracycline chemotherapy, patients with the FLT3 ITD mutation (n=10) had higher rates of relapse (30% vs. 2.5%), lower rates of remission (70% vs 87.5%), and lower 3-year Leukemia-Free Survival (44.4% vs. 84.4%). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1554 check_entity AN5170-2 FLT3 ITD mutation FLT3 NCBI:2322 gene acute promyelocytic leukemia DOID:0060318 prognostic;risk 47958-4 PubMed:24981688 In a study of 171 APL patients treated with combination ATRA/anthracycline chemotherapy, FLT3 ITD mutations (n=35) were associated with lower 3-year OS compared to the FLT3 ITD-negative group (62% vs. 82%), as well as higher CR achievement failure and early death. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1554 check_entity AN5170-2 FLT3 ITD mutation FLT3 NCBI:2322 gene acute promyelocytic leukemia DOID:0060318 prognostic;risk 47958-4 CIViC:55 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1554 check_entity AN5170-3 FLT3 ITD mutation FLT3 NCBI:2322 gene leukemia DOID:1240 risk 47958-4 PubMed:21482694 In a preclinical trial, the leukemic cell line MV4-11 with the FLT3-ITD mutation and the leukemic cell line RS4;11 with the native FLT3 gene were treated with the tyrosine kinase inhibitors (TKI) ponatinib, sorafenib, and sunitinib. Ponatinib was similarly effective in the growth inhibition of cells harboring the FLT3-ITD mutation (IC50=2 nmol/L) compared to sorafenib (IC50=4 nmol/L) and sunitinib (IC50=12 nmol/L). Conversely, all three TKIs each were not effective in the growth inhibition of cells with native FLT3 (IC50>100 nmol/L). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1555 check_entity AN5170-3 FLT3 ITD mutation FLT3 NCBI:2322 gene leukemia DOID:1240 risk 47958-4 CIViC:55 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::itd:mutation sequence variation in gene FLT3/NCBI:2322 1555 check_entity AN5171-1 FLT3 Mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 prognostic;risk 47958-4 PubMed:14726504 FLT3 mutations did not alter overall survival or remission duration in younger (16-60), cytogenetically normal AML patients with CEBPA mutations. 10/36 patients with CEBPA mutations also had FLT3 mutations (8 FLT3-ITD, 2 FLT3-D835). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene FLT3/NCBI:2322 1556 check_entity AN5171-1 FLT3 Mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 prognostic;risk 47958-4 PubMed:28546144 Midostaurin is FDA-approved for the treatment of newly-diagnosed acute myeloid leukemia patients harboring FLT3 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene FLT3/NCBI:2322 1556 check_entity AN5171-1 FLT3 Mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 prognostic;risk 47958-4 PubMed:28645776 In a phase 1/2 trial, patients with refractory or relapsed AML with FLT3 mutation (n=191; ITD n=162, D835 n=13, ITD-D835 n=16) received gilteritinib. 49% (93/191) of patients achieved an overall response, 9% (n=18) complete remission, 5% (n=10) complete remission with incomplete platelet recovery, 22% (n=42) complete remission with incomplete hematological recovery, and 12% (n=23) reached partial remission. The refractory or relapsed AML FLT wildtype group treated with gilteritinib(n=58) had lower overall response rate (12%), complete remission (2%), complete remission with incomplete platelet recovery (0%), complete remission with incomplete hematological recovery (7%), and fewer reached partiral remission (3%). Also, bone marrow myeloblast reduction was greater in FLT3 mutant patients compared to FLT3 wildtype. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene FLT3/NCBI:2322 1556 check_entity AN5171-1 FLT3 Mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 prognostic;risk 47958-4 PubMed:31665578 In this phase 3 trial (ADMIRAL), 371 patients with relapsed or refractory FLT3-mutated AML (required to have FLT3 ITD or TKD D835 or I836 mutations) were randomly assigned in a 2:1 ratio to receive either gilteritinib (n=247, at a dose of 120 mg per day) or salvage chemotherapy (n=124). Median overall survival in the gilteritinib group was significantly longer than in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P<0.001). Median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The complete remission rate with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). Notably, gilteritinib treatment resulted in similar median overall survival (9.3 months vs. 8.0 months) and percentage of complete remission (20.5% vs. 19.0%) in patients with ITD mutations and patients with TKD mutations. The authors concluded gilteritinib therapy in relapsed or refractory FLT3-mutated AML patients resulted longer survival and improved response versus salvage chemotherapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene FLT3/NCBI:2322 1556 check_entity AN5171-1 FLT3 Mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 prognostic;risk 47958-4 CIViC:515 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene FLT3/NCBI:2322 1556 check_entity AN5172-1 FLT3 Overexpression FLT3 NCBI:2322 gene B-cell adult acute lymphocytic leukemia DOID:0060592 risk 47958-4 PubMed:27181063 A 25-year-old Caucasian male presented with a second relapse of B-ALL. RNA sequencing revealed FLT3 overexpression (also confirmed by IHC). The patient was treated with 22 days of sunitinib, permitting the patient to undergo a bone marrow transplant. A bone marrow biopsy showed complete clearance by variant allele frequency and the patient remains in remission 4-years post matched-unrelated donor allograft. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene FLT3/NCBI:2322 1557 AN5172-1 FLT3 Overexpression FLT3 NCBI:2322 gene B-cell adult acute lymphocytic leukemia DOID:0060592 risk 47958-4 CIViC:599 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene FLT3/NCBI:2322 1557 AN5173-1 FLT3 T227M mutation FLT3 NCBI:2322 gene renal cell carcinoma DOID:4450 risk 47958-4 PubMed:19667267 In 219 patients with mostly Renal Cell Carcinoma and some Gastrointestinal Stromal tumors given sunitinib treatment, FLT3 T227M (rs1933437) was associated with the development of leukopenia. 95% confidence interval of hazard ratio of between .17 and .77. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T227M sequence variation in gene FLT3/NCBI:2322 1558 check_entity AN5173-1 FLT3 T227M mutation FLT3 NCBI:2322 gene renal cell carcinoma DOID:4450 risk 47958-4 CIViC:536 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T227M sequence variation in gene FLT3/NCBI:2322 1558 check_entity AN5174-1 FLT3 TKD MUTATION FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:17965322 Event-free survival was significantly improved in patients with both NPM1 and FLT3-TKD mutations compared to patients with 1) FLT3-TKD mutations alone 2) either NPM1 or FLT3-TKD when FLT3-ITD patients were excluded from the analysis 3) neither FLT3-TKD or NPM1 mutations or FLT3-TKD alone when only de novo, normal karyotype patients were analyzed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::tkd:mutation sequence variation in gene FLT3/NCBI:2322 1559 check_entity AN5174-1 FLT3 TKD MUTATION FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:11290608 WBC counts were not significantly different in AML patients with FLT3 D835 mutations compared to wild type. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::tkd:mutation sequence variation in gene FLT3/NCBI:2322 1559 check_entity AN5174-1 FLT3 TKD MUTATION FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:18230792 Sorafenib is effective in patients with FLT3 internal tandem repeat mutations, but not in patients with wild type or D835 mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::tkd:mutation sequence variation in gene FLT3/NCBI:2322 1559 check_entity AN5174-1 FLT3 TKD MUTATION FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:17940205 In AML patients, FLT3-TKD mutation was associated with poorer disease free survival compared to patients with wild type FLT3. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::tkd:mutation sequence variation in gene FLT3/NCBI:2322 1559 check_entity AN5174-1 FLT3 TKD MUTATION FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 PubMed:20733134 In a phase 2 clinical study of 95 AML/high-risk MDS patients treated with either 50 or 100 mg midostaurin, 35 harbored FLT3 mutations (26 had FLT3 ITD, 9 had FLT3 D835Y mutations). A higher percentage of patients saw blast reductions in the FLT3 mutant group than in the FLT3 wild type group (71 vs 42%). Only one permanent response occurred in a FLT3 mutant patient receiving the 100 mg dose. No differences were observed in toxicity or response rate between the two doses of midostaurin. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::tkd:mutation sequence variation in gene FLT3/NCBI:2322 1559 check_entity AN5174-1 FLT3 TKD MUTATION FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 47958-4 CIViC:56 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::tkd:mutation sequence variation in gene FLT3/NCBI:2322 1559 check_entity AN5175-1 FLT3 Y842C mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 PubMed:22858906 The authors used saturation mutagenesis of FLT3/ITD followed by selection of transfected cells in FLT3 TKI. The FLT3/ITD Y842C mutation produced high-level resistance to KW2449, sorafenib, sunitinib and AGS324 in vitro but remained sensitive to lestaurtinib and midostaurin. Balb/c mice transplanted with the FLT3/ITD Y842C mutation confirmed resistance to sorafenib in vivo but not to lestaurtinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y842C sequence variation in gene FLT3/NCBI:2322 1560 check_entity AN5175-1 FLT3 Y842C mutation FLT3 NCBI:2322 gene acute myeloid leukemia DOID:9119 risk 47958-4 CIViC:2939 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y842C sequence variation in gene FLT3/NCBI:2322 1560 check_entity AN5176-1 FNTB RS11623866 mutation FNTB NCBI:2342 gene ovarian cancer DOID:2394 risk PubMed:26033044 57 from 105 patients in the AGo-OVAR-15 trial were retrospectively genotyped for FNTB polymorphisms. Resistance to lonafarnib-containing treatment was limited to patients with a FNTB rs11623866 (c.-609G > C) GG genotype (HRPFS 6.2, 95%CI = 2.01, 19.41, P = 0.002; HROS 9.6, 95%CI = 1.89, 48.54, P = 0.006). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS11623866 sequence variation in gene FNTB/NCBI:100529261 1561 check_entity AN5176-1 FNTB RS11623866 mutation FNTB NCBI:2342 gene ovarian cancer DOID:2394 risk CIViC:328 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS11623866 sequence variation in gene FNTB/NCBI:100529261 1561 check_entity AN5177-1 FOS Overexpression FOS NCBI:2353 gene colon adenocarcinoma DOID:234 risk PubMed:27022066 A 67-year-old female presents with recurrent metastatic colonic adenocarcinoma. Immunohistochemical and genetic workup showed overexpression of c-JUN and FOS, which presumably signals through the RAAS pathway. The patient was treated with Irbesartan and after 5 weeks of therapy, the CEA value decreased from 18 to 3.1 and there was radiological resolution of the disease. Her 10 month CEA was 1.4. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene FOS/NCBI:2353 1562 AN5177-1 FOS Overexpression FOS NCBI:2353 gene colon adenocarcinoma DOID:234 risk CIViC:636 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene FOS/NCBI:2353 1562 AN5178-1 FOS TRUNCATING FUSION FOS NCBI:2353 gene bone epithelioid hemangioma DOID:6610 diagnostic PubMed:26173738 FOS was found fused with 3 different genes in 3 cases of bone epithelioid hemangioma. The fusion partners were not recurrent, respectively MBNL1, VIM and a lincRNA. The truncation of the FOS gene would result in the loss of the transactivation domain (TAD) in all three cases. Extension of this analysis identified FOS rearrangements in 5/7 additional classic epithelioid hemangiomas of bone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::truncating:fusion sequence variation in gene FOS/NCBI:2353 1563 check_entity AN5178-1 FOS TRUNCATING FUSION FOS NCBI:2353 gene bone epithelioid hemangioma DOID:6610 diagnostic CIViC:720 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::truncating:fusion sequence variation in gene FOS/NCBI:2353 1563 check_entity AN5179-1 FOXL2 C134W mutation FOXL2 NCBI:668 gene granulosa cell tumor DOID:2999 diagnostic 95785-2 PubMed:20693978 FOXL2 C134W mutation was found in 52 / 56 adult granulosa cell tumors, and is absent in other types of sex-cord stromal tumors, and juvenile granulosa tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C134W sequence variation in gene FOXL2/NCBI:668 1564 check_entity AN5179-1 FOXL2 C134W mutation FOXL2 NCBI:668 gene granulosa cell tumor DOID:2999 diagnostic 95785-2 CIViC:198 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C134W sequence variation in gene FOXL2/NCBI:668 1564 check_entity AN5179-2 FOXL2 C134W mutation FOXL2 NCBI:668 gene ovarian sex-cord stromal tumor DOID:0080369 diagnostic 95785-2 PubMed:26033501 FOXL2 mutations were found in 94% of pathologically confirmed A-GCTs (95/101), in one of eight juvenile granulosa cell tumours (J-GCTs), and in two of 19 SLCTs. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C134W sequence variation in gene FOXL2/NCBI:668 1565 check_entity AN5179-2 FOXL2 C134W mutation FOXL2 NCBI:668 gene ovarian sex-cord stromal tumor DOID:0080369 diagnostic 95785-2 CIViC:198 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C134W sequence variation in gene FOXL2/NCBI:668 1565 check_entity AN5180-1 FOXO1 PAX3::FOXO1 mutation FOXO1 NCBI:2308 gene alveolar rhabdomyosarcoma DOID:4051 diagnostic;prognostic;risk PubMed:12039929 In a cohort of 171 uniformly treated pediatric rhabdomyosarcoma (RMS) patients, 78 patients had alveolar rhabdomyosarcoma (ARMS). Of ARMS patients, 55% harbored a PAX3-FOXO1 fusion, 22% harbored a PAX7-FOXO1 fusion, and 23% were fusion negative. In contrast, all of the embryonal RMS or undifferentiated sarcoma patients (n=93) were fusion-negative. The authors concluded that PAX7-FOXO1 and PAX2-FOXO1 fusions are ARMS tumor specific. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PAX3::FOXO1 sequence variation in gene FOXO1/NCBI:2308 1566 check_entity AN5180-1 FOXO1 PAX3::FOXO1 mutation FOXO1 NCBI:2308 gene alveolar rhabdomyosarcoma DOID:4051 diagnostic;prognostic;risk PubMed:28446439 5 PAX3-FOXO1 fusion positive rhabdomyosarcoma cell lines exhibited greater sensitivity to BET bromodomain inhibitors than fusion negative lines and introduction of the PAX3-FOXO1 fusion to fibroblasts was sufficient to drive an 11 fold increase in sensitivity. The BET inhibitor JQ1 was efficacious in a PAX3-FOXO1 xenograft model. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PAX3::FOXO1 sequence variation in gene FOXO1/NCBI:2308 1566 check_entity AN5180-1 FOXO1 PAX3::FOXO1 mutation FOXO1 NCBI:2308 gene alveolar rhabdomyosarcoma DOID:4051 diagnostic;prognostic;risk PubMed:24436047 In this study, a total of 147 rhabdomyosarcomas/normal pairs were analyzed, 44 by whole genome sequencing and 103 tumors by whole exome sequencing. 50 cases classified as alveolar rhabdomyosarcoma histologically had either PAX3::FOXO1 fusion (n=35) or PAX7::FOXO1 fusion (n=15). Three other tumors harbored alternative PAX fusions (2 PAX3::NCOA1, 1 PAX3::INO80D). Unsupervised clustering of transcriptome expression showed that those cases clustered closely to the other alveolar rhabdomyosarcomas that had the classical PAX3/7::FOXO1 fusion. The remaining cases (n=94), including 7 alveolar rhabdomyosarcoma histology tumors were fusion negative. The latter showed somatic mutation and expression profile more consistent with embryonal rhabdomyosarcomas. This data supports PAX3/PAX7::FOXO1 fusions as diagnostic events in alveolar rhabdomyosarcomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PAX3::FOXO1 sequence variation in gene FOXO1/NCBI:2308 1566 check_entity AN5180-1 FOXO1 PAX3::FOXO1 mutation FOXO1 NCBI:2308 gene alveolar rhabdomyosarcoma DOID:4051 diagnostic;prognostic;risk CIViC:2455 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PAX3::FOXO1 sequence variation in gene FOXO1/NCBI:2308 1566 check_entity AN5181-1 FOXO1 PAX7::FOXO1 mutation FOXO1 NCBI:2308 gene alveolar rhabdomyosarcoma DOID:4051 diagnostic;prognostic PubMed:12039929 In a cohort of 171 uniformly treated pediatric rhabdomyosarcoma (RMS) patients, 78 patients had alveolar rhabdomyosarcoma (ARMS). Of ARMS patients, 55% harbored a PAX3-FOXO1 fusion, 22% harbored a PAX7-FOXO1 fusion, and 23% were fusion negative. In contrast, all of the embryonal RMS or undifferentiated sarcoma patients (n=93) were fusion-negative. The authors concluded that PAX7-FOXO1 and PAX3-FOXO1 fusions are ARMS tumor specific. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PAX7::FOXO1 sequence variation in gene FOXO1/NCBI:2308 1567 check_entity AN5181-1 FOXO1 PAX7::FOXO1 mutation FOXO1 NCBI:2308 gene alveolar rhabdomyosarcoma DOID:4051 diagnostic;prognostic PubMed:24436047 In this study, a total of 147 rhabdomyosarcomas/normal pairs were analyzed, 44 by whole genome sequencing and 103 tumors by whole exome sequencing. 50 cases classified as alveolar rhabdomyosarcoma histologically had either PAX3::FOXO1 fusion (n=35) or PAX7::FOXO1 fusion (n=15). Three other tumors harbored alternative PAX fusions (2 PAX3::NCOA1, 1 PAX3::INO80D). Unsupervised clustering of transcriptome expression showed that those cases clustered closely to the other alveolar rhabdomyosarcomas that had the classical PAX3/7::FOXO1 fusion. The remaining cases (n=94), including 7 alveolar rhabdomyosarcoma histology tumors were fusion negative. The latter showed somatic mutation and expression profile more consistent with embryonal rhabdomyosarcomas. This data supports PAX3/PAX7::FOXO1 fusions as diagnostic events in alveolar rhabdomyosarcomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PAX7::FOXO1 sequence variation in gene FOXO1/NCBI:2308 1567 check_entity AN5181-1 FOXO1 PAX7::FOXO1 mutation FOXO1 NCBI:2308 gene alveolar rhabdomyosarcoma DOID:4051 diagnostic;prognostic CIViC:2456 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PAX7::FOXO1 sequence variation in gene FOXO1/NCBI:2308 1567 check_entity AN5182-1 FOXP1 AMPLIFICATION FOXP1 NCBI:27086 gene diffuse large B-cell lymphoma DOID:0050745 diagnostic PubMed:18765795 Amplification of FOXP1 is shown to be associated with ABC DLBCL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FOXP1/NCBI:27086 1568 AN5182-1 FOXP1 AMPLIFICATION FOXP1 NCBI:27086 gene diffuse large B-cell lymphoma DOID:0050745 diagnostic CIViC:153 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene FOXP1/NCBI:27086 1568 AN5183-1 FOXP3 EXPRESSION FOXP3 NCBI:50943 gene breast cancer DOID:1612 risk PubMed:22431701 1,097 patients with breast cancer were evaluated for FOXP3 expression by IHC. FOXP3 expression was found in 405 tumor samples and associated with improved OS in patients treated with anthracycline-based adjuvant chemotherapy (6 cycles of 'FEC100' aka epirubicin + cyclophosphamide + 5-fluorouracil) but not in patients treated with sequential anthracycline->taxane (3 cycles of FEC100 followed by 3 cycles of docetaxel). In-vitro experiments confirmed that FOXP3 expression enhance anthracycline efficacy. The in vitro data consisted of testing the sensitivity of various breast cancer cell lines to anthracyclines after treatment with valproic acid (which increases FOXP3 expression). The authors observed that, while valproic acid has no intrinsic cytotoxic effect on tumor cells, it enhanced the cytotoxic effect of epirubicin specifically in cell lines where FOXP3 expression was increased. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene FOXP3/NCBI:50943 1569 AN5183-1 FOXP3 EXPRESSION FOXP3 NCBI:50943 gene breast cancer DOID:1612 risk CIViC:390 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene FOXP3/NCBI:50943 1569 AN5184-1 FOXR2 Rearrangement FOXR2 NCBI:139628 gene CNS neuroblastoma with FOXR2 activation DOID:0080906 diagnostic PubMed:26919435 Genome-wide DNA methylation profiles of 323 tumors with an institutional diagnosis of primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) has identified four novel methylation profiles. One of those profiles included CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2) which was seen in 14% (44/323) of the tumors. Genome-wide sequencing detected gene rearrangements involving the full-length coding sequence of FOXR2 with fusion partners JMJD1C, LOC550643, JPX, MAGEH1, or MAGED2 that resulted in high expression of FOXR2. The authors proposed that CNS NB-FOXR2 defines a specific molecular subtype of CNS neuroblastoma tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene FOXR2/NCBI:139628 1570 check_entity AN5184-1 FOXR2 Rearrangement FOXR2 NCBI:139628 gene CNS neuroblastoma with FOXR2 activation DOID:0080906 diagnostic PubMed:33536079 DNA methylation profiling of 84 CNS-PNET tumors identified four molecular groups of CNS-PNET. One of the molecular group was CNS neuroblastoma with forkhead box R2 (FOXR2) activation (CNS_NBL) which was presented in 20 cases (24%). RNA sequencing of 14 CNS_NBL tumors detected gene fusion transcripts involving the FOXR2 gene and fusion partners, FOXR2 (Xp11.21; intergenic duplication involving FOXR2 coding sequence [CDS]), LINC00486 (2p22), TM7SF3 (12p11.23), and FRMD4A (10p11.3). All 14 CNS_NBL tumors showed high level of FOXR2 gene expression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene FOXR2/NCBI:139628 1570 check_entity AN5184-1 FOXR2 Rearrangement FOXR2 NCBI:139628 gene CNS neuroblastoma with FOXR2 activation DOID:0080906 diagnostic CIViC:4620 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene FOXR2/NCBI:139628 1570 check_entity AN5185-1 GADD45A rs681673 mutation GADD45A NCBI:1647 gene ovarian cancer DOID:2394 diagnostic PubMed:26422378 GADD45A (1506T>C) association with ovarian cancer was investigated with 258 ovarian cancer patients and 332 age matched healthy women as controls using sequence analysis. A significant difference in genotype distribution was observed between cases and controls (TT vs. TC vs. CC, P = 0.0021). A statistically significant difference in the GADD454A (1506T>C) variant between the controls groups was found in correlation with an increased risk of ovarian cancer (P<0.001, OR = 1.71, 95% CI 1.28–2.29). Presence of the GADD45A (1506T>C) variant was also found to have higher GADD45A mRNA expression, longer ovarian cancer relapse free survival and overall survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::rs681673 sequence variation in gene GADD45A/NCBI:1647 1571 check_entity AN5185-1 GADD45A rs681673 mutation GADD45A NCBI:1647 gene ovarian cancer DOID:2394 diagnostic CIViC:686 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::rs681673 sequence variation in gene GADD45A/NCBI:1647 1571 check_entity AN5186-1 GAS6 EXPRESSION GAS6 NCBI:2621 gene oral squamous cell carcinoma DOID:0050866 prognostic PubMed:26207647 128 patients with oral squamous cell carcinoma (OSCC) and 145 normal control subjects were evaluated for the concentration of GAS6 in their plasma serum. OSCC patients were found to be associated with a significantly higher level of GAS6 in serum ( P = .05 ). Furthermore, within the OSCC patients, increased GAS6 serum concentration was associated with higher stage tumors ( P < .01) , poorly differentiated tumors ( P < .01 ), and increased lymph node metastasis ( OR = 2.79 ; CI = 1.72-4.48 ). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene GAS6/NCBI:2621 1572 AN5186-1 GAS6 EXPRESSION GAS6 NCBI:2621 gene oral squamous cell carcinoma DOID:0050866 prognostic CIViC:648 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene GAS6/NCBI:2621 1572 AN5186-2 GAS6 EXPRESSION GAS6 NCBI:2621 gene prostate cancer DOID:10283 risk PubMed:27153245 Prostate Cancer (PCa) cell lines were either cultured alone, co-cultured with osteoblasts expressing GAS6, or cultured in the presence of media with GAS6 to examine their response to therapy with docetaxel. Docetaxel efficiently induced apoptosis in the cells cultured without any GAS6, but it was not able to do so in the cells that were in media with GAS6 present or that were co-cultured with osteoblasts expressing GAS6. PCa cells in the presence of GAS6 were found to be in G1 phase for a greater duration which may help explain the increased resistance to docetaxel. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene GAS6/NCBI:2621 1573 AN5186-2 GAS6 EXPRESSION GAS6 NCBI:2621 gene prostate cancer DOID:10283 risk CIViC:648 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene GAS6/NCBI:2621 1573 AN5187-1 GATA2 EXPRESSION GATA2 NCBI:2624 gene lung adenocarcinoma DOID:3910 risk 95771-2 PubMed:22541434 Targeting overactive GATA2-mediated pathways with inhibitors bortezomib and fasudil led to dramatic tumor regression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene GATA2/NCBI:2624 1574 AN5187-1 GATA2 EXPRESSION GATA2 NCBI:2624 gene lung adenocarcinoma DOID:3910 risk 95771-2 CIViC:57 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene GATA2/NCBI:2624 1574 AN5188-1 GLI1 ACTB::GLI1 mutation GLI1 NCBI:2735 gene pericytoma with t(7;12) DOID:0080896 diagnostic PubMed:15555571 Pericytoma with t(7;12) is a soft tissue tumor characterized by fusion of the ACTB and GLI genes through the translocation t(7;12)(p22;q13). In this study the genomic breakpoints of 5 cases were characterized. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ACTB::GLI1 sequence variation in gene GLI1/NCBI:2735 1575 check_entity AN5188-1 GLI1 ACTB::GLI1 mutation GLI1 NCBI:2735 gene pericytoma with t(7;12) DOID:0080896 diagnostic CIViC:761 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ACTB::GLI1 sequence variation in gene GLI1/NCBI:2735 1575 check_entity AN5189-1 GNA11 Mutation GNA11 NCBI:2767 gene uveal melanoma DOID:6039 risk 100020-7 PubMed:26397223 Preclinical study in uveal melanoma cell lines. Cell lines (n=5) with GNAQ (92.1, Omm1.3, Mel270, Mel202) or GNA11 (Omm1) mutation were more sensitive to BRD4 inhibition with JQ1 than GNAQ/11 wild type (n=3) cell line. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene GNA11/NCBI:2767 1576 check_entity AN5189-1 GNA11 Mutation GNA11 NCBI:2767 gene uveal melanoma DOID:6039 risk 100020-7 PubMed:22805292 Phase 1 study of trametinib in 97 patients with melanoma (16 with uveal melanoma). Analysis in patients with uveal melanoma identified GNAQ and GNA11 mutations in six patients, in which three SD and three PD were the best responses. One patient with a GNA11 mutation identified by Illumina genotyping stayed on study treatment for >40 weeks. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene GNA11/NCBI:2767 1576 check_entity AN5189-1 GNA11 Mutation GNA11 NCBI:2767 gene uveal melanoma DOID:6039 risk 100020-7 PubMed:24141786 Preclinical study in uveal melanoma. Increased PKC activity was found in uveal melanoma cell lines with GNA11 or GNAQ mutations (n=6) compared to GNA wt cell lines (n=4) and could be induced by introducing these mutations into wt cell lines. Cell lines carrying GNA mutations were more sensitive to PKC inhibition with AEB071 and AHT956 in vitro and in vivo. Combined inhibition of MEK and PKC with AEB071 and PD0325901led to sustained MAPK-signalling blockade and induced apoptosis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene GNA11/NCBI:2767 1576 check_entity AN5189-1 GNA11 Mutation GNA11 NCBI:2767 gene uveal melanoma DOID:6039 risk 100020-7 PubMed:28103611 In total, 77 patients with metastatic melanoma (62% cutaneous, 30% uveal, 8% mucosal) were admitted into a randomized phase II trial assessing the efficacy of Cabozantinib. Patients received cabozantinib 100 mg/d during a 12-week lead-in. Patients with stable disease (SD; RECIST) at week 12 were randomized to cabozantinib or placebo. During lead-in phase, 55% of evaluable patients showed reduction in target lesion size (59% uveal melanoma). Uveal melanoma cohort included 23 patients, 9 with GNAQ (n=5) and GNA11 (n=4) mutations. Responses were reported in mutational patients. In the uveal melanoma cohort, 61% of patients (14/23) had SD at week 12, and no patient had a PR, resulting in an overall disease control rate of 61%. The median PFS for the 23 patients with uveal melanoma was 4.8 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene GNA11/NCBI:2767 1576 check_entity AN5189-1 GNA11 Mutation GNA11 NCBI:2767 gene uveal melanoma DOID:6039 risk 100020-7 CIViC:502 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene GNA11/NCBI:2767 1576 check_entity AN5190-1 GNA11 Q209 mutation GNA11 NCBI:2767 gene uveal melanoma DOID:6039 risk 100020-7 PubMed:24938562 101 patients with metastatic uveal melanoma were randomized 1:1 to receive selumetinib or chemotherapy. Median PFS among patients randomized to chemotherapy was 7 weeks (95% CI, 4.3-8.4 weeks; median treatment duration, 8 weeks; interquartile range [IQR], 4.3-16 weeks) vs. 15.9 weeks with selumetinib (95% CI, 8.4-21.1 weeks; median treatment duration, 16.1 weeks; IQR, 8.1-25.3 weeks) (hazard ratio, 0.46; 95% CI, 0.30-0.71; P < 0.001). Most patients (80/96 evaluable harbored a mutation in exon 5 of GNAQ or GNA11) but PFS benefit from Selumetinib compared to chemotherapy was greater in the GNAQ and GNA11 wild-type population (25.9 weeks [range, 3.7-40.4 weeks] vs 15.4 weeks [range, 8.1-16.9 weeks]). However, PFS was still better with Selumetinib than chemotherapy in the GNA mutant population (hazard ratio 0.55, 95% CI, 0.34-0.87; P = 0.01). The difference was explained by potential GNAQ or GNA11 mutations outside of exon 5 in the GNA wild-type population. Another three mutations in exon 4 were retrospectively identified in the wild-type population and one had a major response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q209 sequence variation in gene GNA11/NCBI:2767 1577 check_entity AN5190-1 GNA11 Q209 mutation GNA11 NCBI:2767 gene uveal melanoma DOID:6039 risk 100020-7 CIViC:554 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q209 sequence variation in gene GNA11/NCBI:2767 1577 check_entity AN5191-1 GNAQ Mutation GNAQ NCBI:2776 gene uveal melanoma DOID:6039 risk 100021-5 PubMed:26397223 Preclinical study in uveal melanoma cell lines. Cell lines (n=4) with GNAQ mutation (92.1, Omm1.3, Mel270, Mel202) were more sensitive to BRD4 inhibition with JQ1 than GNAQ/GNA11 wild type (n=3) cell line. JQ1 also inhibited growth of a GNAQ mutant cell line (92.1) in a mouse xenograft model compared to vehicle (N=5 mice/group). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene GNAQ/NCBI:2776 1578 check_entity AN5191-1 GNAQ Mutation GNAQ NCBI:2776 gene uveal melanoma DOID:6039 risk 100021-5 PubMed:22805292 Phase 1 study of trametinib in 97 patients with melanoma (16 with uveal melanoma). Analysis in patients with uveal melanoma identified GNAQ and GNA11 mutations in six patients, in which three SD and three PD were the best responses. One patient with a GNA11 mutation identified by Illumina genotyping stayed on study treatment for >40 weeks. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene GNAQ/NCBI:2776 1578 check_entity AN5191-1 GNAQ Mutation GNAQ NCBI:2776 gene uveal melanoma DOID:6039 risk 100021-5 PubMed:24141786 Preclinical study in uveal melanoma. Increased PKC activity was found in uveal melanoma cell lines with GNA11 or GNAQ mutations (n=6) compared to GNA wt cell lines (n=4) and could be induced by introducing these mutations into wt cell lines. Cell lines carrying GNA mutations were more sensitive to PKC inhibition with AEB071 and AHT956 in vitro and in vivo. Combined inhibition of MEK and PKC with AEB071 and PD0325901led to sustained MAPK-signalling blockade and induced apoptosis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene GNAQ/NCBI:2776 1578 check_entity AN5191-1 GNAQ Mutation GNAQ NCBI:2776 gene uveal melanoma DOID:6039 risk 100021-5 PubMed:28103611 Patients with metastatic melanoma (n=77; 48 cutaneous, 23 uveal, 6 mucosal) were enrolled in a phase II randomised discontinuation trial assessing cabozantinib. Patients received 100 mg cabozantinib daily for 12 weeks. Patients with stable disease (SD; RECIST; n=26) were randomly assigned to cabozantinib (n=13) or placebo (n=13). In the uveal melanoma cohort, 61% of patients (14/23, 61%) had SD at week 12. 9 patients had either a GNAQ (n=5) or GNA11 (n=4) mutation; only 10 patients were analyzed. Patients with GNAQ mutations remained on the study treatment from 1.4-10.3 months. The median PFS for the 23 patients with uveal melanoma was 4.8 months (41% PFS at 6 months) and median OS was 12.6 months. In the entire cohort, median overall PFS was 3.8 months (33% PFS at 6 months). After randomisation, median PFS for cabozantinib patients was 4.1 months and 2.8 months for placebo (HR 0.59, p=0.284). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene GNAQ/NCBI:2776 1578 check_entity AN5191-1 GNAQ Mutation GNAQ NCBI:2776 gene uveal melanoma DOID:6039 risk 100021-5 CIViC:501 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene GNAQ/NCBI:2776 1578 check_entity AN5192-1 GNAQ Q209 mutation GNAQ NCBI:2776 gene uveal melanoma DOID:6039 risk 100021-5 PubMed:24938562 101 patients with metastatic uveal melanoma were randomized 1:1 to receive selumetinib or chemotherapy. Median PFS among patients randomized to chemotherapy was 7 weeks (95% CI, 4.3-8.4 weeks; median treatment duration, 8 weeks; interquartile range [IQR], 4.3-16 weeks) vs. 15.9 weeks with selumetinib (95% CI, 8.4-21.1 weeks; median treatment duration, 16.1 weeks; IQR, 8.1-25.3 weeks) (hazard ratio, 0.46; 95% CI, 0.30-0.71; P < 0.001). Most patients (80/96 evaluable harbored a mutation in exon 5 of GNAQ or GNA11) but PFS benefit from Selumetinib compared to chemotherapy was greater in the GNAQ and GNA11 wild-type population (25.9 weeks [range, 3.7-40.4 weeks] vs 15.4 weeks [range, 8.1-16.9 weeks]). However, PFS was still better with Selumetinib than chemotherapy in the GNA mutant population (hazard ratio 0.55, 95% CI, 0.34-0.87; P = 0.01). The difference was explained by potential GNAQ or GNA11 mutations outside of exon 5 in the GNA wild-type population. Another three mutations in exon 4 were retrospectively identified in the wild-type population and one had a major response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q209 sequence variation in gene GNAQ/NCBI:2776 1579 check_entity AN5192-1 GNAQ Q209 mutation GNAQ NCBI:2776 gene uveal melanoma DOID:6039 risk 100021-5 PubMed:23434733 Phase 1 study of MAPK1/2 inhibitor BAY 86-9766. 53 patients were evaluated for efficacy, one patients achieved a PR and 11 patients had stable disease. One ocular melanoma patient with prolonged stable disease, who later went on to complete 28 courses, was positive for GNAQ Q209L and PTEN R173S mutations. The PTEN mutation was identified only in the postdose biopsy and not in the predose biopsy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q209 sequence variation in gene GNAQ/NCBI:2776 1579 check_entity AN5192-1 GNAQ Q209 mutation GNAQ NCBI:2776 gene uveal melanoma DOID:6039 risk 100021-5 CIViC:503 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q209 sequence variation in gene GNAQ/NCBI:2776 1579 check_entity AN5193-1 GNAQ Q209P mutation GNAQ NCBI:2776 gene skin melanoma DOID:8923 risk 100021-5 PubMed:24504448 A 26-year old patient presented with vemurafenib resistant BRAF-mutated (V600E) cutaneous melanoma. Five of his metastases were evaluated using whole genome sequencing. A GNAQ (Q209P) mutation was identified as unanimously present in all five tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q209P sequence variation in gene GNAQ/NCBI:2776 1580 check_entity AN5193-1 GNAQ Q209P mutation GNAQ NCBI:2776 gene skin melanoma DOID:8923 risk 100021-5 CIViC:600 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q209P sequence variation in gene GNAQ/NCBI:2776 1580 check_entity AN5194-1 GNAS R201 mutation GNAS NCBI:2778 gene pseudomyxoma peritonei DOID:3559 prognostic 41758-4 PubMed:27154293 Significantly shorter median progression-free survival was observed in relapsed pseudomyxoma peritonei patients with GNAS mutations (N=9; 5.3 months) as compared to wild-type (N=6; not reached; p < 0.007). The results were externally validated on a previous series of 11 peritoneal pseudomyxoma patients (5.1 vs 13 months; HR for progression 11.26, 95 % CI 3.62–35.06; log-rank test p < 0.0001). 14/15 patients evaluated also harbored KRAS exon 2 mutations but no NRAS or BRAF mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R201 sequence variation in gene GNAS/NCBI:2778 1581 check_entity AN5194-1 GNAS R201 mutation GNAS NCBI:2778 gene pseudomyxoma peritonei DOID:3559 prognostic 41758-4 CIViC:850 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R201 sequence variation in gene GNAS/NCBI:2778 1581 check_entity AN5195-1 GNAS R201C mutation GNAS NCBI:2778 gene colorectal cancer DOID:9256 risk 41758-4 PubMed:27729313 Phase 1b study of vemurafenib, cetuximab and irinotecan in 19 BRAF V600E mutant colorectal cancer patients. cfDNA panel sequencing was performed in 10 patients after disease progression. One patient acquired a novel GNAS1 R201C mutation at disease progression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R201C sequence variation in gene GNAS/NCBI:2778 1582 check_entity AN5195-1 GNAS R201C mutation GNAS NCBI:2778 gene colorectal cancer DOID:9256 risk 41758-4 CIViC:804 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R201C sequence variation in gene GNAS/NCBI:2778 1582 check_entity AN5196-1 GNAS R201H mutation GNAS NCBI:2778 gene thyroid gland follicular carcinoma DOID:3962 risk 41758-4 PubMed:26788326 A 79 year old patient with prior history of graves' disease presented with follicular thyroid carcinoma. Two mutations NRAS p.Q61K and GNAS p.R201H were detected. The thyroid cancer manifested as a 13.5 cm mass. There were minimal lung, humerus and T9 spine metastases, and exhibited a very good response to the radioactive iodine treatment after he had underwent total thyroidectomy and bilateral neck dissection. They also screened other 23 fatal cases and revealed that none of them had GNAS p.R201H mutation. But two of them had NRAS p.Q61K mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R201H sequence variation in gene GNAS/NCBI:2778 1583 check_entity AN5196-1 GNAS R201H mutation GNAS NCBI:2778 gene thyroid gland follicular carcinoma DOID:3962 risk 41758-4 CIViC:1293 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R201H sequence variation in gene GNAS/NCBI:2778 1583 check_entity AN5197-1 GNAS c.393T>C mutation GNAS NCBI:2778 gene bladder urothelial carcinoma DOID:4006 prognostic 41758-4 PubMed:15824158 This study demostrated that the progression-free survival, metastasis-free survival, and cancer-specific survival was significantly increased in patients with T393 homozygosity i.e. TT genotypes (56%, 84%, 82%) compared with CC genotypes (35%, 53%, 58%). In multivariate Cox proportional hazard analysis, the T393C polymorphism was an independent prognostic factor for clinical outcome. Homozygous CC patients were at highest risk for progression [odds ratio (OR), 1.94; P = 0.020], metastasis (OR, 3.49; P = 0.005), and tumor-related death (OR, 2.49; P = 0.031) compared with TT genotypes. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.393t>c:mutation sequence variation in gene GNAS/NCBI:2778 1584 check_entity AN5197-1 GNAS c.393T>C mutation GNAS NCBI:2778 gene bladder urothelial carcinoma DOID:4006 prognostic 41758-4 CIViC:851 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.393t>c:mutation sequence variation in gene GNAS/NCBI:2778 1584 check_entity AN5197-2 GNAS c.393T>C mutation GNAS NCBI:2778 gene breast carcinoma DOID:3459 prognostic 41758-4 PubMed:17186357 This study showed that the carriers of the T allele had a significantly less favourable course of the disease when compared to carriers of the homozygous CC genotype. GNAS 393C homozygous patients of pT2-4 stages displayed a significantly lower risk for death than T393 homozygous patients, with heterozygous patients being at intermediate risk. Ten-year survival rates were 63% for CC, 40% for TC and 23% for TT genotypes, respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.393t>c:mutation sequence variation in gene GNAS/NCBI:2778 1585 check_entity AN5197-2 GNAS c.393T>C mutation GNAS NCBI:2778 gene breast carcinoma DOID:3459 prognostic 41758-4 CIViC:851 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.393t>c:mutation sequence variation in gene GNAS/NCBI:2778 1585 check_entity AN5197-3 GNAS c.393T>C mutation GNAS NCBI:2778 gene chronic lymphocytic leukemia DOID:1040 prognostic 41758-4 PubMed:17020971 In a retrospective study of 144 patients with B-cell chronic lymphocytic leukemia, the median progression-free survival was significantly different between GNAS T393C genotypes (TT 130 months; TC 100 months; CC 31 months; P = 0.0066) and an independent prognostic factor for progression-free survival by multivariable analysis [hazard ratio (HR) CC versus TT 2.7; P = 0.010]. CC genotypes were at highest risk for death compared with T-alleles (median overall survival 197 vs 310 months, respectively) in both univariate (HR, 4.8; P < 0.0001) and multivariable analysis (HR, 5.6; P = 0.002). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.393t>c:mutation sequence variation in gene GNAS/NCBI:2778 1586 check_entity AN5197-3 GNAS c.393T>C mutation GNAS NCBI:2778 gene chronic lymphocytic leukemia DOID:1040 prognostic 41758-4 CIViC:851 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.393t>c:mutation sequence variation in gene GNAS/NCBI:2778 1586 check_entity AN5197-4 GNAS c.393T>C mutation GNAS NCBI:2778 gene clear cell renal cell carcinoma DOID:4467 prognostic 41758-4 PubMed:16467086 In this study, Kaplan-Meier curves for tumor progression, development of metastasis, and tumor-related death showed a significant association of the T393C polymorphism with outcome (5-year cancer-specific survival rates: TT, 91%; TC, 81%; CC, 69%; P = 0.015). Multivariate Cox proportional analysis of a 10-year follow-up confirmed the T393C polymorphism as an independent prognostic factor in clear cell renal cell carcinoma. Homozygous CC patients were at highest risk for progression (hazard ratio, 2.48; P = 0.009) or tumor-related death (hazard ratio, 3.15; P = 0.018) compared with T-allele carriers. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.393t>c:mutation sequence variation in gene GNAS/NCBI:2778 1587 check_entity AN5197-4 GNAS c.393T>C mutation GNAS NCBI:2778 gene clear cell renal cell carcinoma DOID:4467 prognostic 41758-4 CIViC:851 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.393t>c:mutation sequence variation in gene GNAS/NCBI:2778 1587 check_entity AN5197-5 GNAS c.393T>C mutation GNAS NCBI:2778 gene colorectal cancer DOID:9256 prognostic 41758-4 PubMed:16033819 In a retrospective study of 151 patients with sporadic colorectal cancer, 5-year survival rate was significantly higher in patients with International Union Against Cancer (UICC) stages I to II (mean follow-up, 43 months) and the GNAS1 T393C polymorphism-associated TT genotypes (87.8%) compared with TC (71.0%) and CC genotypes (50.0%; P = 0.009). No genotype effect could be observed for UICC stages III to IV. In multivariate Cox proportional analysis the T393C polymorphism was an independent prognostic factor for survival. Compatible with a gene-dose effect, homozygous CC patients were at highest risk for death (hazard ratio, 12.1; P = 0.006) compared with TT genotypes and heterozygous patients had an intermediate risk. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.393t>c:mutation sequence variation in gene GNAS/NCBI:2778 1588 check_entity AN5197-5 GNAS c.393T>C mutation GNAS NCBI:2778 gene colorectal cancer DOID:9256 prognostic 41758-4 CIViC:851 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.393t>c:mutation sequence variation in gene GNAS/NCBI:2778 1588 check_entity AN5197-6 GNAS c.393T>C mutation GNAS NCBI:2778 gene esophageal cancer DOID:5041 risk 41758-4 PubMed:19274060 Overall, 63% of the patients in the T-allele group (TT + CT), i.e with the T393C genotype, were minor responders with more than 10% residual vital tumor cells in resection specimens, whereas T(-) genotypes (CC) showed a major histopathological response with less than 10% residual vital tumor cells in 80%. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.393t>c:mutation sequence variation in gene GNAS/NCBI:2778 1589 check_entity AN5197-6 GNAS c.393T>C mutation GNAS NCBI:2778 gene esophageal cancer DOID:5041 risk 41758-4 CIViC:851 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.393t>c:mutation sequence variation in gene GNAS/NCBI:2778 1589 check_entity AN5197-7 GNAS c.393T>C mutation GNAS NCBI:2778 gene intrahepatic cholangiocarcinoma DOID:4928 prognostic 41758-4 PubMed:17356712 Intrahepatic cholangiocarcinomas of patients with homozygous TT genotypes revealed a higher proliferation rate and a lower apoptotic rate.This study demonstrated a significant association of both disease-specific OS and recurrence-free survival with the homozygous TT genotype of the GNAS1 gene (hazard ratio = 2.47; 95% CI = 1.03–7.28). Patients with T393 homozygosity exhibit a decreased survival time regardless of their resection status and show earlier tumor recurrence. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.393t>c:mutation sequence variation in gene GNAS/NCBI:2778 1590 check_entity AN5197-7 GNAS c.393T>C mutation GNAS NCBI:2778 gene intrahepatic cholangiocarcinoma DOID:4928 prognostic 41758-4 CIViC:851 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.393t>c:mutation sequence variation in gene GNAS/NCBI:2778 1590 check_entity AN5197-8 GNAS c.393T>C mutation GNAS NCBI:2778 gene lung non-small cell carcinoma DOID:3908 risk 41758-4 PubMed:24758907 The disease control rate of patients with GNAS1 T393C CC genotype was lower than that of patients with variant genotype (TT or CT) (46.2% vs 73.8%, P=0.039). Univariate analysis identified gender, smoking history, histology and GNAS1 T393C polymorphism as predictive marker of PFS (P=0.04, P<0.001, P<0.001 and P=0.005). Multivariate analysis of factors, including smoking history, performance status score, histology, GNAS1 T393C polymorphism demonstrated that GNAS1 T393C polymorphism was correlated independently with PFS (P=0.007). The data suggests the role of GNAS1 T393C CC genotype as a poor predictive marker both of DCR and PFS in advanced NSCLC patients treated with tyrosine kinase inhibitor. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.393t>c:mutation sequence variation in gene GNAS/NCBI:2778 1591 check_entity AN5197-8 GNAS c.393T>C mutation GNAS NCBI:2778 gene lung non-small cell carcinoma DOID:3908 risk 41758-4 CIViC:851 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.393t>c:mutation sequence variation in gene GNAS/NCBI:2778 1591 check_entity AN5197-9 GNAS c.393T>C mutation GNAS NCBI:2778 gene melanoma DOID:1909 prognostic 41758-4 PubMed:21156401 This study showed that GNAS1 T393C SNP represents a genetic host factor for predicting tumor progression in patients with malignant melanoma. Carriers of the C-allele showed a significantly more severe tumor progression as estimated from the time period to develop metastasis (HR 2.2, 95% CI 1.1-3.2, p = 0.017). Proportions of 5-year metastasis-free intervals were 87.1% for TT genotypes and 66.0% for C-allele carriers. Moreover, multivariable Cox regression analysis including tumor stage and melanoma subtype proved the T393C polymorphism to be an independent factor for metastasis (p = 0.012). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.393t>c:mutation sequence variation in gene GNAS/NCBI:2778 1592 check_entity AN5197-9 GNAS c.393T>C mutation GNAS NCBI:2778 gene melanoma DOID:1909 prognostic 41758-4 CIViC:851 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.393t>c:mutation sequence variation in gene GNAS/NCBI:2778 1592 check_entity AN5198-1 GSTP1 Deletion GSTP1 NCBI:2950 gene ovarian carcinoma DOID:4001 risk PubMed:25010864 Stable GSTP1 knockdown in ovarian carcinoma A2780 cell lines showed increased sensitivity to platinum-based chemotherapy drugs carboplatin, cisplatinum, carboplatin, and paclitaxel. For each drug, 3 biological replicates were performed for this study, and effectiveness was evaluated using an MTT assay. There was not a significant difference in sensitivity to other chemotherapy drugs such as gemcitabine, topotecan, and doxorubicin. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene GSTP1/NCBI:2950 1593 check_entity AN5198-1 GSTP1 Deletion GSTP1 NCBI:2950 gene ovarian carcinoma DOID:4001 risk CIViC:246 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene GSTP1/NCBI:2950 1593 check_entity AN5199-1 GSTP1 I105V mutation GSTP1 NCBI:2950 gene colorectal cancer DOID:9256 risk PubMed:19922504 Patients with the GSTP1 I105V variant had greater response to FOLFOX-4 treatment, longer progression-free survival, and longer overall survival. 166 Chinese patients with metastatic colorectal carcinoma who had been treated with FOLFOX-4 were used in this study. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I105V sequence variation in gene GSTP1/NCBI:2950 1594 check_entity AN5199-1 GSTP1 I105V mutation GSTP1 NCBI:2950 gene colorectal cancer DOID:9256 risk CIViC:255 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I105V sequence variation in gene GSTP1/NCBI:2950 1594 check_entity AN5200-1 H3-3A G34R mutation H3-3A NCBI:3020 gene diffuse glioma, H3 G34 mutant DOID:0080880 diagnostic PubMed:22286216 Whole-genome sequencing (WGS) was performed on the diffuse intrinsic pontine gliomas (DIPGs) and matched germline DNA of 7 pediatric patients. Targeted sequencing was performed on an additional 43 DIPGs and 36 non-brainstem pediatric glioblastomas (non-BS-PGs). Authors identified the G34R variant in 5/36 (14%) non-BS-PGs (age between 7 and 16 years). No histone H3 mutations were found in any other pediatric brain tumors including 7 low-grade brainstem gliomas, 15 low-grade non-brainstem gliomas, 38 medulloblastomas, and 22 ependymomas. H3F3A G34R was also not found in an additional 170 non-central nervous system pediatric tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G34R sequence variation in gene H3-3A/NCBI:3020 1595 check_entity AN5200-1 H3-3A G34R mutation H3-3A NCBI:3020 gene diffuse glioma, H3 G34 mutant DOID:0080880 diagnostic CIViC:3247 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G34R sequence variation in gene H3-3A/NCBI:3020 1595 check_entity AN5201-1 H3-3A G34W mutation H3-3A NCBI:3020 gene bone giant cell tumor DOID:4305 diagnostic PubMed:24162739 Behjati et al queried 53 samples of giant cell tumors of bone, which is a cancer typically identified in young adults, for histone gene variants. They identified 92% (49/53) with histone 3.3 variants exclusively in H3F3A (which were G34W or, in one case, G34L). Of the 53 samples, 12 were aged 25 or less. The authors queried these mutations in 268 other bone and cartilage cancers and did not identify G34W variant in any, although one G34R was identified in an osteosarcoma. The authors discuss these results as having diagnostic utility. Keyword: pediatric assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G34W sequence variation in gene H3-3A/NCBI:3020 1596 check_entity AN5201-1 H3-3A G34W mutation H3-3A NCBI:3020 gene bone giant cell tumor DOID:4305 diagnostic CIViC:2294 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G34W sequence variation in gene H3-3A/NCBI:3020 1596 check_entity AN5202-1 H3-3A K28M mutation H3-3A NCBI:3020 gene brain glioblastoma multiforme DOID:3073 diagnostic PubMed:22286216 Whole genome sequencing (WGS) was performed on the diffuse intrinsic pontine gliomas (DIPGs) and matched germline DNA of 7 pediatric patients. Targeted sequencing was performed on an additional 43 DIPGs and 36 non-brainstem pediatric glioblastomas (non-BS-PGs). Authors identified H3-3A K27M mutations in 30/50 (60%) of pediatric DIPGs (including 4/7 WGS samples) and 7/36 (19%) pediatric non-brainstem glioblastomas. The authors comment that the K27M mutation appeared exclusive to pediatric high grade gliomas, with H3F3A p.K27M mutation in one of 9 pediatric anaplastic astrocytomas (Grade III), but no histone H3 mutations found in any other pediatric brain tumors including 7 low-grade brainstem gliomas, 15 low-grade non-brainstem gliomas, 38 medulloblastomas, and 22 ependymomas. H3 K27M was not found in an additional 170 non-central nervous system pediatric tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K28M sequence variation in gene H3-3A/NCBI:3020 1597 check_entity AN5202-1 H3-3A K28M mutation H3-3A NCBI:3020 gene brain glioblastoma multiforme DOID:3073 diagnostic CIViC:2289 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K28M sequence variation in gene H3-3A/NCBI:3020 1597 check_entity AN5202-2 H3-3A K28M mutation H3-3A NCBI:3020 gene diffuse midline glioma, H3 K27M-mutant DOID:0080684 diagnostic PubMed:24705251 Wu et al analyzed 127 pediatric HGGs, including diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGGs (NBS-HGGs) by whole genome, whole exome, and/or transcriptome sequencing. In addition to ACVR1, they identified 41 recurrent K27M mutations in H3F3A (H3.3, 41/112 = 36.6%), and in 14 HIST1H3B (H3.1, 14/112, 12.5%) in NBS-HGGs and DIPGs. The authors focus on ACVR1 mutations, as H3F3A and HIST1H3A mutations in pediatric gliomas have previously been reported. However, this evidence helps confirm potential diagnostic utility of H3F3A K27M mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K28M sequence variation in gene H3-3A/NCBI:3020 1598 check_entity AN5202-2 H3-3A K28M mutation H3-3A NCBI:3020 gene diffuse midline glioma, H3 K27M-mutant DOID:0080684 diagnostic PubMed:22286216 Whole genome sequencing (WGS) was performed on the diffuse intrinsic pontine gliomas (DIPGs) and matched germline DNA of 7 pediatric patients. Targeted sequencing was performed on an additional 43 DIPGs and 36 non-brainstem pediatric glioblastomas (non-BS-PGs). Authors identified K27M mutations in 30/50 (60%) of pediatric DIPGs (including 4/7 WGS samples) and 7/36 (19%) pediatric non-brainstem glioblastomas. The authors comment that the K27M mutation appeared exclusive to pediatric high grade gliomas, with H3F3A p.K27M mutation in one of 9 pediatric anaplastic astrocytomas (Grade III), but no histone H3 mutations found in any other pediatric brain tumors including 7 low-grade brainstem gliomas, 15 low-grade non-brainstem gliomas, 38 medulloblastomas, and 22 ependymomas. H3 K27M was not found in an additional 170 non-central nervous system pediatric tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K28M sequence variation in gene H3-3A/NCBI:3020 1598 check_entity AN5202-2 H3-3A K28M mutation H3-3A NCBI:3020 gene diffuse midline glioma, H3 K27M-mutant DOID:0080684 diagnostic CIViC:2289 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K28M sequence variation in gene H3-3A/NCBI:3020 1598 check_entity AN5202-3 H3-3A K28M mutation H3-3A NCBI:3020 gene brain glioma DOID:0060108 risk PubMed:172409 In a phase 2 trial, patients with H3 K27M mutant glioma have been treated with DRD2 antagonist ONC201. Among 29 patients, 1 patient experienced complete clinical regression lasting >14 months, and 3 patients experienced durable partial response by RANO. 10 patients had a best response of stable disease by RANO, with a few of these patients showing substantial tumor regression in some lesions. Author concluded that ONC201 is well tolerated and has clinical activity against K27M-mutated glioma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K28M sequence variation in gene H3-3A/NCBI:3020 1599 check_entity AN5202-3 H3-3A K28M mutation H3-3A NCBI:3020 gene brain glioma DOID:0060108 risk CIViC:2289 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K28M sequence variation in gene H3-3A/NCBI:3020 1599 check_entity AN5203-1 H3-3A MUTATION H3-3A NCBI:3020 gene childhood low-grade glioma DOID:0080830 prognostic PubMed:29948154 Using Sanger sequencing, H3F3A mutations in patients with pediatric low-grade gliomas (PLGGs) were identified (K27M: 13/280; G34R: 5/280). Kaplan-Meier survival analysis showed that H3F3A mutations were associated with shorter progression-free survival (PFS) and overall survival (OS) [15 cases with H3F3A mutation (n=15) vs wt (n=197); p<0.0001 for both OS and PFS]. A further multivariate analysis indicated H3F3A mutation as an independent, unfavorable prognosis marker for both PFS [HR 2.76 (95% CI 1.10–6.94); p = 0.031] and OS [HR 3.96 (95% CI 1.36–11.53); p = 0.012]. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene H3-3A/NCBI:3020 1600 check_entity AN5203-1 H3-3A MUTATION H3-3A NCBI:3020 gene childhood low-grade glioma DOID:0080830 prognostic CIViC:2521 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene H3-3A/NCBI:3020 1600 check_entity AN5204-1 H3-3B K36M mutation H3-3B NCBI:3021 gene chondroblastoma DOID:2649 diagnostic PubMed:24162739 Behjati et al identified K36M mutations in a set of 77 chondroblastomas. Chondroblastoma is a typically a pediatric or early adult cancer. Of the 77, 5 had K36M mutations in H3F3A, 68 had K36M in H3F3B and 4 were WT. Of the 77, 65 of the cases were 25 years old or less. Of those, 3 had K36M in H3F3A and 59 had K36M in H3F3B with 3 being WT (See Supplementary Table 1). Thus, 59/65 (90.7%) cases at age 25 or less had K36M mutations in H3F3B. Behjati et al screened over 268 other bone and cartilage tumor types, and identified only 1 K36M H3F3B mutation (a clear cell chondrosarcoma). The authors conclude discussing the remarkable specificity of these mutations and implications for immediate diagnostic utility. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K36M sequence variation in gene H3-3B/NCBI:3020 1601 check_entity AN5204-1 H3-3B K36M mutation H3-3B NCBI:3021 gene chondroblastoma DOID:2649 diagnostic CIViC:2293 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K36M sequence variation in gene H3-3B/NCBI:3020 1601 check_entity AN5205-1 H3C2 K27M mutation H3C2 NCBI:8358 gene brain glioblastoma multiforme DOID:3073 diagnostic PubMed:22286216 Whole-genome sequencing (WGS) was performed on the diffuse intrinsic pontine gliomas (DIPGs) and matched germline DNA of 7 pediatric patients. Targeted sequencing was performed on an additional 43 DIPGs and 36 non-brainstem pediatric glioblastomas (non-BS-PGs). Authors identified the H3C2 K27M variant in 9/50 (18%) DIPGs (age between 4 and 12 years) and 1/36 (3%) non-BS-PGs (age of 4 years). The authors comment that the K27M mutation appeared exclusive to pediatric high grade gliomas, but no histone H3 mutations found in any other pediatric brain tumors including 7 low-grade brainstem gliomas, 15 low-grade non-brainstem gliomas, 38 medulloblastomas, and 22 ependymomas. H3 K27M was not found in an additional 170 non-central nervous system pediatric tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K27M sequence variation in gene H3C2/NCBI:8350 1602 check_entity AN5205-1 H3C2 K27M mutation H3C2 NCBI:8358 gene brain glioblastoma multiforme DOID:3073 diagnostic CIViC:2684 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K27M sequence variation in gene H3C2/NCBI:8350 1602 check_entity AN5205-2 H3C2 K27M mutation H3C2 NCBI:8358 gene diffuse midline glioma, H3 K27M-mutant DOID:0080684 diagnostic PubMed:22286216 Whole-genome sequencing (WGS) was performed on the diffuse intrinsic pontine gliomas (DIPGs) and matched germline DNA of 7 pediatric patients. Targeted sequencing was performed on an additional 43 DIPGs and 36 non-brainstem pediatric glioblastomas (non-BS-PGs). Authors identified the HIST1H3B K27M variant in 9/50 (18%) DIPGs (age between 3 and 12 years) and 1/36 (3%) non-BS-PGs (age of 4 years). Similar mutations in this and other H3 genes were highly recurrent in DIPG and not detected in other pediatric CNS tumors, including low-grade brainstem and non-brainstem gliomas, medulloblastomas, and ependymomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K27M sequence variation in gene H3C2/NCBI:8350 1603 check_entity AN5205-2 H3C2 K27M mutation H3C2 NCBI:8358 gene diffuse midline glioma, H3 K27M-mutant DOID:0080684 diagnostic CIViC:2684 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K27M sequence variation in gene H3C2/NCBI:8350 1603 check_entity AN5206-1 HAVCR2 Overexpression HAVCR2 NCBI:84868 gene lung non-small cell carcinoma DOID:3908 risk PubMed:26883990 In a preclinical study in an immunocompetent mouse model of lung adenocarcinoma, upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3, aka HAVCR2) was observed after progression under PD-1 antibody. A survival advantage was observed with the addition of a TIM-3 blocking antibody. Two patients who developed adaptive resistance to anti-PD-1 treatment also showed TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene HAVCR2/NCBI:84868 1604 AN5206-1 HAVCR2 Overexpression HAVCR2 NCBI:84868 gene lung non-small cell carcinoma DOID:3908 risk CIViC:482 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene HAVCR2/NCBI:84868 1604 AN5207-1 HGF EXPRESSION HGF NCBI:3082 gene glioblastoma DOID:3068 risk PubMed:22203985 Three metastatic glioblastoma cell lines were compared with their parental cell lines with regard to differential gene expression. HGF signalling was among the top pathways identified. Exogenous HFG led to an increase in MET activity (except in one cell line with high endogenous HGF levels) which was abrogated by MET inhibitor SGX523. Three HGF autocrine cell lines were grown in mice and showed significantly increased sensitivity to SGX523 than three non-HGF autocrine cell lines (P<0.05). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene HGF/NCBI:3082 1605 AN5207-1 HGF EXPRESSION HGF NCBI:3082 gene glioblastoma DOID:3068 risk CIViC:667 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene HGF/NCBI:3082 1605 AN5208-1 HIF1A 3' UTR Polymorphism HIF1A NCBI:3091 gene pancreatic adenocarcinoma DOID:4074 prognostic PubMed:26872370 The HIF1A rs2057482 SNP was genotyped in 410 pancreatic ductal adenocarcinoma cases and 490 healthy controls. The CC genotype was significantly correlated with PDAC risk (OR = 1.719, 95% CI: 1.293-2.286) and shorter overall survival (OS, P<0.0001), compared with the CT/TT alleles Group. After multivariate Analysis, CC-HIF1A and HIF-1α expression were still significantly associated with OS (P<0.0001). This SNP is expected to reduce MiR-199a induced repression of HIF-1α Expression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition HIF1A 3' UTR Polymorphism [biomarker_term_in_review] 1606 not_mapped AN5208-1 HIF1A 3' UTR Polymorphism HIF1A NCBI:3091 gene pancreatic adenocarcinoma DOID:4074 prognostic CIViC:429 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition HIF1A 3' UTR Polymorphism [biomarker_term_in_review] 1606 not_mapped AN5209-1 HIF1A EXPRESSION HIF1A NCBI:3091 gene renal cell carcinoma DOID:4450 risk PubMed:23881929 Immunohistochemical staining for HIF1A was performed on tumor samples from 65 patients that received pazopanib as part of VEG102616, of which 17 were classified as low expression and 48 were classified as high expression. The response rates of patients with low and high HIF1a expression to pazopanib were 52.9% and 29.1% (p=0.13), and there was no significant difference in PFS between the two groups (p=0.25). The authors concluded that HIF1a expression levels are not associated with clinical response to pazopanib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene HIF1A/NCBI:3091 1607 AN5209-1 HIF1A EXPRESSION HIF1A NCBI:3091 gene renal cell carcinoma DOID:4450 risk CIViC:656 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene HIF1A/NCBI:3091 1607 AN5210-1 HIF1A OVEREXPRESSION HIF1A NCBI:3091 gene colorectal cancer DOID:9256 prognostic PubMed:20363910 HIF1A overexpression was assessed by IHC in 731 colorectal cancers from two prospective cohort studies. 142 (19%) tumors showed HIF1A overexpression. Overexpression of HIF1A was associated with higher colorectal cancer-specific mortality in Kaplan-Meier analysis (log-rank test, P < 0.0001), univariate Cox regression (hazard ratio = 1.84; 95% confidence interval, 1.37 to 2.47; P < 0.0001) and multivariate analysis (adjusted hazard ratio = 1.72; 95% confidence interval, 1.26 to 2.36; P = 0.0007, adjusted for clinical and tumoral features: microsatellite instability, TP53 (p53), PTGS2 (cyclooxygenase-2), CpG island methylator phenotype, and KRAS, BRAF, PIK3CA, and LINE-1 methylation). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene HIF1A/NCBI:3091 1608 AN5210-1 HIF1A OVEREXPRESSION HIF1A NCBI:3091 gene colorectal cancer DOID:9256 prognostic CIViC:430 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene HIF1A/NCBI:3091 1608 AN5210-2 HIF1A OVEREXPRESSION HIF1A NCBI:3091 gene sarcoma DOID:1115 prognostic PubMed:17103226 Expression of HIF1A was analyzed by IHC in 49 soft-tissue sarcomas (29 malignant fibrous histiocytomas, 12 synovial sarcomas, 4 leiomyosarcomas and 4 malignant peripheral nerve sheath tumors). High (18.4%) or moderate (35.4%) expression of HIF-1alpha was significatnly associated with shorter overall survival rate in comparison with those with a weak or negative expression in univariate analysis (P = 0.029; log-rank test) and multivariate analysis (P = 0.018). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene HIF1A/NCBI:3091 1609 AN5210-2 HIF1A OVEREXPRESSION HIF1A NCBI:3091 gene sarcoma DOID:1115 prognostic CIViC:430 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene HIF1A/NCBI:3091 1609 AN5211-1 HLA-C COPY-NEUTRAL LOSS OF HETEROZYGOSITY HLA-C NCBI:3107 gene colorectal cancer DOID:9256 risk PubMed:27959684 A patient with metastatic colorectal cancer was enrolled in a phase 2 clinical trial (NCT01174121). 24 cultures of tumor-infiltrating lymphocytes were expanded from 3 lung metastasis resections. After cultures were tested for reactivity, the patient was infused with 1.48 x 10^11 tumor-infiltrating lymphocytes (75% CD8+ T cells) that were specifically reactive to KRAS G12D and HLA-C*08:02. A single lesion that progressed after 9 months still expressed the KRAS G12D mutation. Whole-exome analysis revealed copy-neutral loss of heterozygosity at chromosome 6, encoding the HLA locus and resulting in loss of the targeted HLA-C*08:02 allele. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition HLA-C COPY-NEUTRAL LOSS OF HETEROZYGOSITY [biomarker_term_in_review] 1610 not_mapped AN5211-1 HLA-C COPY-NEUTRAL LOSS OF HETEROZYGOSITY HLA-C NCBI:3107 gene colorectal cancer DOID:9256 risk CIViC:799 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition HLA-C COPY-NEUTRAL LOSS OF HETEROZYGOSITY [biomarker_term_in_review] 1610 not_mapped AN5212-1 HLA-DRA EXPRESSION HLA-DRA NCBI:3122 gene skin melanoma DOID:8923 risk PubMed:26822383 Melanoma patients treated with Anti-PD1 or anti-PD-L1(nivolumab, pembrolizumab, MPDL3280A) therapy were analyzed for expression of HLA-DRA (the primary antigen-presenting molecule of the MHC-II pathway). In a discovery cohort, 30 patients underwent IHC for HLA-DRA. 11/14 (79%) patients with positive HLA-DR staining, had complete (n=3) or partial (n=8) response. 6/16 (38%) HLA-DR non-expressing melanomas responded to therapy (overall response rate 79 versus 38%, Fisher’s exact test P=0.033). This finding was confirmed in a second independent data set of 23 melanoma patients with 6/8 (75%) of HLA-DR(+) tumours in comparison to 4/15 (27%) HLA-DR(−) responding (Fisher’s exact test P=0.025). Preclinical models confirmed the result. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene HLA-DRA/NCBI:3122 1611 AN5212-1 HLA-DRA EXPRESSION HLA-DRA NCBI:3122 gene skin melanoma DOID:8923 risk CIViC:419 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene HLA-DRA/NCBI:3122 1611 AN5213-1 HMOX1 EXPRESSION HMOX1 NCBI:3162 gene renal cell carcinoma DOID:4450 risk PubMed:26309414 In 66 patients with advanced renal cell carcinoma, high expression of heme oxygenase-1 (HO-1) was associated with poor overall response rate (2.6% versus 53.6%, P<0.01), clinical benefit rate (47.4% versus 92.9%, P<0.01), shorter progression-free survival (4.4 versus 42 months, P=0.022) and poor overall survival (χ (2)=4.775, P=0.029) in patients receiving sorafenib or sunitinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene HMOX1/NCBI:3162 1612 AN5213-1 HMOX1 EXPRESSION HMOX1 NCBI:3162 gene renal cell carcinoma DOID:4450 risk CIViC:340 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene HMOX1/NCBI:3162 1612 AN5214-1 HOXB13 G84E mutation HOXB13 NCBI:10481 gene prostate cancer DOID:10283 diagnostic PubMed:26108461 G84E (rs138213197) substitution in HOXB13 is associated with an increased risk for prostate cancer. 49 out of 9012 male patients in the Mayo Clinic Biobank were carriers. 31% of patients were diagnosed with cancer (n=2,595). Cancer diagnosis was more common in G84E carriers than in non-carriers (51.5% vs 30.6%, P = 0.004). G84E was highly prevalent in patients with prostate cancer than those without cancer (P < 0.0001). Evidence also supported a possible link between G84E with bladder cancer (P = 0.06) and leukemia (P = 0.01). Patient family history indicated a history of prostate cancer with a first degree relative was more common when compared to non-carriers (36.2% vs. 16.0%, P = 0.0003). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G84E sequence variation in gene HOXB13/NCBI:10481 1613 check_entity AN5214-1 HOXB13 G84E mutation HOXB13 NCBI:10481 gene prostate cancer DOID:10283 diagnostic PubMed:27626483 Meta-analysis of prostate cancer with sixteen case-control studies including 50,048 cases and 123,211 controls. In a random effect model the pooled OR (3.38 (95% CI: 2.45–4.66)) of the studies supported the link between HOXB13 G84E variant and a susceptibility to prostate cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G84E sequence variation in gene HOXB13/NCBI:10481 1613 check_entity AN5214-1 HOXB13 G84E mutation HOXB13 NCBI:10481 gene prostate cancer DOID:10283 diagnostic CIViC:753 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G84E sequence variation in gene HOXB13/NCBI:10481 1613 check_entity AN5215-1 HRAS G13D mutation HRAS NCBI:3265 gene colorectal cancer DOID:9256 risk 21698-6 PubMed:26561417 Case report of a patient with metastatic colorectal carcinoma and a novel HRAS G13D mutation showed resistance to treatment with panitumumab. In vitro models of HRAS G13D confirmed resistance mechanism in the same study. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13D sequence variation in gene HRAS/NCBI:3265 1614 check_entity AN5215-1 HRAS G13D mutation HRAS NCBI:3265 gene colorectal cancer DOID:9256 risk 21698-6 CIViC:270 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13D sequence variation in gene HRAS/NCBI:3265 1614 check_entity AN5215-2 HRAS G13D mutation HRAS NCBI:3265 gene skin squamous cell carcinoma DOID:3151 risk 21698-6 PubMed:22256804 In a retrospective study of 23 patients with BRAF V600 mutation (a known vemurafenib sensitizing mutation) that developed cutaneous squamous-cell carcinoma upon treatment with vemurafenib monotherapy, a patient harboring HRAS G13D co-mutation (n=1) was reported to be resistant to vemurafenib treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13D sequence variation in gene HRAS/NCBI:3265 1615 check_entity AN5215-2 HRAS G13D mutation HRAS NCBI:3265 gene skin squamous cell carcinoma DOID:3151 risk 21698-6 CIViC:270 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13D sequence variation in gene HRAS/NCBI:3265 1615 check_entity AN5216-1 HRAS Mutation HRAS NCBI:3265 gene bladder urothelial carcinoma DOID:4006 risk 21698-6 PubMed:32636318 4 of 16 patients with urothelial carcinoma harboring HRAS hotspot point mutations and 1 patient with an HRAS frameshift insertion had a partial response to the farnesyltransferase inhibitor tipifarnib while none of the 6 patients with wild-type HRAS responded. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene HRAS/NCBI:3265 1616 check_entity AN5216-1 HRAS Mutation HRAS NCBI:3265 gene bladder urothelial carcinoma DOID:4006 risk 21698-6 CIViC:271 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene HRAS/NCBI:3265 1616 check_entity AN5216-2 HRAS Mutation HRAS NCBI:3265 gene cancer DOID:162 risk 21698-6 PubMed:26544513 A pre-clinical study in 10 solid cancer cell lines. HRAS mutations (Q61L, Q61R and G12V) sensitized cell lines toward MEK inhibitors (AZD6244/selumetinib, MEK162 and PD0325901) and mTOR inhibitors (Everolimus and AZD8055). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene HRAS/NCBI:3265 1617 check_entity AN5216-2 HRAS Mutation HRAS NCBI:3265 gene cancer DOID:162 risk 21698-6 PubMed:35363510 In this phase II study of the arm E of the NCI-COG pediatric MATCH trial, 20 patients (median age: 14) were treated with Selumetinib. High-grade glioma (n=7) and rhabdomyosarcoma (n=7) were the most common types of cancers in this cohort. There was no objective response (PR or CR), the best overall response being SD, in three patients. The 6-month PFS rate was 15% (95% CI; 4-34). 25% of the patients had grade 3 or higher AEs, possibly attributed to selumetinib treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene HRAS/NCBI:3265 1617 check_entity AN5216-2 HRAS Mutation HRAS NCBI:3265 gene cancer DOID:162 risk 21698-6 CIViC:271 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene HRAS/NCBI:3265 1617 check_entity AN5216-2 HRAS Mutation HRAS NCBI:3265 gene cancer DOID:162 risk 21698-6 CIViC:4715 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene HRAS/NCBI:3265 1617 check_entity AN5216-2 HRAS Mutation HRAS NCBI:3265 gene cancer DOID:162 risk 21698-6 CIViC:4748 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene HRAS/NCBI:3265 1617 check_entity AN5216-3 HRAS Mutation HRAS NCBI:3265 gene head and neck squamous cell carcinoma DOID:5520 risk 21698-6 PubMed:33750196 In a phase II HNSCC trial, an objective response rate of 55% was seen in HRAS-mutant patients (11 of 20) treated with the farnesyltransferase inhibitor tipifarnib with a PFS of 5.6 months and an OS of 15.6 months (providing the allele fraction was at least 20%). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene HRAS/NCBI:3265 1618 check_entity AN5216-3 HRAS Mutation HRAS NCBI:3265 gene head and neck squamous cell carcinoma DOID:5520 risk 21698-6 CIViC:271 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene HRAS/NCBI:3265 1618 check_entity AN5217-1 HRAS Q61 mutation HRAS NCBI:3265 gene thyroid gland follicular carcinoma DOID:3962 prognostic 21698-6 PubMed:25448848 Follicular thyroid cancers harboring RAS mutations have limited aggressiveness in the absence of TERT mutations. 2/2 follicular thyroid cancer patients with co-mutations in NRAS (10 Q61R and 1 Q61K) or HRAS (2 Q61R and 1 Q61K) and TERT promoter mutations had persistent or recurrent disease compared to 1/11 patients with only a RAS mutation (100% vs 8%, P=0.03). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61 sequence variation in gene HRAS/NCBI:3265 1619 check_entity AN5217-1 HRAS Q61 mutation HRAS NCBI:3265 gene thyroid gland follicular carcinoma DOID:3962 prognostic 21698-6 CIViC:2443 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61 sequence variation in gene HRAS/NCBI:3265 1619 check_entity AN5218-1 HSPA5 EXPRESSION HSPA5 NCBI:3309 gene colorectal cancer DOID:9256 risk PubMed:23456958 Expression of GRP78 (HSPA5) in colorectal cancer patients (n=396, by IHC) showed improved benefit from adjuvant chemotherapy in stage III patients (52% vs. 28%; p = 0.026). In vitro, GRP78 inhibition reduced response to 5-FU. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene HSPA5/NCBI:3309 1620 AN5218-1 HSPA5 EXPRESSION HSPA5 NCBI:3309 gene colorectal cancer DOID:9256 risk CIViC:382 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene HSPA5/NCBI:3309 1620 AN5219-1 HSPB1 EXPRESSION HSPB1 NCBI:3315 gene pancreatic ductal adenocarcinoma DOID:3498 risk 95278-8 PubMed:22004109 HSP27 (HSPB1) expression in pancreatic adenocarcinoma cell lines was associated with sensitivity to treatment with gemcitabine. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene HSPB1/NCBI:3315 1621 AN5219-1 HSPB1 EXPRESSION HSPB1 NCBI:3315 gene pancreatic ductal adenocarcinoma DOID:3498 risk 95278-8 CIViC:396 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene HSPB1/NCBI:3315 1621 AN5220-1 HSPH1 NUCLEAR EXPRESSION HSPH1 NCBI:10808 gene gastric adenocarcinoma DOID:3717 prognostic;risk PubMed:26943774 HSP110 (HSPH1) expression was immunohistochemically assessed using a tissue microarray in 210 gastric cancer patients. The overall survival rate was significantly lower in patients with high nuclear expression (N=121, 2+ moderate/3+ strong staining) than patients with low nuclear staining (N=89, 0 no/1+ weak staining)(P = 0.0169). Multivariate regression analysis identified expression of nuclear HSP110 as an independent prognostic factor for gastric cancer outcome (P = 0.0068). This was not found for cytoplasmic expression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene HSPH1/NCBI:10808 1622 AN5220-1 HSPH1 NUCLEAR EXPRESSION HSPH1 NCBI:10808 gene gastric adenocarcinoma DOID:3717 prognostic;risk CIViC:486 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene HSPH1/NCBI:10808 1622 AN5221-1 HSPH1 T17 DELETION HSPH1 NCBI:10808 gene colorectal cancer DOID:9256 risk PubMed:24512910 329 consecutive patients with stage II–III colorectal tumors with MSI after surgical resection at tertiary medical centers were screened for HSP110 T(17) by PCR. Patients underwent adjuvant chemotherapy with 5-fluorouracil and oxaliplatin. Patients with large HSP110 T(17) deletions (≥5 bp; 18 of 77 patients, 23.4%) had longer times of relapse-free survival than patients with small or no deletions (≤4 bp; 59 of 77 patients, 76.6%) in multivariate analysis (hazard ratio, 0.16; 95% confidence interval, 0.012–0.8; P = .03). A significant interaction between chemotherapy and T17 deletion was found (P =.009). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::t17:deletion sequence variation in gene HSPH1/NCBI:10808 1623 check_entity AN5221-1 HSPH1 T17 DELETION HSPH1 NCBI:10808 gene colorectal cancer DOID:9256 risk CIViC:487 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::t17:deletion sequence variation in gene HSPH1/NCBI:10808 1623 check_entity AN5222-1 IDH1 Mutation IDH1 NCBI:3417 gene acute myeloid leukemia DOID:9119 risk 100022-3 PubMed:29860938 I phase 1 trial for patients with IDH1-mutated AML, patients who received ivosidenib (AG-120). The rate of complete remission was 21.6%, the over all response rate was 30.4%. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene IDH1/NCBI:3417 1624 check_entity AN5222-1 IDH1 Mutation IDH1 NCBI:3417 gene acute myeloid leukemia DOID:9119 risk 100022-3 PubMed:30725494 In this case series, 7 elderly patients with secondary AML (sAML) not eligible for intensive chemotherapy and refractory to HMA (including 1 patient with antecedent myeloproliferative neoplasm) were treated with venetoclax monotherapy. Three of 7 patients showed response. Of these: 2 patients achieved complete remission (1 of which was mutated for IDH2). One patient with IDH1 mutation showed PB blast clearance (derived anti-leukemic benefit) but BM was not performed to evaluate response. Venetoclax responders had high BCL‐2 and/or BIM expression levels in myeloblasts, and the response was significantly associated with OS. BCL-2 and BIM expression levels can potentially identifer venetoclax responders. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene IDH1/NCBI:3417 1624 check_entity AN5222-1 IDH1 Mutation IDH1 NCBI:3417 gene acute myeloid leukemia DOID:9119 risk 100022-3 CIViC:641 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene IDH1/NCBI:3417 1624 check_entity AN5222-2 IDH1 Mutation IDH1 NCBI:3417 gene brain glioma DOID:0060108 prognostic;risk 100022-3 PubMed:26061751 Genomewide analysis of 250 low-grade adult gliomas revealed that patients with a wildtype IDH1/2 had significantly shorter overall survival than those with a mutated IDH gene (HR 7.4; 95%CI: 4.0-13.8). The median survival for patients with low grade gliomas was 1.7 years for patients with wild-type IDH (N=55); 6.3 years for patients with mutated IDH and no 1p/19q co-deletion (N=139); and 8.0 years for patients with IDH mutation and a 1p/19q co-deletion (N=84). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene IDH1/NCBI:3417 1625 check_entity AN5222-2 IDH1 Mutation IDH1 NCBI:3417 gene brain glioma DOID:0060108 prognostic;risk 100022-3 PubMed:28148839 Mutations in isocitrate dehydrogenase 1 and 2, which result in overproduction of 2-hydroxyglutarate (2HG). 2HG is considered to be an oncometabolite, or a metabolite that promotes carcinogenesis, and inhibitors of mutant isocitrate dehydrogenase are in development to target this process. The authors discovered that 2HG overproduction impairs homologous recombination used in DNA repair and sensitizes cancer cells to treatment with PARP inhibitors, another class of cancer drugs that are already in clinical use. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene IDH1/NCBI:3417 1625 check_entity AN5222-2 IDH1 Mutation IDH1 NCBI:3417 gene brain glioma DOID:0060108 prognostic;risk 100022-3 CIViC:641 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene IDH1/NCBI:3417 1625 check_entity AN5222-3 IDH1 Mutation IDH1 NCBI:3417 gene cholangiocarcinoma DOID:4947 risk 100022-3 PubMed:31300360 In a phase1 trial, 73 patients with cholangiocarcinoma harboring IDH1 mutations were treated with mutant IDH1 inhibitor ivosidenib. The response rate was 5%, median progression free survival was 3.8 months, and median overall survival was 13.8 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene IDH1/NCBI:3417 1626 check_entity AN5222-3 IDH1 Mutation IDH1 NCBI:3417 gene cholangiocarcinoma DOID:4947 risk 100022-3 CIViC:641 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene IDH1/NCBI:3417 1626 check_entity AN5222-4 IDH1 Mutation IDH1 NCBI:3417 gene chondrosarcoma DOID:3371 prognostic 100022-3 PubMed:31615936 In a retrospective study, the authors evaluated the association between IDH1/IDH2 mutation and prognosis in patients with high-grade central chondrosarcoma. Although no association was discovered between IDH mutation status and the patient's overall survival, IDH1/IDH2 mutation was found to be associated with longer relapse free and metastasis free survival in high-grade chondrosarcomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene IDH1/NCBI:3417 1627 check_entity AN5222-4 IDH1 Mutation IDH1 NCBI:3417 gene chondrosarcoma DOID:3371 prognostic 100022-3 CIViC:641 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene IDH1/NCBI:3417 1627 check_entity AN5223-1 IDH1 R132 mutation IDH1 NCBI:3417 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic 100022-3 PubMed:20805365 Mutation status of IDH1 did not change event-free survival of patients with an NPM1 mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132 sequence variation in gene IDH1/NCBI:3417 1628 check_entity AN5223-1 IDH1 R132 mutation IDH1 NCBI:3417 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic 100022-3 PubMed:20376086 In leukemia patients, IDH1 R132 mutation is associated with adults and normal karyotype. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132 sequence variation in gene IDH1/NCBI:3417 1628 check_entity AN5223-1 IDH1 R132 mutation IDH1 NCBI:3417 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic 100022-3 PubMed:20368538 The complete remission and overall survival rates in patients with IDH1 R132 mutation is not significantly different from those who do not have this mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132 sequence variation in gene IDH1/NCBI:3417 1628 check_entity AN5223-1 IDH1 R132 mutation IDH1 NCBI:3417 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic 100022-3 CIViC:58 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132 sequence variation in gene IDH1/NCBI:3417 1628 check_entity AN5223-2 IDH1 R132 mutation IDH1 NCBI:3417 gene cholangiocarcinoma DOID:4947 risk 100022-3 PubMed:32416072 The multicenter randomized double-blind phase 3 study included patients with IDH1-mutant cholangiocarcinoma who had progressed on previous therapy. Patients were randomly assigned to Ivosidenib or placebo. Placebo to Ivosidenib crossover was permitted on radiological progression. The primary endpoint was progression-free survival by independent central review. Progression-free survival was significantly improved with Ivosidenib compared with the placebo (median 2.7, vs 1.4 months; hazard ratio 0.37; 95% CI 0.25-0.54; one-side p<0.0001). Median overall survival was 10.8 months for the Ivosidenib group versus 9.7 months for the placebo group (HR 0.69 [95% CI 0.44-1.10]; p=0.060) in which 35 patients were crossover from the placebo group. In a prespecified exploratory analysis, the rank-preserving structural failure time (RPSFT) method was used to reconstruct the survival curve for patients receiving a placebo as if crossover had never occurred. RPSFT assumes that the treatment effect is the same for all patients, regardless of when the treatment is given. The RPSFT-adjusted median overall survival was 6.0 months for the placebo group (HR 0.46 [95% CI 0.28-0.75]; p=0.0008). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132 sequence variation in gene IDH1/NCBI:3417 1629 check_entity AN5223-2 IDH1 R132 mutation IDH1 NCBI:3417 gene cholangiocarcinoma DOID:4947 risk 100022-3 CIViC:58 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132 sequence variation in gene IDH1/NCBI:3417 1629 check_entity AN5223-3 IDH1 R132 mutation IDH1 NCBI:3417 gene glioblastoma DOID:3068 prognostic 100022-3 PubMed:20127344 In patients with glioblastoma, those harboring IDH1 R132 mutation has higher overall survival compared to those who do not have IDH1 mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132 sequence variation in gene IDH1/NCBI:3417 1630 check_entity AN5223-3 IDH1 R132 mutation IDH1 NCBI:3417 gene glioblastoma DOID:3068 prognostic 100022-3 PubMed:19228619 In patients with a glioblastoma, those with mutations at R132 of IDH1 had better overall survival than wild-type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132 sequence variation in gene IDH1/NCBI:3417 1630 check_entity AN5223-3 IDH1 R132 mutation IDH1 NCBI:3417 gene glioblastoma DOID:3068 prognostic 100022-3 CIViC:58 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132 sequence variation in gene IDH1/NCBI:3417 1630 check_entity AN5223-4 IDH1 R132 mutation IDH1 NCBI:3417 gene high grade glioma DOID:3070 risk 100022-3 PubMed:22199315 In a clinical study of 63 recurrent glioma patients, the combined cohort of patients treated with either bevacizumab or sunitinib showed that those harboring IDH1 codon 132 mutation were associated with improved overall survival (OS 7.53 vs. 4.83 months; P=0.04), as compared to patients with wild-type IDH1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132 sequence variation in gene IDH1/NCBI:3417 1631 check_entity AN5223-4 IDH1 R132 mutation IDH1 NCBI:3417 gene high grade glioma DOID:3070 risk 100022-3 CIViC:58 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132 sequence variation in gene IDH1/NCBI:3417 1631 check_entity AN5223-5 IDH1 R132 mutation IDH1 NCBI:3417 gene intrahepatic cholangiocarcinoma DOID:4928 risk 100022-3 PubMed:27231123 Through a high-throughput drug screen of a large panel of cancer cell lines, including 17 biliary tract cancers, this work found that IDH mutant (IDHm) ICC cells demonstrate a striking response to the multikinase inhibitor dasatinib, identifying SRC as a critical dasatinib target in IDHm ICC. Dasatinib-treated IDHm xenografts exhibited pronounced apoptosis and tumor regression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132 sequence variation in gene IDH1/NCBI:3417 1632 check_entity AN5223-5 IDH1 R132 mutation IDH1 NCBI:3417 gene intrahepatic cholangiocarcinoma DOID:4928 risk 100022-3 CIViC:58 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132 sequence variation in gene IDH1/NCBI:3417 1632 check_entity AN5223-6 IDH1 R132 mutation IDH1 NCBI:3417 gene malignant astrocytoma DOID:3069 prognostic 100022-3 PubMed:19933982 In patients with astrocytoma, the presence of IDH1 R132 mutation is prognostic for better survival compared to patients who harbor wild type mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132 sequence variation in gene IDH1/NCBI:3417 1633 check_entity AN5223-6 IDH1 R132 mutation IDH1 NCBI:3417 gene malignant astrocytoma DOID:3069 prognostic 100022-3 PubMed:19228619 In patients with anaplastic astrocytoma, those with mutations at R132 of IDH1 had better overall survival than wild-type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132 sequence variation in gene IDH1/NCBI:3417 1633 check_entity AN5223-6 IDH1 R132 mutation IDH1 NCBI:3417 gene malignant astrocytoma DOID:3069 prognostic 100022-3 CIViC:58 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132 sequence variation in gene IDH1/NCBI:3417 1633 check_entity AN5223-7 IDH1 R132 mutation IDH1 NCBI:3417 gene myelodysplastic syndrome DOID:0050908 prognostic 100022-3 PubMed:20494930 IDH1 R132 mutation in patients suffering from myelodysplastic syndromes is associated with worse overall survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132 sequence variation in gene IDH1/NCBI:3417 1634 check_entity AN5223-7 IDH1 R132 mutation IDH1 NCBI:3417 gene myelodysplastic syndrome DOID:0050908 prognostic 100022-3 CIViC:58 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132 sequence variation in gene IDH1/NCBI:3417 1634 check_entity AN5224-1 IDH1 R132C mutation IDH1 NCBI:3417 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 100022-3 PubMed:20538800 IDH1 R132 mutation is associated with patients of older age, high platelet count during diagnosis, cytogenic normalcy and NPM1 mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132C sequence variation in gene IDH1/NCBI:3417 1635 check_entity AN5224-1 IDH1 R132C mutation IDH1 NCBI:3417 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 100022-3 PubMed:26436839 Newly developed allosteric inhibitors (GSK321) of IDH1 led to granulocytic differentiation in-vitro and in-vivo. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132C sequence variation in gene IDH1/NCBI:3417 1635 check_entity AN5224-1 IDH1 R132C mutation IDH1 NCBI:3417 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 100022-3 PubMed:25583779 In a clinical study of 17 relapsed or refractory AML patients harboring IDH1 mutations, these patients were associated with response to AG-120 monotherapy; 4/7 patients who achieved a response experienced complete remission. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132C sequence variation in gene IDH1/NCBI:3417 1635 check_entity AN5224-1 IDH1 R132C mutation IDH1 NCBI:3417 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 100022-3 PubMed:24333121 In an experimental study of acute myeloid leukemia (AML) cell lines expressing IDH1 R132C, IDH1 R132G, or IDH1 R132H mutations were associated with increased sensitivity to small molecule glutaminase inhibitor, bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) as compared to AML cell lines expressing wild-type IDH1. Sensitivity was determined by assessing cell growth. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132C sequence variation in gene IDH1/NCBI:3417 1635 check_entity AN5224-1 IDH1 R132C mutation IDH1 NCBI:3417 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 100022-3 CIViC:59 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132C sequence variation in gene IDH1/NCBI:3417 1635 check_entity AN5224-2 IDH1 R132C mutation IDH1 NCBI:3417 gene brain glioma DOID:0060108 risk 100022-3 PubMed:20975057 In a study of 189 low-grade gliomas, IDH (IDH1 or IDH2) mutations were found in 132 patients (70%). IDH mutations were associated with improved rate of response to temozolomide as compared to patients with wildtype IDH (61% vs. 17% , P=0.01). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132C sequence variation in gene IDH1/NCBI:3417 1636 check_entity AN5224-2 IDH1 R132C mutation IDH1 NCBI:3417 gene brain glioma DOID:0060108 risk 100022-3 CIViC:59 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132C sequence variation in gene IDH1/NCBI:3417 1636 check_entity AN5224-3 IDH1 R132C mutation IDH1 NCBI:3417 gene cancer DOID:162 risk 100022-3 PubMed:28148839 IDH1 R132C mutation confers a switch of function mutation where the mutated protein produces 2-hydroxyglutarate (2HG), rather than α-ketoglutarate (αKG). The novel metabolite induces a homologous recombination (HR) defect that sensitizes the tumor cells to poly (ADP-ribose) polymerase (PARP) inhibitors. PARP inhibitor sensititivity was tested in vivo in HeLa cells where the R132C mutation was create with CRISPR, the HCT116 colon cancer cell line where R132C mutation was created with recombinant adeno-associated virus (rAAV), and the HT1080 human sarcoma cell line which already has R132C. The results were then duplicated in non-commercial glioma cell lines: 6 IDH1 R132 mutant; 4 IDH1 wt. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132C sequence variation in gene IDH1/NCBI:3417 1637 check_entity AN5224-3 IDH1 R132C mutation IDH1 NCBI:3417 gene cancer DOID:162 risk 100022-3 CIViC:59 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132C sequence variation in gene IDH1/NCBI:3417 1637 check_entity AN5224-4 IDH1 R132C mutation IDH1 NCBI:3417 gene high grade glioma DOID:3070 risk 100022-3 PubMed:23558169 In an experimental in vitro study, glioma cells expressing IDH1 R132C were associated with sensitivity to AGI-5198 (IC50: 0.16M vs. IC50 > 100.00M), as compared to cells expressing wild-type IDH1. Sensitivity was determined by assessing cell growth. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132C sequence variation in gene IDH1/NCBI:3417 1638 check_entity AN5224-4 IDH1 R132C mutation IDH1 NCBI:3417 gene high grade glioma DOID:3070 risk 100022-3 CIViC:59 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132C sequence variation in gene IDH1/NCBI:3417 1638 check_entity AN5225-1 IDH1 R132H mutation IDH1 NCBI:3417 gene oligodendroglioma DOID:3181 risk 100022-3 PubMed:23558169 In pre-clinical studies, an IDH1 inhibitor (AG-5198) impaired growth of glioma / anaplastic oligodendroglioma cell lines with IDH1 R132H mutations. A phase I clinical trial of the AG-120 IDH1 inhibitor in IDH1 mutant positive solid tumors, including glioma is currently underway. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132H sequence variation in gene IDH1/NCBI:3417 1639 check_entity AN5225-1 IDH1 R132H mutation IDH1 NCBI:3417 gene oligodendroglioma DOID:3181 risk 100022-3 CIViC:416 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132H sequence variation in gene IDH1/NCBI:3417 1639 check_entity AN5225-2 IDH1 R132H mutation IDH1 NCBI:3417 gene pancreatic ductal adenocarcinoma DOID:3498 risk 100022-3 PubMed:27466707 A 48-year-old female was diagnosed with metastatic pancreatic ductal adenocarcinoma and subsequently started on standard of care chemotherapy, during which her hepatic lesions progressed. Detailed molecular profiling was performed on a biopsy from a liver lesion that demonstrated an IDH1 mutation, R132H. The patient subsequently received a mutant IDH1 inhibitor (AG-120), but with no response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132H sequence variation in gene IDH1/NCBI:3417 1640 check_entity AN5225-2 IDH1 R132H mutation IDH1 NCBI:3417 gene pancreatic ductal adenocarcinoma DOID:3498 risk 100022-3 CIViC:416 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R132H sequence variation in gene IDH1/NCBI:3417 1640 check_entity AN5226-1 IDH2 Mutation IDH2 NCBI:3418 gene acute myeloid leukemia DOID:9119 prognostic;risk 100023-1 PubMed:20421455 In patients with IDH2 R140 and R172 mutation, the presence of mutation does not impact overall survival or disease free survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene IDH2/NCBI:3418 1641 check_entity AN5226-1 IDH2 Mutation IDH2 NCBI:3418 gene acute myeloid leukemia DOID:9119 prognostic;risk 100023-1 PubMed:28193778 Mutations in IDH1 or IDH2 are identified in approximately 20% of patients with AML.This study report the discovery and characterization of AG-221, orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed oncometobolite 2HG production and induced cellular differentiation in primary human IDH2 mutated AML cells in vivo and in xenograft mouse models, providing a statistically significant benefit in an aggressive IDH2 R140Q-mutant AML xenograft mouse model. Clinical trials are ongoing. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene IDH2/NCBI:3418 1641 check_entity AN5226-1 IDH2 Mutation IDH2 NCBI:3418 gene acute myeloid leukemia DOID:9119 prognostic;risk 100023-1 PubMed:28588020 A first-in-human phase 1/2 trial assessing the pharmacology, safety and activity of Enasidenib in IDH2-mutant myeloid hematoblastosis patients. In the AML subgroup (n=176, (n=130 R140; n=45 R172; n=1 Other)) of included patients (n=239) the overall response rate was 40.3%, with median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) with complete response was 19.7 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene IDH2/NCBI:3418 1641 check_entity AN5226-1 IDH2 Mutation IDH2 NCBI:3418 gene acute myeloid leukemia DOID:9119 prognostic;risk 100023-1 PubMed:30725494 In this case series, 7 elderly patients with secondary AML (sAML) not eligible for intensive chemotherapy and refractory to HMA (including 1 patient with antecedent myeloproliferative neoplasm) were treated with venetoclax monotherapy. Three of 7 patients showed response. Of these: 2 patients achieved complete remission (1 of which was mutated for IDH2). One patient with IDH1 mutation showed PB blast clearance (derived anti-leukemic benefit) but BM was not performed to evaluate response. Venetoclax responders had high BCL‐2 and/or BIM expression levels in myeloblasts, and the response was significantly associated with OS. BCL-2 and BIM expression levels can potentially identifer venetoclax responders. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene IDH2/NCBI:3418 1641 check_entity AN5226-1 IDH2 Mutation IDH2 NCBI:3418 gene acute myeloid leukemia DOID:9119 prognostic;risk 100023-1 CIViC:566 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene IDH2/NCBI:3418 1641 check_entity AN5226-2 IDH2 Mutation IDH2 NCBI:3418 gene brain glioma DOID:0060108 prognostic 100023-1 PubMed:26061751 Genomewide analysis of 250 low-grade adult gliomas revealed that patients with a wildtype IDH1/2 had significantly shorter overall survival than those with a mutated IDH gene (HR 7.4; 95%CI: 4.0-13.8). The median survival for patients with low grade gliomas was 1.7 years for patients with wild-type IDH (N=55); 6.3 years for patients with mutated IDH and no 1p/19q co-deletion (N=139); and 8.0 years for patients with IDH mutation and a 1p/19q co-deletion (N=84). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene IDH2/NCBI:3418 1642 check_entity AN5226-2 IDH2 Mutation IDH2 NCBI:3418 gene brain glioma DOID:0060108 prognostic 100023-1 CIViC:566 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene IDH2/NCBI:3418 1642 check_entity AN5226-3 IDH2 Mutation IDH2 NCBI:3418 gene chondrosarcoma DOID:3371 prognostic 100023-1 PubMed:31615936 In a retrospective study, the authors evaluated the association between IDH1/IDH2 mutation and prognosis in patients with high-grade central chondrosarcoma. Although no association was discovered between IDH mutation status and the patient's overall survival, IDH1/IDH2 mutation was found to be associated with longer relapse free and metastasis free survival in high-grade chondrosarcomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene IDH2/NCBI:3418 1643 check_entity AN5226-3 IDH2 Mutation IDH2 NCBI:3418 gene chondrosarcoma DOID:3371 prognostic 100023-1 CIViC:566 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene IDH2/NCBI:3418 1643 check_entity AN5227-1 IDH2 R140 mutation IDH2 NCBI:3418 gene acute myeloid leukemia DOID:9119 prognostic 100023-1 PubMed:22616558 In this meta-analysis of adult non-promyelocytic AML (11 studies), patients with IDH2 R140 or R172 mutations had event free survival and overall survival similar to those with wild-type IDH2. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R140 sequence variation in gene IDH2/NCBI:3418 1644 check_entity AN5227-1 IDH2 R140 mutation IDH2 NCBI:3418 gene acute myeloid leukemia DOID:9119 prognostic 100023-1 PubMed:21596855 In AML, patients with IDH2 R140 mutation have improved overall survival compared to those with wild-type IDH2. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R140 sequence variation in gene IDH2/NCBI:3418 1644 check_entity AN5227-1 IDH2 R140 mutation IDH2 NCBI:3418 gene acute myeloid leukemia DOID:9119 prognostic 100023-1 PubMed:21997850 In patients with acute myeloid leukemia, the presence of IDH2 R140Q (n = 7), IDH2 R172K (n = 3) or IDH1 R132 (N=4) mutations did not confer prognostic value (overall survival) compared to wild-type IDH1/2 patients overall (N=102; P=0.177). IDH1/2 mutations were significantly more common in cytogenetically normal AML (P=0.004). IDH1/2 mutations did also not confer an overall survival benefit in patients with an intermediate risk karyotype (N=68, P=0.484). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R140 sequence variation in gene IDH2/NCBI:3418 1644 check_entity AN5227-1 IDH2 R140 mutation IDH2 NCBI:3418 gene acute myeloid leukemia DOID:9119 prognostic 100023-1 CIViC:62 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R140 sequence variation in gene IDH2/NCBI:3418 1644 check_entity AN5227-2 IDH2 R140 mutation IDH2 NCBI:3418 gene myelodysplastic syndrome DOID:0050908 prognostic 100023-1 PubMed:21997850 In patients with myelodysplastic syndrome, the presence of IDH2 R140Q (N=3) or IDH1 R132 (N=2) mutations did not confer prognostic value (overall survival) compared to wild-type IDH1/2 patients (N=61; P=0.794). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R140 sequence variation in gene IDH2/NCBI:3418 1645 check_entity AN5227-2 IDH2 R140 mutation IDH2 NCBI:3418 gene myelodysplastic syndrome DOID:0050908 prognostic 100023-1 PubMed:22033490 R140Q mutation in IDH2 does not have prognostic value in patients with MDS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R140 sequence variation in gene IDH2/NCBI:3418 1645 check_entity AN5227-2 IDH2 R140 mutation IDH2 NCBI:3418 gene myelodysplastic syndrome DOID:0050908 prognostic 100023-1 CIViC:62 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R140 sequence variation in gene IDH2/NCBI:3418 1645 check_entity AN5228-1 IDH2 R172 mutation IDH2 NCBI:3418 gene acute myeloid leukemia DOID:9119 prognostic 100023-1 PubMed:27276561 In a study of 1,540 patients with Acute Myeloid Leukemia, 18 patients had a mutation in IDH2(R172). IDH2(R172) mutations rarely showed co-mutation with NPM1 (odds ratio= 0.06; P=4x10-5), whereas IDH2(R140) mutations showed strong co-mutation with NPM1 (odds ratio= 3.6; P=5x10-10). In an absence of gene fusion products, patients with IDH2(R172) mutations showed higher survival rates when compared to mutations in NPM1, chromatin-spliceosome mutations and TP53–aneuploidy. Patients with IDH2(R172) mutations showed worse prognosis when compared to CEBPA(biallelic) mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R172 sequence variation in gene IDH2/NCBI:3418 1646 check_entity AN5228-1 IDH2 R172 mutation IDH2 NCBI:3418 gene acute myeloid leukemia DOID:9119 prognostic 100023-1 CIViC:199 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R172 sequence variation in gene IDH2/NCBI:3418 1646 check_entity AN5228-2 IDH2 R172 mutation IDH2 NCBI:3418 gene glioblastoma DOID:3068 prognostic 100023-1 PubMed:19228619 In patients with a glioblastoma, those with mutations at R172 of IDH2 had better overall survival than wild-type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R172 sequence variation in gene IDH2/NCBI:3418 1647 check_entity AN5228-2 IDH2 R172 mutation IDH2 NCBI:3418 gene glioblastoma DOID:3068 prognostic 100023-1 CIViC:199 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R172 sequence variation in gene IDH2/NCBI:3418 1647 check_entity AN5228-3 IDH2 R172 mutation IDH2 NCBI:3418 gene malignant astrocytoma DOID:3069 prognostic 100023-1 PubMed:19228619 In patients with anaplastic astrocytoma, those with mutations at R172 of IDH2 had better overall survival than wild-type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R172 sequence variation in gene IDH2/NCBI:3418 1648 check_entity AN5228-3 IDH2 R172 mutation IDH2 NCBI:3418 gene malignant astrocytoma DOID:3069 prognostic 100023-1 CIViC:199 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R172 sequence variation in gene IDH2/NCBI:3418 1648 check_entity AN5228-4 IDH2 R172 mutation IDH2 NCBI:3418 gene peripheral T-cell lymphoma DOID:0050749 diagnostic;prognostic 100023-1 PubMed:26268241 In patients with angioimmunoblastic T-cell lymphoma (a subtype of peripheral T-cell lymphoma), IDH2 R172 mutations (N=16) had no impact on overall survival when compared to patients with wildtype IDH2 (N=24). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R172 sequence variation in gene IDH2/NCBI:3418 1649 check_entity AN5228-4 IDH2 R172 mutation IDH2 NCBI:3418 gene peripheral T-cell lymphoma DOID:0050749 diagnostic;prognostic 100023-1 PubMed:22215888 IDH2 R172 mutations were frequently observed in patients with the angioimmunoblastic T-cell lymphoma subtype of peripheral T-cell lymphomas but not observed in other subtypes. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R172 sequence variation in gene IDH2/NCBI:3418 1649 check_entity AN5228-4 IDH2 R172 mutation IDH2 NCBI:3418 gene peripheral T-cell lymphoma DOID:0050749 diagnostic;prognostic 100023-1 CIViC:199 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R172 sequence variation in gene IDH2/NCBI:3418 1649 check_entity AN5229-1 IDH2 R172K mutation IDH2 NCBI:3418 gene acute myeloid leukemia DOID:9119 prognostic 100023-1 PubMed:22616558 AML patients with IDH2 mutations such as R172K have event free survival and overall survival similar to those with wild-type IDH2. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R172K sequence variation in gene IDH2/NCBI:3418 1650 check_entity AN5229-1 IDH2 R172K mutation IDH2 NCBI:3418 gene acute myeloid leukemia DOID:9119 prognostic 100023-1 PubMed:21596855 In AML, patients with an IDH2 R172K mutation have worse overall survival compared to those with wild-type IDH2. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R172K sequence variation in gene IDH2/NCBI:3418 1650 check_entity AN5229-1 IDH2 R172K mutation IDH2 NCBI:3418 gene acute myeloid leukemia DOID:9119 prognostic 100023-1 CIViC:63 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R172K sequence variation in gene IDH2/NCBI:3418 1650 check_entity AN5229-2 IDH2 R172K mutation IDH2 NCBI:3418 gene myelodysplastic syndrome DOID:0050908 prognostic 100023-1 PubMed:21997850 In patients suffering from MDS, the presence of IDH2 mutations such as R172K do not confer prognostic value (overall survival). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R172K sequence variation in gene IDH2/NCBI:3418 1651 check_entity AN5229-2 IDH2 R172K mutation IDH2 NCBI:3418 gene myelodysplastic syndrome DOID:0050908 prognostic 100023-1 CIViC:63 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R172K sequence variation in gene IDH2/NCBI:3418 1651 check_entity AN5230-1 IGF1R EXPRESSION IGF1R NCBI:3480 gene lung non-small cell carcinoma DOID:3908 risk PubMed:23619944 Expression of IGF1R in NSCLC cell lines (n=17) was associated with resistance to EGFR inhibitor gefitinib, however, knock-in or knock-out of IGF1R did not affect gefitinib sensitivity. IGF1R expression was also higher in patients with disease progression after gefitinib therapy in a clinical cohort (n=98). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene IGF1R/NCBI:3480 1652 AN5230-1 IGF1R EXPRESSION IGF1R NCBI:3480 gene lung non-small cell carcinoma DOID:3908 risk CIViC:376 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene IGF1R/NCBI:3480 1652 AN5231-1 IGF1R NUCLEAR EXPRESSION IGF1R NCBI:3480 gene sarcoma DOID:1115 risk PubMed:22682017 IGF-1R nuclear immunostaining (IHC) was observed in 9 out of 16 samples of patients with different sarcomas (osteosarcoma, ewing sarcoma, liposarcoma, synovialsarcoma, desmoplastic tumor, rhabdomyosarcoma). Exclusive nuclear immunostaining was associated with better progression free survival and overall survival after therapy with IGF1R antibodies (R1507, IMC-A12, SCH 717454 and CP-751.871). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene IGF1R/NCBI:3480 1653 AN5231-1 IGF1R NUCLEAR EXPRESSION IGF1R NCBI:3480 gene sarcoma DOID:1115 risk CIViC:387 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene IGF1R/NCBI:3480 1653 AN5232-1 IGF1R Overexpression IGF1R NCBI:3480 gene breast cancer DOID:1612 risk PubMed:26706833 A randomized phase III trial of hormone sensitive (ER or PR positive) early stage breast cancer (Dutch TEAM cohort, n=2,446) examined the addition of metformin to exemestane for 155 patients. IGF1R IHC was performed and patients classified as IGF1R high (n=105) or low (n=50). In IGF1R-high patients, combining metformin with exemestane was associated with significant RFS (HR 1.12, 95% CI 0.57–2.23 for sequential treatment with metformin, HR 0.73 95% CI 0.56–0.94 for exemestane only, and HR 0.32, 95% CI 0.10–1.00 for exemestane with metformin, p = 0.02, compared to the sequential treatment arm). There was also significant association with OS (HR for OS 1.72, 95% CI 0.96–3.08 for sequential treatment with metformin, HR 0.80, 95% CI 0.62–1.03 for exemestane only, and HR 0.67, 95% CI 0.31–1.45 for exemestane with metformin, p = 0.03, compared to the sequential treatment arm). The authors conclude that adding metformin to exemestane for patients with IGF1R-high expression may have clinical benefit. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene IGF1R/NCBI:3480 1654 AN5232-1 IGF1R Overexpression IGF1R NCBI:3480 gene breast cancer DOID:1612 risk CIViC:3128 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene IGF1R/NCBI:3480 1654 AN5233-1 IGF2 Overexpression IGF2 NCBI:3481 gene prostate cancer DOID:10283 risk PubMed:25670080 Increased IGF2 expression was shown to mediate chemotherapy resistance in several prostate cancer cell lines. The IGF1R/INSR inhibitor OSI-906 did not have a significant effect on chemotherapy resistant castration-resistant prostate cancer cell lines, as measured by colony formation assay. Similarly, in vivo experiments showed no difference between OSI-906 and control treatment in terms of tumor growth and survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene IGF2/NCBI:3481 1655 AN5233-1 IGF2 Overexpression IGF2 NCBI:3481 gene prostate cancer DOID:10283 risk CIViC:156 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene IGF2/NCBI:3481 1655 AN5234-1 IKZF1 Deletion IKZF1 NCBI:10320 gene acute lymphoblastic leukemia DOID:9952 prognostic PubMed:19770381 IKZF1 deletions in patients with BCR-ABL–positive adult acute lymphoblastic leukemia were associated with reduced disease-free survival compared to wild type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene IKZF1/NCBI:10320 1656 check_entity AN5234-1 IKZF1 Deletion IKZF1 NCBI:10320 gene acute lymphoblastic leukemia DOID:9952 prognostic PubMed:20445578 A targeted copy number screen of 131 precursor B-ALL cases revealed that IKZF1 deletions are significantly associated with poor relapse-free and overall survival rates. Furthermore non-high-risk patients with IKZF1 deletions exhibited a ~12-fold higher relative relapse rate than those without IKZF1 deletions. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene IKZF1/NCBI:10320 1656 check_entity AN5234-1 IKZF1 Deletion IKZF1 NCBI:10320 gene acute lymphoblastic leukemia DOID:9952 prognostic CIViC:200 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene IKZF1/NCBI:10320 1656 check_entity AN5234-2 IKZF1 Deletion IKZF1 NCBI:10320 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 prognostic;risk PubMed:22699455 In children with bone marrow relapsed B-cell precursor acute lymphoblastic leukemia, those with deletions of IKZF1 had worse event-free and overall survival than patients without deletions (N=68 vs 136, 0.30 vs 0.51, P=0.002; 0.36 vs 0.60, P=0.001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene IKZF1/NCBI:10320 1657 check_entity AN5234-2 IKZF1 Deletion IKZF1 NCBI:10320 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 prognostic;risk PubMed:24366361 IKZF1 deletions are associated with poor outcome in patients with childhood BCR-ABL–positive B-cell precursor acute lymphoblastic leukemia even when treated with imatinib. This phenomenon was observed in patients treated in the pre-TKI era as well as those treated with imatinib when compared to wild-type patients undergoing similar treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene IKZF1/NCBI:10320 1657 check_entity AN5234-2 IKZF1 Deletion IKZF1 NCBI:10320 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 prognostic;risk PubMed:24740809 In patients with Philadelphia Chromosome negative B-cell precursor acute lymphoblastic leukemia, focal deletion involving 3-5 exons of IKZF1 was associated with higher cumulative incidence of relapse (CIR) than wildtype IKZF1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene IKZF1/NCBI:10320 1657 check_entity AN5234-2 IKZF1 Deletion IKZF1 NCBI:10320 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 prognostic;risk PubMed:30044693 This prospective study reports the prognosis of patients with B-ALL and an IKZF1 deletion and the impact of intensification of treatment in this subgroup. In 50 patients from the MS2003 cohort, the 5-year cumulative risk for relapse (CIR) associated with IKZF1 deletion was significantly higher than those without the deletion (CIR= 30.4% vs. 8.1%, p=8.7x10^-7). Of those in the MS2010 cohort with IKZF1 deletions, the study showed improvement in CIR and CID in both BCR-ABL1 positive, who were treated with imatinib and intensification therapy (CIR decreased from 66.7% to 20%), and BCR-ABL1 negative, who were treated with intensification therapy only (CIR decreased from 20.5% to 11.4%). Overall survival was also significantly improved for patients with IKZF1 deletion in both groups. Intensification therapy was achieved with higher doses of methotrexate 5g/m2, more blocks of delayed intensification, and for HR patients, two fludarabine-cytarabine-daunorubicin blocks. The study was not randomized, did not include IKZF1 mutation status, and did not consider all substratifications of IKZF1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene IKZF1/NCBI:10320 1657 check_entity AN5234-2 IKZF1 Deletion IKZF1 NCBI:10320 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 prognostic;risk PubMed:25335741 A meta-analysis of 15 published studies including 5021 patients with B-ALL showed that IKZF1 had an unfavorable impact on event-free survival (HR=2.32) and overall survival (HR=2.56). The correlation occurred in both high-risk (HR=4.41) groups and non-high risk groups (HR=3.58). 14/15 studies were done in pediatric populations (ages 1-18). The summary HR was 2.74 for pediatric patients with B-ALL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene IKZF1/NCBI:10320 1657 check_entity AN5234-2 IKZF1 Deletion IKZF1 NCBI:10320 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 prognostic;risk PubMed:27815723 A meta-analysis of 8 published studies including 1008 adult patients (all patients were >14 years old) with B-ALL showed that IKZF 1 deletion had a negative impact on overall survival (HR=1.4, 95% CI 1.13–1.73) and event-free survival (EFS) (HR=1.67, 95% CI 1.28–2.17). In addition, IKZF1 deletion could independently predict unfavorable OS (HR=1.6) and EFS (HR= 1.67) in BCR-ABL1-negative but not BCR-ABL1 positive patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene IKZF1/NCBI:10320 1657 check_entity AN5234-2 IKZF1 Deletion IKZF1 NCBI:10320 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 prognostic;risk PubMed:29507076 This study reports on a cohort of NCI high-risk, Ph-negative pediatric patients with B-ALL. Twenty eight out of 94 patients (~30%) were found to harbor IKZF1 deletions, which were associated with male sex (P=0.45), Hispanic ethnicity (P=0.011) and an inferior outcome. IKZF1 deletion was associated with inferior event-free survival (EFS) in univariate (HR: 3.21, P=0.002) and multivariate analysis (HR: 2.64, P=0.016). IKZF1 deletion was associated with inferior disease-free survival (DFS) in univariate analysis (HR: 3.27, P=0.008) and showed a trend toward inferior DFS in multivariate analysis (HR: 2.7, P=0.087). The IKZF1 deletion was an independent predictor of adverse outcome, irrespective of the presence of a kinase-activating fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene IKZF1/NCBI:10320 1657 check_entity AN5234-2 IKZF1 Deletion IKZF1 NCBI:10320 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 prognostic;risk CIViC:200 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene IKZF1/NCBI:10320 1657 check_entity AN5235-1 IKZF1 IKZF1 deletion IKZF1 NCBI:10320 gene childhood B-cell acute lymphoblastic leukemia DOID:0080146 prognostic PubMed:19129520 This study reports on two pediatric cohorts with B-ALL. In the first cohort of 221 high risk, BCR-ABL1-negative pediatric patients, 55.2% of IKZF1 positive patients had a hematologic relapse, 73.4% of IKZF1 positive patients had any relapse, and 74.6% of IKZF1 positive patients had an event (hematologic relapse, any relapse, a second malignant condition or death) as compared to 14%, 25.2%, and 27.1%, respectively, without an IKZF1 alteration. In a less selected cohort of 258 patients with both standard and high risk disease, with common aneuploidies including BCR-ABL1, 46.3% of IKZF1 positive patients had a hematologic relapse, 48.4% of IKZF1 positive patients had any relapse, and 60.5% of IKZF1 positive patients had an event as compared to 22.5%, 25.6%, and 27.6%, respectively, without an IKZF1 alteration. IKZF1 alteration is defined as a deletion or mutation in the gene. Gene expression profiles were found to be similar to BCR-ABL1 positive B-ALL, even when the BCR-ABL1 translocation was not present. The study concludes that IKZF1 alterations are associated with a very poor outcome in B-ALL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene IKZF1/NCBI:10320 1658 check_entity AN5235-1 IKZF1 IKZF1 deletion IKZF1 NCBI:10320 gene childhood B-cell acute lymphoblastic leukemia DOID:0080146 prognostic CIViC:2613 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene IKZF1/NCBI:10320 1658 check_entity AN5236-1 IKZF1 IKZF1 mutation IKZF1 NCBI:10320 gene childhood B-cell acute lymphoblastic leukemia DOID:0080146 prognostic PubMed:19129520 This study reports on two pediatric cohorts with B-ALL. In the first cohort of 221 high risk, BCR-ABL1-negative pediatric patients, 55.2% of IKZF1 positive patients had a hematologic relapse, 73.4% of IKZF1 positive patients had any relapse, and 74.6% of IKZF1 positive patients had an event (hematologic relapse, any relapse, a second malignant condition or death) as compared to 14%, 25.2%, and 27.1%, respectively, without an IKZF1 alteration. In a less selected cohort of 258 patients with both standard and high risk disease, with common aneuploidies including BCR-ABL1, 46.3% of IKZF1 positive patients had a hematologic relapse, 48.4% of IKZF1 positive patients had any relapse, and 60.5% of IKZF1 positive patients had an event as compared to 22.5%, 25.6%, and 27.6%, respectively, without an IKZF1 alteration. IKZF1 alteration is defined as a deletion or mutation in the gene. Gene expression profiles were found to be similar to BCR-ABL1 positive B-ALL, even when the BCR-ABL1 translocation was not present. The study concludes that IKZF1 alterations are associated with a very poor outcome in B-ALL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene IKZF1/NCBI:10320 1659 check_entity AN5236-1 IKZF1 IKZF1 mutation IKZF1 NCBI:10320 gene childhood B-cell acute lymphoblastic leukemia DOID:0080146 prognostic CIViC:2613 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene IKZF1/NCBI:10320 1659 check_entity AN5237-1 IL6 Overexpression IL6 NCBI:3569 gene rhabdomyosarcoma DOID:3247 risk PubMed:28672024 Treatment with bazedoxifene inhibited cell colony formation in rhabdomyosarcoma cell lines RH30 and RD. Addition of excess IL6 reduced the inhibitory effect of bazedoxifene on colony formation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene IL6/NCBI:3569 1660 AN5237-1 IL6 Overexpression IL6 NCBI:3569 gene rhabdomyosarcoma DOID:3247 risk CIViC:2780 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene IL6/NCBI:3569 1660 AN5238-1 JAK1 OVEREXPRESSION JAK1 NCBI:3716 gene lung non-small cell carcinoma DOID:3908 risk PubMed:22333600 Overexpression of JAK1 in 22 lung cancer cell lines was associated with sensitivity to PKC-inhibitor enzastaurin. Silencing of JAK1 (by small molecule JAK 1/2/3 inhibitor) led to resistance. Overexpression of JAK1 (lentiviral mediated) led to sensitivity to enzastaurin. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene JAK1/NCBI:3716 1661 AN5238-1 JAK1 OVEREXPRESSION JAK1 NCBI:3716 gene lung non-small cell carcinoma DOID:3908 risk CIViC:392 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene JAK1/NCBI:3716 1661 AN5238-2 JAK1 OVEREXPRESSION JAK1 NCBI:3716 gene sarcoma DOID:1115 risk PubMed:31372595 Sequencing of an 8-year old patient diagnosed with a left tentorial-based CNS sarcoma discovered an EWSR1-ATF fusion and IL6 and JAK1 overexpression. Patient was treated with ruxolitinib based on overexpression of JAK1. Stable disease per RECIST and improvement of Lansky score from 60 to 90-100 was observed for 5 months. After ruxolitinib discontinuation, the patient's symptoms worsened and lung lesions progressed. Ruxolitinib was started again per family request and patient again had stable disease and improvement in body weight and Lansky score. Dose reduction was required because of myelosuppression and patient death occurred 23 months after relapse. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene JAK1/NCBI:3716 1662 AN5238-2 JAK1 OVEREXPRESSION JAK1 NCBI:3716 gene sarcoma DOID:1115 risk CIViC:392 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene JAK1/NCBI:3716 1662 AN5239-1 JAK1 Q503* mutation JAK1 NCBI:3716 gene skin melanoma DOID:8923 risk PubMed:27433843 Paired tumor samples were analyzed from four patients with metastatic melanoma and initial response with a subsequent relapse under pembrolizumab (PD-1 checkpoint inhibitor) therapy. Baseline biopsies were obtained before therapy initiation with pembrolizumab (before prior vemurafenib treatment in patient 1). A JAK1 Q503* mutation was observed at the time of relapse in patient 1. This mutation was one of 3 new homozygous mutations in this patient (53 new mutations total) and the tumor was described to be genetically similar to the pre-treatment tumor. CRIPR-Cas9 mediated modelling of the JAK1 mutation in a melanoma cell line led to a loss of response to interferon alpha, beta and gamma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q503* sequence variation in gene JAK1/NCBI:3716 1663 check_entity AN5239-1 JAK1 Q503* mutation JAK1 NCBI:3716 gene skin melanoma DOID:8923 risk CIViC:610 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q503* sequence variation in gene JAK1/NCBI:3716 1663 check_entity AN5240-1 JAK1 S703I mutation JAK1 NCBI:3716 gene hepatocellular carcinoma DOID:684 risk PubMed:26701727 A JAK1 S703I mutation was found to activate the JAK-STAT signaling pathway in vitro and in vivo in hepatocellular carcinoma. Ruxolitinib causes the suppression of JAK-STAT signaling pathway in PDX models bearing JAK1 S703I mutation and delays tumor progression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S703I sequence variation in gene JAK1/NCBI:3716 1664 check_entity AN5240-1 JAK1 S703I mutation JAK1 NCBI:3716 gene hepatocellular carcinoma DOID:684 risk CIViC:800 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S703I sequence variation in gene JAK1/NCBI:3716 1664 check_entity AN5241-1 JAK2 ATF7IP::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:25207766 In the study involving 1725 B-ALL patients, 264 were identified by microarray-based algorithm to have a Ph-like expression signature. Next generation sequencing (RNAseq, WGS, and/or WES) performed on 154 Ph-like patients revealed 91% possessed genomic alterations activating kinase signaling with 96 (62%) involving rearrangements. In one male patient, an in-frame ATF7IP-JAK2 fusion (exon 13 and exon 17) with the tyrosine kinase domain intact was identified and confirmed by RT-PCR, Sanger and FISH. This patient also harbored an IKZF1 deletion, was designated NCI high risk and Ph-like non-CRLF2. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ATF7IP::JAK2 sequence variation in gene JAK2/NCBI:3717 1665 check_entity AN5241-1 JAK2 ATF7IP::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:27870571 In B-lymphoblastic leukemia/lymphoma (B-ALL), the presence of this fusion is associated with so-called BCR/ABL1 like (Ph-like) subtype of the disease. The ATF7IP-JAK2 fusion is rare; in this study involving 798 B-ALL patients of which 194 had clinical characteristics of Ph-like ALL, two cases with the ATF7IP-JAK2 fusion were observed. There is pre-clinical and case-study evidence that the presence of JAK2 fusions in B-ALL predicts sensitivity to JAK2 inhibitors; clinical trials are ongoing to evaluate efficacy of adding JAK2 inhibitors to treatment of Ph-like B-ALL cases with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ATF7IP::JAK2 sequence variation in gene JAK2/NCBI:3717 1665 check_entity AN5241-1 JAK2 ATF7IP::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 CIViC:2715 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ATF7IP::JAK2 sequence variation in gene JAK2/NCBI:3717 1665 check_entity AN5242-1 JAK2 BCR::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:25207766 In the study involving 1725 B-ALL patients, 264 were identified by microarray-based algorithm to have a Ph-like expression signature. Next generation sequencing (RNAseq, WGS, and/or WES) performed on 154 Ph-like patients revealed 91% possessed genomic alterations activating kinase signaling with 96 (62%) involving rearrangements. In two male patients, in-frame BCR-JAK2 fusions (exon 1 and exon 19 (FISH validated); exon 1 and exons 15&17) with the tyrosine kinase domain intact were identified and confirmed by RT-PCR, Sanger. Both patients harbored an IKZF1 deletion and were designated Ph-like non-CRLF2. One patient was NCI childhood high risk while the other was young adult. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::JAK2 sequence variation in gene JAK2/NCBI:3717 1666 check_entity AN5242-1 JAK2 BCR::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:28408464 In this study which included 1389 cases of high-risk pediatric B-ALL, 284 were identified by TaqMan Low Density Array to have a Ph-like gene expression signature. RT-PCR or RNAseq performed on the 129 CRLF2 negative patients revealed that 4.9% of them had JAK2 rearrangements including two patients with a BCR-JAK2 fusion. These fusions were confirmed by Sanger sequencing and identified alternate breakpoint in BCR. All fusion-positive patient cases in this study were confirmed to have in-frame fusion of the 5′ partner to the 3′ kinase gene and retention of the tyrosine kinase domain of the 3′ fusion partner. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::JAK2 sequence variation in gene JAK2/NCBI:3717 1666 check_entity AN5242-1 JAK2 BCR::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:27870571 In B-lymphoblastic leukemia/lymphoma (B-ALL), the presence of this fusion is associated with so-called BCR/ABL1 like (Ph-like) subtype of the disease. In this study involving 798 B-ALL patients of which 194 had clinical characteristics of Ph-like ALL, only one case with the BCR-JAK2 fusion was observed. There is pre-clinical and case-study evidence that the presence of JAK2 fusions in B-ALL predicts sensitivity to JAK2 inhibitors; clinical trials are ongoing to evaluate efficacy of adding JAK2 inhibitors to treatment of Ph-like B-ALL cases with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::JAK2 sequence variation in gene JAK2/NCBI:3717 1666 check_entity AN5242-1 JAK2 BCR::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:27894077 In this study involving 574 pediatric B-ALL patients (from a Dutch/German cohort), 77 were shown to be Ph-like cases identified by hierarchical clustering of gene expression data. In one male patient with Ph-like disease, an in-frame BCR-JAK2 fusion involving exon 1 of BCR and exon 17 of JAK2 was identified. This fusion was confirmed by RT-PCR and targeted ligation amplification (TLA). A concurrent IKZF1 exon 2-3 deletion was detected. The patient experienced complete remission after induction but relapsed shortly after. . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::JAK2 sequence variation in gene JAK2/NCBI:3717 1666 check_entity AN5242-1 JAK2 BCR::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 CIViC:2729 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::JAK2 sequence variation in gene JAK2/NCBI:3717 1666 check_entity AN5243-1 JAK2 EBF1::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:25207766 In the study involving 1725 B-ALL patients, 264 were identified by microarray-based algorithm to have a Ph-like expression signature. Next generation sequencing (RNAseq, WGS, and/or WES) performed on 154 Ph-like patients revealed 91% possessed genomic alterations activating kinase signaling with 96 (62%) involving rearrangements. In one adolescent female, an in-frame EBF1-JAK2 fusion (exon 14 and exon 17) with the tyrosine kinase domain intact was identified and confirmed by RT-PCR and Sanger. This patient also harbored an IKZF1 deletion and was designated Ph-like non CRLF2. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EBF1::JAK2 sequence variation in gene JAK2/NCBI:3717 1667 check_entity AN5243-1 JAK2 EBF1::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 CIViC:2716 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EBF1::JAK2 sequence variation in gene JAK2/NCBI:3717 1667 check_entity AN5244-1 JAK2 ETV6::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:25207766 In the study involving 1725 B-ALL patients, 264 were identified by microarray-based algorithm to have a Ph-like expression signature. Next generation sequencing (RNAseq, WGS, and/or WES) performed on 154 Ph-like patients revealed 91% possessed genomic alterations activating kinase signaling with 96 (62%) involving rearrangements. In two patients, an in-frame ETV6-JAK2 fusion (exon 4 and exon 17; exon 5 and exon 17) with the tyrosine kinase domain intact was identified and confirmed by RT-PCR, FISH, and/or Sanger. One patients was shown to also harbored an IKZF1 deletion and was designated Ph-like non CRLF2. This information was not provided for the second fusion patient. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::JAK2 sequence variation in gene JAK2/NCBI:3717 1668 check_entity AN5244-1 JAK2 ETV6::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:27870571 In B-lymphoblastic leukemia/lymphoma (B-ALL), the presence of this fusion is associated with so-called BCR/ABL1 like (Ph-like) subtype of the disease. In this study involving 798 B-ALL patients of which 194 had clinical characteristics of Ph-like ALL, only one case with the ETV6-JAK2 fusion was observed. There is pre-clinical and case-study evidence that the presence of JAK2 fusions in B-ALL predicts sensitivity to JAK2 inhibitors; clinical trials are ongoing to evaluate efficacy of adding JAK2 inhibitors to treatment of Ph-like B-ALL cases with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::JAK2 sequence variation in gene JAK2/NCBI:3717 1668 check_entity AN5244-1 JAK2 ETV6::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:28408464 In this study which included 1389 cases of high-risk pediatric B-ALL, 284 were identified by TaqMan Low Density Array to have a Ph-like gene expression signature. RT-PCR or RNAseq performed on CRLF2 negative patients revealed 4.9% had JAK2 rearrangements including one individual who had an ETV6-JAK2 fusion that was confirmed by Sanger sequencing. This patient was designated PH-like non CRLF2. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::JAK2 sequence variation in gene JAK2/NCBI:3717 1668 check_entity AN5244-1 JAK2 ETV6::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 CIViC:2728 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::JAK2 sequence variation in gene JAK2/NCBI:3717 1668 check_entity AN5245-1 JAK2 F694L mutation JAK2 NCBI:3717 gene childhood B-cell acute lymphoblastic leukemia DOID:0080146 risk 48726-4 PubMed:27860260 A 17-year-old Native American female with B-ALL had persistent MRD at the end of induction. In addition to a complex karyotype, sequencing revealed a novel F694L mutation in JAK2, a p.Cys119_Ile121delinsTrpGlyLeu in IKZF1, and a IGH-CRLF2 translocation, all consistent with BCR-ABL1 like B-ALL. In addition to conventional cytotoxic therapy, the patient was started on 40 mg/m2/day ruxolitinib TKI BID for 2 weeks on, 2 weeks off, and MRD diminished to <0.01% prior to allogeneic transplant. The patient was in remission with 100% engraftment from a full match sibling at day 100 post-transplant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F694L sequence variation in gene JAK2/NCBI:3717 1669 check_entity AN5245-1 JAK2 F694L mutation JAK2 NCBI:3717 gene childhood B-cell acute lymphoblastic leukemia DOID:0080146 risk 48726-4 CIViC:2460 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F694L sequence variation in gene JAK2/NCBI:3717 1669 check_entity AN5246-1 JAK2 GOLGA5::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 risk 48726-4 PubMed:29773603 A 10-year-old Caucasian boy with high risk B-cell acute lymphoblastic leukemia failed induction therapy. The patient had a complex karyotype and microarray revealed a 9p duplication involving JAK2 and deletions of IKZF1, PAX5, and CDKN2A. RNA studies demonstrated a Ph-like ALL expression signature but did not identify the underlying kinase fusion. Research level RNA sequencing identified a GOLGA5-JAK2 fusion which was confirmed by other methods and patient cells were introduced to patient-derived xenograft models that demonstrated a response to ruxolitinib. Therefore, 40mg/m2 ruxolitinib was added to the patient’s multiagent chemotherapy regiment. The treatment was well tolerated and the patient demonstrated significant clinical response by the end of consolidation, though MRD ≥ 0.01% was detected by flow cytometry. The patient received CART therapy and achieved MRD negative remission, then underwent HSCT, and remained in remission with full donor chimerism at 2-months post-HSCT. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::GOLGA5::JAK2 sequence variation in gene JAK2/NCBI:3717 1670 check_entity AN5246-1 JAK2 GOLGA5::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 risk 48726-4 CIViC:3083 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::GOLGA5::JAK2 sequence variation in gene JAK2/NCBI:3717 1670 check_entity AN5247-1 JAK2 OFD1::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:26404892 To identify potentially druggable kinase fusions, this study of 278 B-ALL patients (all BCR-ABL1 negative), 34 (12.2%) harbored an IKZF1 deletion as determined by MLPA. Sufficient RNA from 16/34 of these IKZF1 deleted patients underwent mRNA sequencing and detected fusions were validated with RT-PCR and Sanger. Seven patients with clinical characteristics of Ph-like ALL were confirmed to harbor kinase fusions. The novel in-frame OFD1-JAK2 fusion (Exon 22 to Exon 13) was detected in an 11-year-old boy with hyperleukocytosis (185.8e9/l), no response to prednisolone therapy, and classified as NCI high risk. The authors hypothesize this fusion could constitutively activate the JAK-STAT pathway. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::OFD1::JAK2 sequence variation in gene JAK2/NCBI:3717 1671 check_entity AN5247-1 JAK2 OFD1::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:27176795 In this study involving 373 high risk pediatric B-ALL cases with no recurrent fusions, 29 were kinase-fusion positive as determined by mRNA-seq or mRT-PCR and validated by RT-PCR and Sanger. One case, a 3-year-old male harbored the in-frame OFD1-JAK2 fusion (exon 22 and exon 13) and had an IZKF1 deletion as determined by MLPA. This patient had a high white blood cell count (185,000/ul) and failed induction along with a poor response to prednisolone. Following stem cell transplant, the patient remained in continuous complete remission. Gene set enrichment analysis revealed a positive enrichment score (.48) indicating this patient’s expression signature was similar to the signature of BCR-ABL1 positive patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::OFD1::JAK2 sequence variation in gene JAK2/NCBI:3717 1671 check_entity AN5247-1 JAK2 OFD1::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 CIViC:2843 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::OFD1::JAK2 sequence variation in gene JAK2/NCBI:3717 1671 check_entity AN5248-1 JAK2 PAX5::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:25207766 In the study involving 1725 B-ALL patients, 264 were identified by microarray-based algorithm to have a Ph-like expression signature. Next generation sequencing (RNAseq, WGS, and/or WES) performed on 154 Ph-like patients revealed 91% possessed genomic alterations activating kinase signaling with 96 (62%) involving rearrangements. In seven patients, an in-frame PAX5-JAK2 fusion (exon 5 and exon 19) with the tyrosine kinase domain intact was identified and confirmed by RT-PCR and Sanger. FISH validated the presence of the fusion in 2 patients. All patients were designated Ph-like non-CRLF2 and 5/7 had IKZF1 deletion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PAX5::JAK2 sequence variation in gene JAK2/NCBI:3717 1672 check_entity AN5248-1 JAK2 PAX5::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:28408464 In this study which included 1389 cases of high-risk pediatric B-ALL, 284 were identified by TaqMan Low Density Array to have a Ph-like gene expression signature. RT-PCR or RNAseq performed on CRLF2 negative patients revealed 4.9% had JAK2 rearrangements. Four individuals had a PAX5-JAK2 fusion that was identified and confirmed by Sanger sequencing. These patients were designated Ph-like non CRLF2. All fusion-positive patient cases in this study were confirmed to have in-frame fusion of the 5′ partner to the 3′ kinase gene and retention of the tyrosine kinase domain of the 3′ fusion partner. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PAX5::JAK2 sequence variation in gene JAK2/NCBI:3717 1672 check_entity AN5248-1 JAK2 PAX5::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:27176795 In B-lymphoblastic leukemia/lymphoma (B-ALL), the presence of this fusion is associated with so-called BCR/ABL1 like (Ph-like) subtype of the disease. In this study involving 373 high risk pediatric B-ALL cases of which 29 were kinase-fusion positive patients, only one case with the PAX5-JAK2 fusion was observed. There is pre-clinical and case-study evidence that the presence of JAK2 fusions in B-ALL predicts sensitivity to JAK2 inhibitors; clinical trials are ongoing to evaluate efficacy of adding JAK2 inhibitors to treatment of Ph-like B-ALL cases with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PAX5::JAK2 sequence variation in gene JAK2/NCBI:3717 1672 check_entity AN5248-1 JAK2 PAX5::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 CIViC:2730 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PAX5::JAK2 sequence variation in gene JAK2/NCBI:3717 1672 check_entity AN5249-1 JAK2 PCM1::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:28408464 The PCM1-JAK2 fusion is typically associated with 'myeloid/lymphoid neoplasms with eosinophilia and gene rearrangements', which is a specific disease entity according to WHO classification. However, in this study, which investigated 1389 high-risk pediatric B-ALL cases, 284 of whom had a Ph-like gene signature (identified by TaqMan Low Density Array) the PCM1-JAK2 fusion was detected in association with Ph-like B-ALL in one individual. This fusion was detected by RT-PCR and was confirmed by Sanger sequencing. This patient was designated PH-like non CRLF2. All fusion-positive patient cases in this study were confirmed to have in-frame fusion of the 5′ partner to the 3′ kinase gene and retention of the tyrosine kinase domain of the 3′ fusion partner. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PCM1::JAK2 sequence variation in gene JAK2/NCBI:3717 1673 check_entity AN5249-1 JAK2 PCM1::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 CIViC:567 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PCM1::JAK2 sequence variation in gene JAK2/NCBI:3717 1673 check_entity AN5249-2 JAK2 PCM1::JAK2 mutation JAK2 NCBI:3717 gene hematologic cancer DOID:2531 diagnostic 48726-4 PubMed:27069254 The 2016 World Health Organization guidelines for the classification of myeloid malignancies and acute leukemia describes a new class of disease defined by myeloid or lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PCM1::JAK2 sequence variation in gene JAK2/NCBI:3717 1674 check_entity AN5249-2 JAK2 PCM1::JAK2 mutation JAK2 NCBI:3717 gene hematologic cancer DOID:2531 diagnostic 48726-4 CIViC:567 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PCM1::JAK2 sequence variation in gene JAK2/NCBI:3717 1674 check_entity AN5250-1 JAK2 PPFIBP1::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:25207766 In the study involving 1725 B-ALL patients, 264 were identified by microarray-based algorithm to have a Ph-like expression signature. Next generation sequencing (RNAseq, WGS, and/or WES) performed on 154 Ph-like patients revealed 91% possessed genomic alterations activating kinase signaling with 96 (62%) involving rearrangements. In one young adult male patient, an in-frame PPFIBP1-JAK2 fusion (exon 12 and exon 19) with the tyrosine kinase domain intact was identified and confirmed by RT-PCR, Sanger, and FISH. This patient also harbored an IKZF1 deletion and was designated Ph-like non-CRLF2. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PPFIBP1::JAK2 sequence variation in gene JAK2/NCBI:3717 1675 check_entity AN5250-1 JAK2 PPFIBP1::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:27870571 In B-lymphoblastic leukemia/lymphoma (B-ALL), the presence of this fusion is associated with so-called BCR/ABL1 like (Ph-like) subtype of the disease.The PPFIBP1-JAK2 fusion is rare; In this study involving 798 B-ALL patients of which 194 had clinical characteristics of Ph-like ALL, only one case with the PPFIBP1-JAK2 fusion was observed. There is pre-clinical and case-study evidence that the presence of JAK2 fusions in B-ALL predicts sensitivity to JAK2 inhibitors; clinical trials are ongoing to evaluate efficacy of adding JAK2 inhibitors to treatment of Ph-like B-ALL cases with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PPFIBP1::JAK2 sequence variation in gene JAK2/NCBI:3717 1675 check_entity AN5250-1 JAK2 PPFIBP1::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 CIViC:2717 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PPFIBP1::JAK2 sequence variation in gene JAK2/NCBI:3717 1675 check_entity AN5251-1 JAK2 RFX3::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:28408464 This study included 1389 cases of high-risk pediatric B-ALL, out of which 284 were identified by TaqMan Low Density Array to have a Ph-like gene expression signature. RT-PCR or RNAseq performed on the 129 CRLF2 negative patients revealed that 4.9% of them had JAK2 rearrangements including one patient with a rare and novel RFX3-JAK2 fusion. All fusion-positive patient cases in this study were confirmed to have in-frame fusion of the 5′ partner to the 3′ kinase gene and retention of the tyrosine kinase domain of the 3′ fusion partner. In B-lymphoblastic leukemia/lymphoma (B-ALL), the presence of this fusion is associated with so-called BCR/ABL1 like (Ph-like) subtype of the disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RFX3::JAK2 sequence variation in gene JAK2/NCBI:3717 1676 check_entity AN5251-1 JAK2 RFX3::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 CIViC:2734 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RFX3::JAK2 sequence variation in gene JAK2/NCBI:3717 1676 check_entity AN5252-1 JAK2 SMU1::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:27870571 In B-lymphoblastic leukemia/lymphoma (B-ALL), the presence of this fusion is associated with so-called BCR/ABL1 like (Ph-like) subtype of the disease. The SMU1-JAK2 fusion is rare; in this study involving 798 B-ALL patients of which 194 had clinical characteristics of Ph-like ALL, only one case with the SMU1-JAK2 fusion was observed. SMU1 was detected as a novel JAK2 partner in Ph-like B-ALL. There is pre-clinical and case-study evidence that the presence of JAK2 fusions in B-ALL predicts sensitivity to JAK2 inhibitors; clinical trials are ongoing to evaluate efficacy of adding JAK2 inhibitors to treatment of Ph-like B-ALL cases with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SMU1::JAK2 sequence variation in gene JAK2/NCBI:3717 1677 check_entity AN5252-1 JAK2 SMU1::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 CIViC:2844 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SMU1::JAK2 sequence variation in gene JAK2/NCBI:3717 1677 check_entity AN5253-1 JAK2 SNX29::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:27428428 In B-lymphoblastic leukemia/lymphoma (B-ALL), the presence of this fusion is associated with so-called BCR/ABL1 like (Ph-like) subtype of the disease. The SNX29-JAK2 fusion is rare; in this study involving 383 B-ALL patients (179 adult and 204 pediatric) of which 13 (8 adult, 5 pediatric) had Ph-like expression signature, only one case (adult) with the SNX29-JAK2 fusion was observed. There is pre-clinical and case-study evidence that the presence of JAK2 fusions in B-ALL predicts sensitivity to JAK2 inhibitors; clinical trials are ongoing to evaluate efficacy of adding JAK2 inhibitors to treatment of Ph-like B-ALL cases with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SNX29::JAK2 sequence variation in gene JAK2/NCBI:3717 1678 check_entity AN5253-1 JAK2 SNX29::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 CIViC:2845 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SNX29::JAK2 sequence variation in gene JAK2/NCBI:3717 1678 check_entity AN5254-1 JAK2 SSBP2::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic;risk 48726-4 PubMed:25207766 The SSBP2-JAK2 fusion was identified in a 14 yo male with Ph-like B-ALL, a t(5;9)(q12;p1?3), and a WBC of 160,000. Following 4-drug induction therapy the patient had an MRD of 5.5%, indicating a poor response. After two additional weeks of induction, intermittent ruxolitinib was added to his regimen and a bone marrow performed 3 weeks after the addition of ruxolitinib showed 1% MRD. Following consolidation, the bone marrow showed 0.3% MRD. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SSBP2::JAK2 sequence variation in gene JAK2/NCBI:3717 1679 check_entity AN5254-1 JAK2 SSBP2::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic;risk 48726-4 PubMed:27870571 In B-lymphoblastic leukemia/lymphoma (B-ALL), the presence of this fusion is associated with so-called BCR/ABL1 like (Ph-like) subtype of the disease.The SSBP2-JAK2 fusion is rare; In this study involving 798 B-ALL patients of which 194 had clinical characteristics of Ph-like ALL, two cases with the SSBP2-JAK2 fusion were observed. There is pre-clinical and case-study evidence that the presence of JAK2 fusions in B-ALL predicts sensitivity to JAK2 inhibitors; clinical trials are ongoing to evaluate efficacy of adding JAK2 inhibitors to treatment of Ph-like B-ALL cases with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SSBP2::JAK2 sequence variation in gene JAK2/NCBI:3717 1679 check_entity AN5254-1 JAK2 SSBP2::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic;risk 48726-4 PubMed:28408464 In this study which included 1389 cases of high-risk pediatric B-ALL, 284 were identified by TaqMan Low Density Array to have a Ph-like gene expression signature. RT-PCR or RNAseq performed on CRLF2 negative patients revealed 4.9% had JAK2 rearrangements including two individuals that had an SSBP2-JAK2 fusion that were confirmed by Sanger sequencing. These patients were designated PH-like non CRLF2. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SSBP2::JAK2 sequence variation in gene JAK2/NCBI:3717 1679 check_entity AN5254-1 JAK2 SSBP2::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic;risk 48726-4 CIViC:2530 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SSBP2::JAK2 sequence variation in gene JAK2/NCBI:3717 1679 check_entity AN5255-1 JAK2 STRN3::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:25207766 In the study involving 1725 B-ALL patients, 264 were identified by microarray-based algorithm to have a Ph-like expression signature. Next generation sequencing (RNAseq, WGS, and/or WES) performed on 154 Ph-like patients revealed 91% possessed genomic alterations activating kinase signaling with 96 (62%) involving rearrangements. In one childhood NCI high risk female, an in-frame STRN3-JAK2 fusion (exon 9 and exon 17) with the tyrosine kinase domain intact was identified and confirmed by RT-PCR and Sanger. This patient also harbored an IKZF1 frameshift and deletion and was designated Ph-like non CRLF2. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::STRN3::JAK2 sequence variation in gene JAK2/NCBI:3717 1680 check_entity AN5255-1 JAK2 STRN3::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 CIViC:2718 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::STRN3::JAK2 sequence variation in gene JAK2/NCBI:3717 1680 check_entity AN5256-1 JAK2 Splice Site (c.1641+2T>G) JAK2 NCBI:3717 gene melanoma DOID:1909 risk 48726-4 PubMed:27433843 In a retrospective study of four relapsed, malignant melanoma patients, JAK2 (c.1641+2T>G) F547 splice site mutation was associated with acquired resistance to pembrolizumab monotherapy in one patient. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.1641+2T>G) sequence variation in gene JAK2/NCBI:3717 1681 check_entity AN5256-1 JAK2 Splice Site (c.1641+2T>G) JAK2 NCBI:3717 gene melanoma DOID:1909 risk 48726-4 CIViC:1589 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.1641+2T>G) sequence variation in gene JAK2/NCBI:3717 1681 check_entity AN5257-1 JAK2 TERF2::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:25207766 In the study involving 1725 B-ALL patients, 264 were identified by microarray-based algorithm to have a Ph-like expression signature. Next generation sequencing (RNAseq, WGS, and/or WES) performed on 154 Ph-like patients revealed 91% possessed genomic alterations activating kinase signaling with 96 (62%) involving rearrangements. In one adolescent female, an in-frame TERF2-JAK2 fusion (exon 8 and exon 19) with the tyrosine kinase domain intact was identified and confirmed by RT-PCR and Sanger. This patient also harbored an IKZF1 deletion and was designated Ph-like non CRLF2. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::TERF2::JAK2 sequence variation in gene JAK2/NCBI:3717 1682 check_entity AN5257-1 JAK2 TERF2::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 CIViC:2731 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::TERF2::JAK2 sequence variation in gene JAK2/NCBI:3717 1682 check_entity AN5258-1 JAK2 TPR::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:25207766 In the study involving 1725 B-ALL patients, 264 were identified by microarray-based algorithm to have a Ph-like expression signature. Next generation sequencing (RNAseq, WGS, and/or WES) performed on 154 Ph-like patients revealed 91% possessed genomic alterations activating kinase signaling with 96 (62%) involving rearrangements. In one young adult male, an in-frame TPR-JAK2 fusion (exon 39 and exon 17) with the tyrosine kinase domain intact was identified and confirmed by RT-PCR, Sanger and FISH. This patient also harbored an IKZF1 deletion and was designated Ph-like non CRLF2. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::TPR::JAK2 sequence variation in gene JAK2/NCBI:3717 1683 check_entity AN5258-1 JAK2 TPR::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 CIViC:2719 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::TPR::JAK2 sequence variation in gene JAK2/NCBI:3717 1683 check_entity AN5259-1 JAK2 USP25::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:28408464 In B-lymphoblastic leukemia/lymphoma (B-ALL), the presence of this fusion is associated with so-called BCR/ABL1 like (Ph-like) subtype of the disease. The USP25-JAK2 fusion is rare; this study involved 1389 cases of high risk pediatric B-ALL. Of those, 284 had Ph-like expression signature, and only one of those cases had the USP25-JAK2 fusion. USP25 was detected as a novel JAK2 partner in Ph-like B-ALL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::USP25::JAK2 sequence variation in gene JAK2/NCBI:3717 1684 check_entity AN5259-1 JAK2 USP25::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 CIViC:2732 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::USP25::JAK2 sequence variation in gene JAK2/NCBI:3717 1684 check_entity AN5260-1 JAK2 V617F mutation JAK2 NCBI:3717 gene bone marrow cancer DOID:4960 diagnostic 48726-4 PubMed:19287384 The SNP rs10974944 in the Jak2 locus is associated with increased predisposition for JAK2 V617F mutation and its associated cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V617F sequence variation in gene JAK2/NCBI:3717 1685 check_entity AN5260-1 JAK2 V617F mutation JAK2 NCBI:3717 gene bone marrow cancer DOID:4960 diagnostic 48726-4 CIViC:64 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V617F sequence variation in gene JAK2/NCBI:3717 1685 check_entity AN5260-2 JAK2 V617F mutation JAK2 NCBI:3717 gene chronic myeloid leukemia DOID:8552 diagnostic 48726-4 PubMed:16081687 JAK2 V617F is associated with myeloid malignanices (AML, MDS, CMML/atypical CML). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V617F sequence variation in gene JAK2/NCBI:3717 1686 check_entity AN5260-2 JAK2 V617F mutation JAK2 NCBI:3717 gene chronic myeloid leukemia DOID:8552 diagnostic 48726-4 CIViC:64 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V617F sequence variation in gene JAK2/NCBI:3717 1686 check_entity AN5260-3 JAK2 V617F mutation JAK2 NCBI:3717 gene polycythemia vera DOID:8997 risk 48726-4 PubMed:16709929 In patients with JAK2 V617F, the use of pegylated IFN-alpha-2a leads to reduction in the percentage of cells harboring JAK2 V617F. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V617F sequence variation in gene JAK2/NCBI:3717 1687 check_entity AN5260-3 JAK2 V617F mutation JAK2 NCBI:3717 gene polycythemia vera DOID:8997 risk 48726-4 PubMed:18394554 TG101348 effectively inhibits STAT5 signaling in JAK2 V617F cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V617F sequence variation in gene JAK2/NCBI:3717 1687 check_entity AN5260-3 JAK2 V617F mutation JAK2 NCBI:3717 gene polycythemia vera DOID:8997 risk 48726-4 CIViC:64 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V617F sequence variation in gene JAK2/NCBI:3717 1687 check_entity AN5260-4 JAK2 V617F mutation JAK2 NCBI:3717 gene acute myeloid leukemia DOID:9119 diagnostic 48726-4 PubMed:16081687 JAK2 V617F is not associated with lymphoid leukemia (B-lineage ALL, T-ALL or CLL). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V617F sequence variation in gene JAK2/NCBI:3717 1688 check_entity AN5260-4 JAK2 V617F mutation JAK2 NCBI:3717 gene acute myeloid leukemia DOID:9119 diagnostic 48726-4 CIViC:64 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V617F sequence variation in gene JAK2/NCBI:3717 1688 check_entity AN5261-1 JAK2 ZNF274::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:28408464 This study included 1389 cases of high-risk pediatric B-ALL, out of which 284 were identified by TaqMan Low Density Array to have a Ph-like gene expression signature. RT-PCR or RNAseq performed on the 129 CRLF2 negative patients revealed that 4.9% of them had JAK2 rearrangements including one patient with a rare and novel ZNF274-JAK2 fusion. All fusion-positive patient cases in this study were confirmed to have in-frame fusion of the 5′ partner to the 3′ kinase gene and retention of the tyrosine kinase domain of the 3′ fusion partner. In B-lymphoblastic leukemia/lymphoma (B-ALL), the presence of this fusion is associated with so-called BCR/ABL1 like (Ph-like) subtype of the disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ZNF274::JAK2 sequence variation in gene JAK2/NCBI:3717 1689 check_entity AN5261-1 JAK2 ZNF274::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 CIViC:2733 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ZNF274::JAK2 sequence variation in gene JAK2/NCBI:3717 1689 check_entity AN5262-1 JAK2 ZNF430::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 PubMed:27870571 In B-lymphoblastic leukemia/lymphoma (B-ALL), the presence of this fusion is associated with so-called BCR/ABL1 like (Ph-like) subtype of the disease. The ZNF430-JAK2 fusion is rare; in this study involving 798 adult B-ALL patients of which 194 had Ph-like expression signature, only one case with the ZNF430-JAK2 fusion was observed. ZNF430 was detected as a novel JAK2 partner in Ph-like B-ALL. There is pre-clinical and case-study evidence that the presence of JAK2 fusions in B-ALL predicts sensitivity to JAK2 inhibitors; clinical trials are ongoing to evaluate efficacy of adding JAK2 inhibitors to treatment of Ph-like B-ALL cases with JAK2 fusions (Clinicaltrials.gov Identifier: NCT02723994). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ZNF430::JAK2 sequence variation in gene JAK2/NCBI:3717 1690 check_entity AN5262-1 JAK2 ZNF430::JAK2 mutation JAK2 NCBI:3717 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 diagnostic 48726-4 CIViC:2846 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ZNF430::JAK2 sequence variation in gene JAK2/NCBI:3717 1690 check_entity AN5263-1 JAK2 c.1641+1dup mutation JAK2 NCBI:3717 gene skin melanoma DOID:8923 risk 48726-4 PubMed:27433843 Paired tumor samples were analyzed from four patients with metastatic melanoma and initial response with a subsequent relapse under pembrolizumab (PD-1 checkpoint inhibitor) therapy. Baseline biopsies were obtained before therapy initiation with pembrolizumab. A JAK2 F547 splice site mutation was observed at the time of relapse in patient 2. RNA sequencing revealed an in-frame stop codon after exon 12. The JAK2 mutation was the only homozygous mutation (allele frequency >85%) of 76 new nonsynonymous mutations in patient 2. Cell line modelling of baseline and relapse JAK2 mutational status revealed a loss of response to interferon gamma and loss of JAK2 protein. This loss of response was also modeled in another cell line. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.1641+1dup:mutation sequence variation in gene JAK2/NCBI:3717 1691 check_entity AN5263-1 JAK2 c.1641+1dup mutation JAK2 NCBI:3717 gene skin melanoma DOID:8923 risk 48726-4 CIViC:611 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.1641+1dup:mutation sequence variation in gene JAK2/NCBI:3717 1691 check_entity AN5264-1 JUN Overexpression JUN NCBI:3725 gene colorectal adenocarcinoma DOID:0050861 risk PubMed:27022066 A 67-year-old female presents with recurrent metastatic colonic adenocarcinoma. Immunohistochemical and genetic workup showed overexpression of c-JUN and FOS, which presumably signals through the RAAS pathway. The patient was treated with irbesartan and after 5 weeks of therapy, the CEA value decreased from 18 to 3.1 and there was radiological resolution of the disease. Her 10 month CEA was 1.4. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene JUN/NCBI:3725 1692 AN5264-1 JUN Overexpression JUN NCBI:3725 gene colorectal adenocarcinoma DOID:0050861 risk CIViC:635 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene JUN/NCBI:3725 1692 AN5265-1 KDR A1065T mutation KDR NCBI:3791 gene angiosarcoma DOID:0001816 risk PubMed:19723655 COS-7 cells were transiently transfected with expression constructs encoding cDNAs for wild-type or A1065T-mutant KDR. Autophosphorylation was observed on tyrosine of mutant cells, but not wild-type cells, which were starved from serum for 6 hours without rhVEGF stimulation. Decreased phosphorylation in mutant cells was noted after treatment with either sunitinib or sorafenib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A1065T sequence variation in gene KDR/NCBI:3791 1693 check_entity AN5265-1 KDR A1065T mutation KDR NCBI:3791 gene angiosarcoma DOID:0001816 risk CIViC:463 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A1065T sequence variation in gene KDR/NCBI:3791 1693 check_entity AN5266-1 KDR D717V mutation KDR NCBI:3791 gene angiosarcoma DOID:0001816 risk PubMed:19723655 COS-7 cells were transiently transfected with expression constructs encoding cDNAs for wild-type or D717V-mutant KDR. Autophosphorylation was observed on tyrosine of mutant cells, but not wild-type cells, which were starved from serum for 6 hours without rhVEGF stimulation. Decreased phosphorylation in mutant cells was noted after treatment with either sunitinib or sorafenib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D717V sequence variation in gene KDR/NCBI:3791 1694 check_entity AN5266-1 KDR D717V mutation KDR NCBI:3791 gene angiosarcoma DOID:0001816 risk CIViC:464 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D717V sequence variation in gene KDR/NCBI:3791 1694 check_entity AN5267-1 KDR R1032Q mutation KDR NCBI:3791 gene colorectal cancer DOID:9256 risk PubMed:29588308 R1032Q affects the gene's universal kinase catalytic motif. The authors found that injection of mice with COLO-320 cells that harbor this mutation resulted in tumor generation, indicating that this mutation could have oncogenic potential. In vitro kinase assays showed R1032Q reduced VEGFR2 kinase activity. Using proliferation studies with the COLO-320 cell-line, the authors observed sensitivity to 4 tyrosine kinase inhibitors. Treatment of the MDST8 colorectal cancer cell line carrying the R1032Q mutation with cabozantinib resulted in significant reduction in cell growth and increased ERK phosphorylation levels. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R1032Q sequence variation in gene KDR/NCBI:3791 1695 check_entity AN5267-1 KDR R1032Q mutation KDR NCBI:3791 gene colorectal cancer DOID:9256 risk CIViC:3218 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R1032Q sequence variation in gene KDR/NCBI:3791 1695 check_entity AN5268-1 KDR R961W mutation KDR NCBI:3791 gene colorectal adenocarcinoma DOID:0050861 risk PubMed:27004155 Case Report of a 84-year-old woman with stage IVb CRC after progression under 5-fluorouracil and bevacizumab. NGS revealed a frameshift mutation in APC, a missense mutation in KRAS. Variants of uncertain significance were: a missense variant in ERBB2 and a missense variant in KDR at amino acid 961 converting the wild type residue, Arginine, to Tryptophan (frequency 28.25%). Because of the high frequency of the KDR (VEGFR2) mutation, the patient was considered a suitable candidate for a VEGFR inhibitor and received regorafenib monotherapy, which is approved for this situation, at 80mg daily which was later reduced to 40mg daily and had CEA normalization as well as partial metabolic and radiologic response. The patient remained almost asymptomatic and without disease progression after 39 weeks. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R961W sequence variation in gene KDR/NCBI:3791 1696 check_entity AN5268-1 KDR R961W mutation KDR NCBI:3791 gene colorectal adenocarcinoma DOID:0050861 risk CIViC:498 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R961W sequence variation in gene KDR/NCBI:3791 1696 check_entity AN5269-1 KIF23 EXPRESSION KIF23 NCBI:9493 gene hepatocellular carcinoma DOID:684 prognostic PubMed:26674738 KIF23 variant 1 was found to be expressed in the cDNA of tumor tissues from a large cohort of HCC patients of chinese descent via PCR. This expression was absent in the normal tissues of these patients for this isoform. Using IHC and custom generated antibody, the overall survival with respect to KIF23 V1 expression was evaluated using the kaplan-meier method with a log rank test. It was found that positive KIF23 V1 staining was correlated with longer overall survival over a period of 5 years (p=.0052). This pattern was seen to a lesser degree over a period of 3 years (p=.1604). KIF23 V1 expression was independent of gender, age, tumor size, or TNM stage (multivariate cox regression). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene KIF23/NCBI:9493 1697 AN5269-1 KIF23 EXPRESSION KIF23 NCBI:9493 gene hepatocellular carcinoma DOID:684 prognostic CIViC:681 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene KIF23/NCBI:9493 1697 AN5270-1 KIT A502_Y503insAY KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 PubMed:18955458 In an in vitro study, Chinese hamster ovary cells expressing KIT A502_Y503INSAY demonstrated comparable sensitivity to sunitinib treatment compared to CHO cells expressing ligand activated wild-type KIT (IC50<100 nmol/L). Sensitivity was determined by assessing KIT auto-phosphorylation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT A502_Y503insAY [biomarker_term_in_review] 1698 not_mapped AN5270-1 KIT A502_Y503insAY KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 CIViC:1466 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT A502_Y503insAY [biomarker_term_in_review] 1698 not_mapped AN5270-2 KIT A502_Y503insAY KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:25239608 In an in vitro study, an IL3 independent Ba/F3 cell line expressing KIT A502_Y503insAY primary activating mutation demonstrated insensitivity to regorafenib (IC50: 138nmol/L), imatinib (IC50: 143nmol/L), and ponatinib (IC50: 56nmol/L) treatments. In comparison, sensitizing KIT mutation del550-557 showed IC50 22, 13 and 3 nmol/L for these drugs respectively. IC50 was determined by assessing cell viability. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT A502_Y503insAY [biomarker_term_in_review] 1699 not_mapped AN5270-2 KIT A502_Y503insAY KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:1466 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT A502_Y503insAY [biomarker_term_in_review] 1699 not_mapped AN5271-1 KIT A829P mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:25239608 Ponatinib possesses potent activity against A829P KIT mutant cells in preclinical experiments. A preclinical study tested the effect of a tyrosine kinase inhibitor (TKI) on Ba/F3 cell lines with representative primary ponatinib-sensitizing mutation del 557-558, which induced IL-3 independent growth, and secondary mutation A829P. The cells were tested for Ponatinib resistance. Ba/F3 cells with del 557-558 and A829P mutations (IC50 for growth inhibition: 2 nM) did not show resistance towards Ponatinib compared to Ba/F3 cells with the del 557-558 mutation alone (IC50: 3 nM). Ponatinib was shown to inhibit KIT phosphorylation in moderate concentrations. Similarly, GIST-T1/829 cells with 560-578 deletion/A829P mutations (IC50 = 16 nM) were not resistant to Ponatinib compared to GIST T1 cells with 560-578 deletion alone (IC50 = 5 nM). Ponatinib inhibited phosphorylation in KIT, ERK, and AKT at moderate to high concentrations in GIST-T1/829 cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A829P sequence variation in gene KIT/NCBI:3815 1700 check_entity AN5271-1 KIT A829P mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:964 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A829P sequence variation in gene KIT/NCBI:3815 1700 check_entity AN5272-1 KIT Amplification KIT NCBI:3815 gene mucosal melanoma DOID:0050929 risk 55201-8 PubMed:23775962 Phase 2 trial in metastatic mucosal, acral or chronically sun-damaged melanoma. Twenty-five patients were enrolled (24 evaluable). Eight patients (33%) had tumors with KIT mutations, 11 (46%) with KIT amplifications, and five (21%) with both. Median follow-up was 10.6 months. Best overall response rate was statistically significantly different by mutation status: 7 of 13 or 54% KIT mutated v 0% KIT amplified only. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene KIT/NCBI:3815 1701 AN5272-1 KIT Amplification KIT NCBI:3815 gene mucosal melanoma DOID:0050929 risk 55201-8 CIViC:582 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene KIT/NCBI:3815 1701 AN5273-1 KIT C809G mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:16954519 147 patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib (CSTI571-B2222). Specimens from 43 pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. C809G was observed as a secondary KIT mutation in one patient with secondary imatinib resistance. In vitro, C809G showed imatinib resistance both in isolation and when coexpressed with K642E + N822H (the primary KIT mutations, found on the same allele, for this patient). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C809G sequence variation in gene KIT/NCBI:3815 1702 check_entity AN5273-1 KIT C809G mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:1238 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C809G sequence variation in gene KIT/NCBI:3815 1702 check_entity AN5274-1 KIT D579del KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:18955458 Patient 74 from a larger cohort of genotyped patients (n= 78) with imatinib resistant or intolerant gastrointestinal stromal tumors (GISTs) harbored a primary (pre-imatinib treatment) KIT D579 deletion. Following failure of imatinib, the GIST was again genotyped, but no secondary mutations were found. The patient took 50 mg sunitinib per day on a treatment schedule of four weeks on/two weeks off. The patient experienced stable disease for less than six months. Time to progression was censored at 10 weeks and overall survival was 85 weeks. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT D579del [biomarker_term_in_review] 1703 not_mapped AN5274-1 KIT D579del KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:951 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT D579del [biomarker_term_in_review] 1703 not_mapped AN5275-1 KIT D816E mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:25239608 Several preclinical studies were done in order to test the effects of various tyrosine kinase inhibitors (TKIs) on KIT-mutant cell lines derived from Gastrointestinal Stromal Tumor (GIST) patients with primary mutation 560-578 deletion and secondary mutation D816E. The cells were tested for Imatinib and Sunitinib resistances. GIST-T1/816 cells with 560-578 deletion and D816E mutations were resistant towards Imatinib and Sunitinib (Imatinib IC50: 604 nM and Sunitinib IC50: 3111 nM) compared to GIST-T1 cells with the 560-578 deletion mutation alone (Imatinib IC50: 30 nM and Sunitinib IC50: 15 nM). Imatinib inhibited phosphorylation in KIT and ERK at high concentrations. Sunitinib did not inhibit phosphorylation in KIT, ERK, or AKT at all. Additionally, Ba/F3 cells were mutagenized with N-ethyl-N-nitrosourea and incubated with varying concentrations of Sunitinib and Imatinib separately. In Imatinib incubated cells, D816E mutations were seen in less than 5% of resistant Ba/F3 cell clones only in the lowest concentration. In Imatinib incubated cells, D816E mutations were seen in approximately 10% of resistant Ba/F3 cell clones. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D816E sequence variation in gene KIT/NCBI:3815 1704 check_entity AN5275-1 KIT D816E mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:1467 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D816E sequence variation in gene KIT/NCBI:3815 1704 check_entity AN5276-1 KIT D816H mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:16954519 '147 patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib (CSTI571-B2222). Specimens from 43 pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. D816H was observed as a secondary KIT mutation in two patients with secondary imatinib resistance. The mutation was shown to occur at a hotspot (D816) of previously reported secondary KIT mutations in imatinib resistant GISTs. When co-expressed with V560D (imatinib sensitive) in vitro D816H showed ''extreme'' imatinib resistance. It was also highly resistant in isolation.' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D816H sequence variation in gene KIT/NCBI:3815 1705 check_entity AN5276-1 KIT D816H mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:957 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D816H sequence variation in gene KIT/NCBI:3815 1705 check_entity AN5277-1 KIT D816V mutation KIT NCBI:3815 gene acute myeloid leukemia DOID:9119 prognostic 55201-8 PubMed:16384925 In acute myloid leukemia patients, D816 mutation is associated with earlier relapse and poorer prognosis than wildtype KIT. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D816V sequence variation in gene KIT/NCBI:3815 1706 check_entity AN5277-1 KIT D816V mutation KIT NCBI:3815 gene acute myeloid leukemia DOID:9119 prognostic 55201-8 CIViC:65 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D816V sequence variation in gene KIT/NCBI:3815 1706 check_entity AN5277-2 KIT D816V mutation KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 PubMed:14645423 In an in vitro study of imatinib sensitivity, KIT D816V was cloned into a plasmid by site-directed mutagenesis of KIT WT cDNA. Chinese hamster ovary cells were transiently transfected with the plasmid. Cells were treated with control media or media containing various concentrations of imatinib for 90 minutes. Protein lysates from the transfected cells were examined for phosphorylated tyrosine, a measure of KIT activation. Cells expressing KIT D816V were resistant to imatinib up to 10 umol/L. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D816V sequence variation in gene KIT/NCBI:3815 1707 check_entity AN5277-2 KIT D816V mutation KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 PubMed:25317746 In an in vitro study, COS-7 cells expressing KIT D816V activating mutation demonstrated resistance to 1uM dasatinib treatment. In a separate in vitro study, TF-1 cells expressing KIT D816V activating mutation demonstrated resistance to 1 and 10 uM imatinib treatment. Sensitivity was determined by assessing reduced mutant KIT auto-phosphorylation with addition of inhibitors. No reduction in D816V autophosphorylation was observed with inhibitor treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D816V sequence variation in gene KIT/NCBI:3815 1707 check_entity AN5277-2 KIT D816V mutation KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 CIViC:65 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D816V sequence variation in gene KIT/NCBI:3815 1707 check_entity AN5277-3 KIT D816V mutation KIT NCBI:3815 gene systemic mastocytosis DOID:349 prognostic;risk 55201-8 PubMed:27355533 In a phase II clinical trial, 60% of patients (N=89) with advanced systemic mastocytosis responded to treatment with midostaurin. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D816V sequence variation in gene KIT/NCBI:3815 1708 check_entity AN5277-3 KIT D816V mutation KIT NCBI:3815 gene systemic mastocytosis DOID:349 prognostic;risk 55201-8 PubMed:26464169 The D816V+ advanced systemic mastocytosis patients with additional mutations in SRSF2 (N=30), ASLX1 (N=20), or RUNX1 (N=16) exhibited lower overall survival over 14 years as compared to D816V+ patients with wildtype SRSF2 (N=40), ASXL1(N=50), or RUNX1 (N=54). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D816V sequence variation in gene KIT/NCBI:3815 1708 check_entity AN5277-3 KIT D816V mutation KIT NCBI:3815 gene systemic mastocytosis DOID:349 prognostic;risk 55201-8 CIViC:65 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D816V sequence variation in gene KIT/NCBI:3815 1708 check_entity AN5278-1 KIT D820A mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:16954519 147 patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib (CSTI571-B2222). Specimens from 43 pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. D820A was observed as a secondary KIT mutation in one patient with secondary imatinib resistance. The mutation was shown to occur at a hotspot (D820) of previously reported secondary KIT mutations in imatinib resistant GISTs. A cell line derived from a separate patient with the same primary (V560D) and secondary (D820A) mutations showed moderately increased resistance to imatinib compared to reports for GIST lines with primary exon 11 KIT mutations alone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D820A sequence variation in gene KIT/NCBI:3815 1709 check_entity AN5278-1 KIT D820A mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:1239 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D820A sequence variation in gene KIT/NCBI:3815 1709 check_entity AN5279-1 KIT D820G mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:16954519 '147 patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib (CSTI571-B2222). Specimens from 43 pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. D820G was observed as a secondary KIT mutation in two patients with secondary imatinib resistance. The mutation was shown to occur at a hotspot (D820) of previously reported secondary KIT mutations in imatinib resistant GISTs. When co-expressed with V560D (imatinib sensitive) in vitro D820G showed ''extreme'' imatinib resistance.' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D820G sequence variation in gene KIT/NCBI:3815 1710 check_entity AN5279-1 KIT D820G mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:1240 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D820G sequence variation in gene KIT/NCBI:3815 1710 check_entity AN5280-1 KIT D820Y mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:22614970 This retrospective study of a phase 2 clinical trial (NCT01068769) examined regorafenib safety and efficacy in advanced gastrointestinal stromal tumor (GIST) patients refractory to at least imatinib and sunitinib. Three patients whose GIST harbored KIT D820Y experienced clinical benefit (defined as complete response, partial response, stable disease >16 weeks) in response to regorafenib. One patient remained on study without disease progression for >11 months, one patient developed disease progression at 5.7 months, and the other patient underwent surgical removal of all residual disease after 7 months, but continued on regorafenib. Immunoblotting of matched pre- and post- treatment GIST biopsies from these patients demonstrated decreased levels of KIT phosphorylation in response to regorafenib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D820Y sequence variation in gene KIT/NCBI:3815 1711 check_entity AN5280-1 KIT D820Y mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:960 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D820Y sequence variation in gene KIT/NCBI:3815 1711 check_entity AN5280-2 KIT D820Y mutation KIT NCBI:3815 gene melanoma DOID:1909 risk 55201-8 PubMed:21642685 FFPE tumor specimens from 295 melanoma patients were screened for KIT amplification and mutation. Of these, 51 patients had variants in KIT and 28 of these were treated with imatinib mesylate at 400 mg orally, twice daily with 25 patients eligible for response evaluation. None of the patients had mutations in BRAF, NRAS, or GNAQ. Two patients achieved a durable complete response, two achieved a durable partial response, and 5 achieved stable disease >12 weeks with a median survival of 46.3 weeks. One patient harboring a somatic D820Y mutation at roughly 50% variant allele frequency (1:1 with wild type) displayed Imatinib mesylate–resistance and disease progression, which is consistent with resistant mechanisms described in Gastro-Intestinal Stromal Tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D820Y sequence variation in gene KIT/NCBI:3815 1712 check_entity AN5280-2 KIT D820Y mutation KIT NCBI:3815 gene melanoma DOID:1909 risk 55201-8 PubMed:19035443 28 acral or mucosal melanomas were examined for KIT expression and mutations (exons 11, 13, 17, and 18). Two of 19 melanomas examined harbored KIT mutations, with one subject harboring a D820Y mutation. Western blotting showed KIT phosphorylation (Y219) in this case and the SM3 cell line harboring the D820Y mutation. The SM3 cell line showed significant growth inhibition with sunitinib exposures of 1uM and 10uM while imatinib showed no activity. The authors comment that this indicates a potential role for sunitinib in growth inhibition of acral melanomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D820Y sequence variation in gene KIT/NCBI:3815 1712 check_entity AN5280-2 KIT D820Y mutation KIT NCBI:3815 gene melanoma DOID:1909 risk 55201-8 CIViC:960 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D820Y sequence variation in gene KIT/NCBI:3815 1712 check_entity AN5281-1 KIT EXPRESSION KIT NCBI:3815 gene endometrial cancer DOID:1380 risk 55201-8 PubMed:18607592 Case Report of a 42-year old patient with low-grade endometrial stromal sarcoma. IHC was focally positive for CD117. Imatinib mesylate led to complete metabolic response (PET-CT). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene KIT/NCBI:3815 1713 AN5281-1 KIT EXPRESSION KIT NCBI:3815 gene endometrial cancer DOID:1380 risk 55201-8 PubMed:16487996 Case Report of a 41-year old patient with high-grade stromal endometrial sarcoma and a large abdominal and retroperitoneal mass progressing after chemotherapy. IHC for c-Kit was positive and treatment with imatinib led to an objective Response. Surgery was performed and the patient was free of disease two years later. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene KIT/NCBI:3815 1713 AN5281-1 KIT EXPRESSION KIT NCBI:3815 gene endometrial cancer DOID:1380 risk 55201-8 CIViC:425 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene KIT/NCBI:3815 1713 AN5281-2 KIT EXPRESSION KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:18955451 In a prospective phase III study (SWOG S0033/CALGB 150105) of 407 patients with gastrointestinal stromal tumors (GISTs), 397 patients were observed to be CD117-positive (i.e. KIT-positive) and 10 patients were CD117-negative. Patients were treated with either 400mg or 800mg of imatinib per day. When compared to CD117-positive, GISTs, CD117-negative GISTs did not show significant difference in median time to progression (18.3 months vs. 20.5 months; P = 0.46), however, CD-117-negative GISTs showed reduced overall survival relative to CD-117-positive GISTs (25.8 months vs. 57.1 months; P= 0.01). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene KIT/NCBI:3815 1714 AN5281-2 KIT EXPRESSION KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:425 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene KIT/NCBI:3815 1714 AN5281-3 KIT EXPRESSION KIT NCBI:3815 gene glioblastoma DOID:3068 risk 55201-8 PubMed:24311637 Phase II trial of sunitinib in 40 patients with first recurrence of primary glioblastoma. Median PFS 2.2 mo, median OS 9.2 mo, 5 stable disease >=6 months, no objective responses, so primary study endpoint was not met. However, IHC of multiple receptor kinases was performed, and protein expression of KIT in vascular endothelial cells was associated with longer PFS (P = .017; HR, 2.564; 95% CI, 1.180–5.570). All 5 with stable disease were KIT+ in vascular endothelial cells. Note KIT staining was not observed in tumour cells. No association with OS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene KIT/NCBI:3815 1715 AN5281-3 KIT EXPRESSION KIT NCBI:3815 gene glioblastoma DOID:3068 risk 55201-8 CIViC:425 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene KIT/NCBI:3815 1715 AN5282-1 KIT Exon 11 Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 diagnostic;prognostic;risk 55201-8 PubMed:16551858 There is no significant association between wildtype KIT or KIT mutations in exon 9 or 11 in survival among GIST patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:11:mutation sequence variation in gene KIT/NCBI:3815 1716 check_entity AN5282-1 KIT Exon 11 Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 diagnostic;prognostic;risk 55201-8 PubMed:10485475 KIT mutation is associated with larger, more invasive tumors, greater pathologic histology and older patients compared to tumors with wildtype KIT. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:11:mutation sequence variation in gene KIT/NCBI:3815 1716 check_entity AN5282-1 KIT Exon 11 Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 diagnostic;prognostic;risk 55201-8 PubMed:12000708 KIT mutations were identified in morphologically benign, incidentally discovered GISTs at a rate similar to that seen in advanced, metastatic GIST patients indicating is not a prognostic marker for GIST. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:11:mutation sequence variation in gene KIT/NCBI:3815 1716 check_entity AN5282-1 KIT Exon 11 Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 diagnostic;prognostic;risk 55201-8 PubMed:14645423 This prospective study of 127 pretreatment patients with metastatic gastrointestinal stromal tumors (GISTs) examined the relationship between kinase (KIT and PDGFRA) genotype and treatment outcome for patients enrolled in a randomized phase II trial of imatinib (CSTI571B 2222). 85 patients harbored KIT exon 11 mutated GISTs: 71 had an in-frame deletion and 15 had unspecified point mutations (3 codon 557 cases, 3 codon 559 cases, 6 codon 560 cases and 2 codon 576 cases). Of patients harboring KIT exon 11 mutated GISTs, 71 (83.5%) had a partial response, 7 had stable disease, 4 had progressive disease and 3 were nonassessable. Patients with KIT exon 11 mutations were significantly more likely to have a partial response than those with KIT exon 9 mutations (P=.0006) or double WT kinases (WT KIT and WT PDGFRA; P < .0001). The presence of a KIT exon 11 mutation was the strongest predictor of response (Hazard ratio= 7.85). Patients harboring KIT exon 11 mutant GISTs experienced longer event free survival (median: 687 days) than those with KIT exon 9 mutant or double WT kinase GISTs (200 days and 82 days, respectively). Furthermore, patients whose tumors expressed an exon 11 mutant KIT had improved overall survival compared to patients whose tumor expressed an exon 9 mutant KIT (P = .0034) or double WT kinases (P <.0001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:11:mutation sequence variation in gene KIT/NCBI:3815 1716 check_entity AN5282-1 KIT Exon 11 Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 diagnostic;prognostic;risk 55201-8 PubMed:18955451 This prospective study of 397 patients with incurable (i.e. metastatic or unresectable) CD117-positive Gastrointestinal stromal tumors (GISTs) examined the relationship between KIT genotype and treatment outcome for patients enrolled in the North American phase III study SWOG S0033/CALGB 150105 who were treated with either 400mg or 800mg of imatinib per day. The study found that patients whose tumors harbored mutations in KIT exon 11 had signficantly superior responses to imatinib, regardless of dose, than those whose tumors harbored wildtype KIT or KIT exon 9 mutations. This is evidenced by the findings that imatinib-treated patients whose tumors contained KIT exon 11 mutations had longer overall survival compared to those with exon 9 mutations (60.0mo vs.38.4mo, P=0.011) or wildtype KIT (60mo vs. 49.0mo, P=0.049). Patients with exon 11 mutations had improved progression-free survival in comparison to those with exon 9 mutations (24.7mo vs. 16.7mo, P=0.0013) or wildtype KIT (24.7mo vs. 12.8mo, P=0.005). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:11:mutation sequence variation in gene KIT/NCBI:3815 1716 check_entity AN5282-1 KIT Exon 11 Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 diagnostic;prognostic;risk 55201-8 PubMed:18955458 In a phase I/II trial of sunitinib efficacy on imatinib resistant or intolerant gastrointestinal stromal tumor (GIST) patients (n=77), patients harboring primary (pre-imatinib treatment) KIT exon 11 mutant GISTs (n=44) treated with sunitinib experienced shorter progression free survival (5.1 vs 19.0 months, P = .0356) and overall survival (12.3 vs 30.5 months, P=0.0132) as compared to patients with wild-type KIT (n=9). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:11:mutation sequence variation in gene KIT/NCBI:3815 1716 check_entity AN5282-1 KIT Exon 11 Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 diagnostic;prognostic;risk 55201-8 PubMed:23177515 This international, placebo controlled prospective phase 3 clinical trial (NCT01271712) examined safety and efficacy of regorafenib in patients with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) who failed previous treatments with at least imatinib or sunitinib. Progression free survival was measured for 199 patients treated with either daily 160mg regorafenib (n=133) or a matching placebo (n= 66). Overall, median PFS was 7.4 months in the regorafenib group and 1.7 months in the placebo group (HR= .22, P <.001). Patients with KIT exon 11 mutations (n=51) treated with regorafenib were associated with similarly favorable progression free survival (HR: 0.212), as compared to patients with treated with placebo. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:11:mutation sequence variation in gene KIT/NCBI:3815 1716 check_entity AN5282-1 KIT Exon 11 Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 diagnostic;prognostic;risk 55201-8 PubMed:22614970 This retrospective study of a phase 2 clinical trial (NCT01068769) examined regorafenib safety and efficacy in advanced gastrointestinal stromal tumor (GIST) patients who failed previous treatments with imatinib and sunitinib. Of 30 genotyped patients treated with regorafenib, those with KIT exon 11 mutant GISTs (n=19) experienced significantly increased progression free survival (P=0.01), as compared to patients with KIT exon 9 mutant GISTs (n=3). Median PFS for the entire cohort was 10.0 months. Regorafenib treatment induced clinical benefit (defined as complete response, partial response, stable disease > 16 weeks) in 16/19 patients with KIT exon 11 mutant GISTs. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:11:mutation sequence variation in gene KIT/NCBI:3815 1716 check_entity AN5282-1 KIT Exon 11 Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 diagnostic;prognostic;risk 55201-8 PubMed:27371698 This phase II clinical trial of regorafenib (NCT01068769) examined the long term safety and efficacy of regorafenib in patients with metastatic and/or unresectable gastrointestinal stromal tumors (GISTs) who failed previous treatments with imatinib. Patients whose GISTs harbored KIT exon 11 mutations (n=19) experienced higher rates of clinical benefit (defined as complete response, partial response, or stable disease lasting >16 weeks) than patients whose GISTs harbored KIT exon 9 mutations. 15/19 patients with exon 11 mutant GISTs experienced clinical benefit (including 2 PRs). KIT exon 11 mutant GISTs treated with regorafenib monotherapy were associated with improved median progression free survival (13.4 months vs. 5.7 and 1.6 months, P<0.0001), as compared to patients with KIT exon 9 mutation (n=2) and patients with KIT wildtype, non-succinate dehydrogenase-deficient tumors (n=2). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:11:mutation sequence variation in gene KIT/NCBI:3815 1716 check_entity AN5282-1 KIT Exon 11 Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 diagnostic;prognostic;risk 55201-8 CIViC:66 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:11:mutation sequence variation in gene KIT/NCBI:3815 1716 check_entity AN5282-2 KIT Exon 11 Mutation KIT NCBI:3815 gene lung cancer DOID:1324 prognostic 55201-8 PubMed:15217946 KIT mutations detected in 5/60 patients showed no prognostic significance in patients with small cell lung cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:11:mutation sequence variation in gene KIT/NCBI:3815 1717 check_entity AN5282-2 KIT Exon 11 Mutation KIT NCBI:3815 gene lung cancer DOID:1324 prognostic 55201-8 CIViC:66 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:11:mutation sequence variation in gene KIT/NCBI:3815 1717 check_entity AN5282-3 KIT Exon 11 Mutation KIT NCBI:3815 gene melanoma DOID:1909 risk 55201-8 PubMed:23775962 Melanoma patients with KIT mutation but not KIT amplification showed response to imatinib treatment in a small cohort of patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:11:mutation sequence variation in gene KIT/NCBI:3815 1718 check_entity AN5282-3 KIT Exon 11 Mutation KIT NCBI:3815 gene melanoma DOID:1909 risk 55201-8 PubMed:22261812 10 melanoma patients were evaluated after sunitinib treatment, among which 3 out of the 4 patients with KIT exon 11 mutations showed either complete or partial response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:11:mutation sequence variation in gene KIT/NCBI:3815 1718 check_entity AN5282-3 KIT Exon 11 Mutation KIT NCBI:3815 gene melanoma DOID:1909 risk 55201-8 CIViC:66 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:11:mutation sequence variation in gene KIT/NCBI:3815 1718 check_entity AN5283-1 KIT Exon 13 Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:14645423 This prospective study of 127 patients with metastatic gastrointestinal stromal tumors (GISTs) examined the relationship between kinase (KIT and PDGFRA) genotype and treatment outcome for patients enrolled in a randomized phase II trial of imatinib (CSTI571B 2222). Two patients' GISTs harbored KIT exon 13 mutations, and both experienced partial responses to imatinib. The authors conclude that this uncommon variant is sensitive to imatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:13:mutation sequence variation in gene KIT/NCBI:3815 1719 check_entity AN5283-1 KIT Exon 13 Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:2512 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:13:mutation sequence variation in gene KIT/NCBI:3815 1719 check_entity AN5284-1 KIT Exon 14 Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 prognostic 55201-8 PubMed:16551858 GIST patients with exon 14 KIT mutations had reduced overall survival compared to patients wiltype for KIT. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:14:mutation sequence variation in gene KIT/NCBI:3815 1720 check_entity AN5284-1 KIT Exon 14 Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 prognostic 55201-8 CIViC:69 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:14:mutation sequence variation in gene KIT/NCBI:3815 1720 check_entity AN5285-1 KIT Exon 9 Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:16624552 In a phase III clinical trial comparing different doses of imatinib in GIST patients, KIT exon 9 mutations were associated with significantly improved progression free survival (P=0.0013) and a 61% relative risk reduction in response to the higher dose regimen (N=31; 800mg/daily) when compared to the lower dose regimen (N=27; 400 mg/daily; HR 0.329; 95% CI 0.218–0.706). The same dose dependent responses were not observed with KIT exon 11 mutations (N=130 vs 118; P=0.25; HR 0.821; 95% CI 0.585–1.151) or with wild-type KIT (N=25 vs 27; P=0.07; HR 1.823; 95% CI 0.938–3.543). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:9:mutation sequence variation in gene KIT/NCBI:3815 1721 check_entity AN5285-1 KIT Exon 9 Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:22439647 Primary tumor genotyping of 89 patients with metastatic GIST given 2nd-line sunitinib treatment after prior imatinib therapy failure, revealed an improved response to sunitinib in patients with KIT exon 9 mutations or with wild-type KIT compared those with KIT exon 11 or PDGFRA mutations. 1-year progression free survival rates for exon 9 mutants and wild type were 68% and 57%, compared with 34% and 15% for exon 11 and PDGFRA mutants. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:9:mutation sequence variation in gene KIT/NCBI:3815 1721 check_entity AN5285-1 KIT Exon 9 Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:18955458 In a study of 78 patients with gastrointestinal stromal tumors treated with sunitinib, patients with Kit exon 9 mutations or wildtype (lacking KIT or PDGFRA mutations) showed increased progression free survival and overall survival compared to patients with Kit exon 11 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:9:mutation sequence variation in gene KIT/NCBI:3815 1721 check_entity AN5285-1 KIT Exon 9 Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:14645423 This prospective study of 127 patients with metastatic gastrointestinal stromal tumors (GISTs) examined the relationship between KIT genotype and treatment outcome for patients enrolled in a randomized phase II trial of imatinib (CSTI571B 2222). 23 patients harbored KIT exon 9 mutated GISTs: 22 harbored A502_503Ydup and 1 harbored F506_F508dup. Of patients harboring KIT exon 9 mutated GISTs, 11 (47.8%) had a partial response, 6 had stable disease, 4 had progressive disease and 2 were nonassessable. Patients with KIT exon 9 mutant GISTs were significantly more likely to have a partial response than those with WT KIT (P = .013), though significantly less likely than those with KIT exon 11 mutated GISTs (P = .0006). Patients harboring KIT exon 9 mutant GISTs experienced longer event free survival (median: 200 days) than those with WT KIT GISTs (82 days). Furthermore, there was a signficant difference in overall survival between patients with KIT exon 9 mutant and double WT kinase GISTs (P = .0067). There was no significant difference in the rate of treatment failure for patients with exon 9 mutation compared with those with no KIT or PDGFRA mutation (P = .14). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:9:mutation sequence variation in gene KIT/NCBI:3815 1721 check_entity AN5285-1 KIT Exon 9 Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:18955451 This prospective study of 397 patients with incurable (i.e. metastatic or unresectable) CD117-positive Gastrointestinal stromal tumors (GISTs) examined the relationship between KIT genotype and treatment outcome for patients enrolled in the North American phase III study SWOG S0033/CALGB 150105 who were treated with either 400mg or 800mg of imatinib per day. Of 33 patients with KIT exon-9 mutant GISTs, 31 harbored KIT A502_Y503 internal tandom duplication, one harbored K484_G487del (KHNG). Of the KIT exon 9 mutant patients, 14 were treated with 400mg daily and 19 were treated with 800mg daily. Patients with KIT exon-9 mutant GISTs had a significantly higher response rate when treated with 800mg compared with 400mg (CR/PR 17% vs 67% for 400mg and 800mg, respectively; OR, 9.05; p = .02). However, the authors report that there was not a significant difference in time to progression or overall survival between the two dose groups for patients harboring KIT exon-9 mutant GISTs. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:9:mutation sequence variation in gene KIT/NCBI:3815 1721 check_entity AN5285-1 KIT Exon 9 Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:27371698 This phase II clinical trial of regorafenib (NCT01068769) examined the long term safety and efficacy of regorafenib monotherapy in patients with metastatic and/or unresectable gastrointestinal stromal tumors (GISTs) who failed previous treatments with imatinib. In response to regorafenib monotherapy, patients whose GISTs harbored KIT exon 9 mutations experienced lower rates of clinical benefit (defined as complete response, partial response, or stable disease lasting >16 weeks) than patients whose GISTs harbored KIT exon 11 mutations or KIT/PDGFR wildtype SDH-deficient patients. Of 3 patients with KIT exon 9 mutant GISTs, 2 experienced clinical benefit (including one PR), and the median progression free survival was 5.7 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:9:mutation sequence variation in gene KIT/NCBI:3815 1721 check_entity AN5285-1 KIT Exon 9 Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:22614970 This retrospective study of a phase 2 clinical trial (NCT01068769) examined regorafenib safety and efficacy in advanced gastrointestinal stromal tumor (GIST) patients who failed previous treatments with at least imatinib and sunitinib. Of 30 genotyped patients treated with regorafenib, those with KIT exon 9 mutant GISTs (n=3) experienced decreased progression free survival as compared to patients with KIT exon 11 mutated GISTs (n=19) or wildtype (lacking KIT or PDGFRA mutations) GISTs (n= 8). The difference in PFS was significant between Exon 9 and 11 mutant GISTs (P = .01). Median PFS for the whole cohort was 10.0 months. Regorafenib treatment induced clinical benefit (defined as complete response, partial response, stable disease <16 weeks) in 2/3 patients with KIT exon 9 mutant GISTs. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:9:mutation sequence variation in gene KIT/NCBI:3815 1721 check_entity AN5285-1 KIT Exon 9 Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:23177515 This international, placebo controlled prospective phase 3 clinical trial (NCT01271712) examined safety and efficacy of regorafenib in patients with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) who failed previous treatments with at least imatinib or sunitinib. Progression free survival was measured for 199 patients treated with either daily 160mg regorafenib (n=133) or a matching placebo (n= 66). Overall, median PFS was 7.4 months in the regorafenib group and 1.7 months in the placebo group (HR= .22, P <.001). Patients with KIT exon 9 mutations (n=15) treated with regorafenib were associated with a similarly favorable progression free survival (HR: 0.239), as compared to patients with treated with placebo. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:9:mutation sequence variation in gene KIT/NCBI:3815 1721 check_entity AN5285-1 KIT Exon 9 Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:505 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:9:mutation sequence variation in gene KIT/NCBI:3815 1721 check_entity AN5286-1 KIT F506_F508DUP mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:18955451 This patient was part of a larger cohort of 397 patients with incurable (i.e. metastatic or unresectable) CD117-positive Gastrointestinal stromal tumors (GISTs) enrolled in the North American phase III study SWOG S0033/CALGB 150105. Patients in the study were treated with either 400mg or 800mg of imatinib per day. This patient's GIST harbored a tandem reduplication of KIT codons 506 to 508 (FAF) after F508 (F506_F508dup). The patient's response to imatinib was not assessed but the TTP was 10.6 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::f506_f508dup:mutation sequence variation in gene KIT/NCBI:3815 1722 check_entity AN5286-1 KIT F506_F508DUP mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:2494 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::f506_f508dup:mutation sequence variation in gene KIT/NCBI:3815 1722 check_entity AN5287-1 KIT Internal Duplication KIT NCBI:3815 gene malignant anus melanoma DOID:14145 risk 55201-8 PubMed:18421059 In a case study, a patient with anal melanoma harboring a 7 codon duplication in the juxtamambrane region (exon 11) of KIT showed marked response 4 months after imatinib treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT Internal Duplication [biomarker_term_in_review] 1723 not_mapped AN5287-1 KIT Internal Duplication KIT NCBI:3815 gene malignant anus melanoma DOID:14145 risk 55201-8 CIViC:67 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT Internal Duplication [biomarker_term_in_review] 1723 not_mapped AN5288-1 KIT K484_G487DEL KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:18955451 This patient was from a larger cohort of 397 patients with incurable (i.e. metastatic or unresectable) CD117-positive Gastrointestinal stromal tumors (GISTs) enrolled in the North American phase III study SWOG S0033/CALGB 150105. Patients in the study were treated with either 400mg or 800mg of imatinib per day. This patient's GIST harbored a homozygous deletion of KIT codons 484 to 487 (KHNG; K484_G487del). The patient's response to imatinib was not assessed, and the TTP was 46.9 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT K484_G487DEL [biomarker_term_in_review] 1724 not_mapped AN5288-1 KIT K484_G487DEL KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:2495 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT K484_G487DEL [biomarker_term_in_review] 1724 not_mapped AN5289-1 KIT K550_K558del KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:18955458 Patient 3 from a larger cohort of genotyped patients (n= 78) with imatinib resistant or intolerant gastrointestinal stromal tumors (GISTs) harbored a primary (pre-imatinib treatment) KIT K550_K558 deletion. Following failure of imatinib, the GIST was again genotyped, but no secondary mutations were found. The patient started on 50mg sunitinib on a schedule of two weeks on/two weeks off. This patient experienced stable disease less than 6 months; time to progresssion of 14 weeks and overall survival of 17 weeks (Table A1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT K550_K558del [biomarker_term_in_review] 1725 not_mapped AN5289-1 KIT K550_K558del KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:923 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT K550_K558del [biomarker_term_in_review] 1725 not_mapped AN5290-1 KIT K550_K559DEL KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:18955458 Patient 78 from a larger cohort of genotyped patients (n= 78) with imatinib resistant or intolerant gastrointestinal stromal tumors (GISTs) harbored a primary (pre-imatinib treatment) KIT K550_V559 deletion. Following failure of imatinib, the GIST was again genotyped, but no secondary mutations were found. The patient started on 50mg sunitinib on a schedule of two weeks on/one weeks off. This patient experienced partial response; time to progression and overall survival were censored at 54 weeks and 84 weeks (Table A1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT K550_K559DEL [biomarker_term_in_review] 1726 not_mapped AN5290-1 KIT K550_K559DEL KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:2565 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT K550_K559DEL [biomarker_term_in_review] 1726 not_mapped AN5291-1 KIT K550_W557del KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:25239608 In an in vitro study, an IL3 independent Ba/F3 cell line expressing KIT K550_W557del primary activating mutation demonstrated sensitivity to imatinib (IC50: 13nmol/L), sunitinib (IC50: 5nmol/L), regorafenib (IC50: 22nmol/L), and ponatinib (IC50: 3nmol/L) treatments. IC50 was determined by assessing cell viability. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT K550_W557del [biomarker_term_in_review] 1727 not_mapped AN5291-1 KIT K550_W557del KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:922 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT K550_W557del [biomarker_term_in_review] 1727 not_mapped AN5292-1 KIT K558_V559del KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:18955458 Patient 47 from a larger cohort of genotyped patients (n= 78) with imatinib resistant or intolerant gastrointestinal stromal tumors (GISTs) harbored a primary (pre-imatinib treatment) KIT K558_V559 deletion. Following failure of imatinib, the GIST was again genotyped, but no secondary mutations were found. The patient took 50 mg sunitinib per day on a treatment schedule of two weeks on/one week off. The patient experienced progressive disease. Time to progression was censored at 5 weeks, and overall survival was 60 weeks. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT K558_V559del [biomarker_term_in_review] 1728 not_mapped AN5292-1 KIT K558_V559del KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:938 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT K558_V559del [biomarker_term_in_review] 1728 not_mapped AN5293-1 KIT K558delinsNP KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:25239608 In an in vitro study, an IL3 independent Ba/F3 cell line expressing KIT K558NP primary activating mutation demonstrated sensitivity to imatinib (IC50: 2nmol/L), sunitinib (IC50: 2nmol/L ), regorafenib (IC50: 4nmol/L), and ponatinib (IC50: 1nmol/L) treatments. IC50 was determined by assessing cell viability. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT K558delinsNP [biomarker_term_in_review] 1729 not_mapped AN5293-1 KIT K558delinsNP KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:1457 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT K558delinsNP [biomarker_term_in_review] 1729 not_mapped AN5294-1 KIT K642E mutation KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 PubMed:14645423 In an in vitro study of imatinib sensitivity, KIT K642E was cloned into a plasmid by site-directed mutagenesis of KIT WT cDNA. Chinese hamster ovary cells were transiently transfected with the plasmid. Cells were treated with control media or media containing various concentrations of imatinib for 90 minutes. Then, protein lysates from the transfected cells were examined for phosphorylated tyrosine, a measure of KIT activation. Cells expressing KIT K642E were as sensitive to imatinib as ligand activated wildtype KIT (IC50: 100-200 nmol/L). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K642E sequence variation in gene KIT/NCBI:3815 1730 check_entity AN5294-1 KIT K642E mutation KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 CIViC:952 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K642E sequence variation in gene KIT/NCBI:3815 1730 check_entity AN5294-2 KIT K642E mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:25239608 The GIST882 patient derived cell line expressing KIT K642E mutation demonstrated sensitivity to ponatinib (IC50: 31nmol/L) and sunitinib (IC50: 54nmol/L) treatments. In comparison, the insensitve KIT-independent GIST226 cell line showed IC50 >2807nmol/L and >5000nmol/L for these drugs respectively. IC50 was determined by assessing cell viability. The GIST882 cell line only showed reduced levels of phospho-KIT and phospho-ERK at high concentrations for ponatinib and sunitinib, while phospho-AKT levels were reduced at all concentrations for ponatinib and sunitinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K642E sequence variation in gene KIT/NCBI:3815 1731 check_entity AN5294-2 KIT K642E mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:952 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K642E sequence variation in gene KIT/NCBI:3815 1731 check_entity AN5294-3 KIT K642E mutation KIT NCBI:3815 gene melanoma DOID:1909 risk 55201-8 PubMed:21523734 In a phase 2 clinical trial of 39 stage 3/4 chemotherapy-naive unresectable melanoma patients, a subungual melanoma patient harboring the KIT K642E mutation was reported to have a partial response to dasatinib monotherapy of 24 weeks with a 56% tumor reduction. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K642E sequence variation in gene KIT/NCBI:3815 1732 check_entity AN5294-3 KIT K642E mutation KIT NCBI:3815 gene melanoma DOID:1909 risk 55201-8 CIViC:952 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K642E sequence variation in gene KIT/NCBI:3815 1732 check_entity AN5294-4 KIT K642E mutation KIT NCBI:3815 gene mucosal melanoma DOID:0050929 risk 55201-8 PubMed:18510589 A 69 y.o. woman presented with metastatic mucosal melanoma of the anus. KIT was amplified in the tumor and harbored the K642E mutation. Post surgery with extensive margins, she was given a dose of anti-CTLA-4 antibody and adjuvant radiation therapy for 2.5 weeks. Two weeks post radiation she developed nodules in the same region and testing indicated they were malignant melanoma with high KIT expression. She enrolled in a clinical trial with a dose of 400mg imatinib per day (Nov 2006). Less than 4 weeks later, all nodules had disappeared. Upon a lowered dosage to 200mg of imatinib, the nodules returned and subsequently the dosage was increased to 600mg/day. The patient remained melanoma-free on 600mg imatinib until a follow up in Jan 2008. The authors do not provide further details on patient outcome. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K642E sequence variation in gene KIT/NCBI:3815 1733 check_entity AN5294-4 KIT K642E mutation KIT NCBI:3815 gene mucosal melanoma DOID:0050929 risk 55201-8 CIViC:952 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K642E sequence variation in gene KIT/NCBI:3815 1733 check_entity AN5295-1 KIT L576P mutation KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 PubMed:25317746 In an in vitro study, COS-7 cells expressing KIT L576P activating mutation demonstrated sensitivity to imatinib and dasatinib treatments. Sensitivity was determined by assessing reduced mutant KIT auto-phosphorylation via western blotting with addition of inhibitors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L576P sequence variation in gene KIT/NCBI:3815 1734 check_entity AN5295-1 KIT L576P mutation KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 CIViC:72 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L576P sequence variation in gene KIT/NCBI:3815 1734 check_entity AN5295-2 KIT L576P mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:18955458 Patient 29 from a larger cohort of genotyped patients (n= 78) with imatinib resistant or intolerant gastrointestinal stromal tumors (GISTs) harbored a primary (pre-imatinib treatment) KIT L576P mutation. Following failure of imatinib, the GIST was again genotyped, but no secondary mutations were found. The patient took 50 mg sunitinib per day on a treatment schedule of two weeks on/two weeks off. The patient experienced stable disease for less than 6 months. Time to progression and overall survival were 31 and 29 weeks. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L576P sequence variation in gene KIT/NCBI:3815 1735 check_entity AN5295-2 KIT L576P mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:72 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L576P sequence variation in gene KIT/NCBI:3815 1735 check_entity AN5295-3 KIT L576P mutation KIT NCBI:3815 gene lung non-small cell carcinoma DOID:3908 risk 55201-8 PubMed:17372901 Ba/F3 cells harboring the KIT L576P mutation are sensitive to nilotinib, imatinib and lower concentrations of dasatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L576P sequence variation in gene KIT/NCBI:3815 1736 check_entity AN5295-3 KIT L576P mutation KIT NCBI:3815 gene lung non-small cell carcinoma DOID:3908 risk 55201-8 CIViC:72 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L576P sequence variation in gene KIT/NCBI:3815 1736 check_entity AN5295-4 KIT L576P mutation KIT NCBI:3815 gene melanoma DOID:1909 risk 55201-8 PubMed:19671763 The melanoma cell line WM3211, which harbors the L576P mutation, is not sensitive to imatinib, nilotinib, and sorafenib. Molecular modeling indicated the L576P mutation alters the conformation of KIT and reduces the binding affinity of imatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L576P sequence variation in gene KIT/NCBI:3815 1737 check_entity AN5295-4 KIT L576P mutation KIT NCBI:3815 gene melanoma DOID:1909 risk 55201-8 CIViC:72 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L576P sequence variation in gene KIT/NCBI:3815 1737 check_entity AN5296-1 KIT M541L mutation KIT NCBI:3815 gene chronic leukemia DOID:1036 risk 55201-8 PubMed:25015329 In 5 patients with KIT M541L mutation-positive chronic eosinophilic leukemia (4 somatic and 1 germline mutation), treatment with low dose imatinib resulted in complete and lasting remission with a median follow up of 74 months and 1 patient relapse at 50 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M541L sequence variation in gene KIT/NCBI:3815 1738 check_entity AN5296-1 KIT M541L mutation KIT NCBI:3815 gene chronic leukemia DOID:1036 risk 55201-8 CIViC:201 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M541L sequence variation in gene KIT/NCBI:3815 1738 check_entity AN5296-2 KIT M541L mutation KIT NCBI:3815 gene chronic myeloid leukemia DOID:8552 diagnostic 55201-8 PubMed:16307017 M541L mutation was not associated with CML in caucasian patients, and was common among healthy controls (8.1%), in contrast to a previous study in a Japanese CML patient population in which M541L was strongly associated with CML disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M541L sequence variation in gene KIT/NCBI:3815 1739 check_entity AN5296-2 KIT M541L mutation KIT NCBI:3815 gene chronic myeloid leukemia DOID:8552 diagnostic 55201-8 CIViC:201 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M541L sequence variation in gene KIT/NCBI:3815 1739 check_entity AN5296-3 KIT M541L mutation KIT NCBI:3815 gene colon signet ring adenocarcinoma DOID:3033 risk 55201-8 PubMed:28595259 In a study of 44 signet ring cell colorectal cancer cases, 25% were found to carry a KIT M541L mutation. The authors speculate that this relatively high frequency of KIT mutations (actionable in other cancer types) suggests that imatinib would be a good candidate genomic targeted therapy for this rare cancer subtype. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M541L sequence variation in gene KIT/NCBI:3815 1740 check_entity AN5296-3 KIT M541L mutation KIT NCBI:3815 gene colon signet ring adenocarcinoma DOID:3033 risk 55201-8 CIViC:201 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M541L sequence variation in gene KIT/NCBI:3815 1740 check_entity AN5297-1 KIT Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:23231951 Human GISTs with different KIT mutations were grafted in 136 nude muce. Mice were then treated with control, imatinib, GDC-0941, or GDC-0941 + imatinib. The combination showed superior antitumor efficacy that was sustained after treatment withdrawal. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KIT/NCBI:3815 1741 check_entity AN5297-1 KIT Mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:384 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KIT/NCBI:3815 1741 check_entity AN5297-2 KIT Mutation KIT NCBI:3815 gene melanoma DOID:1909 risk 55201-8 PubMed:21690468 In a phase II clinical trial of 43 melanoma patients harboring KIT mutations or amplifications, imatinib treatment exhibited significant anti-tumor activity with a median progression free survival of 3.5 months, tumor regression in 41.9% of patients, and a 1-year overall survival rate of 51%. 9/10 partial responses were in patients with exon 11 or 13 KIT mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KIT/NCBI:3815 1742 check_entity AN5297-2 KIT Mutation KIT NCBI:3815 gene melanoma DOID:1909 risk 55201-8 CIViC:384 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KIT/NCBI:3815 1742 check_entity AN5298-1 KIT N822H mutation KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 PubMed:14645423 In an in vitro study of imatinib sensitivity, KIT N822H was cloned into a plasmid by site-directed mutagenesis of KIT WT cDNA. Chinese hamster ovary cells were transiently transfected with the plasmid. Cells were treated with control media or media containing various concentrations of imatinib for 90 minutes. Protein lysates from the transfected cells were examined for phosphorylated tyrosine, a measure of KIT activation. Cells expressing KIT N822H were as sensitive to imatinib as ligand activated wildtype KIT (IC50: 100-200 nmol/L). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N822H sequence variation in gene KIT/NCBI:3815 1743 check_entity AN5298-1 KIT N822H mutation KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 CIViC:961 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N822H sequence variation in gene KIT/NCBI:3815 1743 check_entity AN5299-1 KIT N822K mutation KIT NCBI:3815 gene acute myeloid leukemia DOID:9119 risk 55201-8 PubMed:21482694 In a preclinical trial, the AML cell line Kasumi-1 with the KIT mutation N822K was treated with the tyrosine kinase inhibitors (TKI) ponatinib, sorafenib, and sunitinib. Ponatinib was much more effective in the growth inhibition of cells harboring the KIT mutation (IC50=8 nmol/L) compared to sorafenib (IC50=59 nmol/L) and sunitinib (IC50=56 nmol/L). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N822K sequence variation in gene KIT/NCBI:3815 1744 check_entity AN5299-1 KIT N822K mutation KIT NCBI:3815 gene acute myeloid leukemia DOID:9119 risk 55201-8 CIViC:1237 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N822K sequence variation in gene KIT/NCBI:3815 1744 check_entity AN5299-2 KIT N822K mutation KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 PubMed:14645423 In an in vitro study of imatinib sensitivity, KIT N822K was cloned into a plasmid by site-directed mutagenesis of KIT WT cDNA. Chinese hamster ovary cells were transiently transfected with the plasmid. Cells were treated with control media or media containing various concentrations of imatinib for 90 minutes. Protein lysates from the transfected cells were examined for phosphorylated tyrosine, a measure of KIT activation. Cells expressing KIT N822K were as sensitive to imatinib as ligand activated wildtype KIT (IC50: 100-200 nmol/L). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N822K sequence variation in gene KIT/NCBI:3815 1745 check_entity AN5299-2 KIT N822K mutation KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 CIViC:1237 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N822K sequence variation in gene KIT/NCBI:3815 1745 check_entity AN5299-3 KIT N822K mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:16954519 147 patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib (CSTI571-B2222). Specimens from 43 pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. N822K was observed as a secondary KIT mutation in two patients with secondary imatinib resistance and one patient with primary resistance, and also as a primary mutation in a patient with primary resistance. The mutation was shown to occur at a hotspot (N822) of previously reported secondary KIT mutations in imatinib resistant GISTs. When co-expressed with V560D (imatinib sensitive) in vitro N822K showed moderate imatinib resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N822K sequence variation in gene KIT/NCBI:3815 1746 check_entity AN5299-3 KIT N822K mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:25239608 A preclinical study tested the effect of a tyrosine kinase inhibitor (TKI) on Ba/F3 cell lines with primary ponatinib-sensitizing del 557-558 mutation, which induced IL-3 independent growth, and secondary mutation N822K. The cells were tested for Ponatinib resistance. Ba/F3 cells with del 557-558 and N822K mutations did not show resistance towards Ponatinib (IC50 for growth inhibition: 3 nM) compared to Ba/F3 cells with del 557-558 alone (IC50: 3 nM). Ponatinib inhibited KIT phosphorylation at moderate concentrations. The results suggest that N822K does not induce Ponatinib resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N822K sequence variation in gene KIT/NCBI:3815 1746 check_entity AN5299-3 KIT N822K mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:22614970 This retrospective study of a phase 2 clinical trial (NCT01068769) examined regorafenib safety and efficacy in advanced gastrointestinal stromal tumor (GIST) patients refractory to at least imatinib and sunitinib. One patient whose GIST harbored KIT N882K did not experienced disease progression for >7 months following treatment by regorafenib. Immunoblotting of matched pre- and post- treatment GIST biopsies from this patient demonstrated decreased levels of KIT phosphorylation in response to regorafenib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N822K sequence variation in gene KIT/NCBI:3815 1746 check_entity AN5299-3 KIT N822K mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:1237 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N822K sequence variation in gene KIT/NCBI:3815 1746 check_entity AN5300-1 KIT P551_E554delPMYE KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:25239608 In an in vitro study, an IL3 independent Ba/F3 cell line expressing KIT P551_E554delPMYE primary activating mutation demonstrated sensitivity to ponatinib treatment (IC50: 15nM). IC50 was determined by assessing cell viability. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT P551_E554delPMYE [biomarker_term_in_review] 1747 not_mapped AN5300-1 KIT P551_E554delPMYE KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:1405 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT P551_E554delPMYE [biomarker_term_in_review] 1747 not_mapped AN5301-1 KIT RS3733542 mutation KIT NCBI:3815 gene acute myeloid leukemia DOID:9119 risk 55201-8 PubMed:24178622 Patients with relapsed/refractory AML or 60 years old or more with untreated AML were enrolled on a phase II study of selumetinib and analyzed for mutations in KIT, NRAS, KRAS and FLT3. KIT mutation analysis (N=41) revealed the presence of a synonymous SNP rs3733542 (known population frequency of 20%) in exon 18 of the KIT gene in six of ten (60%) patients assessed as having a response or disease stabilization to selumetinib. In contrast, this SNP was detected in only seven of 31 (23%) patients without a response or disease stabilization (P = 0.027, Chi-squared test). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS3733542 sequence variation in gene KIT/NCBI:3815 1748 check_entity AN5301-1 KIT RS3733542 mutation KIT NCBI:3815 gene acute myeloid leukemia DOID:9119 risk 55201-8 CIViC:478 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS3733542 sequence variation in gene KIT/NCBI:3815 1748 check_entity AN5302-1 KIT S628N mutation KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 PubMed:25317746 In an in vitro study, COS-7 cells expressing KIT S628N activating mutation demonstrated sensitivity to imatinib and dasatinib treatments when compared to the KIT L576P, which was used as an imatinib-sensitive control. Sensitivity was determined by assessing reduced mutant KIT auto-phosphorylation via western blotting with addition of inhibitors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S628N sequence variation in gene KIT/NCBI:3815 1749 check_entity AN5302-1 KIT S628N mutation KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 CIViC:1567 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S628N sequence variation in gene KIT/NCBI:3815 1749 check_entity AN5302-2 KIT S628N mutation KIT NCBI:3815 gene melanoma DOID:1909 risk 55201-8 PubMed:25317746 A melanoma patient harboring the KIT S628N activating mutation underwent second-line imatinib therapy following lung metastatic progression that appeared after an eighth cycle of chemotherapy. The S628N mutation was not present in the blood, which confirmed that it was a somatic mutation. After 3 months of imatinib treatment (300 mg/d for first three weeks, then 400 mg/d), the patient exhibited disease progression and increased tumor size, and after an additional three months of imatinib treatment (400 mg/d), the patient developed multiple supratentorial brain metastases in addition to increased lung metastases and died 5 days later. The authors reported preclinical data which indicated variant sensitivity to imatinib. although this outcome did not coroberate the preclinical result, the authors still concluded the variant may be sensitive. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S628N sequence variation in gene KIT/NCBI:3815 1750 check_entity AN5302-2 KIT S628N mutation KIT NCBI:3815 gene melanoma DOID:1909 risk 55201-8 CIViC:1567 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S628N sequence variation in gene KIT/NCBI:3815 1750 check_entity AN5303-1 KIT T417_D419delinsY KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:18955451 This patient was part of a larger cohort of 397 patients with incurable (i.e. metastatic or unresectable) CD117-positive Gastrointestinal stromal tumors (GISTs) enrolled in the North American phase III study SWOG S0033/CALGB 150105 who were treated with either 400mg or 800mg of imatinib per day. This patient's GIST had a KIT exon 8 deletion/insertion TYD417-419Y. This patient represents the first reported sporadic GIST with a KIT exon 8 mutation as germline DNA from surrounding normal tissue was was KIT wildtype. The patient had an unconfirmed partial response to 400mg daily imatinib (TTP 8.1 months) and a censored OS of 59.3 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT T417_D419delinsY [biomarker_term_in_review] 1751 not_mapped AN5303-1 KIT T417_D419delinsY KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:2493 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT T417_D419delinsY [biomarker_term_in_review] 1751 not_mapped AN5304-1 KIT T670I mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:16954519 '147 patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib (CSTI571-B2222). Specimens from 43 pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. T670I was observed as a secondary KIT mutation in one patient with secondary imatinib resistance. The mutation was shown to occur at a hotspot (T670) of previously reported secondary KIT mutations in imatinib resistant GISTs. When co-expressed with V560D (imatinib sensitive) in vitro T670I showed ''extreme'' imatinib resistance. It also showed resistance in isolation.' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T670I sequence variation in gene KIT/NCBI:3815 1752 check_entity AN5304-1 KIT T670I mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:25239608 A preclinical study tested the effects of a tyrosine kinase inhibitor (TKI) on Ba/F3 cell lines with representative primary regorafenib-sensitizing mutation del 557-558, which induced IL-3 independent growth, and secondary mutation T670I. The cells were tested for Regorafenib resistance. Ba/F3 cells with del 557-558/T670I mutations (IC50 = 132 +- 25 nM) did show resistance towards Regorafenib compared to Ba/F3 cells with del 557-558 alone (IC50 = 30 +- 14 nM). In addition, Ba/F3 cells were mutagenized with N-ethyl-N-nitrosourea and incubated with varying concentrations of Regorafenib. In Regorafenib incubated cells, T670I mutations were seen in approximately 10% of the resistant cell populations. The results suggest that T670I does induce regorafenib resistance in del 557-558/T670I cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T670I sequence variation in gene KIT/NCBI:3815 1752 check_entity AN5304-1 KIT T670I mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:1241 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T670I sequence variation in gene KIT/NCBI:3815 1752 check_entity AN5305-1 KIT V555_V559DEL KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:18955458 Patient 36 from a larger cohort of genotyped patients (n= 78) with imatinib resistant or intolerant gastrointestinal stromal tumors (GISTs) harbored a primary (pre-imatinib treatment) KIT V555_V559 deletion. Following failure of imatinib, the GIST was again genotyped, but no secondary mutations were found. The patient took 50 mg sunitinib per day on a treatment schedule of four weeks on/two weeks off. The patient experienced progressive disease. Time to progression and overall survival were 10 and 108 weeks. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT V555_V559DEL [biomarker_term_in_review] 1753 not_mapped AN5305-1 KIT V555_V559DEL KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:2564 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT V555_V559DEL [biomarker_term_in_review] 1753 not_mapped AN5306-1 KIT V559D mutation KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 PubMed:16046538 KIT(V559D) were expressed in HEK-293 cells (in vitro). Imatinib, BMS-354825 (dasatinib), PD-180970, MLN-518 (tandutinib), and SU-11248 bind variant V559D with high affinity (Kd =< 20 nM), and inhibit KIT autophosphorylation. Despite similar binding affinities, the cellular activity of BMS-354825 was >10-fold greater than that of SU-11248 or PD-180970, and the authors hypothesize that additional pharmaceutical properties may contribute to the greater cellular potency. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V559D sequence variation in gene KIT/NCBI:3815 1754 check_entity AN5306-1 KIT V559D mutation KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 CIViC:942 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V559D sequence variation in gene KIT/NCBI:3815 1754 check_entity AN5306-2 KIT V559D mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:22114577 A patient with an uncontrolled relapse of c-kit-positive mesenchymal tumor in descending part of the duodenum had received 400mg Imatinib daily for more than 10 years at the time of publication. He responded well to therapy (Karnofsky index 90%). KIT V559D (Exon 11) was identified in the diagnostic biopsy and indicated as a positive predictor of imatinib response with long term usage. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V559D sequence variation in gene KIT/NCBI:3815 1755 check_entity AN5306-2 KIT V559D mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:25239608 In an in vitro kinase study, a KIT V559D primary activating mutant kinase demonstrated sensitivity to imatinib (IC50: 36nmol/L vs. 640nmol/L), regorafenib (IC50: 57nmol/L vs. 533nmol/L), and ponatinib (IC50: 0.8nmol/L vs. 6nmol/L) treatments compared to the wild-type KIT. IC50 was determined by assessing kinase activity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V559D sequence variation in gene KIT/NCBI:3815 1755 check_entity AN5306-2 KIT V559D mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:942 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V559D sequence variation in gene KIT/NCBI:3815 1755 check_entity AN5307-1 KIT V560D mutation KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 PubMed:18955458 In an in vitro study, Chinese hamster ovary cells expressing KIT V560D demonstrated comparable sensitivity to sunitinib treatment compared to cells expressing ligand activated wild-type KIT (IC50<100 nmol/L). Sensitivity was determined by assessing KIT auto-phosphorylation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V560D sequence variation in gene KIT/NCBI:3815 1756 check_entity AN5307-1 KIT V560D mutation KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 CIViC:945 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V560D sequence variation in gene KIT/NCBI:3815 1756 check_entity AN5307-2 KIT V560D mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:18955458 Patient 72 from a larger cohort of genotyped patients (n= 78) with imatinib resistant or intolerant gastrointestinal stromal tumors (GISTs) harbored a primary (pre-imatinib treatment) KIT V560D mutation. Following failure of imatinib, the GIST was again genotyped, but no secondary mutations were found. The patient took 50 mg sunitinib per day on a treatment schedule of four weeks on/two weeks off. The patient experienced progressive disease. Time to progression and overall survival were 9 and 33 weeks. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V560D sequence variation in gene KIT/NCBI:3815 1757 check_entity AN5307-2 KIT V560D mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:25239608 In an in vitro study, an IL3 independent Ba/F3 cell line expressing KIT V560D primary activating mutation demonstrated sensitivity to imatinib (IC50: 3nmol/L), sunitinib (IC50: 2nmol/L), regorafenib (IC50: 3nmol/L), and ponatinib (IC50: 2nmol/L) treatments. IC50 was determined by assessing cell viability. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V560D sequence variation in gene KIT/NCBI:3815 1757 check_entity AN5307-2 KIT V560D mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:945 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V560D sequence variation in gene KIT/NCBI:3815 1757 check_entity AN5308-1 KIT V560DEL KIT NCBI:3815 gene thymic carcinoma DOID:3284 risk 55201-8 PubMed:15201427 In a patient with thymic carcinoma, the tumor expressing an activating mutation in exon 11 of KIT (V560del) was sensitive to imatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT V560DEL [biomarker_term_in_review] 1758 not_mapped AN5308-1 KIT V560DEL KIT NCBI:3815 gene thymic carcinoma DOID:3284 risk 55201-8 CIViC:202 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT V560DEL [biomarker_term_in_review] 1758 not_mapped AN5309-1 KIT V560G mutation KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 PubMed:14645423 In an in vitro study of imatinib sensitivity, KIT V560G was cloned into a plasmid by site-directed mutagenesis of KIT WT cDNA. Chinese hamster ovary cells were transiently transfected with the plasmid. The cells were treated with control media or media containing various concentrations of imatinib for 90 minutes. Protein lysates from the transfected cells were examined for the presence of phosphorylated tyrosine, a measure of KIT activation. Cells expressing KIT V560G were as sensitive to imatinib as ligand activated wildtype KIT (IC50: 100-200 nmol/L). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V560G sequence variation in gene KIT/NCBI:3815 1759 check_entity AN5309-1 KIT V560G mutation KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 CIViC:946 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V560G sequence variation in gene KIT/NCBI:3815 1759 check_entity AN5309-2 KIT V560G mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:25239608 In an in vitro kinase study, a KIT V560G primary activating mutant kinase demonstrated sensitivity to imatinib (IC50: 38nmol/L vs. 640nmol/L), regorafenib (IC50: 27nmol/L vs. 533nmol/L), and ponatinib (IC50: 0.3nmol/L vs. 6nmol/L) treatments compared to the wildtype KIT. IC50 was determined by assessing kinase activity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V560G sequence variation in gene KIT/NCBI:3815 1760 check_entity AN5309-2 KIT V560G mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:946 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V560G sequence variation in gene KIT/NCBI:3815 1760 check_entity AN5310-1 KIT V560_L576DEL KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:25239608 A GIST430 patient derived cell line expressing KIT V560_L576del primary activating mutation demonstrated insensitivity to regorafenib (IC50: 191nmol/L) treatment. IC50 was determined by assessing cell viability. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT V560_L576DEL [biomarker_term_in_review] 1761 not_mapped AN5310-1 KIT V560_L576DEL KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:1458 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT V560_L576DEL [biomarker_term_in_review] 1761 not_mapped AN5311-1 KIT V654A mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:16954519 KIT V654A results in imatinib resistance in GIST patient-derived cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V654A sequence variation in gene KIT/NCBI:3815 1762 check_entity AN5311-1 KIT V654A mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:16638875 In GIST tumor cells and patients harboring KIT V654A mutation, SU11248 is effective for those that are refractory to imatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V654A sequence variation in gene KIT/NCBI:3815 1762 check_entity AN5311-1 KIT V654A mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:73 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V654A sequence variation in gene KIT/NCBI:3815 1762 check_entity AN5312-1 KIT W557_K558del KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 PubMed:14645423 In an in vitro study of imatinib sensitivity, KIT W557_K558del was cloned into a plasmid by site-directed mutagenesis of KIT WT cDNA. Chinese hamster ovary cells were transiently transfected with the plasmid. Cells were treated with control media or media containing various concentrations of imatinib for 90 minutes. Protein lysates from the transfected cells were examined for phosphorylated tyrosine, a measure of KIT activation. Cells expressing KIT W557_K558del were as sensitive to imatinib as ligand activated wildtype KIT (IC50: 100-200 nmol/L). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT W557_K558del [biomarker_term_in_review] 1763 not_mapped AN5312-1 KIT W557_K558del KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 CIViC:935 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT W557_K558del [biomarker_term_in_review] 1763 not_mapped AN5312-2 KIT W557_K558del KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:18955458 Patients 11, 69, and 73 from a larger cohort of genotyped patients (n= 78) with imatinib resistant or intolerant gastrointestinal stromal tumors (GISTs) harbored a primary (pre-imatinib treatment) KIT W557_K558 deletion. Following failure of imatinib, the GIST was again genotyped, but no secondary mutations were found. Patient 11 started on 25 mg sunitinib daily, for a two week on/two week off schedule. Patients 69 and 73 were on a 50 mg sunitib per day for four weeks on/ two weeks off. All three patients experienced stable disease for less than 6 months. Time to progression for patients 11, 69, and 73: 8, 22, and 10 weeks. Overall survival for patients 11, 69, and 73: 10, 38, and 19 weeks (Table A1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT W557_K558del [biomarker_term_in_review] 1764 not_mapped AN5312-2 KIT W557_K558del KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:25239608 In an in vitro study, an IL3 independent Ba/F3 cell line expressing KIT W557_K558del primary activating mutation demonstrated sensitivity to imatinib (IC50: 27nmol/L) and ponatinib (IC50: 3nmol/L) treatments. IC50 was determined by assessing cell viability. In mice treated in vivo with Ba/F3 cells expressing KIT W557_K558 mutation, tumor volume was significantly reduced in response to both ponatinib and imatinib treatments. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT W557_K558del [biomarker_term_in_review] 1764 not_mapped AN5312-2 KIT W557_K558del KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:935 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT W557_K558del [biomarker_term_in_review] 1764 not_mapped AN5313-1 KIT Wildtype KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:27371698 This phase II clinical trial of regorafenib (NCT01068769) examined the long term safety and efficacy of regorafenib in patients with metastatic and/or unresectable gastrointestinal stromal tumors (GISTs) who failed previous treatments with imatinib. Patients whose GISTs were wildtype for KIT and PDGFR and who were succinate dehydrogenase (SDH) deficient (n=6) experienced higher rates of clinical benefit (defined as complete response, partial response, or stable disease lasting >16 weeks) than patients whose GISTs were wildtype for KIT and PDGFR but were not SDH deficient (n=2). 6/6 patients with SDH deficient GISTs had clinical benefit (including 2 PRs), and their median PFS was 10 months vs 1.6 months for patients with non-SDH deficient GISTs. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT Wildtype [biomarker_term_in_review] 1765 not_mapped AN5313-1 KIT Wildtype KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:2520 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT Wildtype [biomarker_term_in_review] 1765 not_mapped AN5314-1 KIT Y503_F504insAY KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 PubMed:14645423 In an in vitro study of imatinib sensitivity, KIT Y503_F504insAY was cloned into a plasmid by site-directed mutagenesis of KIT WT cDNA. Chinese hamster ovary cells were transiently transfected with the plasmid. Cells were treated with control media or media containing various concentrations of imatinib for 90 minutes. Then, protein lysates from the transfected cells were examined for phosphorylated tyrosine, a measure of KIT activation. Cells expressing KIT Y503_F504insAY were as sensitive to imatinib as ligand activated wildtype KIT (IC50: 100-200 nmol/L). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT Y503_F504insAY [biomarker_term_in_review] 1766 not_mapped AN5314-1 KIT Y503_F504insAY KIT NCBI:3815 gene cancer DOID:162 risk 55201-8 CIViC:920 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KIT Y503_F504insAY [biomarker_term_in_review] 1766 not_mapped AN5315-1 KIT Y823D mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 PubMed:16954519 '147 patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib (CSTI571-B2222). Specimens from 43 pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. Y823D was observed as a secondary KIT mutation in five patients with secondary imatinib resistance. The mutation was shown to occur at a hotspot (Y823) of previously reported secondary KIT mutations in imatinib resistant GISTs. When co-expressed with V560D (imatinib sensitive) in vitro Y823D showed ''extreme'' imatinib resistance.' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y823D sequence variation in gene KIT/NCBI:3815 1767 check_entity AN5315-1 KIT Y823D mutation KIT NCBI:3815 gene gastrointestinal stromal tumor DOID:9253 risk 55201-8 CIViC:963 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y823D sequence variation in gene KIT/NCBI:3815 1767 check_entity AN5316-1 KIT rs17084733 mutation KIT NCBI:3815 gene acral lentiginous melanoma DOID:6367 diagnostic 55201-8 PubMed:21119596 The rs17084733 variant in the 3' UTR of KIT was correlated with susceptibility to melanoma when comparing 70 melanoma patients to 94 healthy individuals from the same community. This variant was most strongly correlated with acral lentigious melanoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::rs17084733 sequence variation in gene KIT/NCBI:3815 1768 check_entity AN5316-1 KIT rs17084733 mutation KIT NCBI:3815 gene acral lentiginous melanoma DOID:6367 diagnostic 55201-8 CIViC:252 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::rs17084733 sequence variation in gene KIT/NCBI:3815 1768 check_entity AN5317-1 KLLN PROMOTER METHYLATION KLLN NCBI:100144748 gene breast cancer DOID:1612 diagnostic PubMed:21177507 123 patients with Cowden or Cowden-like syndrome (from the IRB8458-PTEN series) and 50 unaffected individuals without PTEN variants were analyzed for germline methylation and expression of PTEN and KILLIN. 45 out of 123 patients (37%; 95% CI, 29%-45%) showed hypermethylation of the bidirectional promoter of PTEN and KILLIN. Individuals with KILLIN-promoter methylation had a 3-fold increased prevalence of breast cancer (35/42 vs 24/64; p<0.0001) over individuals with germline PTEN mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KLLN PROMOTER METHYLATION [biomarker_term_in_review] 1769 not_mapped AN5317-1 KLLN PROMOTER METHYLATION KLLN NCBI:100144748 gene breast cancer DOID:1612 diagnostic CIViC:692 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KLLN PROMOTER METHYLATION [biomarker_term_in_review] 1769 not_mapped AN5317-2 KLLN PROMOTER METHYLATION KLLN NCBI:100144748 gene renal cell carcinoma DOID:4450 diagnostic PubMed:21177507 123 patients with Cowden or Cowden-like syndrome (from the IRB8458-PTEN series) and 50 unaffected individuals without PTEN variants were analyzed for germline methylation and expression of PTEN and KILLIN. 45 out of 123 patients (37%; 95% CI, 29%-45%) showed hypermethylation of the bidirectional promoter of PTEN and KILLIN. Individuals with KILLIN-promoter methylation had a greater than 2-fold increase of kidney cancer (4/45 vs 6/155; p=0.004) over individuals with germline PTEN mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KLLN PROMOTER METHYLATION [biomarker_term_in_review] 1770 not_mapped AN5317-2 KLLN PROMOTER METHYLATION KLLN NCBI:100144748 gene renal cell carcinoma DOID:4450 diagnostic CIViC:692 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KLLN PROMOTER METHYLATION [biomarker_term_in_review] 1770 not_mapped AN5318-1 KMT2A KMT2A::MLLT3 mutation KMT2A NCBI:4297 gene acute myeloid leukemia DOID:9119 diagnostic PubMed:19357394 'The MLL-MLLT3 translocation, along with other MLL translocations, are so common in acute myeloid leukemia that the World Health Organization has developed a sub-type of ''AML with t(9;11)(p22;q23); MLLT3-MLL'' under the AML with recurrent genetic abnormalities diagnosis.' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KMT2A::MLLT3 sequence variation in gene KMT2A/NCBI:4297 1771 check_entity AN5318-1 KMT2A KMT2A::MLLT3 mutation KMT2A NCBI:4297 gene acute myeloid leukemia DOID:9119 diagnostic CIViC:428 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KMT2A::MLLT3 sequence variation in gene KMT2A/NCBI:4297 1771 check_entity AN5319-1 KMT2C Loss unp368 NCBI:59508 gene breast cancer DOID:1612 risk PubMed:29755131 In the 746 metastatic breast tumors analyzed,KMT2C mutations were found in 9.8% of tumors, making it one of the most commonly mutated genes in breast cancer. Analysis of the 818 cases in the TCGA dataset demonstrated the majority of KMT2C mutations to be frameshift, truncation, or missense mutations that occur in all breast cancer subtypes with a relatively even distribution. In 283 metastatic breast cancer cases that underwent single agent aromatase therapy, 18 had deletions or truncations of KMTC2C and these 18 patients demonstrated worse progression free survival (PFS 6.6 months; p=.036) than KMT2C wildtype patients (n=260; PFS 12.1 months). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KMT2C Loss [biomarker_term_in_review] 1772 not_mapped AN5319-1 KMT2C Loss unp368 NCBI:59508 gene breast cancer DOID:1612 risk CIViC:4215 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KMT2C Loss [biomarker_term_in_review] 1772 not_mapped AN5320-1 KMT2C MUTATION unp368 NCBI:59508 gene skin squamous cell carcinoma DOID:3151 prognostic PubMed:25303977 Evaluation of 39 aggressive cutaneous squamous cell carcinomas revealed that tumors with a KMT2C mutation were 5x more likely to invade the bone (53% versus 10%; p=0.008). Patients with KMT2C mutations also had significantly shorter recurrent free survival (21.6 versus 167.5; p=0.003) and an increased hazards ratio for death (HR=5.16; 95%CI:1.55 to 17.18). This worse prognosis did not appear to be correlated with bone invasion (p=0.98). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::kmt2c:mutation sequence variation in gene unp368/NCBI: 1773 check_entity AN5320-1 KMT2C MUTATION unp368 NCBI:59508 gene skin squamous cell carcinoma DOID:3151 prognostic CIViC:664 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::kmt2c:mutation sequence variation in gene unp368/NCBI: 1773 check_entity AN5321-1 KMT2D Loss-of-function KMT2D NCBI:8085 gene follicular lymphoma DOID:0050873 diagnostic PubMed:21796119 MLL2 was found to be the most frequently mutated gene in a sample of 31/35 follicular lymphoma patients and was not mutated in normal centroblast samples. Furthermore, MLL2 mutations were as frequently observed as t(14;18) Igh-BCL2 translocations, which are the most common clinically significant genetic event observed in follicular lymphoma. Mutations were predicted to be loss-of-function. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KMT2D Loss-of-function [biomarker_term_in_review] 1774 not_mapped AN5321-1 KMT2D Loss-of-function KMT2D NCBI:8085 gene follicular lymphoma DOID:0050873 diagnostic CIViC:167 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KMT2D Loss-of-function [biomarker_term_in_review] 1774 not_mapped AN5322-1 KRAS A11_G12insGA KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:24642870 FFPE tumor tissue from 1506 colorectal cancer patients was analyzed at codons 12, 13, 61 and 146 by PCR. 672 KRAS mutations were found in 670 patients, and from these, two were inframe insertions, which were located near codon 12. A11_G12insGA was validated by direct sequencing. A11_G12insGA, G12V and wildtype KRAS were transfected into 293FT and NIH3T3 cells. Increased p-ERK and GTP-bound RAS was seen with A11_G12insGA and G12V, but not wildtype. Significantly increased colony formation, and larger tumor size of NIH3T3 cells injected into nude mice was seen with A11_G12insGA and G12V over wildtype cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KRAS A11_G12insGA [biomarker_term_in_review] 1775 not_mapped AN5322-1 KRAS A11_G12insGA KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 CIViC:3210 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KRAS A11_G12insGA [biomarker_term_in_review] 1775 not_mapped AN5323-1 KRAS A146 mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:20619739 This was a retrospective study of 605 patients with metastatic, chemotherapy refractory colorectal cancer treated with cetuximab + chemotherapy. Patients harboring KRAS codon 146 mutant tumors (n=11) did not have a significantly lower response rate than did patients with KRAS wildtype tumors (2/11 [18.2%] vs 101/274 [36.9%]; p =0.34). Authors suggest that KRAS codon 146 mutations may not support resistance to cetuximab. Authors note that these patients were treated with cetuximab prior to widespread adoption of regular KRAS mutational status screening. Patients treated with cetuximab monotherapy were not included. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A146 sequence variation in gene KRAS/NCBI:3845 1776 check_entity AN5323-1 KRAS A146 mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 CIViC:2848 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A146 sequence variation in gene KRAS/NCBI:3845 1776 check_entity AN5324-1 KRAS A146P mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:19603018 In a retrospective study of 68 irinotecan-refractory metastatic colorectal cancer patients, one patient's tumor harbored a KRAS codon 146 mutation but was wildtype for BRAF, and KRAS codons 12, 13, and 61. This patient did not respond to irinotecan and cetuximab combination therapy and experienced progression free survival (PFS) lasting less than 10 months and overall survival (OS) lasting less than 30 months. Median PFS for patients with BRAF, KRAS G12/G13 wildtype tumors harboring mutations in either KRAS codon 146 (n=1) or KRAS codon 61 (n=7) was lower than patients whose tumors were additionally wildtype for KRAS A146 and Q61 (PFS: 3.8 vs 5.3mo, p= 0.023), though there wasn't a significant difference in overall survival (OS: 9.7 vs 14.8 mo, p=0.320). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A146P sequence variation in gene KRAS/NCBI:3845 1777 check_entity AN5324-1 KRAS A146P mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 CIViC:879 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A146P sequence variation in gene KRAS/NCBI:3845 1777 check_entity AN5325-1 KRAS A146T mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:22392911 In 28 out of 40 (70%) metastatic colorectal cancer tumors implanted into mice, the therapeutic combination of the MEK inhibitor AZD6244 and the PI3K/mTor inhibitor BEZ235 resulted in disease stabilization. Mean tumor growth was lower in the tumors treated with AZD6244+ BEZ235 (+77% vs. +267%, P=1E-6) compared to AZD6244 alone and (+77% vs. +222%, P=0.0014) BEZ235 alone. 32/40 tumors harbored KRAS mutations including 2 A146T tumors (1 also harboring PIK3CA E545K) which both showed disease stabilization during doublet therapy but progression on either single agent. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A146T sequence variation in gene KRAS/NCBI:3845 1778 check_entity AN5325-1 KRAS A146T mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:20570890 Preclinical data supporting resistance of Exon 4 mutations, in particular A146T, to cetuximab and sensitivity to PD0325901. This study involved treatment of mice bearing A146T KRAS xenografts treated with PD0325901 or cetuximab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A146T sequence variation in gene KRAS/NCBI:3845 1778 check_entity AN5325-1 KRAS A146T mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:25666295 In a retrospective study of 148 treatment naive metastatic colorectal cancer patients, patients with RAS mutations and wildtype BRAF (n=10), including A146T (N=3), G15D (N=1), and V152M/NRAS V160A, treated with FOLFOX4 plus cetuximab were associated with decreased overall survival (16.3mo vs. 28.5mo, HR:0.43, 95% CI:0.20-0.89, P=0.020) and decreased progression free survival (7.2mo vs. 9.7mo, HR:0.56, 95% CI:0.27-1.16, P=0.11), as compared to patients with wild-type KRAS, NRAS and BRAF. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A146T sequence variation in gene KRAS/NCBI:3845 1778 check_entity AN5325-1 KRAS A146T mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 CIViC:880 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A146T sequence variation in gene KRAS/NCBI:3845 1778 check_entity AN5326-1 KRAS A146V mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:22392911 In 28 out of 40 (70%) metastatic colorectal cancer tumors harboring NRAS, KRAS, BRAF or PIK3CA mutations and implanted into mice, the therapeutic combination of the MEK inhibitor AZD6244 and the PI3K/mTor inhibitor BEZ235 resulted in disease stabilization. Mean tumor growth was lower in the tumors treated with AZD6244+ BEZ235 (+77% vs. +267%, P=1E-6) compared to AZD6244 alone and (+77% vs. +222%, P=0.0014) BEZ235 alone. 32/40 tumors harbored KRAS mutations including 2 tumors with A146V mutations which achieved stable disease with combined therapy but progressive disease in either monotherapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A146V sequence variation in gene KRAS/NCBI:3845 1779 check_entity AN5326-1 KRAS A146V mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 CIViC:318 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A146V sequence variation in gene KRAS/NCBI:3845 1779 check_entity AN5326-2 KRAS A146V mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 risk 21702-6 PubMed:24836576 Case report of a patient with metastatic lung adenocarcinoma. Whole exome sequencing of the metastatic tumor revealed KRAS A146V, STK11 frameshift deletion and ATM alteration. Preclinical evidence led to administration of CDK4 inhibitor LY2835219. Specifically, the PHIAL algorithm nominated this variant as actionable on the basis of a predicted synthetic lethal relationship between activated KRAS and CDK4. The patient achieved stable disease and was on treatment for 16 weeks which was the patients best and only clinical response to any cancer-directed therapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A146V sequence variation in gene KRAS/NCBI:3845 1780 check_entity AN5326-2 KRAS A146V mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 risk 21702-6 CIViC:318 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A146V sequence variation in gene KRAS/NCBI:3845 1780 check_entity AN5327-1 KRAS Amplification KRAS NCBI:3845 gene endometrial cancer DOID:1380 prognostic 21702-6 PubMed:23099803 In this study, KRAS gain (KRAS/CEP12q ratio >1 and <2) or amplification (ratio >2) was detected in 3% (13 of 414) of the primary endometrial carcinomas investigated. Presence of KRAS gain or amplification were highly significantly associated with poor prognosis with a 46% 5-year survival compared with 87% for patients with unamplified status (P<0.001). Amplification of KRAS maintains its independent prognostic impact in Cox multivariate analysis when adjusted for age, histological subtype, grade and FIGO stage (HR=2.6, 95% CI: 1.2–5.8, P=0.02). In contrast, presence of KRAS mutation did not influence prognosis (P=0.67) assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene KRAS/NCBI:3845 1781 AN5327-1 KRAS Amplification KRAS NCBI:3845 gene endometrial cancer DOID:1380 prognostic 21702-6 CIViC:588 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene KRAS/NCBI:3845 1781 AN5327-2 KRAS Amplification KRAS NCBI:3845 gene melanoma DOID:1909 risk 21702-6 PubMed:24265155 In vitro studies of M229 (a human melanoma cell line) endogenously expressing wildtype KRAS and BRAF V600E (a known BRAF sensitizing mutation) found that cells induced to stably over-express wildtype KRAS4a or KRAS4b (via viral transduction with additional copies of KRAS4a or KRAS4b) were more resistant to vemurafenib (a BRAFi) than cells transduced with empty vectors. Resistance was determined by assessing cell survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene KRAS/NCBI:3845 1782 AN5327-2 KRAS Amplification KRAS NCBI:3845 gene melanoma DOID:1909 risk 21702-6 CIViC:588 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene KRAS/NCBI:3845 1782 AN5327-3 KRAS Amplification KRAS NCBI:3845 gene skin melanoma DOID:8923 risk 21702-6 PubMed:26307133 Retrospective analysis of somatic mutations and copy number changes in 119 patients treated with carboplatin, paclitaxel, ± sorafenib (CPS) in the E2603 trial. CPS therapy was associated with improved overall survival compared with CP in patients with tumors positive for KRAS gene copy gains (HR = 0.25; P = 0.035). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene KRAS/NCBI:3845 1783 AN5327-3 KRAS Amplification KRAS NCBI:3845 gene skin melanoma DOID:8923 risk 21702-6 CIViC:588 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene KRAS/NCBI:3845 1783 AN5328-1 KRAS Exon 2 Mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 prognostic;risk 21702-6 PubMed:24559322 KRAS mutation status was not predictive of response to regorafenib treatment in patients that had received standard therapy and progressed within 3 months of their last treatment. KRAS exon 2 variants (G12A, C, D, R, S, V; G13D) were sequenced, among variants in other KRAS exons. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:2:mutation sequence variation in gene KRAS/NCBI:3845 1784 check_entity AN5328-1 KRAS Exon 2 Mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 prognostic;risk 21702-6 PubMed:16618717 Patients with colorectal cancer who harbor KRAS mutation have low response rate to cetuximab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:2:mutation sequence variation in gene KRAS/NCBI:3845 1784 check_entity AN5328-1 KRAS Exon 2 Mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 prognostic;risk 21702-6 PubMed:18946061 KRAS mutation status was assessed in 394 tumor samples from colorectal cancer patients who were randomly assigned to receive cetuximab plus best supportive care or best supportive care alone. 42% of the tumors evaluated had at least one mutation in exon 2. Patients with a colorectal tumor bearing mutated K-ras did not benefit from cetuximab, whereas patients with a tumor bearing wild-type K-ras did benefit from cetuximab. The effectiveness of cetuximab was significantly associated with K-ras mutation status (P=0.01 for overall survival and P<0.001 for progression-free survival). In patients with wild-type K-ras tumors, treatment with cetuximab as compared with supportive care alone significantly improved overall survival. The related clinical trial ID is NCT00079066. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:2:mutation sequence variation in gene KRAS/NCBI:3845 1784 check_entity AN5328-1 KRAS Exon 2 Mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 prognostic;risk 21702-6 PubMed:27037411 102 mCRC patients treated with anti-EGFR therapy were analyzed for 34 hotspot mutations in KRAS, NRAS and BRAF with nanofluidic digital PCR and quantitative PCR. dPCR and qPCR results were correlated to PFS and OS. Analysis of only KRAS exon 2 hotspot mutations showed that patients with more than 1% mutant allele fraction (n = 19/83) had a hazard ratio of 3.43 for PFS (95% CI, 1.67–7.02; P=0.002) and 2.72 for OS (95% CI, 1.52–4.88; P=0.002) compared to wild-type patients or patients with less than 1% mutant allele fraction. Considering all RAS and BRAF mutations, the patients with more than 1% mutant allele fraction (n = 37/65) had a hazard ratio of 4.52 for PFS (95% CI, 2.25–9.07; P<0.001) and 2.5 for OS (95% CI, 1.57–4.02; P<0.001). ROC analysis showed that a cut-off of 1% for any mutated allele offered the best predictive value. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:2:mutation sequence variation in gene KRAS/NCBI:3845 1784 check_entity AN5328-1 KRAS Exon 2 Mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 prognostic;risk 21702-6 PubMed:25322874 31 patients with KRAS exon 2 mutation (codons 12 and 13) were treated with selumetinib and irinotecan. All patients had ECOG status 0 or 1 and confirmed progression after first line therapy with oxaliplatin-based chemotherapy and bevacizumab. Patients with more than one line of therapy, MEK or B-RAF inhibitor treatment or prior irinotecan treatment were excluded. The study was terminated before full accrual due to non-protocol considerations. Three patients had a PR, 16 patients had SD >= 4 weeks. Median PFS for all patients was 105 days, median OS was 267 days. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:2:mutation sequence variation in gene KRAS/NCBI:3845 1784 check_entity AN5328-1 KRAS Exon 2 Mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 prognostic;risk 21702-6 PubMed:17590872 This retrospective study examines outcomes of 158 primary sporadic colorectal cancer patients who had undergone surgical resection and were treated with 5-fluorouracil based chemotherapy. KRAS exon 2 mutations (listed as KRAS exon 1 as it was common at the time of source publication to exclude non-coding exon 1) were not associated with differences in disease specific survival compared to wt KRAS (n = 50 mutant, n = 108 wt; p =0.6077) or in relapse free survival. Authors noted that the tumors of 6 patients harbored both PIK3CA and KRAS mutations, but stated that the presence of PIK3CA mutations did not correlate with the presence of KRAS mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:2:mutation sequence variation in gene KRAS/NCBI:3845 1784 check_entity AN5328-1 KRAS Exon 2 Mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 prognostic;risk 21702-6 PubMed:22180495 This preclinical study examined vemurafenib efficacy on various colorectal cancer cell lines and in vivo via mouse xenograft experiments. Three cell lines harbored KRAS exon 2 mutations and wt BRAF: HCT 116 (KRAS G13D), SW620 (KRAS G12V), LOVO (KRAS G13D). Cell lines with KRAS exon 2 mutations were insensitive to vemurafenib compare those with wt KRAS and BRAF V600E (a known vemurafenib sensitizing mutation; HT29, Colo205, Colo471, LS411N; IC50s >10uM vs 0.025-0.35 uM). Nude, athymic mice with HCT116 or LoVo xenografts did not experience tumor inhibition when treated with vemurafenib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:2:mutation sequence variation in gene KRAS/NCBI:3845 1784 check_entity AN5328-1 KRAS Exon 2 Mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 prognostic;risk 21702-6 CIViC:75 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:2:mutation sequence variation in gene KRAS/NCBI:3845 1784 check_entity AN5328-2 KRAS Exon 2 Mutation KRAS NCBI:3845 gene pancreatic cancer DOID:1793 risk 21702-6 PubMed:21862683 In a retrospective study of 136 pancreatic cancer patients, point mutations in KRAS exon 2 were associated with worse overall survival compared to that of wild-type KRAS (5.8 vs 8.0 months; P = 0.001; multivariate analysis). This difference was largely driven by the subgroup of patients with reduced response to gemcitabine-erlotinib combination therapy (7.5% vs 23.3%) with overall survival of 5.2 vs 9.7 months (N=40 vs 30) compared to those that received other therapies with an overall survival of 7.0 months for both KRAS mutated (N=31) and KRAS wildtype (N=35) patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:2:mutation sequence variation in gene KRAS/NCBI:3845 1785 check_entity AN5328-2 KRAS Exon 2 Mutation KRAS NCBI:3845 gene pancreatic cancer DOID:1793 risk 21702-6 CIViC:75 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:2:mutation sequence variation in gene KRAS/NCBI:3845 1785 check_entity AN5328-3 KRAS Exon 2 Mutation KRAS NCBI:3845 gene pancreatic carcinoma DOID:4905 prognostic;risk 21702-6 PubMed:23435671 KRAS exon 2 was mutated in 121 of 173 (70%) patients with advanced pancreatic cancer and did not show an association with response to erlotinib treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:2:mutation sequence variation in gene KRAS/NCBI:3845 1786 check_entity AN5328-3 KRAS Exon 2 Mutation KRAS NCBI:3845 gene pancreatic carcinoma DOID:4905 prognostic;risk 21702-6 CIViC:75 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:2:mutation sequence variation in gene KRAS/NCBI:3845 1786 check_entity AN5328-4 KRAS Exon 2 Mutation KRAS NCBI:3845 gene rectum cancer DOID:1993 prognostic 21702-6 PubMed:19903786 This study examined outcomes of 240 rectum cancer patients treated with total mesorectal excision therapy. Tumor samples were obtained at the time of surgery and genotyped for KRAS exon 2 mutations (listed as exon 1 in the source, as it was common at the time of publication to exclude non-coding exon 1). KRAS exon 2 mutations were identified in 81 cases. The authors reported that no differences were found in overall survival between patients with and without KRAS exon 2 mutations (P > 0.1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:2:mutation sequence variation in gene KRAS/NCBI:3845 1787 check_entity AN5328-4 KRAS Exon 2 Mutation KRAS NCBI:3845 gene rectum cancer DOID:1993 prognostic 21702-6 CIViC:75 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:2:mutation sequence variation in gene KRAS/NCBI:3845 1787 check_entity AN5329-1 KRAS G10_A11insG KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:24642870 FFPE tumor tissue from 1506 colorectal cancer patients was analyzed at codons 12, 13, 61 and 146 by PCR. 672 KRAS mutations were found in 670 patients, and from these, two were inframe insertions located near codon 12. G10_A11insG was validated by direct sequencing. G10_A11insG, G12V and wildtype KRAS were transfected into 293FT and NIH3T3 cells. Increased p-ERK and GTP-bound RAS was seen with G10_A11insG and G12V, but not wildtype. Significantly increased colony formation, and larger tumor size of NIH3T3 cells injected into nude mice was seen with G10_A11insG and G12V over wildtype cells. Enhanced signaling, clonogenicity, and growth suggest G10_A11insG promotes oncogenic transformation in these cell types. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KRAS G10_A11insG [biomarker_term_in_review] 1788 not_mapped AN5329-1 KRAS G10_A11insG KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 CIViC:3209 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KRAS G10_A11insG [biomarker_term_in_review] 1788 not_mapped AN5330-1 KRAS G12 mutation KRAS NCBI:3845 gene acute leukemia DOID:12603 diagnostic 21702-6 PubMed:24571676 Children with early age leukaemia who had second hand smoke exposure are more likely to harbor KRAS mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12 sequence variation in gene KRAS/NCBI:3845 1789 check_entity AN5330-1 KRAS G12 mutation KRAS NCBI:3845 gene acute leukemia DOID:12603 diagnostic 21702-6 CIViC:76 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12 sequence variation in gene KRAS/NCBI:3845 1789 check_entity AN5330-2 KRAS G12 mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 prognostic 21702-6 PubMed:19934290 In patients with stage III colorectal cancer undergoing chemotherapy, KRAS G12 mutation did not impact overall or disease free survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12 sequence variation in gene KRAS/NCBI:3845 1790 check_entity AN5330-2 KRAS G12 mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 prognostic 21702-6 CIViC:76 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12 sequence variation in gene KRAS/NCBI:3845 1790 check_entity AN5330-3 KRAS G12 mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 diagnostic;prognostic 21702-6 PubMed:18794081 KRAS mutations in lung cancer patients are not associated with smoking history, age or gender. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12 sequence variation in gene KRAS/NCBI:3845 1791 check_entity AN5330-3 KRAS G12 mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 diagnostic;prognostic 21702-6 PubMed:11208838 There is no strong association between KRAS mutation status and overall or progression free survival in patients with NSCLC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12 sequence variation in gene KRAS/NCBI:3845 1791 check_entity AN5330-3 KRAS G12 mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 diagnostic;prognostic 21702-6 PubMed:15597105 A meta-analysis showed KRAS mutation is associated with worse outcome in patients with NSCLC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12 sequence variation in gene KRAS/NCBI:3845 1791 check_entity AN5330-3 KRAS G12 mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 diagnostic;prognostic 21702-6 CIViC:76 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12 sequence variation in gene KRAS/NCBI:3845 1791 check_entity AN5330-4 KRAS G12 mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 prognostic 21702-6 PubMed:18528420 The presence of KRAS mutations in MM patients is prognostic for shorter overall and progression free survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12 sequence variation in gene KRAS/NCBI:3845 1792 check_entity AN5330-4 KRAS G12 mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 prognostic 21702-6 CIViC:76 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12 sequence variation in gene KRAS/NCBI:3845 1792 check_entity AN5331-1 KRAS G12/G13 mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 prognostic;risk 21702-6 PubMed:20619739 Chemotherapy-refractory patients with metastatic colorectal cancer harboring KRAS mutations (primarily G12/G13; n=230 out of 253 total KRAS mutant patients) had lower response rates (17/253; 6.7% vs KRAS wt 126/352; 35.8%; P < .0001), disease control rates and shorter progression free and overall survival following cetuximab plus chemotherapy than those with wildtype KRAS. Authors note that these patients were treated with cetuximab prior to widespead adoption of regular KRAS mutational status screening. Patients treated with cetuximab or panitumumab monotherapy were not included. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::g12/g13:mutation sequence variation in gene KRAS/NCBI:3845 1793 check_entity AN5331-1 KRAS G12/G13 mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 prognostic;risk 21702-6 PubMed:18202412 KRAS mutations were significantly associated with lack of response to cetuximab in patients with advanced colorectal cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::g12/g13:mutation sequence variation in gene KRAS/NCBI:3845 1793 check_entity AN5331-1 KRAS G12/G13 mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 prognostic;risk 21702-6 PubMed:18316791 In a retrospective study of 427 chemotherapy-refractory metastatic colorectal patients treated with either panitumumab monotherapy or best supportive care (BSC), KRAS codon 12 or 13 mutations were observed in 43% of the tumor samples. The effect of panitumumab on PFS in the KRAS wt group was significantly greater than in the KRAS mutant group (HR:0.45, 95% CI:0.34-0.59 vs HR:0.99, 95% CI:0.73-1.36; P<0.0001). None of the 84 panitumumab-treated patients with KRAS mutant tumors responded to treatment (100% positive predictive value for nonresponse in mutant group). In the KRAS wt group treated with panitumumab (n=124), 21 patients had partial response (17%), 42 experienced stable disease (34%). Additionally, patients with KRAS mutations showed no significant improvement between treatment with panitumumab and BSC alone (PFS: 7.4 wk vs 7.3 wk). The authors concluded that their findings support the hypothesis that KRAS mutations confer primary resistance to anti-EGFR antibodies and recommend that KRAS status be evaluated prior to panitumumab administration. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::g12/g13:mutation sequence variation in gene KRAS/NCBI:3845 1793 check_entity AN5331-1 KRAS G12/G13 mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 prognostic;risk 21702-6 PubMed:19603024 This was a retrospective clinical study of 168 metastatic colorectal cancer patients who received first line chemotherapy (5-fluorouracil (5-FU) only, 5-FU + oxaliplatin, 5-FU + irinotecan, or 5-FU + oxaliplatin + irinotecan) alone or with monoclonal antibodies (bevacizumab or cetuximab). It assessed the relationship between KRAS mutation status in primary tumors and post treatment progression free survival (PFS) and overall survival (OS). Of the 168 patients, 106 had wildtype KRAS and 62 had mutations in KRAS—including G12A, G12C, G12D, G12R, G12S, G12V, and G13D. Regardless of first line chemotherapy regimen or use of monoclonal antibody treatment, patients with KRAS-mutated tumors did not have a significantly worse outcome than patients with wtKRAS tumors, as evidenced by non-significant differences in PFS (12.3 vs 11.8 months, respectively) and OS (35.8 and 40.5 months, respectively). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::g12/g13:mutation sequence variation in gene KRAS/NCBI:3845 1793 check_entity AN5331-1 KRAS G12/G13 mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 prognostic;risk 21702-6 PubMed:19223544 Mutational analysis of 109 metastatic colorectal cancer patients was used to examine objective tumor response, progression free survival (PFS), and overall survival (OS) following treatment with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). In univariate analysis, KRAS mutations (G12V, G12S, G12D, G12A, G13V, G13D) were significantly associated with lack of response to panitumumab or cetuximab (objective response rate: 2/32 vs 20/77 for patients harboring KRAS mutated or wildtype tumors, respectively; P = 0.019). Multivariate logistic regression of KRAS mutations, PIK3CA mutations and PTEN protein expression also confirmed an independent effect of KRAS mutations on objective response (p = 0.0029). Authors noted that patients with tumors harboring KRAS mutations (32/108) tended to have decreased PFS and OS compared to those with wild-type tumors though the differences were not statistically significant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::g12/g13:mutation sequence variation in gene KRAS/NCBI:3845 1793 check_entity AN5331-1 KRAS G12/G13 mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 prognostic;risk 21702-6 CIViC:77 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::g12/g13:mutation sequence variation in gene KRAS/NCBI:3845 1793 check_entity AN5331-2 KRAS G12/G13 mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 risk 21702-6 PubMed:15696205 In 60 patients with NSCLC, Exon 2 KRAS mutations were associated with resistance to the EGFR kinase inhibitors gefitinib or erlotinib (9/38 refractory vs 0/21 sensitive patients; P=0.0201). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::g12/g13:mutation sequence variation in gene KRAS/NCBI:3845 1794 check_entity AN5331-2 KRAS G12/G13 mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 risk 21702-6 CIViC:77 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::g12/g13:mutation sequence variation in gene KRAS/NCBI:3845 1794 check_entity AN5331-3 KRAS G12/G13 mutation KRAS NCBI:3845 gene pancreatic adenocarcinoma DOID:4074 risk 21702-6 PubMed:24915778 Adding trametinib to gemcitabine does not improve overall survival (OS), progression-free survival (PFS), overall response rate (ORR) or duration of response (DOR) in patients with untreated metastatic adenocarcinoma of the pancreas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::g12/g13:mutation sequence variation in gene KRAS/NCBI:3845 1795 check_entity AN5331-3 KRAS G12/G13 mutation KRAS NCBI:3845 gene pancreatic adenocarcinoma DOID:4074 risk 21702-6 CIViC:77 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::g12/g13:mutation sequence variation in gene KRAS/NCBI:3845 1795 check_entity AN5332-1 KRAS G12A mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:26161928 In an in vitro study, a human colon adenocarcinoma SW48 cell line virally transduced to express KRAS G12A demonstrated resistance to regorafenib treatment (IC50: 330.13 nM vs. 114.28 nM, P<0.01, reported errantly as 3301.13nM in the source) compared to SW48 cells expressing KRAS wild-type. Resistance was determined by assessing cell viability. Authors concluded that KRAS G12A was more strongly resistant to regorafenib than KRAS wt and other KRAS G12/G13 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12A sequence variation in gene KRAS/NCBI:3845 1796 check_entity AN5332-1 KRAS G12A mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:20619739 This was a retrospective study of 691 cetuximab treated patients with metastatic colorectal cancer. Of those, 22 patients harbored KRAS G12A, were BRAF, NRAS and PIK3CA wt, and had individual response data. Three patients had partial response, 12 had stable disease, and seven progressed. Treatments included cetuximab + irinotecan (n=18), cetuximab monotherapy (n=1), cetuximab + FOLFIRI (n=2), and cetuximab + oxaliplatin + 5FU (n=1). Median PFS was 18 weeks (1-34 weeks), median OS was 35 weeks (1-143 weeks), and median number of previous chemotherapy lines was 2 (0-5). Median age was 62 years old (22-77) and there were 11 males and 11 females. Using these data and data from the larger cohort, authors concluded that KRAS mutation was strongly associated with poor response to cetuximab and suggested that mutation status of KRAS is the most informative compared to BRAF, NRAS, and PIK3CA exon 20 for predicting cetuximab response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12A sequence variation in gene KRAS/NCBI:3845 1796 check_entity AN5332-1 KRAS G12A mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:19223544 In this study, a large cohort of metastatic colorectal cancer patients were treated with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). KRAS, PIK3CA, and PTEN were tested for mutation; KRAS G12A was the only variant noted in the both the primary and metastatic colon tumors of one patient (Patient 29; Supplemental table 1) , and the primary colon tumor of another patient (104; Table S1), who both experienced stable disease following treatment. In the larger cohort, patients with tumors harboring any KRAS mutation had significantly decreased incidence of objective response than patients with wtKRAS tumors. Authors noted that patients with tumors harboring KRAS mutations tended to have decreased PFS and OS compared to those with wild-type tumors though the differences were not statistically significant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12A sequence variation in gene KRAS/NCBI:3845 1796 check_entity AN5332-1 KRAS G12A mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 CIViC:148 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12A sequence variation in gene KRAS/NCBI:3845 1796 check_entity AN5332-2 KRAS G12A mutation KRAS NCBI:3845 gene lung adenocarcinoma DOID:3910 risk 21702-6 PubMed:19794967 KRAS mutations (N=29 G12, N=1 G13) were the primary predictor of EGFR TKI resistance in patients with lung adenocarcinoma (N=83). Overall survival (P=0.001) and progression-free survival (P=0.005) were significantly shorter in mutated patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12A sequence variation in gene KRAS/NCBI:3845 1797 check_entity AN5332-2 KRAS G12A mutation KRAS NCBI:3845 gene lung adenocarcinoma DOID:3910 risk 21702-6 CIViC:148 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12A sequence variation in gene KRAS/NCBI:3845 1797 check_entity AN5332-3 KRAS G12A mutation KRAS NCBI:3845 gene lung cancer DOID:1324 risk 21702-6 PubMed:17409929 In recurrent lung cancer patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib, patients with KRAS mutations had a lower frequency of partial response (PR) and stable disease (SD) and a higher rate of progressive disease (PD) (PR:0, SD:1, PD:15 vs. PR:24, SD:8, PD:14; P=0.0274) compared to wildtype KRAS patients. Patients with KRAS mutations also had a shorter overall survival compared to wildtype KRAS patients (HR:2.542, 95% CI:1.048-6.168, P=0.0390). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12A sequence variation in gene KRAS/NCBI:3845 1798 check_entity AN5332-3 KRAS G12A mutation KRAS NCBI:3845 gene lung cancer DOID:1324 risk 21702-6 CIViC:148 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12A sequence variation in gene KRAS/NCBI:3845 1798 check_entity AN5332-4 KRAS G12A mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 risk 21702-6 PubMed:19284554 In a study of patients receiving melphalan-based therapy, those with KRAS codon 12 mutations were less likely to have a positive response than those with wildtype KRAS (26.9% vs. 58.3%, P=0.015). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12A sequence variation in gene KRAS/NCBI:3845 1799 check_entity AN5332-4 KRAS G12A mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 risk 21702-6 PubMed:11050000 In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12A sequence variation in gene KRAS/NCBI:3845 1799 check_entity AN5332-4 KRAS G12A mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 risk 21702-6 PubMed:12483530 In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12A sequence variation in gene KRAS/NCBI:3845 1799 check_entity AN5332-4 KRAS G12A mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 risk 21702-6 PubMed:16497971 In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12A sequence variation in gene KRAS/NCBI:3845 1799 check_entity AN5332-4 KRAS G12A mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 risk 21702-6 CIViC:148 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12A sequence variation in gene KRAS/NCBI:3845 1799 check_entity AN5333-1 KRAS G12C mutation KRAS NCBI:3845 gene cancer DOID:162 risk 21702-6 PubMed:26739882 Preclinical study to investigate mechanisms of KRAS G12C activity and inhibition with ARS-853, a covalent (irreversible) inhibitor which binds KRAS G12C in the GDP-bound state to prevent activation. Results from a mass spectrometry-based assay to evaluate KRAS activity suggests that G12C mutant KRAS is in a “hyperexcitable” rather than a “statically active” state. ARS-853 targets the inactive state and inhibited proliferation in a subset (3/11) of KRAS G12C mutant cell lines in 2-D growth assays and 11/11 cell lines in soft-agar colony formation and 3-D assays. This effect was specific for KRAS G12C as 12/12 cell lines with other KRAS mutations (including other G12 mutations V, D and A) were not inhibited in either soft-agar assay. Relative resistance to ARS-853 developed after epidermal growth factor (50 ng/mL) administration and the combination of erlotinib or afatinib (EGFR-inhibitors) with ARS-853 greatly potentiated growth arrest, apoptosis and decrease of PI3K and MAPK-signaling over single-agent ARS-853 treatment, even in the presence of added EGF. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12C sequence variation in gene KRAS/NCBI:3845 1800 check_entity AN5333-1 KRAS G12C mutation KRAS NCBI:3845 gene cancer DOID:162 risk 21702-6 CIViC:78 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12C sequence variation in gene KRAS/NCBI:3845 1800 check_entity AN5333-2 KRAS G12C mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:23313110 In a study of 448 metastatic colorectal cancer patients treated with EGFR-TKIs and tested for EGFR and KRAS mutations, 69 tested positive for KRAS mutations. In 38 EGFR wildtype patients treated with erlotinib or gefitinib, those with KRAS G12C mutations (n=24) had shorter progression free survival rates compared to patients with non-G12C KRAS mutations (n=14; 4.3 vs 9 weeks; P = 0.009; HR=2.7). This was true when restricted to patients with an adenocarcinoma subtype only (n=18 vs 12; 4.1 vs 9 weeks; P = 0.007; HR=3.1). Overall survival was not different between groups. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12C sequence variation in gene KRAS/NCBI:3845 1801 check_entity AN5333-2 KRAS G12C mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:22392911 In 28 out of 40 (70%) metastatic colorectal cancer tumors harboring BRAF, KRAS, NRAS or PIK3CA mutations and implanted into mice, the therapeutic combination of the MEK inhibitor AZD6244 and the PI3K/mTor inhibitor BEZ235 resulted in disease stabilization. Mean tumor growth was lower in the tumors treated with AZD6244+ BEZ235 (+77% vs. +267%, P=1E-6) compared to AZD6244 alone and (+77% vs. +222%, P=0.0014) BEZ235 alone. 32/40 tumors harbored KRAS mutations including 4 G12C mutations where disease stabilization occurred in 3/4 treated with BEZ235 or doublet therapy and 2/4 treated with AZD6244 only. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12C sequence variation in gene KRAS/NCBI:3845 1801 check_entity AN5333-2 KRAS G12C mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:18316791 In a retrospective study of 427 metastatic colorectal patients, KRAS mutations were observed in 43% of the tumor samples. Patients with mutations in codon 12 or 13 of KRAS were associated with reduced response to panitumumab compared to wildtype KRAS (HR:0.99, 95% CI:0.73-1.36 vs. HR:0.45, 95% CI:0.34-0.59; P<0.0001). Additionally, patients with KRAS mutations showed no significant improvement between treatment with panitumumab and best supportive care alone (PFS: 7.4 wk vs 7.3 wk). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12C sequence variation in gene KRAS/NCBI:3845 1801 check_entity AN5333-2 KRAS G12C mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:20619739 This was a retrospective study of 691 cetuximab treated patients with metastatic, chemotherapy refractory colorectal cancer. Of those, 16 patients harbored KRAS G12C, were BRAF, NRAS and PIK3CA wt, and had individual response data. One patient had a partial response, 6 had stable disease, and 9 progressed. Treatments included cetuximab + irinotecan (n=15) and cetuximab + FOLFIRI (n=1). Median PFS was 11 weeks (6-65 weeks), median OS was 24 weeks (14-91 weeks), and median number of previous chemotherapy lines was 2 (1-6). Median age was 62 years old (46-73), and there were 8 males and 8 females. Using these data and data from the larger cohort, authors concluded that KRAS mutation was strongly associated with poor response to cetuximab and suggested that mutation status of KRAS is the most informative compared to BRAF, NRAS, and PIK3CA exon 20 for predicting cetuximab response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12C sequence variation in gene KRAS/NCBI:3845 1801 check_entity AN5333-2 KRAS G12C mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:26161928 In an in vitro study, a human colon adenocarcinoma SW48 cell line expressing KRAS G12C mutation demonstrated resistance to regorafenib treatment (IC50: 386.22 nM vs. 114.28 nM, P<0.01) compared to SW48 cells expressing KRAS wild-type. Resistance was determined by assessing cell viability. In vivo, KRAS G12C expressing SW48 cells were injected into NOD/SCID mice. Treatment with regorafenib did not lead to a significant delay of tumor growth. Mice injected with KRAS wt cells did not significantly respond to regorafenib, although a trend was seen toward better response. IHC analysis of mouse tissue revealed no significant change in markers of proliferation (Ki67), angiogenesis (CD31) and apoptosis (TUNEL) in KRAS G12C expressing mice treated with regorafenib compared to KRAS wt expressing mice whose tumors displayed more pronounced changes. Authors concluded that G12C was more resistant to regorafenib than KRAS wt and other common KRAS G12/G13 mutants. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12C sequence variation in gene KRAS/NCBI:3845 1801 check_entity AN5333-2 KRAS G12C mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 CIViC:78 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12C sequence variation in gene KRAS/NCBI:3845 1801 check_entity AN5333-3 KRAS G12C mutation KRAS NCBI:3845 gene lung cancer DOID:1324 diagnostic;risk 21702-6 PubMed:23014527 KRAS G12C occur more frequently in women than men. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12C sequence variation in gene KRAS/NCBI:3845 1802 check_entity AN5333-3 KRAS G12C mutation KRAS NCBI:3845 gene lung cancer DOID:1324 diagnostic;risk 21702-6 PubMed:17409929 In recurrent lung cancer patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib, patients with KRAS mutations had a lower frequency of partial response (PR) and stable disease (SD) and a higher rate of progressive disease (PD) (PR:0, SD:1, PD:15 vs. PR:24, SD:8, PD:14; P=0.0274) compared to wildtype KRAS patients. Patients with KRAS mutations also had a shorter overall survival compared to wildtype KRAS patients (HR:2.542, 95% CI:1.048-6.168, P=0.0390). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12C sequence variation in gene KRAS/NCBI:3845 1802 check_entity AN5333-3 KRAS G12C mutation KRAS NCBI:3845 gene lung cancer DOID:1324 diagnostic;risk 21702-6 CIViC:78 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12C sequence variation in gene KRAS/NCBI:3845 1802 check_entity AN5333-4 KRAS G12C mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 PubMed:26125448 83 patients from a phase II trial (docetaxel + placebo or MEK1/2 inhibitor selumetinib) with KRAS mutant tumors were retrospectively assessed for differences in OS, PFS, ORR and change in tumor size at week 6 according to type of KRAS mutation. G12C, G12D and G12V were the most common mutations (46%, 22%, 11%, respectively). Patients with G12C or G12V mutations receiving selumetinib and docetaxel combined treatment had a trend towards longer OS, PFS and ORR compared to other KRAS mutations, but the differences did not reach statistical significance. Changes in tumor size were similar between groups with the best responses in tumors with G12V mutations. Few differences were observed between groups when treated with docetaxel + placebo. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12C sequence variation in gene KRAS/NCBI:3845 1803 check_entity AN5333-4 KRAS G12C mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 PubMed:22247021 In a study of 48 NSCLC patients, those with G12C or G12V mutant KRAS were associated with decreased progression free survival (1.84 months) compared with other KRAS mutants or with wild-type KRAS (3.35 and 1.95 months). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12C sequence variation in gene KRAS/NCBI:3845 1803 check_entity AN5333-4 KRAS G12C mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 PubMed:34096690 The phase II cohort of the CodeBreaK 100 study (NCT03600883) investigated the activity of the KRAS G12C inhibitor sotorasib in previously treated patients with KRAS G12C-mutated non-small cell lung cancer. A total of 124 patients had measurable disease and were evaluated for response by independent central review. Complete response was seen in four patients and partial response in 42 patients, for an objective response rate of 37.1% (95% CI, 28.6 to 46.2). The median progression-free survival and overall survival were 6.8 (95% CI, 5.1 to 8.2) months and 12.5 months (95% CI, 10.0 to could not be evaluated), respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12C sequence variation in gene KRAS/NCBI:3845 1803 check_entity AN5333-4 KRAS G12C mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 PubMed:37611121 A phase 1 clinical study conducted with Divarasib in a total of 137 patients, of which 60 patients had NSCLC with G12C mutation in the KRAS gene. Confirmed response was noted in 53.4% (95% CI; 39.9 to 66.7) of the patients, with a progression-free survival of 13.1 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12C sequence variation in gene KRAS/NCBI:3845 1803 check_entity AN5333-4 KRAS G12C mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 CIViC:78 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12C sequence variation in gene KRAS/NCBI:3845 1803 check_entity AN5333-5 KRAS G12C mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 risk 21702-6 PubMed:19284554 In a study of patients receiving melphalan-based therapy, those with KRAS codon 12 mutations were less likely to have a positive response than those with wildtype KRAS (26.9% vs. 58.3%, P=0.015). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12C sequence variation in gene KRAS/NCBI:3845 1804 check_entity AN5333-5 KRAS G12C mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 risk 21702-6 PubMed:11050000 In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12C sequence variation in gene KRAS/NCBI:3845 1804 check_entity AN5333-5 KRAS G12C mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 risk 21702-6 PubMed:12483530 In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12C sequence variation in gene KRAS/NCBI:3845 1804 check_entity AN5333-5 KRAS G12C mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 risk 21702-6 PubMed:16497971 In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12C sequence variation in gene KRAS/NCBI:3845 1804 check_entity AN5333-5 KRAS G12C mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 risk 21702-6 CIViC:78 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12C sequence variation in gene KRAS/NCBI:3845 1804 check_entity AN5334-1 KRAS G12D mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 prognostic;risk 21702-6 PubMed:22948721 In 119 metastatic colorectal cancer patients treated with cetuximab-based first-line chemotherapy, KRAS G12D mutations (N=44) were associated with longer overall patient survival when compared to other KRAS G12 mutations (23.3 vs 14-18 months; G12V, A, C, S, R). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1805 check_entity AN5334-1 KRAS G12D mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 prognostic;risk 21702-6 PubMed:27959684 A patient with metastatic colorectal cancer was enrolled in a phase 2 clinical trial (NCT01174121). 24 cultures of tumor-infiltrating lymphocytes were expanded from 3 lung metastasis resections. After cultures were tested for reactivity, the patient was infused with 1.48 x 10^11 tumor-infiltrating lymphocytes (75% CD8+ T cells) that were specifically reactive to KRAS G12D. All 7 metastatic lung lesions regressed 40 days after therapy, and the patient had a 9-month partial response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1805 check_entity AN5334-1 KRAS G12D mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 prognostic;risk 21702-6 PubMed:20619739 One patient participating in a large retrospective study of EGFR monoclonal antibodies in metastatic, treatment refractory colorectal cancer had a tumor which harbored KRAS G12D, was wildtype for NRAS, BRAF and PIK3CA, and had individual response data. This patient was was a 55 year old female treated with panitumumab monotherapy as 3rd line therapy who experienced progressive disease (PFS: 8 weeks; OS: 9 weeks). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1805 check_entity AN5334-1 KRAS G12D mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 prognostic;risk 21702-6 PubMed:22392911 In 28 out of 40 (70%) metastatic colorectal cancer tumors harboring KRAS, NRAS, BRAF or PIK3CA mutations and implanted into mice, the therapeutic combination of the MEK inhibitor AZD6244 and the PI3K/mTor inhibitor BEZ235 resulted in disease stabilization. Mean tumor growth was lower in the tumors treated with AZD6244+ BEZ235 (+77% vs. +267%, P=1E-6) compared to AZD6244 alone and (+77% vs. +222%, P=0.0014) BEZ235 alone. 32/40 tumors studied had KRAS mutations with 9 G12D (2 with PIK3CA H1047R) and 13 other G12 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1805 check_entity AN5334-1 KRAS G12D mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 prognostic;risk 21702-6 PubMed:18316791 In a retrospective study of 427 metastatic colorectal patients, KRAS mutations were observed in 43% of the tumor samples. Patients with mutations in codon 12 or 13 of KRAS were associated with reduced response to panitumumab compared to wildtype KRAS (HR:0.99, 95% CI:0.73-1.36 vs. HR:0.45, 95% CI:0.34-0.59; P<0.0001). Additionally, patients with KRAS mutations showed no significant improvement between treatment with panitumumab and best supportive care alone (PFS: 7.4 wk vs 7.3 wk). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1805 check_entity AN5334-1 KRAS G12D mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 prognostic;risk 21702-6 PubMed:26161928 In an in vitro study, a human colon adenocarcinoma SW48 cell line expressing KRAS G12D mutation demonstrated resistance to regorafenib treatment (IC50: 195.01nM vs. 114.28 nM P<0.01) compared to SW48 cells expressing KRAS wild-type. Resistance was determined by assessing cell viability. Authors concluded that KRAS G12D was more resistant to regorafenib than KRAS wt, and intermediately resistant compared to other common KRAS G12/G13 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1805 check_entity AN5334-1 KRAS G12D mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 prognostic;risk 21702-6 PubMed:19223544 In this study, a large cohort of metastatic colorectal cancer patients were treated with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). KRAS, PIK3CA, and PTEN were tested for mutation; KRAS G12D was the only variant noted in the primary tumor of two patients who experienced stable disease following treatment (Patients 22 and 36; colon and rectum tumors; Supplemental Table 1). In the larger cohort, patients with tumors harboring any KRAS mutation had significantly decreased incidence of objective response than patients with wtKRAS tumors. Authors noted that patients with tumors harboring KRAS mutations tended to have decreased PFS and OS compared to those with wild-type tumors though the differences were not statistically significant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1805 check_entity AN5334-1 KRAS G12D mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 prognostic;risk 21702-6 CIViC:79 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1805 check_entity AN5334-2 KRAS G12D mutation KRAS NCBI:3845 gene hairy cell leukemia DOID:285 risk 21702-6 PubMed:26352686 One patient enrolled in a clinical study to evaluate vemurafenib treatment of BRAF V600E mutant hairy-cell leukemia developed resistance to vemurafenib retreatment. 300-gene targeted sequencing of the patient’s genome revealed activating subclonal KRAS mutations (KRAS G12D, 15.2% allele frequency; KRAS K117N, 1.2%), as well as a RUNX1 A55E mutation (5.9%) that had not been seen prior to vemurafenib treatment or at remission. BRAF V600E allele frequency was detectable (2.4%) at the time of remission but dramatically increased at relapse (64.9%). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1806 check_entity AN5334-2 KRAS G12D mutation KRAS NCBI:3845 gene hairy cell leukemia DOID:285 risk 21702-6 CIViC:79 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1806 check_entity AN5334-3 KRAS G12D mutation KRAS NCBI:3845 gene lung cancer DOID:1324 diagnostic;risk 21702-6 PubMed:23014527 KRAS G12D mutation occurs in never smokers significantly more often than in smokers. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1807 check_entity AN5334-3 KRAS G12D mutation KRAS NCBI:3845 gene lung cancer DOID:1324 diagnostic;risk 21702-6 PubMed:17409929 In recurrent lung cancer patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib, patients with KRAS mutations had a lower frequency of partial response (PR) and stable disease (SD) and a higher rate of progressive disease (PD) (PR:0, SD:1, PD:15 vs. PR:24, SD:8, PD:14; P=0.0274) compared to wildtype KRAS patients. Patients with KRAS mutations also had a shorter overall survival compared to wildtype KRAS patients (HR:2.542, 95% CI:1.048-6.168, P=0.0390). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1807 check_entity AN5334-3 KRAS G12D mutation KRAS NCBI:3845 gene lung cancer DOID:1324 diagnostic;risk 21702-6 CIViC:79 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1807 check_entity AN5334-4 KRAS G12D mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 risk 21702-6 PubMed:23524406 In a patient with V600E-positive NSCLC, KRAS G12D seemed to confer resistance to dabrafenib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1808 check_entity AN5334-4 KRAS G12D mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 risk 21702-6 PubMed:19029981 The use of NVP-BEZ235 in conjunction with ARRY-142886, but not as monotherapy, in a lung cancer model with KRAS G12D mutation led to marked tumor regression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1808 check_entity AN5334-4 KRAS G12D mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 risk 21702-6 CIViC:79 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1808 check_entity AN5334-5 KRAS G12D mutation KRAS NCBI:3845 gene malignant exocrine pancreas neoplasm DOID:1795 prognostic 21702-6 PubMed:23565280 In 171 patients with tumors of the exocrine pancreas, a KRAS G12D mutation (N=60) was associated with shorter overall survival than being wild-type for KRAS (N=21; Hazard Ratio: 95% CI between 1.14 and 2.67). Additionally, KRAS mutations combined with CDKN2A alterations (N=26) showed an even worse OS than those wild-type for both (N=17; HR: 95%CI 1.33-7.10). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1809 check_entity AN5334-5 KRAS G12D mutation KRAS NCBI:3845 gene malignant exocrine pancreas neoplasm DOID:1795 prognostic 21702-6 CIViC:79 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1809 check_entity AN5334-6 KRAS G12D mutation KRAS NCBI:3845 gene melanoma DOID:1909 risk 21702-6 PubMed:24265155 In vitro studies of M229 (a human melanoma cell line) endogenously expressing wildtype KRAS and BRAF V600E (a known BRAF inhibitor sensitizing mutation) found that cells virally induced to stably over-express KRAS4a G12D or KRAS4b G12D were more resistant to vemurafenib (a BRAF inhibitor) than cells transduced with empty vectors (90% vs 10% survival). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1810 check_entity AN5334-6 KRAS G12D mutation KRAS NCBI:3845 gene melanoma DOID:1909 risk 21702-6 CIViC:79 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1810 check_entity AN5334-7 KRAS G12D mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 risk 21702-6 PubMed:19284554 In a study of patients receiving melphalan-based therapy, those with KRAS codon 12 mutations were less likely to have a positive response than those with wildtype KRAS (26.9% vs. 58.3%, P=0.015). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1811 check_entity AN5334-7 KRAS G12D mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 risk 21702-6 PubMed:11050000 In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1811 check_entity AN5334-7 KRAS G12D mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 risk 21702-6 PubMed:12483530 In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1811 check_entity AN5334-7 KRAS G12D mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 risk 21702-6 PubMed:16497971 In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1811 check_entity AN5334-7 KRAS G12D mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 risk 21702-6 CIViC:79 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1811 check_entity AN5334-8 KRAS G12D mutation KRAS NCBI:3845 gene ovarian cancer DOID:2394 risk 21702-6 PubMed:22246397 In an in vitro study, a MCAS cell line expressing KRAS G12D mutation was associated with reduced sensitivity to cetuximab treatment as compared to RMUG-L and OMC-1 cells expressing wild-type KRAS. Resistance was determined by assessing cell growth. Further, in an in vivo experiment, KRAS G12D expressing MCAS xenografts in nude mice had reduced response to cetuximab, as compared to KRAS wild-type expressing RMUG-L xenografts. Resistance was determined by assessing tumor growth. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1812 check_entity AN5334-8 KRAS G12D mutation KRAS NCBI:3845 gene ovarian cancer DOID:2394 risk 21702-6 CIViC:79 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1812 check_entity AN5334-9 KRAS G12D mutation KRAS NCBI:3845 gene pancreatic cancer DOID:1793 prognostic 21702-6 PubMed:27010960 In 219 patients with metastatic pancreatic ductal adenocarcinoma, a multivariate analysis identified KRAS G12D mutations as an independent predictor of poorer prognosis both in patients that have received chemotherapy (N=49/162), and the entire series (N=73/219). HR of 1.84 (P=0.02) and 1.44 (P=0.01), respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1813 check_entity AN5334-9 KRAS G12D mutation KRAS NCBI:3845 gene pancreatic cancer DOID:1793 prognostic 21702-6 CIViC:79 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1813 check_entity AN5334-10 KRAS G12D mutation KRAS NCBI:3845 gene pancreatic carcinoma DOID:4905 risk 21702-6 PubMed:22025163 Among 33 patients treated with pan-AKT inhibitor MK-2206 in this phase 1 study, one patient with pancreatic adenocarcinoma and PTEN loss and a KRAS G12D mutation experienced a decrease of approximately 60% in cancer antigen 19-9 levels and 23% shrinkage in tumor measurements. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1814 check_entity AN5334-10 KRAS G12D mutation KRAS NCBI:3845 gene pancreatic carcinoma DOID:4905 risk 21702-6 CIViC:79 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1814 check_entity AN5334-11 KRAS G12D mutation KRAS NCBI:3845 gene pancreatic ductal carcinoma DOID:3587 prognostic 21702-6 PubMed:27010960 Exon-2 KRAS mutation status was analyzed in 219 patients with pancreatic ductal carcinoma, excluding those who had previously undergone chemotherapy, first-line pancreatic resection, or neoadjuvant treatment with chemotherapy or radiotherapy. 72 patients had wild-type KRAS, 147 had a codon-12 KRAS mutation (G12D, G12V, or G12R) and 73 had a G12D KRAS mutation, specifically. There was no significant difference in overall survival between wild-type patients and patients with any type of exon-12 mutation. However, patients with the G12D mutation exhibited significantly lower overall survival compared to wild-type patients in univariate and multivariate analyses. This difference in overall survival between wild-type and G12D patients persisted in the subset of patients who underwent chemotherapy at any point after enrollment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1815 check_entity AN5334-11 KRAS G12D mutation KRAS NCBI:3845 gene pancreatic ductal carcinoma DOID:3587 prognostic 21702-6 CIViC:79 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene KRAS/NCBI:3845 1815 check_entity AN5335-1 KRAS G12R mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:18316791 In a retrospective study of 427 metastatic colorectal patients, KRAS mutations were observed in 43% of the tumor samples. Patients with mutations in codon 12 or 13 of KRAS were associated with reduced response to panitumumab compared to wildtype KRAS (HR:0.99, 95% CI:0.73-1.36 vs. HR:0.45, 95% CI:0.34-0.59; P<0.0001). Additionally, patients with KRAS mutations showed no significant improvement between treatment with panitumumab and best supportive care alone (PFS: 7.4 wk vs 7.3 wk). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12R sequence variation in gene KRAS/NCBI:3845 1816 check_entity AN5335-1 KRAS G12R mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:20619739 Three patients participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored KRAS G12R, were wildtype for NRAS, BRAF and PIK3CA, and had individual response data. One patient experienced stable disease, and two patients experienced progressive disease. Patient characteristics were as follows: a 67 year old female treated with cetuximab + irinotecan as a 4th line treatment who experienced progressive disease and had PFS of 8 weeks and OS of 17 weeks; a 78 year old female treated with cetuximab + irinotecan as a 3rd line therapy who experienced progressive disease and had PFS of 3 weeks and OS of 10 weeks; and a 55 year old male treated with cetuximab + FOLFIRI as a 3rd line therapy who experienced stable disease and had PFS of 13 weeks and OS of 15 weeks. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12R sequence variation in gene KRAS/NCBI:3845 1816 check_entity AN5335-1 KRAS G12R mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:22722830 In an in vitro study to identify cetuximab-resistant clones following continuous drug treatment, a resistant clone of the Lim1215 colorectal cancer cell line was identified to have the KRAS G12R mutation. No G12R was detected in the parental line despite high-resolution evaluation. Additionally, endogenously expressing KRAS G12R (knock-in) mutation demonstrated resistance to cetuximab treatment, compared to Lim1215 parental cells expressing wild-type KRAS. Resistance was determined by assessing cell viability. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12R sequence variation in gene KRAS/NCBI:3845 1816 check_entity AN5335-1 KRAS G12R mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:26161928 In an in vitro study, a human colon adenocarcinoma SW48 cell line expressing KRAS G12R mutation demonstrated resistance to regorafenib treatment (IC50: 181.77 nM vs. 114.28 nM, P<0.01) compared to SW48 cells expressing KRAS wild-type. Resistance was determined by assessing cell viability. Authors concluded that KRAS G12R was resistant to regorafenib compared to wildtype but was less resistant than other common KRAS G12/G13 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12R sequence variation in gene KRAS/NCBI:3845 1816 check_entity AN5335-1 KRAS G12R mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 CIViC:526 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12R sequence variation in gene KRAS/NCBI:3845 1816 check_entity AN5335-2 KRAS G12R mutation KRAS NCBI:3845 gene pancreatic cancer DOID:1793 prognostic 21702-6 PubMed:22983505 In 242 patients with unresectable pancreatic cancer, the presence of KRAS G12R (N=17) or G12D (N=92) was associated with poorer prognosis (overall survival HR 1.6; 95% confidence interval 1.11-2.28). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12R sequence variation in gene KRAS/NCBI:3845 1817 check_entity AN5335-2 KRAS G12R mutation KRAS NCBI:3845 gene pancreatic cancer DOID:1793 prognostic 21702-6 CIViC:526 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12R sequence variation in gene KRAS/NCBI:3845 1817 check_entity AN5336-1 KRAS G12S mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:18316791 In a retrospective study of 427 metastatic colorectal patients, KRAS mutations were observed in 43% of the tumor samples. Patients with mutations in codon 12 or 13 of KRAS were associated with reduced response to panitumumab compared to wildtype KRAS (HR:0.99, 95% CI:0.73-1.36 vs. HR:0.45, 95% CI:0.34-0.59; P<0.0001). Additionally, patients with KRAS mutations showed no significant improvement between treatment with panitumumab and best supportive care alone (PFS: 7.4 wk vs 7.3 wk). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12S sequence variation in gene KRAS/NCBI:3845 1818 check_entity AN5336-1 KRAS G12S mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:20619739 This was a retrospective study of 691 cetuximab treated patients with metastatic, chemotherapy refractory colorectal cancer. Of those, 16 patients harbored KRAS G12S, were BRAF, NRAS and PIK3CA wt, and had individual response data. Nine patients had stable disease and seven progressed. Treatments included cetuximab + irinotecan (n=13), cetuximab + FOLFIRI (n=1), cetuximab+5FU (n=1), cetuximab + irinotecan + oxaliplatin + bevacizumab (n=1). Median PFS was 12 weeks (2-50 weeks), median OS was 25 weeks (10-135 weeks), and median number of previous chemotherapy lines was 2 (1-6). Median age was 59 years old (31-69), and there were 9 males and 7 females. Using these data and data from the larger cohort, authors concluded that KRAS mutation was strongly associated with poor response to cetuximab and suggested that mutation status of KRAS is the most informative compared to BRAF, NRAS, and PIK3CA exon 20 for predicting cetuximab response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12S sequence variation in gene KRAS/NCBI:3845 1818 check_entity AN5336-1 KRAS G12S mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:26161928 In an in vitro study, a human colon adenocarcinoma SW48 cell line expressing KRAS G12S mutation demonstrated resistance to regorafenib treatment (IC50: 264.23 nM vs. 114.28 nM, P<0.01) compared to SW48 cells expressing KRAS wild-type. Resistance was determined by assessing cell viability. Authors concluded that KRAS G12S was more resistant to regorafenib than KRAS wt, and intermediately resistant compared to other common KRAS G12/G13 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12S sequence variation in gene KRAS/NCBI:3845 1818 check_entity AN5336-1 KRAS G12S mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:19223544 In this study, a large cohort of metastatic colorectal cancer patients were treated with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). KRAS PIK3CA and PTEN were tested for mutation; KRAS G12S was the only variant noted in the primary tumor of one patient who experienced disease progression following treatment (colon tumor of patient 20; Supplemental Table 1). In the larger cohort, patients with tumors harboring any KRAS mutation had significantly decreased incidence of objective response than patients with wtKRAS tumors. Authors noted that patients with tumors harboring KRAS mutations tended to have decreased PFS and OS compared to those with wild-type tumors though the differences were not statistically significant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12S sequence variation in gene KRAS/NCBI:3845 1818 check_entity AN5336-1 KRAS G12S mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 CIViC:887 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12S sequence variation in gene KRAS/NCBI:3845 1818 check_entity AN5336-2 KRAS G12S mutation KRAS NCBI:3845 gene lung cancer DOID:1324 risk 21702-6 PubMed:17409929 In recurrent lung cancer patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib, patients with KRAS mutations had a lower frequency of partial response (PR) and stable disease (SD) and a higher rate of progressive disease (PD) (PR:0, SD:1, PD:15 vs. PR:24, SD:8, PD:14; P=0.0274) compared to wildtype KRAS patients. Patients with KRAS mutations also had a shorter overall survival compared to wildtype KRAS patients (HR:2.542, 95% CI:1.048-6.168, P=0.0390). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12S sequence variation in gene KRAS/NCBI:3845 1819 check_entity AN5336-2 KRAS G12S mutation KRAS NCBI:3845 gene lung cancer DOID:1324 risk 21702-6 CIViC:887 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12S sequence variation in gene KRAS/NCBI:3845 1819 check_entity AN5336-3 KRAS G12S mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 risk 21702-6 PubMed:19284554 In a study of patients receiving melphalan-based therapy, those with KRAS codon 12 mutations were less likely to have a positive response than those with wildtype KRAS (26.9% vs. 58.3%, P=0.015). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12S sequence variation in gene KRAS/NCBI:3845 1820 check_entity AN5336-3 KRAS G12S mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 risk 21702-6 PubMed:11050000 In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12S sequence variation in gene KRAS/NCBI:3845 1820 check_entity AN5336-3 KRAS G12S mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 risk 21702-6 PubMed:12483530 In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12S sequence variation in gene KRAS/NCBI:3845 1820 check_entity AN5336-3 KRAS G12S mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 risk 21702-6 PubMed:16497971 In in vitro experiments, myeloma cell lines expressing activating NRAS and KRAS mutations are less sensitive to the apoptosis-inducing effects of dexamethasone, doxorubicin, and melphalan in comparison to cells with wildtype RAS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12S sequence variation in gene KRAS/NCBI:3845 1820 check_entity AN5336-3 KRAS G12S mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 risk 21702-6 CIViC:887 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12S sequence variation in gene KRAS/NCBI:3845 1820 check_entity AN5337-1 KRAS G12V mutation KRAS NCBI:3845 gene cancer DOID:162 risk 21702-6 PubMed:25232318 Case report of a 59-year-old white female patient (60 pack-years) with a CUP-syndrome. Molecular profiling identified both MET amplification (16 copies) and a KRAS G12V mutation. The patient was treated with crizotinib and experienced a complete normalization of tumor metabolic activity for more than 19 months. Other identified aberrations include CCND1 amplification (8 copies), MYC amplification (9 copies) as well as KRAS G12V, TP53 R273L and CARD11 N184S. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12V sequence variation in gene KRAS/NCBI:3845 1821 check_entity AN5337-1 KRAS G12V mutation KRAS NCBI:3845 gene cancer DOID:162 risk 21702-6 CIViC:421 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12V sequence variation in gene KRAS/NCBI:3845 1821 check_entity AN5337-2 KRAS G12V mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:20978259 Cells harboring KRAS G12V mutation were insensitive to cetuximab treatment in isogenic SW48 cells and in a mouse xenograft model. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12V sequence variation in gene KRAS/NCBI:3845 1822 check_entity AN5337-2 KRAS G12V mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:22392911 In 28 out of 40 (70%) metastatic colorectal cancer tumors harboring KRAS, NRAS, BRAF, or PIK3CA mutations and implanted into mice, the therapeutic combination of the MEK inhibitor AZD6244 and the PI3K/mTor inhibitor BEZ235 resulted in disease stabilization. Mean tumor growth was lower in the tumors treated with AZD6244+ BEZ235 (+77% vs. +267%, P=1E-6) compared to AZD6244 alone and (+77% vs. +222%, P=0.0014) BEZ235 alone. 32/40 tumors harbored KRAS mutations including 8 G12V mutations (3 with PIK3CA mutations) where progressive disease occurred in only 1 tumor upon doublet treatment but 6 tumors in monotherapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12V sequence variation in gene KRAS/NCBI:3845 1822 check_entity AN5337-2 KRAS G12V mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:20619739 This was a retrospective study of 691 cetuximab treated patients with metastatic colorectal cancer. Of those, 39 patients harbored KRAS G12V, were BRAF, NRAS and PIK3CA wt, and had individual response data. Three patients had partial response, 16 had stable disease, and 20 progressed. Treatments included cetuximab + irinotecan (n=30), cetuximab + FOLFIRI (n=2), cetuximab monotherapy (n=2), cetuximab + oxaliplatin + 5FU (n=2), cetuximab + 5FU (n=1), cetuximab + irinotecan + oxaliplatin + 5FU + bevacizumab (n=1), and cetuximab+irinotecan+oxaliplatin+5FU (n=1). Median PFS was 12 weeks (1-37 weeks), median OS was 32 weeks (4-77 weeks), and median number of previous chemotherapy lines was 2 (0-5). Median age was 63 years old (34-76), and there were 21 males and 18 females. Authors concluded that KRAS mutation was strongly associated with poor response to cetuximab and suggested that mutation status of KRAS is the most informative compared to BRAF, NRAS, and PIK3CA exon 20 for predicting cetuximab response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12V sequence variation in gene KRAS/NCBI:3845 1822 check_entity AN5337-2 KRAS G12V mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:18316791 In a retrospective study of 427 metastatic colorectal patients, KRAS mutations were observed in 43% of the tumor samples. Patients with mutations in codon 12 or 13 of KRAS were associated with reduced response to panitumumab compared to wildtype KRAS (HR:0.99, 95% CI:0.73-1.36 vs. HR:0.45, 95% CI:0.34-0.59; P<0.0001). Additionally, patients with KRAS mutations showed no significant improvement between treatment with panitumumab and best supportive care alone (PFS: 7.4 wk vs 7.3 wk). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12V sequence variation in gene KRAS/NCBI:3845 1822 check_entity AN5337-2 KRAS G12V mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:26161928 In an in vitro study, a human colon adenocarcinoma SW48 cell line expressing KRAS G12V mutation demonstrated resistance to regorafenib treatment (IC50: 241.90 nM vs. 114.28 nM, P<0.01) compared to SW48 cells expressing KRAS wildtype. Resistance was determined by assessing cell viability. Regorafenib significantly reduced BRAF, Erk1/2 and Elk phosphorylation compared to wildtype, as assessed by western blot. Authors concluded that KRAS G12A was more resistant to regorafenib than KRAS wt, and intermediately resistant compared to other common KRAS mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12V sequence variation in gene KRAS/NCBI:3845 1822 check_entity AN5337-2 KRAS G12V mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:19223544 In this study, a large cohort of metastatic colorectal cancer patients were treated with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). KRAS, PIK3CA, and PTEN were tested for mutation; KRAS G12V was the only variant noted in the primary rectal tumor of one patient who experienced disease progression (patient 56; Supplemental Table 1), and the primary colon tumors of two patients (9, 13; Supplemental Table 1) who experienced stable disease following treatment. In the larger cohort, patients with tumors harboring any KRAS mutation had significantly decreased incidence of objective response than patients with wtKRAS tumors. Authors noted that patients with tumors harboring KRAS mutations tended to have decreased PFS and OS compared to those with wild-type tumors though the differences were not statistically significant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12V sequence variation in gene KRAS/NCBI:3845 1822 check_entity AN5337-2 KRAS G12V mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 CIViC:421 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12V sequence variation in gene KRAS/NCBI:3845 1822 check_entity AN5337-3 KRAS G12V mutation KRAS NCBI:3845 gene lung cancer DOID:1324 risk 21702-6 PubMed:17409929 In recurrent lung cancer patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib, patients with KRAS mutations had a lower frequency of partial response (PR) and stable disease (SD) and a higher rate of progressive disease (PD) (PR:0, SD:1, PD:15 vs. PR:24, SD:8, PD:14; P=0.0274) compared to wildtype KRAS patients. Patients with KRAS mutations also had a shorter overall survival compared to wildtype KRAS patients (HR:2.542, 95% CI:1.048-6.168, P=0.0390). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12V sequence variation in gene KRAS/NCBI:3845 1823 check_entity AN5337-3 KRAS G12V mutation KRAS NCBI:3845 gene lung cancer DOID:1324 risk 21702-6 CIViC:421 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12V sequence variation in gene KRAS/NCBI:3845 1823 check_entity AN5337-4 KRAS G12V mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 PubMed:20609353 In vivo studies confirmed the activity of PD0332991 (CDK4 inhibitor) on KRAS G12V mutant tumors. 17% (2/12) of mice treated with PD0332991 developed detectable lesions, whereas 75% of mice (3/4) treated with vehicle developed lesions at the end of the treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12V sequence variation in gene KRAS/NCBI:3845 1824 check_entity AN5337-4 KRAS G12V mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 PubMed:26372703 Retrospective analysis of data from 841 patients who underwent surgery and molecular testing for NSCLC. Mutant KRAS was observed in 265 (31.5%) cases and 90 of these were G12V. Patients with KRAS G12V exhibited worse OS and TTR compared with the entire cohort. These results were confirmed using multivariate analyses (non-G12V status, hazard ratio (HR): 0.43 (confidence interval: 0.28–0.65), P<0.0001 for OS. Risk of recurrence was significantly lower for non-KRAS G12V (HR: 0.01, (0.001–0.08), P<0.0001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12V sequence variation in gene KRAS/NCBI:3845 1824 check_entity AN5337-4 KRAS G12V mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 PubMed:26125448 83 patients from a phase II trial (docetaxel + placebo or selumetinib) with KRAS mutant tumors were retrospectively assessed for differences in OS, PFS, ORR and change in tumor size at week 6 according to type of KRAS mutation. G12C, G12D and G12V were the most common mutations (46%, 22%, 11%, respectively). Patients with G12C or G12V mutations receiving combination selumetinib and docetaxel had a trend towards longer OS, PFS and ORR compared to other KRAS mutations. Changes in tumor size were similar between groups with the best responses in tumors with G12V mutations. Few differences were observed between groups when treated with docetaxel + placebo. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12V sequence variation in gene KRAS/NCBI:3845 1824 check_entity AN5337-4 KRAS G12V mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 CIViC:421 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12V sequence variation in gene KRAS/NCBI:3845 1824 check_entity AN5338-1 KRAS G13 mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 prognostic 21702-6 PubMed:18528420 In a retrospective study of 439 patients with multiple myeloma enrolled in a clinical trial, 28 had mutations in KRAS (22/28 in G12/G13). Those with KRAS (but not NRAS) mutations had worse overall (median 19.9 vs 44.3 months, p=0.005) and progression free survival (median 14.7 vs 30.3 months, p<0.001) than those without mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13 sequence variation in gene KRAS/NCBI:3845 1825 check_entity AN5338-1 KRAS G13 mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 prognostic 21702-6 CIViC:80 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13 sequence variation in gene KRAS/NCBI:3845 1825 check_entity AN5339-1 KRAS G13D mutation KRAS NCBI:3845 gene breast cancer DOID:1612 risk 21702-6 PubMed:20453058 This preclinical study tested the efficacy on several breast cancer cell lines of GDC-0941 (pictilisib), a selective inhibitor of all four isoforms of class I PI3-kinases over a range of IC50 values. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. MDA-MB-231 is a basal-type breast cancer cell line which harbors KRAS G13D, and it had an ICD50 of 20uM. To evaluate in vivo efficacy, cells were injected in the mammary fat pad of SCID mice and allowed to grow. Mice injected with MDA-MB-231 and treated with pictilisib saw no reduction in tumor volume compared to untreated control. There was no effect on G1 arrest in pictilisib treated cells; however, phosphorylated AKT (S473) was substantially reduced following pictilisib. Authors note that basal breast cancer cell lines were generally more resistant to pictilisib than luminal lines (p=0.02), and concluded that this cell line was resistant to pictilisib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13D sequence variation in gene KRAS/NCBI:3845 1826 check_entity AN5339-1 KRAS G13D mutation KRAS NCBI:3845 gene breast cancer DOID:1612 risk 21702-6 CIViC:81 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13D sequence variation in gene KRAS/NCBI:3845 1826 check_entity AN5339-2 KRAS G13D mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:20978259 Cells harboring KRAS G13D mutation were sensitive to cetuximab treatment in isogenic SW48 cells and in a mouse xenograft model. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13D sequence variation in gene KRAS/NCBI:3845 1827 check_entity AN5339-2 KRAS G13D mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:26623049 This is a retrospective analysis of 98 patients with metastatic colorectal cancer and KRAS mutations. 23 (23.5%) had KRAS p.G13D-mutated tumors. Of the 98 patients, 31 patients received cetuximab, of these, 9 (29.0%) had KRAS p.G13D mutations. Univariate analysis did not show any differences between these groups. Multivariate analysis showed a trend towards better PFS among patients with a G13D mutation (PFS: HR=0.29; 95% CI: 0.08-1.10; P=0.07; OS: HR=0.23; 95% CI: 0.04-1.54; P=0.13). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13D sequence variation in gene KRAS/NCBI:3845 1827 check_entity AN5339-2 KRAS G13D mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:26371285 12 patients with KRAS G13D mutant, metastatic colorectal cancer were treated with single agent cetuximab in a prospective phase II study. The primary endpoint of the trial was 4-month progression-free survival, with a benefit to treatment evaluated to be 50% of patients were progression free at this point. None of 12 patients achieved response by RECIST 1.1 criteria and three patients (25%) were progression-free at 4 months, with disease control rate at 6 months reaching 0%. Median PFS and OS were 1.9 (95% CI 1.7–3.8) and 7.2 months (95% CI 5.7–9.7). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13D sequence variation in gene KRAS/NCBI:3845 1827 check_entity AN5339-2 KRAS G13D mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:26812186 Meta-analysis encompassing eight randomized controlled trials (n = 5967) for assessment of both overall survival (OS) and progression-free survival (PFS) of patients with KRAS mutant metastatic colorectal cancer. For other KRAS MT the hazard ratio for OS benefit with addition of anti-EGFR mAb therapy was 1.06 (95% confidence interval [CI]; 0.96, 1.17), compared to 1.08 (95% CI; 0.73, 1.60) for KRAS G13D [test for interaction p=0.99]. In contrast, the hazard ratio for KRAS wild-type (WT) tumours was 0.85 (95% CI; 0.76, 0.95). Regarding PFS benefit with anti-EGFR mAbs, the hazard ratio was 1.07 (95% CI; 0.92, 1.26) for other KRAS MT, 0.96 (95% CI; 0.73, 1.27) for KRAS G13D, and 0.68 (95% CI; 0.54, 0.85) for KRAS wild-type. Again, the test for interaction (p=0.46) demonstrated no significant difference in PFS benefit for anti-EGFR mAb therapy between KRAS G13D and other KRAS MT. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13D sequence variation in gene KRAS/NCBI:3845 1827 check_entity AN5339-2 KRAS G13D mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:20619739 Three patients participating in a large retrospective study of EGFR monoclonal antibodies in metastatic, treatment refractory colorectal cancer had tumors which harbored KRAS G13D, were wildtype for NRAS, BRAF and PIK3CA, and had individual response data. All three patients were males treated with panitumumab monotherapy. Their characteristics are as follows: 51 year old who experienced progressive disease (PFS: 8 weeks; OS: 24 weeks) and had three prior lines of chemotherapy; 54 year old who experienced progressive disease (PFS: 8 weeks; OS: 17 weeks) and had two prior lines of chemotherapy; 52 year old who experienced stable disease (PFS: 12 weeks; OS: 46 weeks) and had two prior lines of chemotherapy. Per the authors criteria, the clinical benefit rate is 1/3 and the response rate is 0/3. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13D sequence variation in gene KRAS/NCBI:3845 1827 check_entity AN5339-2 KRAS G13D mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:22392911 In 28 out of 40 (70%) metastatic colorectal cancer tumors harboring KRAS, NRAS, PIK3CA or BRAF mutations and implanted into mice, the therapeutic combination of the MEK inhibitor AZD6244 and the PI3K/mTor inhibitor BEZ235 resulted in disease stabilization. Mean tumor growth was lower in the tumors treated with AZD6244+ BEZ235 (+77% vs. +267%, P=1E-6) compared to AZD6244 alone and (+77% vs. +222%, P=0.0014) BEZ235 alone. 32/40 mice harbored KRAS mutations including 5 G13D mutations where disease stabilization was achieved in 2/5 mice treated with AZD6244 or combination therapy and 0/5 mice treated with BEZ235 alone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13D sequence variation in gene KRAS/NCBI:3845 1827 check_entity AN5339-2 KRAS G13D mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:22722830 In an in vitro study, a Lim1215 colorectal cancer cell line endogenously expressing KRAS G13D mutation demonstrated resistance to cetuximab treatment, compared to Lim1215 parental cells expressing wild-type KRAS. Resistance was determined by assessing cell viability. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13D sequence variation in gene KRAS/NCBI:3845 1827 check_entity AN5339-2 KRAS G13D mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:25666295 In a retrospective study of 148 treatment naive metastatic colorectal cancer patients, patients with RAS mutations (n=10), including KRAS A146T, KRAS G13D, NRAS G12D and NRAS Q179*, treated with FOLFOX4 plus cetuximab were associated with decreased overall survival (16.3mo vs. 28.5mo, HR:0.43, 95% CI:0.20-0.89, P=0.020) and decreased progression free survival (7.2mo vs. 9.7mo, HR:0.56, 95% CI:0.27-1.16, P=0.11), as compared to patients with wild-type KRAS and NRAS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13D sequence variation in gene KRAS/NCBI:3845 1827 check_entity AN5339-2 KRAS G13D mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:26161928 In an in vitro study, a human colon adenocarcinoma SW48 cell line expressing KRAS G13D mutation demonstrated resistance to regorafenib treatment (IC50: 172.23 nM vs. 114.28 nM, P<0.01) compared to SW48 cells expressing KRAS wild-type. Resistance was determined by assessing cell viability. Authors concluded that KRAS G13D is more resistant to regorafenib than KRAS wt, but more sensitive than common KRAS G12 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13D sequence variation in gene KRAS/NCBI:3845 1827 check_entity AN5339-2 KRAS G13D mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:19223544 In this study, a large cohort of metastatic colorectal cancer patients were treated with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). KRAS, PIK3CA, and PTEN were tested for mutation; KRAS G13D was the only variant noted in the primary colon tumors of two patients who experienced partial response following treatment (Patients 37, 47; Supplemental Table 1). In the larger cohort, patients with tumors harboring any KRAS mutation had significantly decreased incidence of objective response than patients with wtKRAS tumors. Authors noted that patients with tumors harboring KRAS mutations tended to have decreased PFS and OS compared to those with wild-type tumors though the differences were not statistically significant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13D sequence variation in gene KRAS/NCBI:3845 1827 check_entity AN5339-2 KRAS G13D mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 CIViC:81 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13D sequence variation in gene KRAS/NCBI:3845 1827 check_entity AN5340-1 KRAS G13V mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:19223544 In this study, a large cohort of metastatic colorectal cancer patients were treated with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). KRAS PIK3CA and PTEN were tested for mutation; KRAS G13V was the only variant noted in the primary colon tumor of one patient who experienced disease progression (Patient 4; Supplemental Table 1) following treatment. In the larger cohort, patients with tumors harboring any KRAS mutation had significantly decreased incidence of objective response than patients with wtKRAS tumors. Authors noted that patients with tumors harboring KRAS mutations tended to have decreased PFS and OS compared to those with wild-type tumors though the differences were not statistically significant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13V sequence variation in gene KRAS/NCBI:3845 1828 check_entity AN5340-1 KRAS G13V mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 CIViC:1425 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13V sequence variation in gene KRAS/NCBI:3845 1828 check_entity AN5341-1 KRAS Mutation KRAS NCBI:3845 gene cancer DOID:162 risk 21702-6 PubMed:22169769 In this screen of 218 solid cancer cell lines, KRAS and BRAF mutations were predictive of response to MEK inhibitor GSK1120212. 40 cell lines harbored a KRAS mutation. In RAF/RAS mutant colon cancer cell lines, co-occurring PIK3CA/PTEN mutations led to a cytostatic (9/10 cell lines) response rather than a cytotoxic response (1/10 cell lines). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1829 check_entity AN5341-1 KRAS Mutation KRAS NCBI:3845 gene cancer DOID:162 risk 21702-6 PubMed:23934108 Preclinical study analyzing the differential response to MEK Inhibitors in KRAS and BRAF mutant cancer cell lines and mouse xenografts. Efficacy of MEK inhibitors (GDC-0623 and G-573) in KRAS-driven tumours is mediated by a hydrogen-bond interaction with S212 in MEK that is critical for blocking MEK feedback phosphorylation by wild-type RAF. This mechanism was distinct from GDC-0973 which is less potent in KRAS mutant tumors. Overall, this work indicates that MEK inhibitors with this mechanism of action will be most effective in patients with both BRAF and KRAS mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1829 check_entity AN5341-1 KRAS Mutation KRAS NCBI:3845 gene cancer DOID:162 risk 21702-6 PubMed:26881434 CDK1 was identified in a preclinical siRNA screen to identify targets in KRAS mutant tumors. Cell viability was evaluated following knockdown of 834 genes in isogenic LIM1215 colorectal cancer cell lines harboring wildtype (parental), G12S, G12D or G12V KRAS. 6 targets identified by this screen were evaluated in a second set of isogenic colorectal cancer cell lines (SW48) harboring wildtype (parental), G12S, G12D, G12V or G13D KRAS where only CDK1 knockdown more profoundly reduced survival in mutant cells compared to wildtype. Results were validated in 5 KRAS mutant (BRAF WT) and 10 KRAS WT colorectal cancer cell lines. Chemical inhibition of CDK1 by AZD5438 in KRAS mutant vs WT pancreatic and colorectal cancer cell lines showed increased efficacy in mutant cell lines. Finally, AZD5438 reduced tumor growth induced by SW620 (KRAS p.G12V) colorectal tumour cells xenografted into immunodeficient mice. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1829 check_entity AN5341-1 KRAS Mutation KRAS NCBI:3845 gene cancer DOID:162 risk 21702-6 PubMed:35363510 In this phase II study of the arm E of the NCI-COG pediatric MATCH trial, 20 patients (median age: 14) were treated with Selumetinib. High-grade glioma (n=7) and rhabdomyosarcoma (n=7) were the most common types of cancers in this cohort. There was no objective response (PR or CR), the best overall response being SD, in three patients. The 6-month PFS rate was 15% (95% CI; 4-34). 25% of the patients had grade 3 or higher AEs, possibly attributed to selumetinib treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1829 check_entity AN5341-1 KRAS Mutation KRAS NCBI:3845 gene cancer DOID:162 risk 21702-6 CIViC:332 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1829 check_entity AN5341-1 KRAS Mutation KRAS NCBI:3845 gene cancer DOID:162 risk 21702-6 CIViC:4715 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1829 check_entity AN5341-1 KRAS Mutation KRAS NCBI:3845 gene cancer DOID:162 risk 21702-6 CIViC:4748 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1829 check_entity AN5341-2 KRAS Mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:21890455 TLR9 agonist immunomodulatory oligonucleotide (IMO) led to inhibited survival of LS174T colorectal cancer and AsPC1 pancreatic cancer cell lines with KRAS mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1830 check_entity AN5341-2 KRAS Mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:20956938 Combined treatment with dasatinib and cetuximab, but not either agent in monotherapy, had an antitumor efficacy in-vitro and in xenografts. These results were based on three KRAS mutant cell lines (LS180, LoVo and HCT116) and two KRAS wild-type cell lines (SW48 and CaCo2). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1830 check_entity AN5341-2 KRAS Mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:25199829 SiRNA Screening in 37 KRAS Mutant colorectal cancer cell lines identified RAF1 and MEK Inhibition as synergistic, whereas MEK Inhibition alone led to quick resistance via upregulation of RAF-signalling. This finding could be reproduced in colorectal and lung cancer cell lines in a second, independent screen. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1830 check_entity AN5341-2 KRAS Mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:24685132 An shDNA Screen identified synergy betwenn ERBB3 Inhibition and MEK Inhibition in KRAS mutated cell lines. Dual EGFR/ERBB2 Inhibitors afatinib and dacomitinib and MEK Inhibition was synergistic in colorectal and lung cancer cell lines. Induction of ERBB3 signalling was also identified in a patient with KRAS mutation after MEK inhibition with trametinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1830 check_entity AN5341-2 KRAS Mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:24947927 Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655). All 25 patients with KRAS mutant colorectal cancer experienced PD. Median days on treatment was 57 (5-269). Among the patients with KRAS mutant cancer, 52% showed decrease in metabolic response (less FDG uptake in FDG-PET analysis). There was not a significant decrease in Ki67 expression between day 1 and day 15 of treatment. The authors concluded that RO4987655 does not have clinical activity in patients with KRAS mutant advanced colorectal cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1830 check_entity AN5341-2 KRAS Mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:23434733 Phase I trial of the mitogen-activated protein kinase 1/2 inhibitor BAY 86-9766. 4 patients with KRAS +/- PIK3CA mutant colorectal cancer. 3 with SD, 1 with PD. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1830 check_entity AN5341-2 KRAS Mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:21985784 Preclinial data from KRAS mutant colorectal cancer cell lines show syngergistic effect on cell viability and apoptosis in vitro and in vivo when MEK and IGF-IR are inhibited concomitantly. In other cell lines, activation of other RTKs (such as MET) were observed upon MEK Inhibition and combination of RTKi and METi also showed synergistic activity. A total of 16 cell lines were used in this study. 6 were KRAS wild type, and 10 harbored various KRAS mutations (G12C, G12D, G12V, G13D, and Q61L). Additional data was obtained from xenografts. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1830 check_entity AN5341-2 KRAS Mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:23828442 Meta-Analysis of 12 studies with 2,266 patients (54 % were KRAS wt). The pooled response rates (RR) for KRAS wild-type (wt) versus mutated (mut) patients were 54.8 and 48.3 %, respectively (OR 1.42, P = 0.02). Median PFS in KRAS wild-type patients was significantly longer than in KRAS mut patients (HR = 0.85; 95 % confidence interval (CI) 0.74-0.98; P = 0.02). Median OS in wild-type KRAS patients compared was significantly better than in KRAS mut patients (HR = 0.65; 95 % CI 0.46-0.92; P = 0.01). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1830 check_entity AN5341-2 KRAS Mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:26709701 Preclinical study in colorectal cancer xenografts. KRAS-G13D or KRAS-G12V mutations were introduced into KRAS-WT SW48 cell line. KRAS wild-type, but not KRAS mutant tumors were sensitive to proteasome inhibitor ixazomib assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1830 check_entity AN5341-2 KRAS Mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:22586653 A cohort of patient-derived xenografts (PDX) from 85 patients with metastatic colorectal cancer was created. PDX were treated with cetuximab and mechanisms of resistance investigated. None of the xenografts harboring KRAS (N=18), NRAS (N=7) or BRAF (N=3) mutations showed a response to cetuximab whereas 1 out of 4 xenografts with a PIK3CA mutation responded to cetuximab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1830 check_entity AN5341-2 KRAS Mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:20619739 This was a retrospective study of 605 patients with metastatic, chemotherapy refractory colorectal cancer treated with cetuximab + chemotherapy. Patients with KRAS mutant tumors (total [n = 253], codon 12 [n=183], 13 [n=47], 59 [n=1], 61 [n=13], 146 [n=9]) had a significantly lower response rate (17/253; 6.7%) compared to patients with KRAS wt tumors (126/352; 35.8%; OR: .13; P < .0001). Patients with KRAS mutant tumors also experienced significant lower disease control rate, shorter median progression free survival and overall survival. Association between KRAS mutation status and outcome was confirmed in multivariate analysis. Authors note that these patients were treated with cetuximab prior to widespread adoption of regular KRAS mutational status screening. Patients treated with cetuximab or panitumumab monotherapy were not included. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1830 check_entity AN5341-2 KRAS Mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:26666244 A phase I study to determine the tolerability and pharmacokinetics of Selumetinib and Cetuximab with an expanded cohort in KRAS-mutant CRC. In the KRAS-mutant CRC dose expansion cohort 14 patients were evaluable for response. Five patients experienced stable disease, nine had progressive disease. Minimal anti-tumor activity was observed in KRAS-mutant refractory metastatic CRC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1830 check_entity AN5341-2 KRAS Mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:27167191 A preclinical study to investigate the efficacy of Binimetinib, Palbociclib and the combination on KRAS mutant colorectal cancer cell lines, cell line-derived and patient-derived xenografts. The combination of MEK and CDK4/6 inhibition inhibited cancer cell growth and caused cell regression in a synergistic manner Combination therapy markedly decreased levels of phosphorylated ribosomal protein S6 both in vitro and in vivo and decreased Ki67 staining in vivo. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1830 check_entity AN5341-2 KRAS Mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:28275037 NCCN guidelines indicate colorectal cancer patients with KRAS mutations should not be treated with the anti-EGFR therapies cetuximab or panitumumab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1830 check_entity AN5341-2 KRAS Mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 CIViC:332 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1830 check_entity AN5341-3 KRAS Mutation KRAS NCBI:3845 gene endometrial cancer DOID:1380 risk 21702-6 PubMed:24166148 94 endometrial cancer samples of women who had been treated with single agent mTOR inhibitors temsirolimus or ridaforolimus were retrospectively analyzed. Mutations were found in 32 of 73 analyzed tumors, 10 of which were KRAS mutations. No predictive biomarkers were identified, including PIK3CA mutations, KRAS mutations or PTEN loss. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1831 check_entity AN5341-3 KRAS Mutation KRAS NCBI:3845 gene endometrial cancer DOID:1380 risk 21702-6 CIViC:332 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1831 check_entity AN5341-4 KRAS Mutation KRAS NCBI:3845 gene hepatocellular carcinoma DOID:684 risk 21702-6 PubMed:25294897 Phase 2 study in Asian patients with unresectable hepatocellular carcinoma. 70 patients received refametinib (BAY 86-9766) plus sorafenib as study treatment. A retrospective biomarker analysis was performed in 69 patients for KRAS, NRAS and BRAF mutations (BEAM technology). 4 patients were identified to harbor RAS mutations. 3 of whom still received study treatment at the cutoff date used for the final data analysis. These 3 patients had achieved confirmed PR, with duration responses ranging from 128 to 382 days. The fourth patient with a RAS mutation discontinued study treatment after 41 days on therapy due to PD. An overall of 4 (6 by modified RECIST) patients achieved PR. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1832 check_entity AN5341-4 KRAS Mutation KRAS NCBI:3845 gene hepatocellular carcinoma DOID:684 risk 21702-6 CIViC:332 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1832 check_entity AN5341-5 KRAS Mutation KRAS NCBI:3845 gene lung adenocarcinoma DOID:3910 prognostic;risk 21702-6 PubMed:21847063 In a study of 30 lung adenocarcinoma patients with documented KRAS mutations, farnesylthiosalicylic acid (Salirasib) mono-therapy resulted in no partial responses and did not improve overall survival rates compared to previously untreated patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1833 check_entity AN5341-5 KRAS Mutation KRAS NCBI:3845 gene lung adenocarcinoma DOID:3910 prognostic;risk 21702-6 PubMed:22810899 In a study of 1036 patients with lung adenocarcinoma, patients with KRAS mutations (n=241) showed worse prognosis (OS: 19 months versus 23 months; HR=1.21; P=0.048). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1833 check_entity AN5341-5 KRAS Mutation KRAS NCBI:3845 gene lung adenocarcinoma DOID:3910 prognostic;risk 21702-6 CIViC:332 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1833 check_entity AN5341-6 KRAS Mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 PubMed:25199829 SiRNA Screening in 37 KRAS Mutant colorectal cancer cell lines identified RAF1 and MEK Inhibition as synergistic, whereas MEK Inhibition alone led to quick resistance via upregulation of RAF-signalling. This finding was reproduced two NSCLC cell lines in a second, independent shRNA screen. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1834 check_entity AN5341-6 KRAS Mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 PubMed:24685132 An shDNA screen identified synergy between ERBB3 Inhibition and MEK Inhibition in KRAS mutated cell lines. Dual EGFR/ERBB2 Inhibitors afatinib and dacomitinib and MEK Inhibition was synergistic in colorectal and lung cancer cell lines. Induction of ERBB3 signalling was also identified in a patient with KRAS mutation after MEK inhibition with trametinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1834 check_entity AN5341-6 KRAS Mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 PubMed:24947927 This was a phase I expansion and pharmacodynamic study of oral MEK inhibitor RO4987655 on advanced cancer. Of 18 patients with KRAS mutant non-small cell lung cancer (NSCLC), 10 experienced clinical benefit: 2 partial responses and 8 patients experiencing stable disease for longer than 8 weeks. The median days on treatment was 58.5 (13-394) with one patient ongoing treatment at the end of the study period (56 weeks). The response rate of patients with KRAS mutant NSCLC was 11%, and 71% showed decrease in metabolic response (less FDG uptake in FDG-PET analysis). All responders showed decreases in FDG-uptake. There was not a significant decrease in Ki67 expression between day 1 and day 15 of treatment. Authors conclude that RO4987655 has some clinical activity in KRAS mutated NSCLC, though patients with KRAS wild-type NSCLC were excluded from this expansion study, so it is not possible to determine whether activity of RO4987655 in NSCLC is related to KRAS mutation status. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1834 check_entity AN5341-6 KRAS Mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 PubMed:23200175 87 patients with KRAS mutant stage IIB-IV NSCLC after first line therapy were randomly assigned (1:1) to oral selumetunib and docetaxel or docetaxel and Placebo. Median OS was 9·4 months (6·8-13·6) in selumetinib group and 5·2 months (95% CI 3·8-non-calculable) in placebo group (hazard ratio [HR] for death 0·80, 80% CI 0·56-1·14; one-sided p=0·21). Median PFS was 5·3 months (4·6-6·4) in selumetinib group and 2·1 months (95% CI 1·4-3·7) in placebo group (HR for progression 0·58, 80% CI 0·42-0·79; one-sided p=0·014). An objective response was observed in 16 (37%) patients in the selumetinib group and none in the placebo group(p<0·0001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1834 check_entity AN5341-6 KRAS Mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 PubMed:22805291 In a phase 1 clinical trial for the use of trametinib for various advanced solid tumors, 22 out of 30 NSCLC patients harbored KRAS mutations. Of those 22 patients with mutant KRAS, 8 saw reductions in tumor size ranging from 6-52% including 2 partial responses. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1834 check_entity AN5341-6 KRAS Mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 PubMed:22025157 In advanced-stage (IIIB or IV) non-small cell lung cancer patients treated with erlotinib and placebo, patients whose tumors harbored KRAS mutations (n=8) had a lower 12-week progression-free survival rate (0% vs. 37%, P=0.0390) compared to wildtype KRAS patients (n=35). Authors concluded that KRAS mutation was associated with poor response to erlotinib monotherapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1834 check_entity AN5341-6 KRAS Mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 PubMed:21258250 In a retrospective study, 166 non-small cell lung cancer (NSCLC) patients that tended to have selected characteristics known to be predictive for TKI sensitivity (i.e. women, never smokers, and patients with ADC) were treated with either gefitinib or erlotinib. KRAS mutations (n=11) were associated with lack of objective response to drug treatment (0.0% vs. 35.7%, p=0.03), no significant difference in overall survival (19.3 vs. 28.6 months, p=0.47), and shorter median time to progression (2.7 vs. 5.6 months, p=0.003) when compared to wild-type KRAS. Through multivariate analyses, it was shown that KRAS mutations were significant predictors of shorter time to progression (HR: 2.43, 95% CI: 1.23-4.79, p=0.01). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1834 check_entity AN5341-6 KRAS Mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 PubMed:28492898 A phase 3 study of selumetinib and docetaxel in KRAS mutant, previously treated NSCLC. 866 were enrolled and 510 randomized. Median progression-free survival was 3.9 months with selumetinib + docetaxel and 2.8 months with placebo + docetaxel. Median overall survival was 8.7 months with selumetinib + docetaxel and 7.9 months with placebo + docetaxel. Objective response rate was 20.1% with selumetinib + docetaxel and 13.7% with placebo + docetaxel. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1834 check_entity AN5341-6 KRAS Mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 PubMed:21969500 Analysis was performed on the placebo group (n=451) of the Phase III study SATURN using erlotinib maintenance therapy for patients with advanced NSCLC who were selected for response or stable disease after first line chemotherpy. The study was not powered for prognostic tests, but it was still found that KRAS Mutant status was a significant negative prognostic factor on progression free survival. (HR, 1.50; 95% CI, 1.06 to 2.12; P=0.20) assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1834 check_entity AN5341-6 KRAS Mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 PubMed:27217383 In this multicenter phase I study of abemaciclib, a total of 225 patients were enrolled: 33 in dose escalation and 192 in tumor-specific cohorts. Radiographic responses were achieved in previously treated patients with breast cancer, NSCLC, and melanoma. The disease control rate for the KRAS-mutant population was 55% (16/29) compared to 39% (13/33) in KRAS wildtype cohort. Stable disease lasting ≥24 weeks was achieved for 31% (9/29) with KRAS-mutant disease vs 12% (4/33) with KRAS wild-type disease. Median PFS was 2.8 months and 1.9 months for the KRAS-mutant and KRAS wild-type populations, respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1834 check_entity AN5341-6 KRAS Mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 PubMed:27876675 This phase I/Ib two-part study evaluated trametinib in combination with anticancer agents docetaxel or pemetrexed in NSCLC with and without KRAS mutations. Confirmed partial response (PR) was observed in 21% (10/47) patients receiving trametinib/docetaxel. The ORR was 18% (4 PR in 22 patients) in KRAS wild-type versus 24% (six PR in 25 patients) in KRAS-mutant NSCLC. Of the 42 patients treated with trametinib/pemetrexed, 14% (6/42) had a PR; the ORR was 17% (4/23) in KRAS-mutated NSCLC versus 11% (2/19) in KRAS wild-type NSCLC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1834 check_entity AN5341-6 KRAS Mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 PubMed:28525386 A meta-analysis of randomized trials to investigate if KRAS mutation status affects survival benefits of immune checkpoint inhibition (ICI) in patients with advanced NSCLC. Of 3 eligible studies using either nivolumab or atezolizumab, 138 patients with KRAS mutant NSCLC and 371 with KRAS wild-type were included. ICI improved overall survival over that with docetaxel in KRAS mutant, previously-treated advanced NSCLC (hazard ratio=0.64 [95% confidence interval, 0.43-0.96], P = 0.03) but not in those with KRAS wild-type tumor (HR = 0.88 [95% CI, 0.68-1.13], P = 0.30). These results suggest that KRAS mutation status may be a potential biomarker for survival benefits to ICIs. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1834 check_entity AN5341-6 KRAS Mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 PubMed:28259530 This meta-analysis of 5 studies with 752 non-small cell lung cancer patients examined the association between PD-L1 expression and KRAS mutation status. KRAS-mutant tumors were marginally more likely to be PD-L1 positive than KRAS-wild type tumors (51% vs 36%; odds ratio: 1.69; 95% CI 1.01-2.84; p = 0.045). Authors concluded that this result contributes to a theoretical basis for including PD-L1 inhibitors in combination with other molecularly targeted drugs in the treatment of patients with KRAS mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1834 check_entity AN5341-6 KRAS Mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 PubMed:25722381 In this phase II trial, trametinib or docetaxel was given to patients with advanced KRAS-mutant NSCLC. Median PFS was 12 weeks in the trametinib arm and 11 weeks in the docetaxel arm (HR 1.14; p = 0.5197). Median OS, while the data are immature, was 8 months in the trametinib arm and was not reached in the docetaxel arm (HR 0.97; P = 0.934). There were 10 (12%) partial responses (PRs) in the trametinib arm and 5 (12%) PRs in the docetaxel arm (P = 1.0000). These data suggest that trametinib is associated with similar PFS and response rates as docetaxel. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1834 check_entity AN5341-6 KRAS Mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 PubMed:26802155 38 KRAS wild-type patients were randomized to erlotinib or combination of selumetinib with erlotinib. 41 KRAS mutant patients were randomized to selumetinib or the combination. The primary end points were progression-free survival (PFS) for the KRAS wild-type cohort and objective response rate (ORR) for the KRAS mutant cohort. Median PFS in the KRAS wild-type arm was 2.4 months for erlotinib alone and 2.1 months for the combination. The ORR in the KRAS mutant group was 0% for selumetinib alone and 10% for the combination. These data suggest no difference in ORR or PFS with combination therapy of over monotherapy in KRAS mutant and KRAS wild-type advanced NSCLC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1834 check_entity AN5341-6 KRAS Mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 PubMed:26209642 222 EGFR-wt patients with advanced NSCLC were randomized to receive docetaxel or erlotinib In this study (4 patients not eligible, leaving 109 in each arm). KRAS was mutated in 25 and 26 out of 109 patients in the erlotinib and docetaxel arm, respectively. KRAS was neither prognostic nor predictive of benefit for either docetaxel or erlotinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1834 check_entity AN5341-6 KRAS Mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 PubMed:20038723 Of the 275 patients assessable for KRAS mutation status, 49 (18%) were positive for KRAS mutation. There were no differences between treatments in OS, PFS, or response rates according to KRAS mutation status, and no evidence that KRAS mutation is a predictive factor for a differential survival effect between gefitinib and docetaxel. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1834 check_entity AN5341-6 KRAS Mutation KRAS NCBI:3845 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21702-6 CIViC:332 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1834 check_entity AN5341-7 KRAS Mutation KRAS NCBI:3845 gene melanoma DOID:1909 risk 21702-6 PubMed:24265155 In a retrospective study of 44 relapsed melanoma patients harboring BRAF V600E or V600K (known BRAF inhibitor sensitizing mutations), MAPK pathway reactivation mechanisms were implicated in acquired resistance to BRAF inhibitor (vemurafenib or dabrafenib) monotherapy. The following MAPK pathway variants were found in progressive tumors with patient matched baseline tumors (some patients donated samples from multiple geographically/temporally distinct progressive tumors): NRAS mutations (G12D, G12R, G13R, Q61K, Q61R, Q61L) in 13/71 (18%) of progressive tumors, KRAS mutations (G12C, G12R, Q61H) in 5/71 (7%) of progressive tumors, mutant BRAF amplification (2-15 fold or 4-75 copies) in 11/57 (19%) of progressive tumors, mutant BRAF alternative splice variants (novel exon boundaries between 1/9, 1/11, 3/9) in 6/48 (13%) of progressive tumor RNA. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1835 check_entity AN5341-7 KRAS Mutation KRAS NCBI:3845 gene melanoma DOID:1909 risk 21702-6 CIViC:332 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1835 check_entity AN5341-8 KRAS Mutation KRAS NCBI:3845 gene ovarian cancer DOID:2394 risk 21702-6 PubMed:25968887 KRAS mutation or amplification predicted sensitivity to decitabine in ovarian cancer cell lines. The authors profiled the response of 45 ovarian, melanoma, and breast cancer cell lines over 9 days of treatment with decitabine. 4 ovarian lines with KRAS mutation were among the most sensitive to decitabine. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1836 check_entity AN5341-8 KRAS Mutation KRAS NCBI:3845 gene ovarian cancer DOID:2394 risk 21702-6 CIViC:332 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1836 check_entity AN5341-9 KRAS Mutation KRAS NCBI:3845 gene ovary serous adenocarcinoma DOID:5744 risk 21702-6 PubMed:32822286 Post hoc analysis of a randomized phase 3 trial (MILO/ENGOT-ov11) suggests a possible association between KRAS mutation and response to binimetinib in patients with pretreated (1-3 lines of prior chemotherapy) recurrent or persistent Low-Grade Serous Carcinomas of the Ovary, Fallopian Tube, or Primary Peritoneum. Of 133 binimetinib-treated patients with individual response and molecular data, 46 harbored KRAS mutations. KRAS mutation status was significantly associated with local best response (P=0.004); 44% of patients with KRAS mutation versus 19% of patients with KRAS WT had CR or PR in the binimetinib arm. KRAS mutation was also associated with prolonged PFS in patients treated with binimetinib (median PFS: KRAS mutant: 17.7 months; KRAS wild-type (WT): 10.8 months; P = .006), but not in patients receiving standard chemotherapy (physicians' choice, median PFS: KRAS mutant: 14.6 months; KRAS WT: 11.5 months; P=.502). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1837 check_entity AN5341-9 KRAS Mutation KRAS NCBI:3845 gene ovary serous adenocarcinoma DOID:5744 risk 21702-6 CIViC:332 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1837 check_entity AN5341-10 KRAS Mutation KRAS NCBI:3845 gene pancreatic adenocarcinoma DOID:4074 risk 21702-6 PubMed:26725216 Inhibition of ERK in 11 KRAS mutant pancreatic cancer cell lines with SCH772984 was more effective than MEK Inhibition. Combined Treatment with PI3K Inhibitor AZD8186 was more effective than either agent alone. Chemical library screen in two cell lines also identified mTOR, AKT Family Inhibitors (Temsirolimus, Everolimus) to act synergistically with ERK Inhibition. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1838 check_entity AN5341-10 KRAS Mutation KRAS NCBI:3845 gene pancreatic adenocarcinoma DOID:4074 risk 21702-6 CIViC:332 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1838 check_entity AN5341-11 KRAS Mutation KRAS NCBI:3845 gene pseudomyxoma peritonei DOID:3559 prognostic 21702-6 PubMed:27502722 40 patients with pseudomyxoma peritonei underwent panel sequencing after cytoreductive surgery and hypertermic intraperitoneal chemotherapy (HIPEC). KRAS mutations were found in 72% of samples and KRAS mutations were independently associated with PFS (p=0.012) after multivariate analysis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1839 check_entity AN5341-11 KRAS Mutation KRAS NCBI:3845 gene pseudomyxoma peritonei DOID:3559 prognostic 21702-6 CIViC:332 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene KRAS/NCBI:3845 1839 check_entity AN5342-1 KRAS Q22* mutation KRAS NCBI:3845 gene colon mucinous adenocarcinoma DOID:3029 risk 21702-6 PubMed:19661358 A 43-year-old female was diagnosed with an adenocarcinoma of the ascending colon and received 6-months of adjuvant chemotherapy. After 5 years of completion of adjuvant chemotherapy, the disease relapsed. EGFR was assessed by immunohistochemistry, and the patient was subsequently treated with the anti-EGFR monoclonal antibody panitumumab. However, there was a rapid clinical worsening, which may possibly be attributed to a somatic mutation in KRAS (Q22*). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q22* sequence variation in gene KRAS/NCBI:3845 1840 check_entity AN5342-1 KRAS Q22* mutation KRAS NCBI:3845 gene colon mucinous adenocarcinoma DOID:3029 risk 21702-6 CIViC:475 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q22* sequence variation in gene KRAS/NCBI:3845 1840 check_entity AN5343-1 KRAS Q61 mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:20619739 This was a retrospective study of 605 patients with metastatic, chemotherapy refractory colorectal cancer treated with cetuximab + chemotherapy. Patients harboring KRAS codon 61 mutations (n=13) had a significantly lower response rate than did patients with KRAS wildtype tumors (0/13 vs 123/345; p= .0055). Authors consider KRAS codon 61 mutations as supporting resistance to cetuximab and suggest that it should be included in KRAS mutation screening. Authors note that these patients were treated with cetuximab prior to widespread adoption of regular KRAS mutational status screening. Patients treated with cetuximab monotherapy were not included. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61 sequence variation in gene KRAS/NCBI:3845 1841 check_entity AN5343-1 KRAS Q61 mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 CIViC:203 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61 sequence variation in gene KRAS/NCBI:3845 1841 check_entity AN5343-2 KRAS Q61 mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 prognostic 21702-6 PubMed:18528420 In a retrospective study of 439 patients with multiple myeloma enrolled in a clinical trial, 28 had mutaions in KRAS. Those with mutations had worse overall and progression free survival than those without mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61 sequence variation in gene KRAS/NCBI:3845 1842 check_entity AN5343-2 KRAS Q61 mutation KRAS NCBI:3845 gene multiple myeloma DOID:9538 prognostic 21702-6 CIViC:203 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61 sequence variation in gene KRAS/NCBI:3845 1842 check_entity AN5344-1 KRAS Q61H mutation KRAS NCBI:3845 gene cancer DOID:162 risk 21702-6 PubMed:20147967 NIH3T3 cells were transfected with control or KRAS Q61H plasmid and focus formation assays were performed. Q61H cells formed approximately 50 foci > 5mm diameter per well, where wt cells formed none, demonstrating Q61H promotes loss of contact inhibition suggestive of oncogenic transformation of NIH3T3 cells. This evidence provides support for the OS2 ClinGen/CGC/VICC evidence code for in vitro functional assays suggesting variant oncogenicity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61H sequence variation in gene KRAS/NCBI:3845 1843 check_entity AN5344-1 KRAS Q61H mutation KRAS NCBI:3845 gene cancer DOID:162 risk 21702-6 CIViC:881 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61H sequence variation in gene KRAS/NCBI:3845 1843 check_entity AN5344-2 KRAS Q61H mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:20619739 Seven patients participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored KRAS Q61H (either c.183A > C or >T) and were wildtype for BRAF and PIK3CA mutations. A 73 year old man who was treated with cetixumab and irinotecan as a fourth line therapy experienced stable disease, with a PFS of 36 weeks and OS of 57 weeks. A 65 year old man who was treated with cetuximab and irinotecan as a 3rd line therapy experienced stable disease with a PFS of 32 weeks and an OS of 51 weeks. A 70 year old female who was treated with cetuximab, oxaliplatin and 5FU as a second line therapy experienced progressive disease after 4 weeks of treatment. A 66 year old male who was treated with cetuximab and irinotecan as a 4th line therapy experienced progression after 6 week and had an OS of 21 weeks. A 71 year old female who was treated with cetuximab and folfiri as a 3rd line therapy experienced progression after 8 weeks and had an OS of 116 weeks. A 77 year old male who was treated with cetuximab and irinotecan as a 4th line therapy experienced progression after 8 weeks and had an overall survival of 17 weeks. A 66 year old male who was treated with cetuximab and irinotecan as a 3rd line therapy experienced stable disease (11 weeks) and an OS of 14 weeks. In this study, authors considered stable disease to be non-response to treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61H sequence variation in gene KRAS/NCBI:3845 1844 check_entity AN5344-2 KRAS Q61H mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:22722830 In a colorectal cancer patient with a KRAS Q61H mutation, KRAS Q61H was reported to be refractory to cetuximab treatment. The patient was treated with cetuximab and irinotecan for 18 months, had a partial response to therapy and then experienced progressive disease with a re-biopsy of the tumor identifying a KRAS Q61H mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61H sequence variation in gene KRAS/NCBI:3845 1844 check_entity AN5344-2 KRAS Q61H mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 CIViC:881 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61H sequence variation in gene KRAS/NCBI:3845 1844 check_entity AN5345-1 KRAS Q61K mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:20619739 Two patients participating in a large retrospective trial of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored KRAS Q61K. One patient was a 61 year old female whose tumor was wildtype for BRAF and PIK3CA. This patient was treated with cetuximab, oxaliplatin, and 5FU, as a second line therapy, and experienced progressive disease 6 weeks following cetuximab administration; overall survival was 90 weeks. The other patient was a 65 year old female whose tumor was wildtype for PIK3CA. The patient was treated with cetuximab and irinotecan as a third line therapy, and experienced progressive disease 10 week following cetuximab. Both patients experienced progressive disease following treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61K sequence variation in gene KRAS/NCBI:3845 1845 check_entity AN5345-1 KRAS Q61K mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 CIViC:884 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61K sequence variation in gene KRAS/NCBI:3845 1845 check_entity AN5346-1 KRAS Q61L mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:20619739 Two patients participating in a large retrospective trial of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored KRAS Q61L. One patient, a 67 year old male, whose tumor was wildtype for BRAF and PIK3CA, was treated with cetuximab and irinotecan as a fourth line therapy. Cetuximab was discontinued due to toxicity and the patient experienced stable disease for 17 weeks and an overall survival of 23 weeks following treatment. The other patient was a 44 year old female whose tumor was wildtype for PIK3CA, BRAF and NRAS. The patient was treated with cetuximab and irinotecan as a third line therapy, and experienced progressive disease 23 weeks following treatment; overall survival was 30 weeks. Both patients experienced progressive disease following treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61L sequence variation in gene KRAS/NCBI:3845 1846 check_entity AN5346-1 KRAS Q61L mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 CIViC:882 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61L sequence variation in gene KRAS/NCBI:3845 1846 check_entity AN5347-1 KRAS Q61R mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:20619739 Two patients participating in a large retrospective trial of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored KRAS Q61R and were wild type for PIK3CA, BRAF, and NRAS. Both were treated with cetuximab and irinotecan as 3rd line treatments. One patient was a 72 year old female who experienced progressive disease 12 weeks following treatment; OS was 20 weeks. The other patient was a 43 year old female who experienced stable disease for the duration of the study and did not progress. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61R sequence variation in gene KRAS/NCBI:3845 1847 check_entity AN5347-1 KRAS Q61R mutation KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 CIViC:883 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61R sequence variation in gene KRAS/NCBI:3845 1847 check_entity AN5348-1 KRAS R164Q mutation KRAS NCBI:3845 gene cancer DOID:162 risk 21702-6 PubMed:20147967 NIH3T3 cells were transfected with control or KRAS R164Q plasmid and focus formation assays were performed. R164Q cells formed 0 foci > 5mm diameter per well, which was the same as wt cells. In contrast, known gain of function mutations KRAS G12V and G12D formed over 70 foci > 5mm diameter average per well. In conclusion, these data suggest that R164Q does not promote oncogenic transformation of NIH3T3 cells by loss of contact inhibition, and gives support for ClinGen/CGC/VICC Oncogenicity Code SBS2. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R164Q sequence variation in gene KRAS/NCBI:3845 1848 check_entity AN5348-1 KRAS R164Q mutation KRAS NCBI:3845 gene cancer DOID:162 risk 21702-6 CIViC:1181 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R164Q sequence variation in gene KRAS/NCBI:3845 1848 check_entity AN5349-1 KRAS RS61764370 mutation KRAS NCBI:3845 gene ovary epithelial cancer DOID:2152 risk 21702-6 PubMed:22139083 The functional variant rs61764370 in the KRAS gene 3' UTR (KRAS-variant) was found to be correlated with platinum-based chemotherapy resistance in patients with Epithelial Ovarian Cancer (EOC). 291 EOC patients without BRCA mutations were used in this study. Furthermore, the researchers tested a KRAS-variant EOC cell line (BG1) and found it has much greater platinum-based chemotherapy resistance than a non-KRAS-variant cell line (CAOV3). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS61764370 sequence variation in gene KRAS/NCBI:3845 1849 check_entity AN5349-1 KRAS RS61764370 mutation KRAS NCBI:3845 gene ovary epithelial cancer DOID:2152 risk 21702-6 CIViC:250 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS61764370 sequence variation in gene KRAS/NCBI:3845 1849 check_entity AN5349-2 KRAS RS61764370 mutation KRAS NCBI:3845 gene head and neck squamous cell carcinoma DOID:5520 risk 21702-6 PubMed:25081901 In the retrospective analysis of 103 HNSSC, the TG/GG rs61764370 variant was associated with poor response to cisplatin (log-rank P = 0.002).There seemed to be some improvement when cetuximab was added to their platinum-based regimen (log-rank P = 0.04). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS61764370 sequence variation in gene KRAS/NCBI:3845 1850 check_entity AN5349-2 KRAS RS61764370 mutation KRAS NCBI:3845 gene head and neck squamous cell carcinoma DOID:5520 risk 21702-6 CIViC:250 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS61764370 sequence variation in gene KRAS/NCBI:3845 1850 check_entity AN5350-1 KRAS Wildtype KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 PubMed:26161928 In an in vitro study, a human colon adenocarcinoma SW48 cell line expressing KRAS wildtype did not demonstrate resistance to regorafenib treatment (IC50: 114.28 nM) compared to SW48 cells expressing various common KRAS G12/G13 mutations. Resistance was determined by assessing cell viability. In vivo, SW48 cells were injected into NOD/SCID mice. Treatment with regorafenib did not lead to a significant delay of tumor growth, although KRAS wt mice trended toward better response than KRAS G12C expressing mice. IHC analysis of mouse tissue revealed more pronounced changes in markers of proliferation (Ki67), angiogenesis (CD31), and apoptosis (TUNEL) in KRAS wt mice treated with regorafenib compared to KRAS G12C mice whose tumors did not display changes in these markers. Authors concluded that KRAS wildtype was not resistant to regorafenib compared to other common KRAS G12/G13 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KRAS Wildtype [biomarker_term_in_review] 1851 not_mapped AN5350-1 KRAS Wildtype KRAS NCBI:3845 gene colorectal cancer DOID:9256 risk 21702-6 CIViC:3069 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition KRAS Wildtype [biomarker_term_in_review] 1851 not_mapped AN5351-1 KRT18 UNDEREXPRESSION KRT18 NCBI:3875 gene prostate cancer DOID:10283 prognostic PubMed:26892177 Comparison of nuclear matrix protein (NMP) patterns of paclitaxel-resistant PCa cells (DU145-TxR), with that of parental cell (DU145) using two-dimensional electrophoresis, identified cytokeratin 18 (CK18) as downregulated in DU145-TxR cells (validated at mRNA, NMP and total cellular protein levels). An in-vivo assay of xenograft transplantation showed higher tumorigenicity of DU145-TxR cells. Immunohistochemistry showed that CK18 expression in PCa tissues was statistically significant inversely correlated with tumor grade. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene KRT18/NCBI:3875 1852 AN5351-1 KRT18 UNDEREXPRESSION KRT18 NCBI:3875 gene prostate cancer DOID:10283 prognostic CIViC:442 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene KRT18/NCBI:3875 1852 AN5352-1 LEPR UNDEREXPRESSION LEPR NCBI:3953 gene meningioma DOID:3565 prognostic 72863-4 PubMed:26894859 144 cases (discovery set: N=62 discovery; Independent validation set: N = 82) of meningiomas were analyzed for transcriptional features defining aggressive clinical course (recurrent, malignantly progressing or WHO grade III). Meningiomas were categorized into non-recurrent (NR), recurrent (R), and tumors undergoing malignant progression (M). Unsupervised transcriptomic analysis in 62 meningiomas revealed a large set of differentially expressed genes in aggressive subgroups (R+M tumors and WHO grade III, n=332; p<0.01, FC>1.25). Multivariate analysis identified PTTG1 and LEPR mRNA expression independent of gender, WHO grade and extent of resection. The patient group with the longest PFS was characterized by co-occurrence of low PTTG1 and high LEPR mRNA expression. IHC in 36 tumors validated these results on protein level. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene LEPR/NCBI:3953 1853 AN5352-1 LEPR UNDEREXPRESSION LEPR NCBI:3953 gene meningioma DOID:3565 prognostic 72863-4 CIViC:437 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene LEPR/NCBI:3953 1853 AN5353-1 LRP1B DELETION LRP1B NCBI:53353 gene glioblastoma DOID:3068 prognostic PubMed:26428308 A retrospective study of 178 glioblastoma patients found that LRP1B deletion (complete transcript, N=4 or focal transcript deletion of >150kb, N=13) was associated with a lower progress free survival (6.4 months vs. 10.1 months; P = 0.004) and overall free survival (13.4 months vs. 17.8 months; P = 0.001). Multivariate analysis adjusting for age and type of surgery also supported LRP1B deletion being associated with a higher hazard ratio. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene LRP1B/NCBI:53353 1854 check_entity AN5353-1 LRP1B DELETION LRP1B NCBI:53353 gene glioblastoma DOID:3068 prognostic CIViC:643 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene LRP1B/NCBI:53353 1854 check_entity AN5354-1 LRP1B EXON 12-22 DELETION LRP1B NCBI:53353 gene ovarian cancer DOID:2394 risk PubMed:22896685 A minimum common region of deletion of 0.19Mb, encompassing exons 12–22 of LRP1B4 was observed in 4 patients exhibiting acquired treatment resistance. Transfection of mLRP1B4, a fully functional minigene of LRP1B, in IGROV1 and OVCAR4 ovarian cell lines with low expression of LRP1B4 increased sensitivity to liposomal doxorubicin but not doxorubicin. siRNA knockdown of LRP1B4 in JHOS3 and Kuramochi ovarian cancer cell lines decreased sensitivity to liposomal doxorubicin but not doxorubicin. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12-22:deletion sequence variation in gene LRP1B/NCBI:53353 1855 check_entity AN5354-1 LRP1B EXON 12-22 DELETION LRP1B NCBI:53353 gene ovarian cancer DOID:2394 risk CIViC:262 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12-22:deletion sequence variation in gene LRP1B/NCBI:53353 1855 check_entity AN5355-1 LYN OVEREXPRESSION LYN NCBI:4067 gene chronic myeloid leukemia DOID:8552 risk PubMed:18191450 The BCR-ABL1 expressing imatinib-resistant cell line MYL-R overexpresses LYN, an SRC family kinase. Dasatinib showed the most potency against MYL-R compared to the non-resistant MYL cell line (IC50: 6.4nM vs. 6.5 nM), while bafetinib (INNO-406) showed 3.1 times more potency than nilotinib against MYL-R (IC50: 324.1 nM vs. 993.6 nM) as compared to MYL (IC50: 87.7 nM and 84.5 nM). The authors state that this is in line with experiments showing INNO-406 specifically inhibits LYN and LCK, which may provide a more favorable side effect profile than dasatinib, that was shown to strongly inhibit all 8 SRC family kinases. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene LYN/NCBI:4067 1856 AN5355-1 LYN OVEREXPRESSION LYN NCBI:4067 gene chronic myeloid leukemia DOID:8552 risk CIViC:2786 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene LYN/NCBI:4067 1856 AN5356-1 MAGEH1 EXPRESSION MAGEH1 NCBI:28986 gene bile duct adenocarcinoma DOID:4896 risk PubMed:20088962 '10 biliary tract carcinoma cell lines were sorted based on their gemcitabine sensitivity. MAGEH1 protein expression was negatively correlated with sensitivity. In a clinical validation cohort, MAGEH protein expression was found in 4/4 ''non-effective'' cases and 2/5 effective cases based on RECIST criteria after gemcitabine treatment.' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene MAGEH1/NCBI:28986 1857 AN5356-1 MAGEH1 EXPRESSION MAGEH1 NCBI:28986 gene bile duct adenocarcinoma DOID:4896 risk CIViC:402 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene MAGEH1/NCBI:28986 1857 AN5357-1 MAP2K1 C121S mutation MAP2K1 NCBI:5604 gene melanoma DOID:1909 risk 60495-9 PubMed:21383288 A patient with BRAF-mutant melanoma relapsed after treatment with PLX4032 (vemurafenib). The MAP2K1 C121S mutation was identified as a relapse-specific variant and was undetectable in the pre-treatment tumor. In vitro experiments showed that the C121S mutation increased kinase activity and conferred resistance to PLX4032. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C121S sequence variation in gene MAP2K1/NCBI:5604 1858 check_entity AN5357-1 MAP2K1 C121S mutation MAP2K1 NCBI:5604 gene melanoma DOID:1909 risk 60495-9 CIViC:623 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C121S sequence variation in gene MAP2K1/NCBI:5604 1858 check_entity AN5358-1 MAP2K1 K57N mutation MAP2K1 NCBI:5604 gene lung adenocarcinoma DOID:3910 prognostic;risk 60495-9 PubMed:25351745 In a study of 6,024 lung adenocarcinomas, 36 conferred MEK1 mutations whereby 64% (n=23) were K57N and 19% (n=7) were Q56P. Median overall survival of MEK1-mutated tumors was not significantly different from KRAS-mutated tumors (14.9 vs 13.7 months) or BRAP-mutated tumors (14.9 vs. 20.9 months). MEK1-mutated tumors were significantly inferior compared to EGFR-mutated tumors (14.9 vs. 35.9 months; HR=2.64, p=0.01), ALK-rearranged tumors (14.9 vs. 35.9 months; HR, 2.64; P = 0.01), ROS1-rearranged tumors (14.9 vs. 76 months; HR, 4.00; P = 0.02), and RET-rearranged tumors (14.9 months vs. not reached; HR, 3.25; P = 0.03). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K57N sequence variation in gene MAP2K1/NCBI:5604 1859 check_entity AN5358-1 MAP2K1 K57N mutation MAP2K1 NCBI:5604 gene lung adenocarcinoma DOID:3910 prognostic;risk 60495-9 PubMed:18632602 Mutational profiling of 207 lung adenocarcinomas identified in 2 of with activating mutation in exon 2 of MEK1 (K57N) in the nonkinase portion of the kinase. Neither of these two tumors harbored known mutations in other genes encoding components of the EGFR signaling pathway (i.e., EGFR, HER2, KRAS, PIK3CA, and BRAF). Expression of mutant, but not wild-type, MEK1 leads to constitutive activity of extracellular signal-regulated kinase (ERK)-1/2 in human 293T cells and to growth factor-independent proliferation of murine Ba/F3 cells. A selective MEK inhibitor, AZD6244, inhibits mutant-induced ERK activity in 293T cells and growth of mutant-bearing Ba/F3 cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K57N sequence variation in gene MAP2K1/NCBI:5604 1859 check_entity AN5358-1 MAP2K1 K57N mutation MAP2K1 NCBI:5604 gene lung adenocarcinoma DOID:3910 prognostic;risk 60495-9 CIViC:1246 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K57N sequence variation in gene MAP2K1/NCBI:5604 1859 check_entity AN5359-1 MAP2K1 P124S mutation MAP2K1 NCBI:5604 gene melanoma DOID:1909 risk 60495-9 PubMed:19915144 A375 cells expressing MAP2K1 P124S mutation conferred an approximately 5-fold increased resistance to selumetinib (AZD6244) induced growth inhibition when compared to untransduced cells, cells expressing wild-type MAP2K1 or cells expressing a constitutively active form. This mutation also attenuated pERK inhibition by selumetinib in these cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P124S sequence variation in gene MAP2K1/NCBI:5604 1860 check_entity AN5359-1 MAP2K1 P124S mutation MAP2K1 NCBI:5604 gene melanoma DOID:1909 risk 60495-9 CIViC:82 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P124S sequence variation in gene MAP2K1/NCBI:5604 1860 check_entity AN5360-1 MAP2K1 Q56P mutation MAP2K1 NCBI:5604 gene melanoma DOID:1909 risk 60495-9 PubMed:19915144 A375 cells expressing MAP2K1 Q56P mutation conferred an approximately 100-fold increased resistance to selumetinib (AZD6244) induced growth inhibition when compared to untransduced cells, cells expressing wild-type MAP2K1, or cells expressing a constitutively active form. This mutation also attenuated pERK inhibition by selumetinib in these cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q56P sequence variation in gene MAP2K1/NCBI:5604 1861 check_entity AN5360-1 MAP2K1 Q56P mutation MAP2K1 NCBI:5604 gene melanoma DOID:1909 risk 60495-9 CIViC:83 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q56P sequence variation in gene MAP2K1/NCBI:5604 1861 check_entity AN5361-1 MAP2K1 Q56_V60del MAP2K1 NCBI:5604 gene ovarian serous carcinoma DOID:0050933 risk 60495-9 PubMed:26324360 Case report of a 51-year old patient with recurrent low-grade serous ovarian cancer. Selumetinib treatment in a phase-II trial led to a complete and durable response > 5 years. Sequencing (MSK-IMPACT Panel) was performed on the patients tumor and germline and identified a 15-bp in-frame deletion of MAP2K1 (8.3% of tumor reads but 0% in germline). In-silico modelling suggested loss of negative feedback on kinase activity from this deletion.In-vitro expression of the MEK1 Q56_V60 deletion as well as the previously characterized MEK1 F53L mutation in 293H cells resulted in elevated levels of phosphorylated ERK and phosphorylated ribosomal protein S6 kinase as compared with wild-type MEK1 as well as increased colony formation and tumor growth in-vivo. Selumetinib treatment of MEK1-transfected cells confirmed retained sensitivity to MEK inhibition and inhibition of colony formation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MAP2K1 Q56_V60del [biomarker_term_in_review] 1862 not_mapped AN5361-1 MAP2K1 Q56_V60del MAP2K1 NCBI:5604 gene ovarian serous carcinoma DOID:0050933 risk 60495-9 CIViC:651 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MAP2K1 Q56_V60del [biomarker_term_in_review] 1862 not_mapped AN5362-1 MAP2K7 E116K mutation MAP2K7 NCBI:5609 gene lung cancer DOID:1324 prognostic PubMed:27028764 Study examined rare SNPs on MAP2K7 among a discovery and two validation cohorts. It was discovered that the E116K genotype was associated with a reduced median survival time of 4 and 7 months for E/K or K/K genotypes (P=2.61E-7) and an increased cancer death risk for heterozygous (HR=1.49) and homozygous (HR=1.94) genotypes for a pooled cohort. Further nude mice harboring this variant showed increased xenograft growth and metastasis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E116K sequence variation in gene MAP2K7/NCBI:5609 1863 check_entity AN5362-1 MAP2K7 E116K mutation MAP2K7 NCBI:5609 gene lung cancer DOID:1324 prognostic CIViC:562 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E116K sequence variation in gene MAP2K7/NCBI:5609 1863 check_entity AN5363-1 MAPK1 Amplification MAPK1 NCBI:5594 gene lung non-small cell carcinoma DOID:3908 risk PubMed:22961667 Resistance to WZ4002 was induced in cell lines. Amplification of MAPK1 or downregulation of ERK-pathway inhibitors led to resistance to EGFR inhibition with WZ4002. Chemical inhibition (MEK inhibition with either CI-1040 or GSK1120212) or shRNA knockdown of MAPK1 resensitized cells to EGFR inhibition with WZ4002 in-vitro. Additionally, MAPK1 amplification was identified in 1/21 erlotinib-resistant NSCLC patients. MAPK1 amplification was not observed in the pretreatment tumor, only the post-treatment resistant tumor which lacked other more common drug-resistance mechanisms EGFR T790M or MET amplification. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MAPK1/NCBI:5594 1864 AN5363-1 MAPK1 Amplification MAPK1 NCBI:5594 gene lung non-small cell carcinoma DOID:3908 risk CIViC:317 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MAPK1/NCBI:5594 1864 AN5364-1 MAPK1 E322K mutation MAPK1 NCBI:5594 gene head and neck squamous cell carcinoma DOID:5520 risk PubMed:26181029 Case report of a patient with stage IVA HNSCC with near-complete histologic response after 13 days of neoadjuvant erlotinib. Whole-exome sequencing of the pre-treatment tumor revealed a MAPK1 E322K mutation (allelic fraction 0.13). In-vitro studies in two HNSCC cell lines showed enhanced EGFR phosphorylation and erlotinib sensitivity in the mutant line compared with the wild-type line. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E322K sequence variation in gene MAPK1/NCBI:5594 1865 check_entity AN5364-1 MAPK1 E322K mutation MAPK1 NCBI:5594 gene head and neck squamous cell carcinoma DOID:5520 risk CIViC:316 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E322K sequence variation in gene MAPK1/NCBI:5594 1865 check_entity AN5365-1 MDM2 EXPRESSION MDM2 NCBI:4193 gene malignant pleural mesothelioma DOID:7474 prognostic;risk PubMed:25668009 72 patients with malignant pleural mesothelioma were analyzed, MDM2 immunoexpression was assessed in 65 patients. MDM2 mRNA and protein expression correlated with poor OS and PFS for patients treated with cisplatin and pemetrexed (standard of care therapy). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene MDM2/NCBI:4193 1866 AN5365-1 MDM2 EXPRESSION MDM2 NCBI:4193 gene malignant pleural mesothelioma DOID:7474 prognostic;risk CIViC:339 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene MDM2/NCBI:4193 1866 AN5366-1 MDM2 RS34886328 mutation MDM2 NCBI:4193 gene esophagus squamous cell carcinoma DOID:3748 prognostic PubMed:27414035 124 esophageal squamous cell carcinoma patients with radical resection were genotyped using MassArray. Patients with the DEL/A +AA genotype of MDM2 rs34886328 had a notably increased overall survival (HR = 0.27, 95% CI: 0.13–0.56, P = 4.7×10−4, Pc = 0.003) and increased disease free survival (HR = 0.22, 95% CI: 0.11–0.43, P < .0001) when compared to patients without this mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS34886328 sequence variation in gene MDM2/NCBI:4193 1867 check_entity AN5366-1 MDM2 RS34886328 mutation MDM2 NCBI:4193 gene esophagus squamous cell carcinoma DOID:3748 prognostic CIViC:638 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS34886328 sequence variation in gene MDM2/NCBI:4193 1867 check_entity AN5367-1 MDM2 SNP309 mutation MDM2 NCBI:4193 gene head and neck cancer DOID:11934 prognostic PubMed:26916894 66 HNSCC patients treated with chemoradiation were assessed for survival after a follow-up time of 10 years. Median OS was significantly shorter in patients with MDM2 SNP309 GG or GT genotypes compared with the TT genotype (p = 0.002). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::snp309:mutation sequence variation in gene MDM2/NCBI:4193 1868 check_entity AN5367-1 MDM2 SNP309 mutation MDM2 NCBI:4193 gene head and neck cancer DOID:11934 prognostic CIViC:491 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::snp309:mutation sequence variation in gene MDM2/NCBI:4193 1868 check_entity AN5368-1 MEN1 FRAMESHIFT TRUNCATION MEN1 NCBI:4221 gene thyroid gland Hurthle cell carcinoma DOID:8161 diagnostic 35288-0 PubMed:25625803 Two patients diagnosed with oncocytic thyroid carcinoma (hurthle cell thyroid carcinoma) were evaluated for MEN1 mutations. One tumor showed 592-end deletion of MEN1 and the other showed a 521 frameshift mutation. These mutations are similar to the ones seen in MEN1 syndrome inducing endocrine gland tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MEN1 FRAMESHIFT TRUNCATION [biomarker_term_in_review] 1869 not_mapped AN5368-1 MEN1 FRAMESHIFT TRUNCATION MEN1 NCBI:4221 gene thyroid gland Hurthle cell carcinoma DOID:8161 diagnostic 35288-0 CIViC:663 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MEN1 FRAMESHIFT TRUNCATION [biomarker_term_in_review] 1869 not_mapped AN5369-1 MERTK OVEREXPRESSION MERTK NCBI:10461 gene melanoma DOID:1909 risk PubMed:23585477 Highest MERTK expression was observed in metastatic melanomas, followed by primary melanomas, and lowest in benign nevi. Over half of melanoma cell lines overexpressed MERTK compared with normal human melanocytes; however, overexpression did not correlate with mutations in BRAF or RAS. MERTK inhibition via shRNA reduced MERTK-mediated downstream signaling, reduced colony formation by up to 59%, and diminished tumor volume by 60% in a human melanoma murine xenograft model. Treatment of melanoma cells with UNC1062, a novel MERTK-selective small-molecule tyrosine kinase inhibitor, reduced activation of MERTK-mediated downstream signaling, induced apoptosis in culture, reduced colony formation in soft agar, and inhibited invasion of melanoma cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene MERTK/NCBI:10461 1870 AN5369-1 MERTK OVEREXPRESSION MERTK NCBI:10461 gene melanoma DOID:1909 risk CIViC:1273 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene MERTK/NCBI:10461 1870 AN5370-1 MET Amplification MET NCBI:4233 gene cancer DOID:162 risk 100026-4 PubMed:25232318 Case report of a 59-year-old white female patient (60 pack-years) with a CUP-syndrome. Molecular profiling identified both MET amplification (16 copies) and a KRAS G12V mutation. The patient was treated with crizotinib and experienced a complete normalization of tumor metabolic activity for more than 19 months. Other identified aberrations include CCND1 amplification (8 copies), MYC amplification (9 copies) as well as KRAS G12V, TP53 R273L and CARD11 N184S. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MET/NCBI:4233 1871 AN5370-1 MET Amplification MET NCBI:4233 gene cancer DOID:162 risk 100026-4 CIViC:266 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MET/NCBI:4233 1871 AN5370-2 MET Amplification MET NCBI:4233 gene colorectal cancer DOID:9256 risk 100026-4 PubMed:27325282 Case report of a patient with BRAF V600E mutant metastatic colorectal cancer. Combined EGFR and BRAF inhibition (panitumumab and vemurafenib) showed an initial partial response for 4 months. Re-biopsy at the time of progression showed a MET amplification and overexpression (IHC, ISH) but no secondary mutations in candidate resistance genes (EGFR, KRAS, NRAS, MAP2K1). MET amplification was also present in a subset of tumor cells in the pretreatment sample. MET amplification was also identified in 3/17 (18%) chemonaive BRAF V600E colorectal cancer tumor tissues. Overexpression of MET in a BRAF mutant CRC cell line (WiDr) confered resistance to combined vemurafenib and panitumumab. The addition of crizotinib to this combination restored sensitivity in vitro. The patient was started on combined vemurafenib and crizotinib in January 2016 and had a metabolic, clinical and tumor marker response that was ongoing at the time of publication (06/16) without significant toxicity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MET/NCBI:4233 1872 AN5370-2 MET Amplification MET NCBI:4233 gene colorectal cancer DOID:9256 risk 100026-4 PubMed:23729478 Functional studies show that MET activation confers resistance to anti-EGFR therapy both in vitro and in vivo. Notably, in patient-derived colorectal cancer xenografts, MET amplification correlated with resistance to EGFR blockade, which could be overcome by MET kinase inhibitors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MET/NCBI:4233 1872 AN5370-2 MET Amplification MET NCBI:4233 gene colorectal cancer DOID:9256 risk 100026-4 CIViC:266 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MET/NCBI:4233 1872 AN5370-3 MET Amplification MET NCBI:4233 gene gastric adenocarcinoma DOID:3717 risk 100026-4 PubMed:22389872 A case-study describing a patient with MET polysomy, MET over-expression and evidence of autocrine HGF-production (the growth factor ligand of MET). The patient initially achieved a complete response on MET-Inhibitor MetMAb (Onartuzumab) for 2 years and mixed response after recurrence with resistance in some of the newly developing metastases. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MET/NCBI:4233 1873 AN5370-3 MET Amplification MET NCBI:4233 gene gastric adenocarcinoma DOID:3717 risk 100026-4 CIViC:266 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MET/NCBI:4233 1873 AN5370-4 MET Amplification MET NCBI:4233 gene glioblastoma DOID:3068 risk 100026-4 PubMed:22162573 A 62 year old female was diagnosed with glioblastoma (GBM) WHO grade 4. Treatment included radiation, temozolomide and cediranib. MET amplification was found by FISH, and ALK and MET inhibitor crizotinib treatment was started. A 40% reduction in size of contrast enhancing lesion was seen. After 6 months, progressive disease was seen and crizotinib withdrawn. The authors state this is a first report of response to prospective MET targeted therapy in GBM. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MET/NCBI:4233 1874 AN5370-4 MET Amplification MET NCBI:4233 gene glioblastoma DOID:3068 risk 100026-4 CIViC:266 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MET/NCBI:4233 1874 AN5370-5 MET Amplification MET NCBI:4233 gene lung adenocarcinoma DOID:3910 risk 100026-4 PubMed:26724472 Case report of a patient with MET amplification without high-level MET/CEP7 ratio, MET exon 14 mutation or overexpression who achieved rapid response to crizotinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MET/NCBI:4233 1875 AN5370-5 MET Amplification MET NCBI:4233 gene lung adenocarcinoma DOID:3910 risk 100026-4 PubMed:23470965 155 patients with lung adenocarcinomas underwent rebiopsy and genotyping (EGFR, AKT1, BRAF, ERBB2, KRAS, MEK1, NRAS, PIK3CA and FISH for MET and HER2) after the development of acquired resistance to EGFR inhibitors (gefitinib or erlotinib). MET amplification was seen in 4 of 75 patients tested (no baseline samples available). One patient had small cell transformation and MET amplification, two patients had EGFR T790M mutation and MET amplification. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MET/NCBI:4233 1875 AN5370-5 MET Amplification MET NCBI:4233 gene lung adenocarcinoma DOID:3910 risk 100026-4 PubMed:25922291 In an evaluation of a patient with crizotinib-sensitive lung adenocarcinoma, an MET-Amplification was identified using CGP. The patient attained a reduction in the target lesions by 38.7%, and the patient maintained response for at least 5 months post-treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MET/NCBI:4233 1875 AN5370-5 MET Amplification MET NCBI:4233 gene lung adenocarcinoma DOID:3910 risk 100026-4 CIViC:266 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MET/NCBI:4233 1875 AN5370-6 MET Amplification MET NCBI:4233 gene lung non-small cell carcinoma DOID:3908 risk 100026-4 PubMed:17463250 In this study a gefitinib-sensitive cell-line (HCC827), acquired gefitinib resistance (HCC827 GR) by a focal amplification of MET. Resistance was conferred by the MET amplification driving ERBB3 (HER3)-dependent activation of PI3K. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MET/NCBI:4233 1876 AN5370-6 MET Amplification MET NCBI:4233 gene lung non-small cell carcinoma DOID:3908 risk 100026-4 PubMed:21623265 A case-study of an ALK-negative patient with MET amplification (MET/CEP7 ratio >5.0) who achieved a durable partial response to MET/ALK-inhibitor crizotinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MET/NCBI:4233 1876 AN5370-6 MET Amplification MET NCBI:4233 gene lung non-small cell carcinoma DOID:3908 risk 100026-4 PubMed:21716144 2 MET amplified NSCLC cell lines (EBC-1 and H1993), as well as 2 EGFR mutant and 2 MET and EGFR wild type cell lines were treated with ALK and MET inhibitor crizotinib, and the MET amplified cells had IC50 100 fold lower than the non MET amplified cell lines. Both crizotinib treatment and siRNA against MET increased apoptotic markers in MET amplified cells but not controls, indicating that crizotinib targeting of amplified MET was inducing the apoptotic effects. Tumors caused by MET amplified EBC-1 cells injected into mice were significantly inhibited with crizotinib treatment, while tumors from non-MET amplified cells showed no substantial effect. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MET/NCBI:4233 1876 AN5370-6 MET Amplification MET NCBI:4233 gene lung non-small cell carcinoma DOID:3908 risk 100026-4 PubMed:27664533 Case report of two patients with MET amplification (MET:CEP7 ratio ≥5) and no concomitant MET exon 14 deletion. A response to crizotinib was observed in both cases suggesting that MET amplification may predict response to this drug even in the absence of MET exon 14 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MET/NCBI:4233 1876 AN5370-6 MET Amplification MET NCBI:4233 gene lung non-small cell carcinoma DOID:3908 risk 100026-4 PubMed:26729443 64-year old female (non-smoker) was diagnosed with NSCLC. A c.3028 G->A mutation was identified in exon 14 resulting in exon 14 skipping. Further, amplification of the MET gene was observed. The patient was given crizotinib and CT scans showed a positive response after 8 weeks of treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MET/NCBI:4233 1876 AN5370-6 MET Amplification MET NCBI:4233 gene lung non-small cell carcinoma DOID:3908 risk 100026-4 CIViC:266 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MET/NCBI:4233 1876 AN5370-6 MET Amplification MET NCBI:4233 gene lung non-small cell carcinoma DOID:3908 risk 100026-4 CIViC:4366 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MET/NCBI:4233 1876 AN5370-7 MET Amplification MET NCBI:4233 gene lung squamous cell carcinoma DOID:3907 risk 100026-4 PubMed:24192513 Case report of a 73 year old patient with advanced squamous cell carcinoma of the lung that tested negative for EGFR, KRAS and PIK3CA mutations and ALK and ROS1 rearrangements. c-MET amplification was detected by FISH. Crizotinib led to a partial response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MET/NCBI:4233 1877 AN5370-7 MET Amplification MET NCBI:4233 gene lung squamous cell carcinoma DOID:3907 risk 100026-4 CIViC:266 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MET/NCBI:4233 1877 AN5371-1 MET D1228N mutation MET NCBI:4233 gene lung non-small cell carcinoma DOID:3908 risk 100026-4 PubMed:27343442 Case report of a patient with NSCLC harboring a MET exon 14 skipping mutation and initial response to crizotinib. A second biopsy at the time of progression revealed an acquired MET D1228N mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D1228N sequence variation in gene MET/NCBI:4233 1878 check_entity AN5371-1 MET D1228N mutation MET NCBI:4233 gene lung non-small cell carcinoma DOID:3908 risk 100026-4 CIViC:645 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D1228N sequence variation in gene MET/NCBI:4233 1878 check_entity AN5372-1 MET D1228V mutation MET NCBI:4233 gene lung non-small cell carcinoma DOID:3908 risk 100026-4 PubMed:27694386 Case report of a patient with lung adenocarcinoma harboring both a mutation in EGFR and an amplification of MET. After progression on erlotinib the patient was treated with combined type I MET (savolitinib) and EGFR (osimertinib) inhibition and responded. When resistance developed, a new MET kinase domain mutation, D1228V, was detected. Drug binding predictions and in vitro studies demonstrated that the D1228V mutation induces resistance to type I but not type II MET TKIs. The patient was treated with erlotinib (EGFR TKI) combined with cabozantinib, a type II MET inhibitor, and had a response which continued at the time of report (5 months). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D1228V sequence variation in gene MET/NCBI:4233 1879 check_entity AN5372-1 MET D1228V mutation MET NCBI:4233 gene lung non-small cell carcinoma DOID:3908 risk 100026-4 CIViC:776 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D1228V sequence variation in gene MET/NCBI:4233 1879 check_entity AN5373-1 MET Exon 14 Skipping Mutation MET NCBI:4233 gene cancer DOID:162 risk 100026-4 PubMed:26547802 The creation of a cell line model (HEK293) with MET exon 14 deletion (using the CRISPR/Cas9 system) led to enhanced cellular growth and sensitivity to the MET inhibitor crizotinib. MET exon 14 deletion results in an in-frame deletion in the MET protein. Recurrent splice site mutations that result in exon 14 skipping have been observed in ~3% of all lung cancers. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:14:skipping:mutation sequence variation in gene MET/NCBI:4233 1880 check_entity AN5373-1 MET Exon 14 Skipping Mutation MET NCBI:4233 gene cancer DOID:162 risk 100026-4 PubMed:25971938 MET exon 14 skipping was modelled in vitro by expressing human MET cDNA with exon 14 deletion in HEK293 cells and mouse MET with homologous exon 15 deletion in NIH3T3 cells. NIH3T3 cells expressing MET with exon 15 deletion showed dose dependent inhibition of cell proliferation upon treatment with capmatinib, with significantly lower cell survival compared to control cells. In addition, HEK293 cells expressing MET with exon 14 deletion had increased ERK phosphorylation, while NIH3T3 cells expressing mouse MET with exon 15 deletion had increased MET phosphorylation and increased anchorage-independent colony formation compared to wt MET. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:14:skipping:mutation sequence variation in gene MET/NCBI:4233 1880 check_entity AN5373-1 MET Exon 14 Skipping Mutation MET NCBI:4233 gene cancer DOID:162 risk 100026-4 CIViC:320 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:14:skipping:mutation sequence variation in gene MET/NCBI:4233 1880 check_entity AN5373-2 MET Exon 14 Skipping Mutation MET NCBI:4233 gene histiocytic and dendritic cell cancer DOID:5621 risk 100026-4 PubMed:25971938 An 84 year old never-smoker with an upper chest mass was found to have stage 3 histiocytic sarcoma. Genomic profiling discovered a MET exon 14 variant c.2888-5_2944del62, as well as TP53 p.R175H and ZMYM3 c.3008-1G>A. After four months of crizotinib treatment tumour volume had decreased by >60%, however the patient showed progression at 11 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:14:skipping:mutation sequence variation in gene MET/NCBI:4233 1881 check_entity AN5373-2 MET Exon 14 Skipping Mutation MET NCBI:4233 gene histiocytic and dendritic cell cancer DOID:5621 risk 100026-4 CIViC:320 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:14:skipping:mutation sequence variation in gene MET/NCBI:4233 1881 check_entity AN5373-3 MET Exon 14 Skipping Mutation MET NCBI:4233 gene lung adenocarcinoma DOID:3910 risk 100026-4 PubMed:25971939 We now report responses to the MET inhibitors crizotinib and cabozantinib in four patients with stage IV lung adenocarcinomas harboring mutations leading to MET exon 14 skipping. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:14:skipping:mutation sequence variation in gene MET/NCBI:4233 1882 check_entity AN5373-3 MET Exon 14 Skipping Mutation MET NCBI:4233 gene lung adenocarcinoma DOID:3910 risk 100026-4 PubMed:26729443 A single patient with a MET c.3028G>A (splice donor site of exon 14) mutation exhibited clinical sensitivity to the c-Met inhibitor crizotinib. Exon 14 skipping was detected using qRT-PCR. Response to the therapy was demonstrated by comparing CAT scans obtained before treatment to those obtained during treatment (at 2 months of crizotinib therapy). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:14:skipping:mutation sequence variation in gene MET/NCBI:4233 1882 check_entity AN5373-3 MET Exon 14 Skipping Mutation MET NCBI:4233 gene lung adenocarcinoma DOID:3910 risk 100026-4 PubMed:25971938 A patient with MET c.3028+1G>T mutation (METex14) had partial response (tumor reduction of 61%) after 13 months capmatinib. MET gene copy number was four, MET FISH 13.8 copy number, and IHC 3+. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:14:skipping:mutation sequence variation in gene MET/NCBI:4233 1882 check_entity AN5373-3 MET Exon 14 Skipping Mutation MET NCBI:4233 gene lung adenocarcinoma DOID:3910 risk 100026-4 PubMed:26845194 Case report of a patient with lung adenocarcinoma harboring a MET exon 14 skipping mutation and major response to crizotinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:14:skipping:mutation sequence variation in gene MET/NCBI:4233 1882 check_entity AN5373-3 MET Exon 14 Skipping Mutation MET NCBI:4233 gene lung adenocarcinoma DOID:3910 risk 100026-4 PubMed:25769807 In a never-smoking metastatic lung adenocarcinoma patient harboring a MET splice site mutation (c.2887-18_2887-7del12) treated with crizotinib monotherapy, was associated with a response as evident by the reduced size of tumors. Prior to identification of the MET splice site mutation, the patient was treated with stereotactic radiotherapy, palliative radiation, and a single cycle of pemetrexed; subsequently, the patient was treated with crizotinib, but progressed at 8 weeks of treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:14:skipping:mutation sequence variation in gene MET/NCBI:4233 1882 check_entity AN5373-3 MET Exon 14 Skipping Mutation MET NCBI:4233 gene lung adenocarcinoma DOID:3910 risk 100026-4 CIViC:320 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:14:skipping:mutation sequence variation in gene MET/NCBI:4233 1882 check_entity AN5373-4 MET Exon 14 Skipping Mutation MET NCBI:4233 gene lung non-small cell carcinoma DOID:3908 risk 100026-4 PubMed:160289 In a interim analysis of Phase II trial for MET exon 14 skipping NSCLC, 34 patients received MEK selective inhibitor tepotinib. 9/15 (60.0%) evaluable patients had a confirmed PR and 3 (20.0%) had SD. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:14:skipping:mutation sequence variation in gene MET/NCBI:4233 1883 check_entity AN5373-4 MET Exon 14 Skipping Mutation MET NCBI:4233 gene lung non-small cell carcinoma DOID:3908 risk 100026-4 PubMed:123413 Pts with MET exon 14-altered NSCLC were enrolled into an expansion cohort of the phase I PROFILE 1001 study (NCT00585195) and received crizotinib. Responses were assessed. By data-cut off 18 pts with MET exon 14-altered NSCLC had enrolled and 17 received treatment (15 response-evaluable). Antitumor activity per RECIST was documented in 10/15 pts: 5 with confirmed PRs and 5 with unconfirmed PRs. Median PFS could not be calculated, with no deaths or PD by the data cut-off. Treatment-related AEs were generally tolerable, and were most commonly edema, nausea, vision disorder, bradycardia, and vomiting. AEs were mostly grade 1 or 2, with one grade 3 edema, and no grade 4/5 AEs. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:14:skipping:mutation sequence variation in gene MET/NCBI:4233 1883 check_entity AN5373-4 MET Exon 14 Skipping Mutation MET NCBI:4233 gene lung non-small cell carcinoma DOID:3908 risk 100026-4 PubMed:26892698 In this case Report, a 67-year old female patient with a lung adenocarcinoma displaying a MET exon 14 donor splice site mutation (D1028N) detected using next generation sequencing. Within 5 weeks of crizotinib therapy, a partial response was observed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:14:skipping:mutation sequence variation in gene MET/NCBI:4233 1883 check_entity AN5373-4 MET Exon 14 Skipping Mutation MET NCBI:4233 gene lung non-small cell carcinoma DOID:3908 risk 100026-4 PubMed:32877583 In a phase 2 trial, a total of 364 patients with non-small cell lung cancer and MET alterations were assigned to cohorts based on prior treatment and type of MET alteration. A total of 97 patients, from cohorts 4 (pretreated) and 5b (no previous treatment), had MET exon 14 skipping mutations. Among pretreated (1-2 lines of therapy) patients with NSCLC with a MET exon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients. Overall response rate was 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously. The median duration of response was 9.7 months (95% CI, 5.6 to 13.0) for cohort 4 and 12.6 months (95% CI, 5.6 to could not be estimated) for cohort 5b. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:14:skipping:mutation sequence variation in gene MET/NCBI:4233 1883 check_entity AN5373-4 MET Exon 14 Skipping Mutation MET NCBI:4233 gene lung non-small cell carcinoma DOID:3908 risk 100026-4 CIViC:320 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:14:skipping:mutation sequence variation in gene MET/NCBI:4233 1883 check_entity AN5374-1 MET MET::ATXN7L1 mutation MET NCBI:4233 gene lung non-small cell carcinoma DOID:3908 risk 100026-4 PubMed:30339198 Case Report of a a 56-year-old female (never-smoker) patient with stage IV NSCLC. NGS revealed a MET–ATXN7L1 fusion. No additional known driver gene alterations were identified. Following progression after three months of chemotherapy [paclitaxel (135 mg/m2 days 1 and 8; carboplatin AUC = 5 day 1)], the patient received crizotinib treatment (250 mg/b.i.d. orally) and exhibited a partial response that lasted for 4 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::MET::ATXN7L1 sequence variation in gene MET/NCBI:4233 1884 check_entity AN5374-1 MET MET::ATXN7L1 mutation MET NCBI:4233 gene lung non-small cell carcinoma DOID:3908 risk 100026-4 CIViC:2763 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::MET::ATXN7L1 sequence variation in gene MET/NCBI:4233 1884 check_entity AN5375-1 MET Mutation MET NCBI:4233 gene papillary renal cell carcinoma DOID:4465 risk 100026-4 PubMed:23213094 In a retrospective analysis of 74 patients with papillary renal cell carcinoma, treated with foretinib, MET germline mutation was associated with improved response rate. A response was observed in 5 of 10 (50%) vs. 5 of 57 (8.8%) patients with and without germline MET mutations, respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene MET/NCBI:4233 1885 check_entity AN5375-1 MET Mutation MET NCBI:4233 gene papillary renal cell carcinoma DOID:4465 risk 100026-4 CIViC:319 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene MET/NCBI:4233 1885 check_entity AN5376-1 MET Overexpression MET NCBI:4233 gene skin melanoma DOID:8923 risk 100026-4 PubMed:26359985 Whole exome sequencing, transcriptome and methylome alterations in 48 melanoma samples with acquired resistance to BRAFi +/- MEKi therapy compared to patient-matched baseline melanoma tissues were analyzed. 39% of resistant melanomas were not accounted for by any validated mutational mechanism. c-MET was overexpressed in 21 of 48 (44%) resistant samples. Methylome analysis revealed three CpG clusters (C1–3) with differential methylation to be negatively correlated with differential c-MET mRNA expression. In nearly all (90%) pairwise comparisons of tumors and cell lines, differential c-MET mRNA expression could be accounted for by at least one differential CpG cluster methylation (Δβ ≥ 10% and FDR adjusted p ≤ 0.05). In contrast, only 48% displayed a concordant differential expression pattern of at least one c-MET transcription factor. In an independent study, c-MET was overexpressed in 8 of 35 (23%) MAPKi-resistant tumors from 7 of 26 (27%) patients. In two human BRAF V600E mutant cell lines, BRAFi treatment led to progressive methylation-expression changes akin to observations across MAPKi-sensitive versus resistant tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene MET/NCBI:4233 1886 AN5376-1 MET Overexpression MET NCBI:4233 gene skin melanoma DOID:8923 risk 100026-4 PubMed:23802768 FFPE tumours from patients enrolled in the BRIM2 (n = 59) and BRIM3 (n = 150) trials of vemurafenib in advanced BRAF mutant (V600E/K) melanoma were analyzed for MET expression (IHC). Pretreatment MET expression was frequent at the ≥1 + cutoff (BRIM3, 31%; BRIM2, 49%), but relatively infrequent at the ≥2 + cutoff (BRIM3, 9%; BRIM2, 19%). Retrospective subset analyses showed that, irrespective of the cutoff used or the treatment arm, MET expression did not show prognostic significance, in terms of objective response rate, progression-free survival, or overall survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene MET/NCBI:4233 1886 AN5376-1 MET Overexpression MET NCBI:4233 gene skin melanoma DOID:8923 risk 100026-4 CIViC:617 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene MET/NCBI:4233 1886 AN5376-2 MET Overexpression MET NCBI:4233 gene stomach carcinoma DOID:5517 risk 100026-4 PubMed:28958504 In this randomised, double-blind, placebo-controlled phase 3 trial, 609 patients with MET+ (expression of at least 1+ intensity on 25% or more tumor cells) gastric cancer or gastroesophageal adenocarcinoma were randomized to chemotherapy (epirubicin, cisplatin, capecitabine) with placebo or MET inhibitor rilotumumab. Study treatment was stopped early because of a higher number of deaths in the rilotumumab arm. Median overall survival was 8·8 months (95% CI 7·7-10·2) in the rilotumumab group compared with 10·7 months (9·6-12·4) in the placebo group (stratified hazard ratio 1·34, 95% CI 1·10-1·63; p=0·003). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene MET/NCBI:4233 1887 AN5376-2 MET Overexpression MET NCBI:4233 gene stomach carcinoma DOID:5517 risk 100026-4 CIViC:617 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene MET/NCBI:4233 1887 AN5376-3 MET Overexpression MET NCBI:4233 gene uveal melanoma DOID:6039 risk 100026-4 PubMed:24140933 c-MET and ligand HGF were expressed by 6 uveal melanoma cell lines in-vitro. GNA-mutant cell lines (n=3) showed stronger expression of ligand and receptor as well as more receptor phosphorylation. SiRNA mediated MET-knockdown reduced cell migration but not cell growth. Crizotinib treatment led to a decrease in cell growth and migration. At 25 nmol/L of crizotinib, only the migration of G-protein mutant cells lines and not G-protein wild type cell lines was decreased. Crizotinib did not lead to a reduction in tumor volume of two cell lines in vivo but reduced the formation of macrometastases (luciferase activity, p=0.03). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene MET/NCBI:4233 1888 AN5376-3 MET Overexpression MET NCBI:4233 gene uveal melanoma DOID:6039 risk 100026-4 PubMed:25952648 In this study the authors screened for growth factors that elicited resistance in newly characterized metastatic uveal melanoma cell lines to clinical-grade MEK inhibitors, trametinib and selumetinib, showing that neuregulin 1 (NRG1) and hepatocyte growth factor (HGF) provide resistance to MEK inhibition. Trametinib enhances the responsiveness to NRG1 and sustained HGF-mediated activation of AKT. Targeting ERBB3 and cMET could overcome resistance to trametinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene MET/NCBI:4233 1888 AN5376-3 MET Overexpression MET NCBI:4233 gene uveal melanoma DOID:6039 risk 100026-4 CIViC:617 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene MET/NCBI:4233 1888 AN5377-1 MET R1004G mutation MET NCBI:4233 gene head and neck cancer DOID:11934 risk 100026-4 PubMed:31391294 A patient with platinum-refractory oral cavity head and neck squamous carcinoma underwent comprehensive genomic profiling that identified an activating MET R1004G mutation. The patient showed a rapid response to the treatment of crizotinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R1004G sequence variation in gene MET/NCBI:4233 1889 check_entity AN5377-1 MET R1004G mutation MET NCBI:4233 gene head and neck cancer DOID:11934 risk 100026-4 CIViC:2643 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R1004G sequence variation in gene MET/NCBI:4233 1889 check_entity AN5378-1 MET Splice Site (c.3028G>A) MET NCBI:4233 gene lung non-small cell carcinoma DOID:3908 risk 100026-4 PubMed:26729443 64-year old female (non-smoker) was diagnosed with NSCLC. A c.3028 G->A mutation was identified in exon 14 resulting in exon 14 skipping. Further, amplification of the MET gene was observed. The patient was given crizotinib and CT scans showed a positive response after 8 weeks of treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.3028G>A) sequence variation in gene MET/NCBI:4233 1890 check_entity AN5378-1 MET Splice Site (c.3028G>A) MET NCBI:4233 gene lung non-small cell carcinoma DOID:3908 risk 100026-4 CIViC:4366 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.3028G>A) sequence variation in gene MET/NCBI:4233 1890 check_entity AN5379-1 MGMT Promoter Methylation MGMT NCBI:4255 gene glioblastoma DOID:3068 prognostic;risk PubMed:11070098 MGMT promoter methylation was associated with increased overall and disease-free survival as well as tumor regression in patients with gliomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MGMT Promoter Methylation [biomarker_term_in_review] 1891 not_mapped AN5379-1 MGMT Promoter Methylation MGMT NCBI:4255 gene glioblastoma DOID:3068 prognostic;risk PubMed:15758010 In a randomized clinical trial, patients with MGMT promoter methylation benefitted from temozolomide. This benefit was also methylation status dependent, as those without methylation did not see increased survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MGMT Promoter Methylation [biomarker_term_in_review] 1891 not_mapped AN5379-1 MGMT Promoter Methylation MGMT NCBI:4255 gene glioblastoma DOID:3068 prognostic;risk CIViC:85 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MGMT Promoter Methylation [biomarker_term_in_review] 1891 not_mapped AN5379-2 MGMT Promoter Methylation MGMT NCBI:4255 gene oligodendroglioma DOID:3181 prognostic PubMed:19901104 In a study of 152 anaplastic oligodendroglial tumors, 121 samples had MGMT promoter methylation. Those with promoter methylation had better progression-free and overall survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MGMT Promoter Methylation [biomarker_term_in_review] 1892 not_mapped AN5379-2 MGMT Promoter Methylation MGMT NCBI:4255 gene oligodendroglioma DOID:3181 prognostic CIViC:85 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MGMT Promoter Methylation [biomarker_term_in_review] 1892 not_mapped AN5380-1 MGMT RS16906252 mutation MGMT NCBI:4255 gene glioblastoma DOID:3068 risk PubMed:25910840 The T allele of the rs16906252 SNP was associated with MGMT methylation and low protein expression. Germline presence of the T allele increased the risk of glioblastoma development (adjusted odds ratio, 1.96; P = .013). Temozolomide treatment led to better survival in patients with the rs16906252 T genotype irrespective of methylation status. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS16906252 sequence variation in gene MGMT/NCBI:4255 1893 check_entity AN5380-1 MGMT RS16906252 mutation MGMT NCBI:4255 gene glioblastoma DOID:3068 risk CIViC:334 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS16906252 sequence variation in gene MGMT/NCBI:4255 1893 check_entity AN5381-1 MGMT Underexpression MGMT NCBI:4255 gene glioblastoma DOID:3068 risk PubMed:17442989 In this study, patients with low MGMT expression, compared with patients with high MGMT expression, had a significantly higher response rate (55% v 7%, respectively; P = .004) and improved PFS (median, 5.5 v 1.9 months, respectively; P = .009) and OS (median, 16 v 5 months, respectively; P = .003). Among patients with MGMT data available for analysis, radiotherapy was started and completed in 91% of patients with low MGMT expression. In contrast, among patients with high MGMT expression, only 64% started radiotherapy, and 43% completed it. These results suggest that neoadjuvant chemotherapy may be feasible for inoperable glioblastoma patients expressing low levels of MGMT without compromising subsequent treatment with radiotherapy, whereas patients with high MGMT expression are less likely to respond and more likely to experience progression before or during radiotherapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene MGMT/NCBI:4255 1894 AN5381-1 MGMT Underexpression MGMT NCBI:4255 gene glioblastoma DOID:3068 risk PubMed:21331613 In 41 glioblastomas treated with temozolomide (TMZ) therapy (MGMT-immunopositive: n = 22, negative: n = 19), both progression free survival and overall survival were significantly better in MGMT-immunonegative glioblastomas. (PFS: P = 0.0015, OS: P = 0.0384). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene MGMT/NCBI:4255 1894 AN5381-1 MGMT Underexpression MGMT NCBI:4255 gene glioblastoma DOID:3068 risk CIViC:1229 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene MGMT/NCBI:4255 1894 AN5381-2 MGMT Underexpression MGMT NCBI:4255 gene high grade glioma DOID:3070 risk PubMed:21365007 This study showed that low MGMT mRNA expression was strongly predictive for prolonged time to progression, treatment response, and length of survival in univariate and multivariate models (p<0.0001). The degree of MGMT mRNA expression was highly correlated with the MGMT promoter methylation status (p<0.0001); however, discordant findings were seen in 12 glioblastoma patients. Patients with methylated tumors with high MGMT mRNA expression (N = 6) did significantly worse than those with low transcriptional activity (p<0.01). Conversely, unmethylated tumors with low MGMT mRNA expression (N = 6) did better than their counterparts. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene MGMT/NCBI:4255 1895 AN5381-2 MGMT Underexpression MGMT NCBI:4255 gene high grade glioma DOID:3070 risk CIViC:1229 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene MGMT/NCBI:4255 1895 AN5381-3 MGMT Underexpression MGMT NCBI:4255 gene neuroendocrine tumor DOID:169 risk PubMed:19118063 Among those patients who received temozolomide-based therapy in this study, the median progression-free survival for patients whose tumors showed intact MGMT expression was 9.3 months compared with 19.2 months for patients with MGMT-deficient tumors (P = 0.11). The median overall survival for patients whose tumors showed intact MGMT expression was 19.1 months; the median overall survival for patients with MGMT deficient tumors was not reached. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene MGMT/NCBI:4255 1896 AN5381-3 MGMT Underexpression MGMT NCBI:4255 gene neuroendocrine tumor DOID:169 risk CIViC:1229 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene MGMT/NCBI:4255 1896 AN5381-4 MGMT Underexpression MGMT NCBI:4255 gene oligodendroglioma DOID:3181 risk PubMed:16541434 In this study, loss of chromosome 1p and low MGMT protein expression were associated with objective response (P < .003 and P < .04, respectively). However, only 54% of the study group had evaluation of 1p/19q status, and MGMT protein expression was studied in only 33%. Therefore, the association between 1p deletion and low MGMT protein expression was statistically significant when evaluated further and verified in the extended group of 31 patients with low-grade oligodendrogliomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene MGMT/NCBI:4255 1897 AN5381-4 MGMT Underexpression MGMT NCBI:4255 gene oligodendroglioma DOID:3181 risk CIViC:1229 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene MGMT/NCBI:4255 1897 AN5382-1 MIR218-1 EXPRESSION MIR218-1 NCBI:407000 gene colorectal cancer DOID:9256 prognostic PubMed:26442524 Researchers examined the prognostic role of miR-218 expression in CRC tumor samples when receiving 5-FU based treatment. CRC samples from patients who received first-line 5-FU-based adjuvant chemotherapy were stratified into two groups (complete/partial response and stable/progressive disease) based on RECIST criteria. miR-218 expression levels were found to be significantly higher in the complete/partial response group. Further Kaplan-Meier survival analysis revealed that in groups with higher miR-218 expression, overall survival was significantly greater. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene MIR218-1/NCBI:407000 1898 AN5382-1 MIR218-1 EXPRESSION MIR218-1 NCBI:407000 gene colorectal cancer DOID:9256 prognostic CIViC:472 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene MIR218-1/NCBI:407000 1898 AN5383-1 MIR218-1 UNDEREXPRESSION MIR218-1 NCBI:407000 gene pancreatic cancer DOID:1793 prognostic PubMed:26662432 The study found mir-218 was significantly under-expressed when compared to matched adjacent normal tissue in 107 samples via qPCR. Further, low expression of mir-218 was revealed to be associated with lower overall survival (p < .001), and multivariate analysis revealed that low expression of mir-218 as an independent predictor of poor prognosis (p < .007). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene MIR218-1/NCBI:407000 1899 AN5383-1 MIR218-1 UNDEREXPRESSION MIR218-1 NCBI:407000 gene pancreatic cancer DOID:1793 prognostic CIViC:494 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene MIR218-1/NCBI:407000 1899 AN5384-1 MKI67 EXPRESSION MKI67 NCBI:4288 gene breast cancer DOID:1612 prognostic PubMed:26341751 A quantitative meta-analysis was performed to assess optimal IHC-calculated cutoff values for the prognostic use of proliferative biomarker Ki67 in breast cancer. The studies included ER positive and negative cases, and the MIB-1 antibody was used in the large majority of studies. 25 studies that employed multivariate analysis were used, and a hazard ratio of 2.05 for overall survival was obtained when Ki67 cutoff value was set at greater or equal to 25%. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene MKI67/NCBI:4288 1900 AN5384-1 MKI67 EXPRESSION MKI67 NCBI:4288 gene breast cancer DOID:1612 prognostic CIViC:620 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene MKI67/NCBI:4288 1900 AN5384-2 MKI67 EXPRESSION MKI67 NCBI:4288 gene prostate cancer DOID:10283 prognostic PubMed:23329234 293 cases of clinically localized prostate cancer were analyzed on needle-biopsy FFPE tissue microarray, using the MIB-1 antibody against the Ki67 marker of proliferation. IHC staining was used to generate a Ki67 score, and cases were divided into 2 groups with Ki67 score greater or less than 10%. Primary endpoint was death due to prostate cancer. A hazard ratio for high Ki67 values of 3.42 was seen in univariate analysis, and Ki67 score also added significant predictive value in multivariate analysis, with a hazard ratio of 2.78. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene MKI67/NCBI:4288 1901 AN5384-2 MKI67 EXPRESSION MKI67 NCBI:4288 gene prostate cancer DOID:10283 prognostic CIViC:620 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene MKI67/NCBI:4288 1901 AN5385-1 MLH1 *757L mutation MLH1 NCBI:4292 gene villous adenoma DOID:0050869 risk 32630-6 PubMed:25111426 MLH1 *757 L (c.2270A > T), identified in a case of microsatellite-unstable villous adenoma, was confirmed to be somatic in a 39 year old male patient (id: sLS-9) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, as the disease is germline by definition. The patient also harbored an MLH1 c.453+1G > A mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::*757L sequence variation in gene MLH1/NCBI:4292 1902 check_entity AN5385-1 MLH1 *757L mutation MLH1 NCBI:4292 gene villous adenoma DOID:0050869 risk 32630-6 CIViC:729 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::*757L sequence variation in gene MLH1/NCBI:4292 1902 check_entity AN5386-1 MLH1 A424T mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 MLH1 A424T (c.1270G>A), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 45 year old male patient (id: sLS-13) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS which is germline by definition. Patient also harbored a BRAF V600E mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A424T sequence variation in gene MLH1/NCBI:4292 1903 check_entity AN5386-1 MLH1 A424T mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:733 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A424T sequence variation in gene MLH1/NCBI:4292 1903 check_entity AN5387-1 MLH1 A681V mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 This variant (A681V), identified in a case of microsatellite-unstable colorectal cancer was confirmed to be somatic in a 52 year-old male patient with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. Loss of heterozygosity (wildtype allele loss) was also demonstrated. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A681V sequence variation in gene MLH1/NCBI:4292 1904 check_entity AN5387-1 MLH1 A681V mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:741 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A681V sequence variation in gene MLH1/NCBI:4292 1904 check_entity AN5388-1 MLH1 D667FS mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 This variant (D667fs), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 68 year old female patient (id: sLS-7) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. Loss of heterozygosity leading to primarily the D667fs allele detected (90% VAF). This patient also harbored a heterozygous p.V49A variant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::d667fs:mutation sequence variation in gene MLH1/NCBI:4292 1905 check_entity AN5388-1 MLH1 D667FS mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:727 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::d667fs:mutation sequence variation in gene MLH1/NCBI:4292 1905 check_entity AN5389-1 MLH1 E13fs mutation MLH1 NCBI:4292 gene endometrial cancer DOID:1380 risk 32630-6 PubMed:25111426 MLH1 E13fs (c.37del), identified in a case of microsatellite-unstable endometrial cancer, was confirmed to be somatic in a 46 year old female patient (sLS-1) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS. This patient also harbored MLH1 p.G606fs. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::e13fs:mutation sequence variation in gene MLH1/NCBI:4292 1906 check_entity AN5389-1 MLH1 E13fs mutation MLH1 NCBI:4292 gene endometrial cancer DOID:1380 risk 32630-6 CIViC:706 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::e13fs:mutation sequence variation in gene MLH1/NCBI:4292 1906 check_entity AN5390-1 MLH1 EXPRESSION MLH1 NCBI:4292 gene stomach carcinoma DOID:5517 prognostic 32630-6 PubMed:27313181 46 patients with poorly cohesive, signet-cell ring, gastric carcinoma were evaluated for genetic mutations and MLH1 expression (immunohistochemistry). Overall survival rate of MLH1 negative cases were significantly better than MLH1 positive cases (p=0.020). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene MLH1/NCBI:4292 1907 AN5390-1 MLH1 EXPRESSION MLH1 NCBI:4292 gene stomach carcinoma DOID:5517 prognostic 32630-6 CIViC:658 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene MLH1/NCBI:4292 1907 AN5391-1 MLH1 G606FS*2 mutation MLH1 NCBI:4292 gene endometrial cancer DOID:1380 risk 32630-6 PubMed:25111426 MLH1 G606fs*2 (c.1816_1817del), identified in a case of microsatellite-unstable endometrial cancer, was confirmed to be somatic in a 46 year old female patient (sLS-1) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. This patient also harbored a MLH1 p.E13fs*3 mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::g606fs*2:mutation sequence variation in gene MLH1/NCBI:4292 1908 check_entity AN5391-1 MLH1 G606FS*2 mutation MLH1 NCBI:4292 gene endometrial cancer DOID:1380 risk 32630-6 CIViC:711 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::g606fs*2:mutation sequence variation in gene MLH1/NCBI:4292 1908 check_entity AN5392-1 MLH1 G65D mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 This variant (G65D), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 71 year-old male patient (sLS-21) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. This patient also had loss of heterozygosity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G65D sequence variation in gene MLH1/NCBI:4292 1909 check_entity AN5392-1 MLH1 G65D mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:740 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G65D sequence variation in gene MLH1/NCBI:4292 1909 check_entity AN5393-1 MLH1 G67R mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 This variant (G67R), identified in a case of microsatellite-unstable colorectal cancer was confirmed to be somatic in a 61 year-old male patient (sLS-18) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. Loss of heterozygosity of the wildtype allele was demonstrated. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G67R sequence variation in gene MLH1/NCBI:4292 1910 check_entity AN5393-1 MLH1 G67R mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:738 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G67R sequence variation in gene MLH1/NCBI:4292 1910 check_entity AN5394-1 MLH1 I68S mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 MLH1 I68S (c.203 T > G), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 65 year old male patient (id: sLS-20) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, as the disease is germline by definition. Loss of heterozygosity leading to p.I68S at 77% variant allele frequency was demonstrated. The patient also harbored a heterozygous MLH1 p.T117M mutation (38% VAF). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I68S sequence variation in gene MLH1/NCBI:4292 1911 check_entity AN5394-1 MLH1 I68S mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:739 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I68S sequence variation in gene MLH1/NCBI:4292 1911 check_entity AN5395-1 MLH1 K618DEL MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 MLH1 K618del (c.1852_1854del), identified in two cases of microsatellite-unstable colorectal cancer, was confirmed to be somatic in both patients with suspected Lynch Syndrome (LS). Both patients were therefore negative for LS, as it is germline by definition. sLS-2 was a 61 year old male whose tumor harbored MLH1 c.790 + 1G>A concomitantly, retained MLH1 heterozygosity and was wildtype for BRAF. sLS-8 was a 73 year old female whose tumor harbored MLH1 M1L and was wildtype for BRAF. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MLH1 K618DEL [biomarker_term_in_review] 1912 not_mapped AN5395-1 MLH1 K618DEL MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:714 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MLH1 K618DEL [biomarker_term_in_review] 1912 not_mapped AN5396-1 MLH1 Loss MLH1 NCBI:4292 gene cancer DOID:162 risk 32630-6 PubMed:31765263 In this NCI-MATCH trial, 42 patients with 19 different cancers, none of which were colorectal, harbouring MMR deficiency defined by MLH1 or MSH2 loss were treated with Nivolumab. The three most common cancers in the cohort were endometrial adenocarcinoma (n=13), prostate adenocarcinoma (n = 5), and uterine carcinosarcoma (n=4). It was noted that the ORR was 36% (90% CI; 23.5-49.5), 7% of the patients had a complete response, 29% had PRs, 21% had SD, and 23% had progressive disease. The 6-month PFS rate was 51.3% (90% CI; 38.2-64.5), the 8-month PFS rate was 46.2% (90% CI; 33.1-59.3), and the 12-month PFS rate was 31.4% (90% CI; 18.7-44.2). The median survival time reported was 17.3 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MLH1 Loss [biomarker_term_in_review] 1913 not_mapped AN5396-1 MLH1 Loss MLH1 NCBI:4292 gene cancer DOID:162 risk 32630-6 CIViC:4733 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MLH1 Loss [biomarker_term_in_review] 1913 not_mapped AN5397-1 MLH1 M1L mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 MLH1 M1L (c.1A>T), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 73 year old female patient (patient id: sLS-8) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. Loss of heterozygosity resulting in overrepresentation of the M1L allele was observed. Additionally, this patient's tumor harbored a heterozygous MLH1 p.K618del mutation and was wildtype for BRAF. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M1L sequence variation in gene MLH1/NCBI:4292 1914 check_entity AN5397-1 MLH1 M1L mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:728 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M1L sequence variation in gene MLH1/NCBI:4292 1914 check_entity AN5398-1 MLH1 M490T mutation MLH1 NCBI:4292 gene endometrial cancer DOID:1380 risk 32630-6 PubMed:25111426 This variant (M490T), identified in a case of microsatellite-unstable endometrial cancer was confirmed to be somatic in a 69 year-old female patient with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which by definition is a germline condition. The patient also harbored PMS2 R315*, MSH2 p.E483G and MSH6 p.V352I mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M490T sequence variation in gene MLH1/NCBI:4292 1915 check_entity AN5398-1 MLH1 M490T mutation MLH1 NCBI:4292 gene endometrial cancer DOID:1380 risk 32630-6 CIViC:750 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M490T sequence variation in gene MLH1/NCBI:4292 1915 check_entity AN5399-1 MLH1 METHYLATION MLH1 NCBI:4292 gene stomach carcinoma DOID:5517 risk 32630-6 PubMed:24748501 The methylation status of MLH1 was analyzed in a study of 53 paraffin-embedded gastric cancer samples. No association was found between methylation status and clinical factors. The study showed that MLH1 methylation was associated with resistance to treatment with oxaliplatin. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MLH1 METHYLATION [biomarker_term_in_review] 1916 not_mapped AN5399-1 MLH1 METHYLATION MLH1 NCBI:4292 gene stomach carcinoma DOID:5517 risk 32630-6 CIViC:534 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MLH1 METHYLATION [biomarker_term_in_review] 1916 not_mapped AN5400-1 MLH1 N551T mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 MLH1 N551T (c.1652A > C) identified in a case of microsatellite-unstable colorectal cancer was confirmed to be somatic in a 51 year old female patient (id: sLS-12) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS as the disease is germline by definition. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N551T sequence variation in gene MLH1/NCBI:4292 1917 check_entity AN5400-1 MLH1 N551T mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:732 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N551T sequence variation in gene MLH1/NCBI:4292 1917 check_entity AN5401-1 MLH1 P138T mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 This variant (P138T), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be a somatic mutation in a 58 year-old male patient (sLS-23) with suspected Lynch syndrome (LS). The patient was therefore negative for LS, which by definition is a germline condition. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P138T sequence variation in gene MLH1/NCBI:4292 1918 check_entity AN5401-1 MLH1 P138T mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:715 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P138T sequence variation in gene MLH1/NCBI:4292 1918 check_entity AN5402-1 MLH1 P536FS mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 This variant (P536fs), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 59 year-old female patient (sLS-17) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. Loss of heterozygosity of the wildtype allele was demonstrated resulting in higher mutated allele representation (80% variant allele frequency). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::p536fs:mutation sequence variation in gene MLH1/NCBI:4292 1919 check_entity AN5402-1 MLH1 P536FS mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:737 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::p536fs:mutation sequence variation in gene MLH1/NCBI:4292 1919 check_entity AN5403-1 MLH1 Q149* mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 MLH1 Q149* (c.445C > T), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 65 year old female patient with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is a germline disease by definition. This patient also harbored MLH1 p.R226* and MSH6 p.I972F mutations at similar variant allele frequencies. Authors note that the tumor retained MLH1 heterozygosity, was wildtype for BRAF, and harbored two pathogenic variants in MMR. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q149* sequence variation in gene MLH1/NCBI:4292 1920 check_entity AN5403-1 MLH1 Q149* mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:734 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q149* sequence variation in gene MLH1/NCBI:4292 1920 check_entity AN5404-1 MLH1 Q426FS mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 MLH1 Q426fs (c.1276del), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be a somatic mutation in a 46 year old male patient (patient id: sLS-5) with suspected Lynch syndrome (LS). The patient was therefore negative for LS as it is a germline disease, by definition. Loss of heterozygosity of the wildtype allele and wildtype BRAF was observed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::q426fs:mutation sequence variation in gene MLH1/NCBI:4292 1921 check_entity AN5404-1 MLH1 Q426FS mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:725 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::q426fs:mutation sequence variation in gene MLH1/NCBI:4292 1921 check_entity AN5405-1 MLH1 R100* mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 R100* (c.298C > T), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 46 year old female patient with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. Loss of heterozygosity of the wildtype allele was confirmed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R100* sequence variation in gene MLH1/NCBI:4292 1922 check_entity AN5405-1 MLH1 R100* mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:722 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R100* sequence variation in gene MLH1/NCBI:4292 1922 check_entity AN5406-1 MLH1 R226* mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 MLH1 R226* (c.676C > T), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 65 year old female patient (sLS-14) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. This patient also harbored MLH1 p.Q149* and MSH6 p.I972F mutations as similar variant allele frequencies. Authors note that the tumor of this patient was wildtype for BRAF. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R226* sequence variation in gene MLH1/NCBI:4292 1923 check_entity AN5406-1 MLH1 R226* mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:735 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R226* sequence variation in gene MLH1/NCBI:4292 1923 check_entity AN5407-1 MLH1 R265G mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 MLH1 R265G (c.793C > G), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 65 year old female patient (id: sLS-10) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, as the disease is germline by definition. Loss of heterozygosity of the wildtype allele and BRAF wildtype was observed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R265G sequence variation in gene MLH1/NCBI:4292 1924 check_entity AN5407-1 MLH1 R265G mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:730 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R265G sequence variation in gene MLH1/NCBI:4292 1924 check_entity AN5408-1 MLH1 R687FS mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 MLH1 R687fs (c.2059del), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 33 year old male patient (patient id: sLS-3) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS which is germline by definition. Loss of heterozygosity of the wildtype allele was demonstrated. Patient also had a BRAF p.D594G mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::r687fs:mutation sequence variation in gene MLH1/NCBI:4292 1925 check_entity AN5408-1 MLH1 R687FS mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:716 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::r687fs:mutation sequence variation in gene MLH1/NCBI:4292 1925 check_entity AN5409-1 MLH1 T117M mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 MLH1 T117M (c.350C > T), identified in three cases of microsatellite-unstable colorectal cancer, was confirmed to be somatic in patients with suspected Lynch Syndrome (LS). The patients were therefore negative for LS, as the disease is germline by definition. Patient sLS-6 was a 59 year old female whose tumor harbored BRAF V600E and had loss of heterozygosity of MLH1. Patient sLS-19 was a 62 year old female whose tumor harbored loss of heterozygosity at MLH1 and wildtype BRAF. Patient sLS-20 was a 65 year old male whose tumor harbored concomitant MLH1 I68S and BRAF wildtype. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T117M sequence variation in gene MLH1/NCBI:4292 1926 check_entity AN5409-1 MLH1 T117M mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:724 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T117M sequence variation in gene MLH1/NCBI:4292 1926 check_entity AN5410-1 MLH1 V213FS mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 This variant (V213fs), identified in two cases of microsatellite-unstable colorectal cancer, was confirmed to be somatic in both patients (40 year-old female & 70 year-old male) with suspected Lynch Syndrome (LS). The patients were therefore negative for LS, which is by definition a germline disorder. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::v213fs:mutation sequence variation in gene MLH1/NCBI:4292 1927 check_entity AN5410-1 MLH1 V213FS mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:731 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::v213fs:mutation sequence variation in gene MLH1/NCBI:4292 1927 check_entity AN5411-1 MLH1 V49A mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 MLH1 V49A (c.146 T > C), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 68 year old female patient (id: sLS-7) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS as the disease is germline by definition. The patient also harbored a second MLH1 mutation (p.D667fs) which demonstrated loss of heterozygosity and BRAF wildtype. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V49A sequence variation in gene MLH1/NCBI:4292 1928 check_entity AN5411-1 MLH1 V49A mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:726 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V49A sequence variation in gene MLH1/NCBI:4292 1928 check_entity AN5412-1 MLH1 V534R mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 MLH1 V534R (c.1600_1601delinsAG), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be a somatic variant in a 27 year old male patient (id: sLS-24) with suspected Lynch syndrome (LS). The patient was therefore negative for LS which is germline by definition. Authors note that this patient's tumor retained MLH1 heterozygosity and wildtype BRAF. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V534R sequence variation in gene MLH1/NCBI:4292 1929 check_entity AN5412-1 MLH1 V534R mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:709 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V534R sequence variation in gene MLH1/NCBI:4292 1929 check_entity AN5413-1 MLH1 c.790+1G>A mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 MLH1 c.790+1G > A, identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 61 year old male patient (sLS-2) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, as the disease is germline by definition. This patient's tumor also harbored a p.K618del mutation and was wildtype for BRAF. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.790+1g>a:mutation sequence variation in gene MLH1/NCBI:4292 1930 check_entity AN5413-1 MLH1 c.790+1G>A mutation MLH1 NCBI:4292 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:712 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.790+1g>a:mutation sequence variation in gene MLH1/NCBI:4292 1930 check_entity AN5414-1 MMP2 SERUM LEVELS MMP2 NCBI:4313 gene brain glioma DOID:0060108 risk PubMed:24327581 Plasma levels of 11 potential biomarkers were tested at baseline and 2 weeks after bevacizumab initiation in a prospective cohort of 26 patients with recurrent high-grade gliomas. Results were validated in a separate retrospective cohort (n = 50) and also tested in patients treated with cytotoxic agents without bevacizumab (n = 34). MMP2 level was correlated with PFS (hazard ratio, 3.92; 95% confidence interval [CI]:1.46-10.52; P = .007) and OS (hazard ratio, 4.62; 95% CI: 1.58-13.53; P = .005) in the discovery and validation cohorts but not in patients treated without bevacizumab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MMP2 SERUM LEVELS [biomarker_term_in_review] 1931 not_mapped AN5414-1 MMP2 SERUM LEVELS MMP2 NCBI:4313 gene brain glioma DOID:0060108 risk CIViC:483 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MMP2 SERUM LEVELS [biomarker_term_in_review] 1931 not_mapped AN5414-2 MMP2 SERUM LEVELS MMP2 NCBI:4313 gene inflammatory breast carcinoma DOID:6263 risk PubMed:26921265 MMP2 serum levels were assessed (ELISA) at baseline (b) and before surgery in 45 available samples from patients with inflammatory breast cancer treated with bevacizumab-based neoadjuvant therapy. High bMMP2 was correlated with better disease-free survival (DFS, p=0.001) and overall survival (OS, p=0.032). Correlation to DFS was also found after multivariate analysis (p=0.003, Hazard Ratio [HR]: 0.115). bMMP2 was associated with relapse (p=0.002) and death (p=0.049). During treatment, significant increase in MMP2 was observed in 100% of patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MMP2 SERUM LEVELS [biomarker_term_in_review] 1932 not_mapped AN5414-2 MMP2 SERUM LEVELS MMP2 NCBI:4313 gene inflammatory breast carcinoma DOID:6263 risk CIViC:483 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MMP2 SERUM LEVELS [biomarker_term_in_review] 1932 not_mapped AN5415-1 MMP9 SERUM LEVELS MMP9 NCBI:4318 gene inflammatory breast carcinoma DOID:6263 risk PubMed:26921265 MMP9 serum levels were assessed (ELISA) at baseline (b) and before surgery in 45 available samples from patients with inflammatory breast cancer treated with bevacizumab-based neoadjuvant therapy. Low bMMP9 was correlated with better OS (p=0.022) and non-significantly associated with longer DFS (p=0.071). Correlation to DFS was also found after multivariate analysis (p=0.041, HR: 3.511). bMMP9 was associated with death (p=0.035). During treatment, a significant decrease in MMP9 levels (p<0.001) was observed in 87% of patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MMP9 SERUM LEVELS [biomarker_term_in_review] 1933 not_mapped AN5415-1 MMP9 SERUM LEVELS MMP9 NCBI:4318 gene inflammatory breast carcinoma DOID:6263 risk CIViC:484 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MMP9 SERUM LEVELS [biomarker_term_in_review] 1933 not_mapped AN5416-1 MN1 MN1::CXXC5 mutation MN1 NCBI:4330 gene astroblastoma, MN1-altered DOID:0080904 diagnostic 35462-1 PubMed:26919435 The authors studied tumors carrying a diagnosis of CNS primitive neuroectodermal tumors (PNETs). They identified four novel DNA methylation-defined brain tumor groups. One group, designated high-grade neuroepithelial tumor with MN1 alteration (HGNET-MN1), showed recurrent rearrangements of the MN1 gene, located at 22q12.3-qter. It was found in 3% of the 323 cases analyzed and is characterized by gene fusions involving MN1, with fusion partners including BEND2 and CXXC5. The CNS HGNET-MN1 subtype shows a striking female predominance and tends to occur in the second decade of life.This subtype contained cases diagnosed as astroblastoma according to the 2007 WHO classification for CNS tumors assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::MN1::CXXC5 sequence variation in gene MN1/NCBI:4330 1934 check_entity AN5416-1 MN1 MN1::CXXC5 mutation MN1 NCBI:4330 gene astroblastoma, MN1-altered DOID:0080904 diagnostic 35462-1 CIViC:2983 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::MN1::CXXC5 sequence variation in gene MN1/NCBI:4330 1934 check_entity AN5417-1 MRE11 Frameshift MRE11 NCBI:4361 gene prostate cancer DOID:10283 risk PubMed:26510020 One patient in a cohort of 50 patients with metastatic prostate cancer had a frameshift mutation in the MRE11, ATM, MLH3 and NBN genes and showed clinical response to PARP inhibitor olaparib (16 weeks on Treatment). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MRE11 Frameshift [biomarker_term_in_review] 1935 not_mapped AN5417-1 MRE11 Frameshift MRE11 NCBI:4361 gene prostate cancer DOID:10283 risk CIViC:424 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MRE11 Frameshift [biomarker_term_in_review] 1935 not_mapped AN5418-1 MRE11 Loss MRE11 NCBI:4361 gene endometrial cancer DOID:1380 risk PubMed:24927325 One endometrial cell line with decreased MRE11 expression caused by a homozygous poly(T) mutation exhibited increased sensitivity to the PARP inhibitor BMN-673. Loss of MRE11 was identified in 30.7% of endometrial tumors (N=521). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MRE11 Loss [biomarker_term_in_review] 1936 not_mapped AN5418-1 MRE11 Loss MRE11 NCBI:4361 gene endometrial cancer DOID:1380 risk CIViC:366 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MRE11 Loss [biomarker_term_in_review] 1936 not_mapped AN5419-1 MS4A1 Mutation MS4A1 NCBI:931 gene diffuse large B-cell lymphoma DOID:0050745 risk PubMed:32589730 A targeted sequencing study of 135 relapsed/refractory DLBCL patients identified an association between missense mutations in MS4A1 and acquired resistance to R-CHOP. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene MS4A1/NCBI:931 1937 check_entity AN5419-1 MS4A1 Mutation MS4A1 NCBI:931 gene diffuse large B-cell lymphoma DOID:0050745 risk CIViC:3886 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene MS4A1/NCBI:931 1937 check_entity AN5420-1 MSH2 E28FS mutation MSH2 NCBI:4436 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 This variant (E28fs), identified in a case of microsatellite-unstable colorectal cancer was confirmed to be somatic in a 66 year-old male patient with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which by definition is a germline condition.. This patient had two somatic mutations in MSH2 (E28fs, K172*). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::e28fs:mutation sequence variation in gene MSH2/NCBI:4436 1938 check_entity AN5420-1 MSH2 E28FS mutation MSH2 NCBI:4436 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:744 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::e28fs:mutation sequence variation in gene MSH2/NCBI:4436 1938 check_entity AN5421-1 MSH2 E483G mutation MSH2 NCBI:4436 gene endometrial cancer DOID:1380 risk 32630-6 PubMed:25111426 MSH2 E483G (c.1448A > G), identified in a case of microsatellite-unstable endometrial cancer was confirmed to be somatic in a 69 year old female patient (sLS-39) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, as LS is a germline condition by definition. This patient also harbored PMS2 p.R315*, MLH1 p.M490T and MSH6 p.V352I mutations. Authors note that this patient's tumor harbored wildtype BRAF. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E483G sequence variation in gene MSH2/NCBI:4436 1939 check_entity AN5421-1 MSH2 E483G mutation MSH2 NCBI:4436 gene endometrial cancer DOID:1380 risk 32630-6 CIViC:754 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E483G sequence variation in gene MSH2/NCBI:4436 1939 check_entity AN5422-1 MSH2 K172* mutation MSH2 NCBI:4436 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 MSH2 K172*, identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 66 year old male patient (id: sLS-32) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS. This patient had two somatic mutations in MSH2 (E28fs, K172*). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K172* sequence variation in gene MSH2/NCBI:4436 1940 check_entity AN5422-1 MSH2 K172* mutation MSH2 NCBI:4436 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:751 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K172* sequence variation in gene MSH2/NCBI:4436 1940 check_entity AN5423-1 MSH2 Loss MSH2 NCBI:4436 gene cancer DOID:162 risk 32630-6 PubMed:31765263 In this NCI-MATCH trial, 42 patients with 19 different cancers, none of which were colorectal, harbouring MMR deficiency defined by MLH1 or MSH2 loss were treated with Nivolumab. The three most common cancers in the cohort were endometrial adenocarcinoma (n=13), prostate adenocarcinoma (n = 5), and uterine carcinosarcoma (n=4). It was noted that the ORR was 36% (90% CI; 23.5-49.5), 7% of the patients had a complete response, 29% had PRs, 21% had SD, and 23% had progressive disease. The 6-month PFS rate was 51.3% (90% CI; 38.2-64.5), the 8-month PFS rate was 46.2% (90% CI; 33.1-59.3), and the 12-month PFS rate was 31.4% (90% CI; 18.7-44.2). The median survival time reported was 17.3 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MSH2 Loss [biomarker_term_in_review] 1941 not_mapped AN5423-1 MSH2 Loss MSH2 NCBI:4436 gene cancer DOID:162 risk 32630-6 CIViC:4733 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MSH2 Loss [biomarker_term_in_review] 1941 not_mapped AN5423-2 MSH2 Loss MSH2 NCBI:4436 gene transitional cell carcinoma DOID:2671 risk 32630-6 PubMed:26674132 Case report of a 45-year old woman of Japanese descent with recurrent urothelial carcinoma. The patient was identified to harbor mutations in MSH2 (A913fs*2, E226*, E580*) and in MSH6 (R361H) by panel sequencing as well as loss of expression of these genes as confirmed by IHC. Testing also revealed a high mutational load as well as 2+ PD-L1 expression in 80% of the cells. The patient was treated with anti-PD-L1 inhibitor MEDI4736 and MEDI0680 in a phase 1 trial and had a complete remission within 2 months of treatment that was ongoing after 11 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MSH2 Loss [biomarker_term_in_review] 1942 not_mapped AN5423-2 MSH2 Loss MSH2 NCBI:4436 gene transitional cell carcinoma DOID:2671 risk 32630-6 CIViC:786 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MSH2 Loss [biomarker_term_in_review] 1942 not_mapped AN5424-1 MSH2 R383* mutation MSH2 NCBI:4436 gene endometrial cancer DOID:1380 risk 32630-6 PubMed:25111426 This variant (R383*), identified in two patients, was confirmed to be a somatic mutation in both patients' microsatellite-unstable tumors (39 year-old female with endometrial cancer & 34 year-old female with ovarian cancer) with suspected Lynch Syndrome (LS). These patients were therefore negative for LS, which is by definition a germline condition. LOH of the WT allele was confirmed in the case of ovarian cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R383* sequence variation in gene MSH2/NCBI:4436 1943 check_entity AN5424-1 MSH2 R383* mutation MSH2 NCBI:4436 gene endometrial cancer DOID:1380 risk 32630-6 CIViC:708 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R383* sequence variation in gene MSH2/NCBI:4436 1943 check_entity AN5425-1 MSH2 V273FS mutation MSH2 NCBI:4436 gene colorectal cancer DOID:9256 risk 32630-6 PubMed:25111426 This variant (V273fs), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be a somatic mutation in a 61 year-old male patient (sLS-27) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. LOH of the WT allele was demonstrated. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::v273fs:mutation sequence variation in gene MSH2/NCBI:4436 1944 check_entity AN5425-1 MSH2 V273FS mutation MSH2 NCBI:4436 gene colorectal cancer DOID:9256 risk 32630-6 CIViC:743 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::v273fs:mutation sequence variation in gene MSH2/NCBI:4436 1944 check_entity AN5426-1 MSH6 I891FS mutation MSH6 NCBI:2956 gene colorectal cancer DOID:9256 risk 38906-4 PubMed:25111426 This variant (I891fs), identified in a case of microsatellite-unstable colorectal cancer was confirmed to be somatic in a 79 year-old male patient with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::i891fs:mutation sequence variation in gene MSH6/NCBI:2956 1945 check_entity AN5426-1 MSH6 I891FS mutation MSH6 NCBI:2956 gene colorectal cancer DOID:9256 risk 38906-4 CIViC:746 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::i891fs:mutation sequence variation in gene MSH6/NCBI:2956 1945 check_entity AN5427-1 MSH6 LOSS MSH6 NCBI:2956 gene transitional cell carcinoma DOID:2671 risk 38906-4 PubMed:26674132 Case report of a 45-year old woman of Japanese descent with recurrent urothelial carcinoma. The patient was identified to harbor mutations in MSH2 (A913fs*2, E226*, E580*) and in MSH6 (R361H) by panel sequencing as well as loss of expression of these genes as confirmed by IHC. Testing also revealed a high mutational load as well as 2+ PD-L1 expression in 80% of the cells. The patient was treated with anti-PD-L1 inhibitor MEDI4736 and MEDI0680 in a phase 1 trial and had a complete remission within 2 months of treatment that was ongoing after 11 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MSH6 LOSS [biomarker_term_in_review] 1946 not_mapped AN5427-1 MSH6 LOSS MSH6 NCBI:2956 gene transitional cell carcinoma DOID:2671 risk 38906-4 CIViC:787 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition MSH6 LOSS [biomarker_term_in_review] 1946 not_mapped AN5428-1 MSH6 P138T mutation MSH6 NCBI:2956 gene colorectal cancer DOID:9256 risk 38906-4 PubMed:25111426 This variant, identified in a case of microsatellite-unstable colorectal cancer was confirmed to be somatic in a patient with suspected Lynch Syndrome (LS). The patient was therefore negative for LS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P138T sequence variation in gene MSH6/NCBI:2956 1947 check_entity AN5428-1 MSH6 P138T mutation MSH6 NCBI:2956 gene colorectal cancer DOID:9256 risk 38906-4 CIViC:742 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P138T sequence variation in gene MSH6/NCBI:2956 1947 check_entity AN5429-1 MSH6 R1242C mutation MSH6 NCBI:2956 gene colorectal cancer DOID:9256 risk 38906-4 PubMed:25111426 MSH6 R1242C (c.3724C > T), identified in a case of microsatellite-unstable colorectal cancer, was confirmed to be somatic in a 53 year old male patient with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, as LS is a germline condition by definition. The authors note that this patient's tumor was not deficient in mismatch repair (MMR) protein and retained heterozygosity in MSH6. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R1242C sequence variation in gene MSH6/NCBI:2956 1948 check_entity AN5429-1 MSH6 R1242C mutation MSH6 NCBI:2956 gene colorectal cancer DOID:9256 risk 38906-4 CIViC:757 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R1242C sequence variation in gene MSH6/NCBI:2956 1948 check_entity AN5430-1 MSH6 R1242H mutation MSH6 NCBI:2956 gene colorectal cancer DOID:9256 risk 38906-4 PubMed:25111426 This variant (R1242H), identified in a case of microsatellite-unstable colorectal cancer was confirmed to be somatic in a 79 year-old male patient (sLS-37) with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R1242H sequence variation in gene MSH6/NCBI:2956 1949 check_entity AN5430-1 MSH6 R1242H mutation MSH6 NCBI:2956 gene colorectal cancer DOID:9256 risk 38906-4 CIViC:748 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R1242H sequence variation in gene MSH6/NCBI:2956 1949 check_entity AN5431-1 MSH6 V352I mutation MSH6 NCBI:2956 gene endometrial cancer DOID:1380 risk 38906-4 PubMed:25111426 This variant (V352I), identified in a case of microsatellite-unstable endometrial cancer, was confirmed to be somatic in a 69 year-old female patient with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. This patient also harbored PMS2 p.R315*, MLH1 p.M490T and MSH2 p.E483G mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V352I sequence variation in gene MSH6/NCBI:2956 1950 check_entity AN5431-1 MSH6 V352I mutation MSH6 NCBI:2956 gene endometrial cancer DOID:1380 risk 38906-4 CIViC:756 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V352I sequence variation in gene MSH6/NCBI:2956 1950 check_entity AN5432-1 MTAP Underexpression MTAP NCBI:4507 gene breast cancer DOID:1612 risk PubMed:26751376 MTAP and CDKN2A gene (RT-qPCR) and protein (western-blotting) expression as well as promoter methylation status were analyzed in breast cancer patients and seven breast cancer cell lines. Knockdown of MTAP in one cell line with strong endogenous MTAP expression (MDA-MB-435) increased sensitivity to inhibitors of de novo adenine synthesis (5-FU, AZA and MTX), mainly 5-FU. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene MTAP/NCBI:4507 1951 AN5432-1 MTAP Underexpression MTAP NCBI:4507 gene breast cancer DOID:1612 risk CIViC:841 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene MTAP/NCBI:4507 1951 AN5433-1 MTHFR A222V mutation MTHFR NCBI:4524 gene pancreatic cancer DOID:1793 prognostic 21709-1 PubMed:27819322 Study of 1817 PCa cases and 2026 cancer free controls to clarify the association of (MTHFR)c.677C>T (and c.1298A>C ) of pancreatic cancer risk in a population of Han Chinese in Shanghai. Results indicated a lower risk for the heterozygous CT genotype and homozygous TT genotype carriers of (MTHFR)c.677C>T which had a significantly lower risk of developing pancreatic cancer compared with the wild-type CC genotype. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A222V sequence variation in gene MTHFR/NCBI:4524 1952 check_entity AN5433-1 MTHFR A222V mutation MTHFR NCBI:4524 gene pancreatic cancer DOID:1793 prognostic 21709-1 CIViC:254 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A222V sequence variation in gene MTHFR/NCBI:4524 1952 check_entity AN5433-2 MTHFR A222V mutation MTHFR NCBI:4524 gene rectum cancer DOID:1993 risk 21709-1 PubMed:26693073 Patients with the wild type (C/C) MTHFR gene are 2.91 times (95% CI: [1.23, 6.89]) more likely to have a positive response to neoadjuvant CRT and 3.25 times more likely not to experience relapse (95% CI: [1.37, 7.72]) than patients with the heterozygous MTHFR [rs1801133 (C>T)] mutation or the homzygous (T/T). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A222V sequence variation in gene MTHFR/NCBI:4524 1953 check_entity AN5433-2 MTHFR A222V mutation MTHFR NCBI:4524 gene rectum cancer DOID:1993 risk 21709-1 CIViC:254 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A222V sequence variation in gene MTHFR/NCBI:4524 1953 check_entity AN5433-3 MTHFR A222V mutation MTHFR NCBI:4524 gene stomach cancer DOID:10534 risk 21709-1 PubMed:18704422 The MTHFR C667T variant was associated with significantly lower relapse-free survival and overall survival in stomach cancer patients treated with 5-Fluorouracil-based therapies. 116 Chinese patients with histologically confirmed gastric cancer were used in this study, and all patients had radical surgery before treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A222V sequence variation in gene MTHFR/NCBI:4524 1954 check_entity AN5433-3 MTHFR A222V mutation MTHFR NCBI:4524 gene stomach cancer DOID:10534 risk 21709-1 CIViC:254 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A222V sequence variation in gene MTHFR/NCBI:4524 1954 check_entity AN5434-1 MTOR A2034V mutation MTOR NCBI:2475 gene breast cancer DOID:1612 risk PubMed:27279227 MCF-7 breast cancer cell line was exposed to mTOR inhibitor rapamycin until resistance developed. Deep sequencing revealed an MTOR A2034V mutation in the resistant clone. Downstream signalling was independent of inhibitor presence in these clones and expression of the mutation in MDA-MB-468 cells led to resistance. Xenografts of these cells were more resistant to rapamycin than AZD8055 or RapaLink-1 treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A2034V sequence variation in gene MTOR/NCBI:2475 1955 check_entity AN5434-1 MTOR A2034V mutation MTOR NCBI:2475 gene breast cancer DOID:1612 risk CIViC:606 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A2034V sequence variation in gene MTOR/NCBI:2475 1955 check_entity AN5435-1 MTOR C1483Y mutation MTOR NCBI:2475 gene T-cell acute lymphoblastic leukemia DOID:5603 risk PubMed:24631838 Cell lines with various putative activating mutations were tested for sensitivity to rapamycin. The cell line MOLT16, with MTOR mutation C1483Y was hypersensitive to rapamycin treatment (IC50 of 0.75 nmol/L). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C1483Y sequence variation in gene MTOR/NCBI:2475 1956 check_entity AN5435-1 MTOR C1483Y mutation MTOR NCBI:2475 gene T-cell acute lymphoblastic leukemia DOID:5603 risk CIViC:539 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C1483Y sequence variation in gene MTOR/NCBI:2475 1956 check_entity AN5436-1 MTOR E1799K mutation MTOR NCBI:2475 gene clear cell renal cell carcinoma DOID:4467 risk PubMed:24631838 Cell lines with various putative activating mutations were tested for sensitivity to rapamycin. The cell line SNU349, with MTOR mutation E1799K was hypersensitive to rapamycin treatment (IC50 of 0.19 nmol/L). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E1799K sequence variation in gene MTOR/NCBI:2475 1957 check_entity AN5436-1 MTOR E1799K mutation MTOR NCBI:2475 gene clear cell renal cell carcinoma DOID:4467 risk CIViC:540 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E1799K sequence variation in gene MTOR/NCBI:2475 1957 check_entity AN5437-1 MTOR E2014K mutation MTOR NCBI:2475 gene transitional cell carcinoma DOID:2671 risk PubMed:24625776 'A phase 1 clinical trial identified a patient with chemotherapy-refractory urothelial carcinoma who had complete radiographic response lasting 14 months after combined everolimus and pazopanib treatment. This patient was exome sequenced and two mutations co-occurring in MTOR were identified. Expression of these mutations in HEK293T cells demonstrated these were activating mutations. The authors propose that these two activating mutations are the reason for the dramatic response to mTOR inhibition and considered them as ''biologically plausible'' to confer sensitivity to everolimus.' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E2014K sequence variation in gene MTOR/NCBI:2475 1958 check_entity AN5437-1 MTOR E2014K mutation MTOR NCBI:2475 gene transitional cell carcinoma DOID:2671 risk CIViC:4368 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E2014K sequence variation in gene MTOR/NCBI:2475 1958 check_entity AN5438-1 MTOR E2419K mutation MTOR NCBI:2475 gene transitional cell carcinoma DOID:2671 risk PubMed:24625776 'A phase 1 clinical trial identified a patient with chemotherapy-refractory urothelial carcinoma who had complete radiographic response lasting 14 months after combined everolimus and pazopanib treatment. This patient was exome sequenced and two mutations co-occurring in MTOR were identified. Expression of these mutations in HEK293T cells demonstrated these were activating mutations. The authors propose that these two activating mutations are the reason for the dramatic response to mTOR inhibition and considered them as ''biologically plausible'' to confer sensitivity to everolimus.' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E2419K sequence variation in gene MTOR/NCBI:2475 1959 check_entity AN5438-1 MTOR E2419K mutation MTOR NCBI:2475 gene transitional cell carcinoma DOID:2671 risk CIViC:4368 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E2419K sequence variation in gene MTOR/NCBI:2475 1959 check_entity AN5439-1 MTOR F2108L mutation MTOR NCBI:2475 gene breast cancer DOID:1612 risk PubMed:27279227 MCF-7 breast cancer cell line was exposed to mTOR inhibitors AZD8055 or rapamycin until resistance developed. Deep sequencing revealed an MTOR F2108L mutation in rapamycin-resistant clones (RR2 cells). Downstream signalling was independent of inhibitor presence in these clones and expression of the mutations in MDA-MB-468 cells led to resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F2108L sequence variation in gene MTOR/NCBI:2475 1960 check_entity AN5439-1 MTOR F2108L mutation MTOR NCBI:2475 gene breast cancer DOID:1612 risk CIViC:466 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F2108L sequence variation in gene MTOR/NCBI:2475 1960 check_entity AN5439-2 MTOR F2108L mutation MTOR NCBI:2475 gene thyroid gland carcinoma DOID:3963 risk PubMed:25295501 The pretreatment tumor contained a somatic nonsense mutation (Q1178*) in the tumor-suppressor gene TSC2 that inactivates the gene, allowing for activation of the mTOR pathway and resulting in sensitivity to mTOR inhibition by everolimus. The patient received a sustained response to everolimus for 18 months, after which time resistance developed. The resistant tumor had a somatic mutation in MTOR (F2108L), that was not detected in the pretreatment tumor. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F2108L sequence variation in gene MTOR/NCBI:2475 1961 check_entity AN5439-2 MTOR F2108L mutation MTOR NCBI:2475 gene thyroid gland carcinoma DOID:3963 risk CIViC:466 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F2108L sequence variation in gene MTOR/NCBI:2475 1961 check_entity AN5440-1 MTOR H1968Y mutation MTOR NCBI:2475 gene melanoma DOID:1909 risk PubMed:26490311 In a cell line (HEK293T) with expression of H1968Y or P2213S mTOR mutations, LY294002 and AZD5363 were more effective than temsirolimus or BYL719 in suppressing cell growth. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1968Y sequence variation in gene MTOR/NCBI:2475 1962 check_entity AN5440-1 MTOR H1968Y mutation MTOR NCBI:2475 gene melanoma DOID:1909 risk CIViC:279 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1968Y sequence variation in gene MTOR/NCBI:2475 1962 check_entity AN5441-1 MTOR M2327I mutation MTOR NCBI:2475 gene breast cancer DOID:1612 risk PubMed:27279227 MCF-7 breast cancer cell line was exposed to mTOR inhibitor AZD8055 until resistance developed. Deep sequencing revealed an MTOR M2327I mutation in the AZD8055-resistant clone. Downstream signalling was independent of inhibitor presence in these clones and expression of the mutation in MDA-MB-468 cells led to resistance. Tumor volume grew more rapidly in mice with xenografts of M2327I mTOR mutant MCF7 cells treated with AZD8055 than rapamycin or RapaLink-1 treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M2327I sequence variation in gene MTOR/NCBI:2475 1963 check_entity AN5441-1 MTOR M2327I mutation MTOR NCBI:2475 gene breast cancer DOID:1612 risk CIViC:605 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M2327I sequence variation in gene MTOR/NCBI:2475 1963 check_entity AN5442-1 MTOR Mutation MTOR NCBI:2475 gene bladder carcinoma DOID:4007 risk PubMed:24625776 A case-study of a patient with urothelial carcinoma reported exceptional response (14 months) in a phase 1 study of Everolimus and Pazopanib. Mutations E2014K and E2419K were shown to be activating in-vitro. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene MTOR/NCBI:2475 1964 check_entity AN5442-1 MTOR Mutation MTOR NCBI:2475 gene bladder carcinoma DOID:4007 risk CIViC:273 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene MTOR/NCBI:2475 1964 check_entity AN5442-2 MTOR Mutation MTOR NCBI:2475 gene melanoma DOID:1909 prognostic PubMed:26490311 Median overall survival of patients with nonsynonymous mutations in mTOR was shorter. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene MTOR/NCBI:2475 1965 check_entity AN5442-2 MTOR Mutation MTOR NCBI:2475 gene melanoma DOID:1909 prognostic CIViC:273 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene MTOR/NCBI:2475 1965 check_entity AN5443-1 MTOR P2213S mutation MTOR NCBI:2475 gene melanoma DOID:1909 risk PubMed:26490311 In a cell line (HEK293T) with expression of H1968Y or P2213S mTOR mutations, LY294002 and AZD5363 were more effective than temsirolimus or BYL719 in suppressing cell growth. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P2213S sequence variation in gene MTOR/NCBI:2475 1966 check_entity AN5443-1 MTOR P2213S mutation MTOR NCBI:2475 gene melanoma DOID:1909 risk CIViC:280 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P2213S sequence variation in gene MTOR/NCBI:2475 1966 check_entity AN5444-1 MTOR S2215Y mutation MTOR NCBI:2475 gene endometrial adenocarcinoma DOID:2870 risk PubMed:24631838 Cell lines with various putative activating mutations were tested for sensitivity to rapamycin. The cell line JHUEM7 with the MTOR mutation S2215Y was hypersensitive to rapamycin treatment (IC50 of 0.23 nmol/L). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S2215Y sequence variation in gene MTOR/NCBI:2475 1967 check_entity AN5444-1 MTOR S2215Y mutation MTOR NCBI:2475 gene endometrial adenocarcinoma DOID:2870 risk CIViC:538 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S2215Y sequence variation in gene MTOR/NCBI:2475 1967 check_entity AN5445-1 MYB AMPLIFICATION MYB NCBI:4602 gene childhood low-grade glioma DOID:0080830 prognostic 81865-8 PubMed:29948154 MYB amplification was detected in 28 of 263 patients with PLGGs using Fluorescence In situ hybridization (FISH) analysis. The amplification of MYB was strongly associated with greater progression-free survival (p=0.04) but did not affect overall survival (p=0.13) [amplified (n=19) vs not amplified (n=177)]. MYB amplification was not an independent prognostic factor in multivariate analysis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MYB/NCBI:4602 1968 AN5445-1 MYB AMPLIFICATION MYB NCBI:4602 gene childhood low-grade glioma DOID:0080830 prognostic 81865-8 CIViC:2524 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MYB/NCBI:4602 1968 AN5446-1 MYB MYB::QKI mutation MYB NCBI:4602 gene angiocentric glioma DOID:0081261 diagnostic 81865-8 PubMed:26829751 A comprehensive genomic analysis was conducted on 172 cases of pediatric low-grade gliomas (PLGGs) across various histologic subtypes, utilizing whole-genome sequencing (WGS) and/or RNA sequencing. The study identified recurrent somatic alterations in 154 tumors (90%), encompassing all 140 tumors subjected to WGS. Among the seven angiocentric gliomas (AGs) examined, six displayed intrachromosomal deletions leading to MYB::QKI rearrangements, and the remaining one contained a MYB::ESR1 rearrangement. To validate these findings, 12 additional AGs with only formalin-fixed paraffin-embedded (FFPE) tissue were analyzed using fluorescence in situ hybridization (FISH) (n=9) or whole-exome sequencing (WES) and/or array comparative genomic hybridization (aCGH) (n=3). All tested cases were confirmed to harbor MYB rearrangement or deletion, though the specific gene partners were not determined. Functional studies both in vitro and in vivo demonstrated that MYB::QKI rearrangements facilitate tumorigenesis through activating MYB through truncation of a 3' region, driving aberrant MYB::QKI expression through enhancer translocation, and losing a single copy of the QKI tumor suppressor gene. The research concluded that MYB::QKI represents a novel recurrent fusion defining AGs diagnostically. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::MYB::QKI sequence variation in gene MYB/NCBI:4602 1969 check_entity AN5446-1 MYB MYB::QKI mutation MYB NCBI:4602 gene angiocentric glioma DOID:0081261 diagnostic 81865-8 PubMed:26810070 Comprehensive molecular studies through whole genome, whole exome, transcriptome sequencing, genome-wide copy number analysis, clustering analysis by DNA methylation profiling, as well as mutation hotspot analysis by Sanger sequencing and FISH were performed in a cohort of 91 low-grade neuroepithelial tumors (LGNTs) in 2016. Molecular alterations were detected in 31/32 (97%) of LGNTs with an astrocytic morphology, including 17 diffuse astrocytomas and 15 angiocentric gliomas, and the dominant lesions were MYB fusions (21/32; 66%). A MYB::QKI fusion characterized almost all angiocentric gliomas (13/15; 87%) with the reamining two tumors harborting a MYB::ESR1 fusion (1/15) or QKI rearrangement (1/15). The last case with QKI rearrangement had no apparent involvement of MYB or MYBL1, only showing split signals using FISH break-apart probes across QKI. However, the study did not have sufficient derivatives from this tumor for FFPE RNA-seq, so it was unable to determine whether a cryptic MYB::QKI aberration was present in this case, or whether QKI was fused to another gene partner. Most MYB::QKI fusions (78%) were between MYB exon 15 and QKI exon 5. Fusions were also identified between MYB exon 9 and QKI exon 5. These fusions removed the 3'UTR regulatory site or the entire inhibitory C-terminal domain of MYB, leading to its overexpression. Two tumors with a MYB::QKI fusion also harbored a BRAF p.V600E mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::MYB::QKI sequence variation in gene MYB/NCBI:4602 1969 check_entity AN5446-1 MYB MYB::QKI mutation MYB NCBI:4602 gene angiocentric glioma DOID:0081261 diagnostic 81865-8 PubMed:31595312 The study compiled clinicopathologic and molecular features of 46 gliomas with a MYB or MYBL1 alteration diagnosed at a single center. The tumors showed low-grade histopathologic features and were broadly classified as diffuse astrocytoma (n = 11) or angiocentric glioma (n=35). Molecular alterations interrogated by immunohistochemistry (n=46), RNA sequencing (n=29), FISH (n=24), or PCR-based sequencing (n=11) revealed MYB (n=44) or MYBL1 (n=2) alterations in all tumors. MYB and MYBL1 were fused with various gene partners. None had alterations in IDH1, IDH2, TP53, ATRX, or histone H3 genes. Regardless of histopathologic diagnosis or anatomic location, DNA methylome profiling on 35 MYB/MYBL1-altered gliomas formed a single cluster, supporting that MYB/MYBL1-altered gliomas represent a single disease entity with a range of clinical and pathologic characteristics. Only MYB rearrangements were detected in angiocentric gliomas. Of the 35 angiocentric gliomas, 22 had identified gene partners, primarily QKI (n=19), PCDHGA1 (n=1), LOC105378099 (n=1) and ESR1 (n=1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::MYB::QKI sequence variation in gene MYB/NCBI:4602 1969 check_entity AN5446-1 MYB MYB::QKI mutation MYB NCBI:4602 gene angiocentric glioma DOID:0081261 diagnostic 81865-8 CIViC:4217 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::MYB::QKI sequence variation in gene MYB/NCBI:4602 1969 check_entity AN5447-1 MYB Rearrangement MYB NCBI:4602 gene angiocentric glioma DOID:0081261 diagnostic 81865-8 PubMed:23633565 Copy-number analysis was performed on 44 diffuse pediatric low-grade gliomas (PLGGs) to identify recurrent alterations. The most significant event, focal 8q13.1 gain, was observed in 28% (5/18) of diffuse astrocytoma grade IIs (DA2), resulting in partial duplication of the transcription factor MYBL1 with truncation of its C-terminal negative-regulatory domain. A recurrent deletion-truncation breakpoint between exons 10 and 11 of MYB on 6q23.3 was identified in two of four angiocentric gliomas (AGs). This study did not mention the partner genes involved in the MYB rearrangements in the two AGs. The results define clinically relevant molecular subclasses of diffuse PLGGs and highlight a potential role for the MYB family in the biology of low-grade gliomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene MYB/NCBI:4602 1970 check_entity AN5447-1 MYB Rearrangement MYB NCBI:4602 gene angiocentric glioma DOID:0081261 diagnostic 81865-8 CIViC:4218 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene MYB/NCBI:4602 1970 check_entity AN5447-2 MYB Rearrangement MYB NCBI:4602 gene diffuse astrocytoma, MYB- or MYBL1-altered DOID:0081279 diagnostic 81865-8 PubMed:26810070 Comprehensive molecular studies (through whole genome, whole exome, transcriptome sequencing, genome-wide copy number analysis, clustering analysis by DNA methylation profiling, mutation hotspot analysis by Sanger sequencing, and FISH) were performed in a cohort of 91 low-grade neuroepithelial tumors (LGNTs), including diffuse astrocytomas, angiocentric gliomas, gangliogliomas, dysembryoplastic neuroepithelial tumors, oligodendrogliomas, and oligoastrocytomas. Molecular alterations were detected in 31/32 (97%) of LGNTs with an astrocytic morphology, including 17 diffuse astrocytomas and 15 angiocentric gliomas, and no IDH mutations were detected in these tumors. MYB (n=5) or MYBL1 (n=2) rearrangement fusions were detected in 41% (7/17) of diffuse astrocytomas, while the remaining tumors had alternations involving BRAF (n = 4), FGFR1/3 (n = 4), and others (n = 2). The gene partners involving MYB fusions in diffuse astrocytomas included PCDHGA1, LOC154902, and MMP16 and the gene parterners involivng MYBL included MMP16. In contrast, a MYB fusion (most frequently MYB::QKI) characterized almost all angiocentric gliomas (14–15). Only one other tumor across the series (an oligodendroglioma) had a MYB fusion (MYB::MAML2). MYB/MYBL-altered LGNTs clustered together with methylation profiling. The findings in LGNT with a predominantly astrocytic phenotype associating with MYB/MYBL alterations suggest a role of MYB/MYBL in these tumor categories with distinct characteristics. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene MYB/NCBI:4602 1971 check_entity AN5447-2 MYB Rearrangement MYB NCBI:4602 gene diffuse astrocytoma, MYB- or MYBL1-altered DOID:0081279 diagnostic 81865-8 PubMed:31595312 The study compiled the clinicopathologic and molecular features of 46 gliomas with a MYB or MYBL1 alteration diagnosed at a single center. The tumors showed low-grade histopathologic features and were broadly classified as diffuse astrocytoma (n = 11) or angiocentric glioma (n=35). Molecular alterations interrogated by immunohistochemistry (n=46), RNA sequencing (n=29), FISH (n=24), or PCR-based sequencing (n=11) revealed MYB (n=44) or MYBL1 (n=2) alterations in all tumors. None had alterations in IDH1, IDH2, TP53, ATRX, or histone H3 genes. Regardless of histopathologic diagnosis or anatomic location, DNA methylome profiling on 35 MYB/MYBL1-altered gliomas formed a single cluster, supporting that MYB/MYBL1-altered gliomas represent a single disease entity with a range of clinical and pathologic characteristics. Of the 11 diffuse astrocytomas with MYB (n=9) and MYBL1 (n=2) rearrangements, 9 had identified gene partners, including PCDHGA1 (n=5), LOC154902 (n=1), MMP16 (n=1), and MAML2 (n=1) with MYB and MMP16 (n=1) with MYBL1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene MYB/NCBI:4602 1971 check_entity AN5447-2 MYB Rearrangement MYB NCBI:4602 gene diffuse astrocytoma, MYB- or MYBL1-altered DOID:0081279 diagnostic 81865-8 CIViC:4218 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene MYB/NCBI:4602 1971 check_entity AN5448-1 MYBL1 Rearrangement MYBL1 NCBI:4603 gene diffuse astrocytoma, MYB- or MYBL1-altered DOID:0081279 diagnostic PubMed:26810070 Comprehensive molecular studies (through whole genome, whole exome, transcriptome sequencing, genome-wide copy number analysis, clustering analysis by DNA methylation profiling, mutation hotspot analysis by Sanger sequencing, and FISH) were performed in a cohort of 91 low-grade neuroepithelial tumors (LGNTs), including diffuse astrocytomas, angiocentric gliomas, gangliogliomas, dysembryoplastic neuroepithelial tumors, oligodendrogliomas, and oligoastrocytomas. Molecular alterations were detected in 31/32 (97%) of LGNTs with an astrocytic morphology, including 17 diffuse astrocytomas and 15 angiocentric gliomas, and no IDH mutations were detected in these tumors. MYB (n=5) or MYBL1 (n=2) rearrangements were detected in 41% (7/17) of diffuse astrocytomas, while the remaining tumors had alternations involving BRAF (n = 4), FGFR1/3 (n = 4), and others (n = 2). The gene partners involving MYB fusions in diffuse astrocytomas included PCDHGA1, LOC154902, and MMP16, and the gene partners involving MYBL1 included MMP16. In contrast, a MYB fusion (most frequently MYB::QKI) characterized almost all angiocentric gliomas (14 of 15). Only one other tumor across the series (an oligodendroglioma) had a MYB fusion (MYB::MAML2). MYB/MYBL-altered LGNTs clustered together with methylation profiling. The findings in LGNT with a predominantly astrocytic phenotype associating with MYB/MYBL alterations suggest a role of MYB/MYBL in these tumor categories with distinct characteristics. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene MYBL1/NCBI:4603 1972 check_entity AN5448-1 MYBL1 Rearrangement MYBL1 NCBI:4603 gene diffuse astrocytoma, MYB- or MYBL1-altered DOID:0081279 diagnostic PubMed:31563982 Histological, molecular, and clinical analysis of 26 histologically prototypical isomorphic diffuse gliomas with a specific DNA methylation profile distinct from other glial/glio-neuronal brain tumors and normal hemispheric tissue were found to be most closely related to pediatric MYB/MYBL1-altered diffuse astrocytomas and angiocentric gliomas. IDH1/2-wildtype status was verified by Sanger sequencing of 24 cases with sufficient DNA. Integrating copy number and RNA sequencing demonstrated MYBL1 (n=14) or MYB (n=6) alterations in 77% (20/26) of these tumors. Nine tumors had MYBL1 rearrangements (including one involving 5’ of MYBL1) with various gene partners, including MMP16 (n=3), RAD51B (n=1), MAML2 (n=1), ZFHX4 (n=1), TOX (n=1), RP11-586K2.1 (intergenic region) (n=1), and RP11492M23.2 (intergenic region) (n=1). These fusions resulted in a deletion of the C-terminal negative regulatory C-myb domain of MYBL1. Copy number analysis revealed gain or loss involving MYBL1 in 10 tumors, including six with MYBL1 fusion and four without MYBL1 fusions detected. Increased MYBL1 expression was observed in 71% (10/14) of the tumors with MYBL1 alterations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene MYBL1/NCBI:4603 1972 check_entity AN5448-1 MYBL1 Rearrangement MYBL1 NCBI:4603 gene diffuse astrocytoma, MYB- or MYBL1-altered DOID:0081279 diagnostic PubMed:23633565 Copy-number analysis was performed on 44 diffuse pediatric low-grade gliomas (PLGGs) to identify recurrent alterations. The most significant event, focal 8q13.1 gain, was observed in 28% (5/18) of diffuse astrocytoma grade IIs (DA2). All five DA2 samples with 8q focal gains exhibited a common centromeric breakpoint within MYBL1 after exon 9, resulting in partial duplication of MYBL1 with truncation of its C-terminal negative-regulatory domain. Whole-genome sequencing of a MYBL1-rearranged DA2 demonstrated MYBL1 tandem duplication with the telomeric sequence located in MMP16. Truncated MYBL1 transcripts identified in this tumor induced anchorage-independent growth in 3T3 cells and tumor formation in nude mice. Truncated transcripts were also expressed in two additional DA2s with MYBL1 partial duplication. A similar recurrent deletion-truncation breakpoint was identified in two angiocentric gliomas (AGs) in the related gene MYB on 6q23.3. The results define clinically relevant molecular subclasses of diffuse PLGGs and highlight a potential role for the MYB family in the biology of low-grade gliomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene MYBL1/NCBI:4603 1972 check_entity AN5448-1 MYBL1 Rearrangement MYBL1 NCBI:4603 gene diffuse astrocytoma, MYB- or MYBL1-altered DOID:0081279 diagnostic CIViC:4878 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene MYBL1/NCBI:4603 1972 check_entity AN5449-1 MYC Overexpression MYC NCBI:4609 gene lung small cell carcinoma DOID:5409 risk 42794-8 PubMed:28490518 A preclinical study to evaluate the efficacy of targeting the overexpressed CHEK1 cell cycle chekpoint kinase, including both miRNA and Prexasertib-induced inhibition. Both in vitro and in vivo, Prexasertib had strong single agent efficacy and augmented the effect of Olaparib or Cisplatin in either combination, including platinum-resistant models. CHEK1 and MYC overexpression were predictors of response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene MYC/NCBI:4609 1973 AN5449-1 MYC Overexpression MYC NCBI:4609 gene lung small cell carcinoma DOID:5409 risk 42794-8 CIViC:1277 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene MYC/NCBI:4609 1973 AN5449-2 MYC Overexpression MYC NCBI:4609 gene multiple myeloma DOID:9538 risk 42794-8 PubMed:21889194 BET inhibition by JQ1 downregulates MYC transcription, followed by genome-wide downregulation of Myc-dependent target genes. In experimental models of multiple myeloma, a Myc-dependent hematologic malignancy, JQ1 produces a potent antiproliferative effect associated with cell-cycle arrest and cellular senescence. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene MYC/NCBI:4609 1974 AN5449-2 MYC Overexpression MYC NCBI:4609 gene multiple myeloma DOID:9538 risk 42794-8 CIViC:1277 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene MYC/NCBI:4609 1974 AN5450-1 MYCL EXPRESSION MYCL NCBI:4610 gene multiple myeloma DOID:9538 risk PubMed:27276402 Four myeloma cell lines were treated with two different BET inhibitors (I-BET151 or JQ1). Proliferation of three cell lines (KMS11, RPMI8226 and MM1S) but not U266 (only partial inhibition) was strongly inhibited by the BET inhibitors. Microarray analysis showed a downregulation of MYC-dependent genes after treatment. qRT-PCR showed that MYCL1 but not c-MYC and MYCN was expressed in U266 cells and I-BET151 induced downregulation of MYCL1. In contrast, c-MYC but not MYCL was expressed in the other cell lines and I-BET151 induced downregulation of c-MYC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene MYCL/NCBI:4610 1975 AN5450-1 MYCL EXPRESSION MYCL NCBI:4610 gene multiple myeloma DOID:9538 risk CIViC:666 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene MYCL/NCBI:4610 1975 AN5451-1 MYCN Amplification MYCN NCBI:4613 gene neuroblastoma DOID:769 prognostic;risk PubMed:26537256 The drug CBL0137 (a drug that interacts with SSRP1 aka FACT) exhibited a synergistic effect with standard chemotherapy (cyclophosphamide, etoposide, cisplatin, vincristine, etc.) by blocking repair of DNA damage caused by genotoxic drugs, thus creating a synthetic lethal environment in MYCN-amplified neuroblastoma cells. High MYCN expression was found to sensitize neuroblastoma cells to CBL0137. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MYCN/NCBI:4613 1976 AN5451-1 MYCN Amplification MYCN NCBI:4613 gene neuroblastoma DOID:769 prognostic;risk PubMed:25517749 In a cohort of 1596 diagnostic tumor samples taken from patients enrolled in the Children's oncology group (COG) neuroblastoma biology protocol ANBL00B1, 1579 samples were annotated with MYCN amplification status. 1239 (78%) were not MYCN amplified, and 349 (22%) were MYCN amplified. Five year event free survival was 74 +/- 1.6 months in non MYCN amplified cases and 39 +/- 4.1 months in amplified cases. Differences were significant with p<0.0001. Five year overall survival was 83 +/- 1.4 months and non MYCN amplified cases and 46 +/- 4.2 months in amplified cases, with p<0.0001, indicating poor prognosis for MYCN amplified cases. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MYCN/NCBI:4613 1976 AN5451-1 MYCN Amplification MYCN NCBI:4613 gene neuroblastoma DOID:769 prognostic;risk PubMed:26733615 JQ1 and panobinostat synergistically reduced LIN28B gene and N-Myc protein expression, and synergistically induced growth inhibition and apoptosis in neuroblastoma cells, but not normal nonmalignant cells in vitro In neuroblastoma-bearing mice, JQ1 and panobinostat synergistically and considerably reduced N-Myc protein expression in tumor tissues and blocked tumor progression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MYCN/NCBI:4613 1976 AN5451-1 MYCN Amplification MYCN NCBI:4613 gene neuroblastoma DOID:769 prognostic;risk CIViC:294 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene MYCN/NCBI:4613 1976 AN5452-1 MYD88 L265P mutation MYD88 NCBI:4615 gene chronic lymphocytic leukemia DOID:1040 prognostic 82140-5 PubMed:24943832 MYD88 mutations were identified in 24 of 1080 screened CLLs. They were exclusively seen in instances of mutated IGHV genes (18/23, P = 0.0001), a widely recognized prognostic signature for better outcome in CLL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L265P sequence variation in gene MYD88/NCBI:4615 1977 check_entity AN5452-1 MYD88 L265P mutation MYD88 NCBI:4615 gene chronic lymphocytic leukemia DOID:1040 prognostic 82140-5 CIViC:420 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L265P sequence variation in gene MYD88/NCBI:4615 1977 check_entity AN5452-2 MYD88 L265P mutation MYD88 NCBI:4615 gene lymphoplasmacytic lymphoma DOID:0060901 risk 82140-5 PubMed:25853747 A prospective study of ibrutinib in 63 symptomatic patients with Waldenström's macroglobulinemia who had received at least one previous treatment. The response rates were highest among patients with MYD88(L265P) and CXCR4(WT). The MYD88 L265P mutation was present in 56 patients (89%). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L265P sequence variation in gene MYD88/NCBI:4615 1978 check_entity AN5452-2 MYD88 L265P mutation MYD88 NCBI:4615 gene lymphoplasmacytic lymphoma DOID:0060901 risk 82140-5 PubMed:22931316 In a study of 30 patients with Waldenström’s macroglobulinemia, 87% had MYD88(L265P) mutations. Waldenstrom macroglobulinemia cells expressing MYD88(L265P) were treated with an MYD88 homodimerization inhibitor or an IRAK 1/4 kinase inhibitor. The cells showed a decrease in staining of NF-kappa-B p65 phosphorylation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L265P sequence variation in gene MYD88/NCBI:4615 1978 check_entity AN5452-2 MYD88 L265P mutation MYD88 NCBI:4615 gene lymphoplasmacytic lymphoma DOID:0060901 risk 82140-5 CIViC:420 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L265P sequence variation in gene MYD88/NCBI:4615 1978 check_entity AN5453-1 MYD88 Overexpression MYD88 NCBI:4615 gene breast cancer DOID:1612 risk 82140-5 PubMed:26596839 In this retrospective analysis of 211 breast cancer tissues, MYD88 overexpression was correlated with poor survival. In-vitro experiments showed a decrease in sensitivity towards paclitaxel in cell-lines with high MYD88 expression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene MYD88/NCBI:4615 1979 AN5453-1 MYD88 Overexpression MYD88 NCBI:4615 gene breast cancer DOID:1612 risk 82140-5 CIViC:288 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene MYD88/NCBI:4615 1979 AN5454-1 MYOD1 L122R mutation MYOD1 NCBI:4654 gene rhabdomyosarcoma DOID:3247 prognostic PubMed:34166060 This study evaluated 641 cases of rhabdomyosarcoma (RMS), enrolled on Children’s Oncology Group trials (1998-2017) and UK malignant mesenchymal tumor and RMS2005 trials (1995-2016), for mutations in 39 genes previously implicated in RMS. The analysis was done using a custom-capture sequencing assay. MYOD1 L122R variant was identified in 17 cases (3%) and was not restricted to spindle-cell histology, but was also observed in association with other histologic patterns (including cases with densely packed cells that mimicked embryonal rhabdomyosarcoma (ERMS) or RMS not otherwise specified ). MYOD1 mutation showed association with older age, head and neck primary site, and a dismal survival. In both COG and UK patient cohorts, patients with the MYOD1 L122R mutation had rapid disease progression and significantly worse event free survival as compared to the patients with wild-type MYOD1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L122R sequence variation in gene MYOD1/NCBI:4654 1980 check_entity AN5454-1 MYOD1 L122R mutation MYOD1 NCBI:4654 gene rhabdomyosarcoma DOID:3247 prognostic CIViC:2901 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L122R sequence variation in gene MYOD1/NCBI:4654 1980 check_entity AN5454-2 MYOD1 L122R mutation MYOD1 NCBI:4654 gene spindle cell rhabdomyosarcoma DOID:3260 diagnostic;prognostic PubMed:27562493 This study evaluated forty-nine cases of rhabdomyosarcoma (RMS) (17 cases of alveolar RMS, 10 of embryonal RMS, 21 of spindle cell and sclerosing RMS, and a single case of a pleomorphic RMS) for MYOD1 (L122R), PIK3CA (H1047), and PIK3CA (E542/E545) variants. All 10 cases that were positive for the MYOD1 (L122R) variant were either the spindle cell (3/12) or the sclerosing (7/9) subtypes of RMS, while all 10 cases of the embryonal subtype of RMS were negative for the MYOD1 (L122R) variant. The study suggests that the MYOD1 L122R variant is specific for spindle cell and sclerosing subtype of RMS (where it was detected in 10/21 cases or 48%). The study also confirmed the positive relationship between the spindle cell and the sclerosing subtypes of RMS, which both can have the same molecular abnormality (MYOD1 L122R variant) and are now considered to be the same subtype. Finally, the study confirmed the negative correlation between the aforementioned subtypes with the embryonal subtype of rhabdomyosarcoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L122R sequence variation in gene MYOD1/NCBI:4654 1981 check_entity AN5454-2 MYOD1 L122R mutation MYOD1 NCBI:4654 gene spindle cell rhabdomyosarcoma DOID:3260 diagnostic;prognostic PubMed:30604891 This study examined 17 cases of spindle cell/sclerosing rhabdomyosarcoma (SC/SRMS) for the presence of MYOD1 variants. 12 cases harbored a MYOD-1 mutation, of which 8 cases were homozygous for p.L122R, 3 were heterozygous for p.L122R, and 1 was heterozygous for a novel p.E118K variant. There was one case of predominantly spindle cell rhabdomyosarcoma with the MYOD-1 mutation that also contained a PIK3CA mutation. The case with both MYOD-1 and PIK3CA mutations consisted histologically of lipoblasts within focally myxoid stroma, thus demonstrating that the PIK3CA mutation was a secondary aberration while MYOD-1 was the primary neomorphic mutation. On clinical follow-up, seven of the MYOD-1 variant cases experienced local recurrences and/or metastatic disease. In a median of a 13.5 month follow-up, there was 1 patient who passed away, 8 patients who were alive with the disease, and 3 patients who were alive without the disease; there was no correlation with the type of treatment that the patients had received. This supports aggressive clinical course for SC/SRMS positive for MYOD-1 variants, regardless of the presence of a concurrent PIK3CA mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L122R sequence variation in gene MYOD1/NCBI:4654 1981 check_entity AN5454-2 MYOD1 L122R mutation MYOD1 NCBI:4654 gene spindle cell rhabdomyosarcoma DOID:3260 diagnostic;prognostic PubMed:24824843 This study assessed MYOD1 exon 1 mutations in pediatric and adult sclerosing and spindle cell rhabdomyosarcoma. 5 sclerosing (2 pediatric and 3 adults) and 11 spindle cell rhabdomyosarcomas (3 pediatric and 8 adults) were subject to targeted PCR and sanger sequencing of MYOD1 exon 1 hotspot mutation and PIK3CA exon 9 and exon 20 mutations. FISH analysis for MDM2 and CDK4 amplification was also performed. A total of 9 RMS (4 pediatric and 5 adult type) cases were positive for MYOD1 p.L122R hotspot mutation which included all 5 sclerosing RMS and 4/11 spindle cell RMS (2/3 pediatric and 2/8 adult). 3/9 MYOD1-mutant RMS showed additional PIK3CA mutation in exon 9 while no kinase domain (exon 20) mutations were identified. None of the cases harbored MDM2 gene amplification. The recurrent MYOD1 mutation supports spindle cell and sclerosing RMS being a single pathogenic entity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L122R sequence variation in gene MYOD1/NCBI:4654 1981 check_entity AN5454-2 MYOD1 L122R mutation MYOD1 NCBI:4654 gene spindle cell rhabdomyosarcoma DOID:3260 diagnostic;prognostic PubMed:31949721 This study assessed the clinicopathologic and molecular features of 13 spindle cell (SRMS) and 7 spindle cell/sclerosing rhabdomyosarcomas (ScRMS) arising in the head and neck region. Age ranged from 2 months to 57 years. All ScRMS (n=7) and 8/13 SRMS showed MYOD1 p.L122R mutation. A PIK3CA mutation was seen in 7/13 SRMS and 4/7 ScRMS, 8 of which had concomitant MYOD1 mutation. MYOD1 p.L122R mutation is a recurrent event and supports the diagnosis of SRMS and ScRMS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L122R sequence variation in gene MYOD1/NCBI:4654 1981 check_entity AN5454-2 MYOD1 L122R mutation MYOD1 NCBI:4654 gene spindle cell rhabdomyosarcoma DOID:3260 diagnostic;prognostic PubMed:26501226 This study looked at 26 spindle cell and sclerosing rhabdomyosarcomas. 11 were congenital/infantile type diagnosed at birth or within one year of age, 10 of which harbored recurrent fusions involving VGLL2 or NCOA2 genes. The remaining 15 cases were diagnosed in patients older than age of one (2-17 years old); 10 showed MYOD1 p.L122R mutation, 4 of which showed an additional concomitant PIK3CA mutation. Cases with both PIK3CA and MYOD1 mutations were uniformly characterized by a sclerosing histology. MYOD1 mutation was homozygous in 8 cases. Patients with VGLL2 or NCOA2 fusion-positive RMS were alive and well on follow-up (median of 7 years) and none developed distant metastases. 7 of 9 patients with MYOD1 mutant RMS died of the disease with a median of 1.5 years. 3 fusion/MYOD1 negative cases with available follow up show no evidence of disease. This supports a better prognosis for spindle cell / sclerosing rhabdomyosarcoma with VGLL1 or NCOA2 fusions and a worse prognosis for patients with MYOD1 p.L122R mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L122R sequence variation in gene MYOD1/NCBI:4654 1981 check_entity AN5454-2 MYOD1 L122R mutation MYOD1 NCBI:4654 gene spindle cell rhabdomyosarcoma DOID:3260 diagnostic;prognostic CIViC:2901 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L122R sequence variation in gene MYOD1/NCBI:4654 1981 check_entity AN5455-1 NAPRT Promoter Hypermethylation NAPRT NCBI:93100 gene cancer DOID:162 risk PubMed:24097869 Tumor-specific promoter hypermethylation of NAPRT1 led to loss of NAPRT1 expression in most tumor types sensitive to treatment with Nampt inhibitor GNE-617 and nicotinic acid. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition NAPRT Promoter Hypermethylation [biomarker_term_in_review] 1982 not_mapped AN5455-1 NAPRT Promoter Hypermethylation NAPRT NCBI:93100 gene cancer DOID:162 risk CIViC:370 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition NAPRT Promoter Hypermethylation [biomarker_term_in_review] 1982 not_mapped AN5456-1 NCOA2 HEY1::NCOA2 mutation NCOA2 NCBI:10499 gene mesenchymal chondrosarcoma DOID:4545 diagnostic PubMed:22034177 A HEY1-NCOA2 fusion joining exon 4 of HEY1 to exon 13 of NCOA2 was identified in 10 mesenchymal chondrosarcomas but was absent from all other sarcoma types tested including other chondrosarcoma subtypes suggesting this fusion is diagnostic for mesenchymal chondrosarcomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::HEY1::NCOA2 sequence variation in gene NCOA2/NCBI:10499 1983 check_entity AN5456-1 NCOA2 HEY1::NCOA2 mutation NCOA2 NCBI:10499 gene mesenchymal chondrosarcoma DOID:4545 diagnostic PubMed:26146478 6 of 6 patients with mesenchymal chondrosarcoma and sufficient tissue tested positive for NCOA2 rearrangments by FISH supporting that NCOA2 rearrangements (presumably HEY1-NCOA2 translocations) are prevalent in this disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::HEY1::NCOA2 sequence variation in gene NCOA2/NCBI:10499 1983 check_entity AN5456-1 NCOA2 HEY1::NCOA2 mutation NCOA2 NCBI:10499 gene mesenchymal chondrosarcoma DOID:4545 diagnostic PubMed:23252872 FISH was used to detect HEY1-NCOA2 fusions in 10 paraffin embedded samples from patients diagnosed with mesenchymal chondrosarcoma. HEY1 and NCOA2 are located on the same chromosome but generate distinct FISH signals, whereas the HEY1-NCOA2 fusion appears as a single fused dot. Specimens were considered positive for fusion when FISH showed overlapping signals of HEY1 and NCOA2 in greater than 20% of the cells. Overlap signal of over 20% was seen in 8/10 patients. The two patients with no overlap signal were also negative for FISH staining, suggesting insufficient or damaged material for FISH. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::HEY1::NCOA2 sequence variation in gene NCOA2/NCBI:10499 1983 check_entity AN5456-1 NCOA2 HEY1::NCOA2 mutation NCOA2 NCBI:10499 gene mesenchymal chondrosarcoma DOID:4545 diagnostic PubMed:24124145 Meningeal hemangiopericytoma (HPC) and mesenchymal chondrosarcoma (MC) are aggressive neoplasms with overlapping clinical presentations and morphology. Thirteen FFPE samples of MC (9 females, 4 males) from ages 19 to 54 and Eighteen cases of meningeal HPC (8 females, 10 males) from ages from 24 to 73 years were tested using RT-PCR for the presence of HEY1-NCOA2 fusion. Of cases with evaluable RNA, 6/6 MC cases were positive for the fusion, but 0/11 meningeal HPC cases were fusion positive. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::HEY1::NCOA2 sequence variation in gene NCOA2/NCBI:10499 1983 check_entity AN5456-1 NCOA2 HEY1::NCOA2 mutation NCOA2 NCBI:10499 gene mesenchymal chondrosarcoma DOID:4545 diagnostic CIViC:2454 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::HEY1::NCOA2 sequence variation in gene NCOA2/NCBI:10499 1983 check_entity AN5457-1 NCOA3 AMPLIFICATION NCOA3 NCBI:8202 gene breast cancer DOID:1612 prognostic PubMed:23322234 In patients with breast cancer, those with amplification of NCOA3 had shorter disease-specific survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene NCOA3/NCBI:8202 1984 AN5457-1 NCOA3 AMPLIFICATION NCOA3 NCBI:8202 gene breast cancer DOID:1612 prognostic CIViC:204 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene NCOA3/NCBI:8202 1984 AN5458-1 NCOA3 OVEREXPRESSION NCOA3 NCBI:8202 gene breast cancer DOID:1612 prognostic PubMed:23322234 High expression determined by immunohistochemistry of NCOA3 was found in 571 out of 1,836 breast cancer samples. Those with high expression had worse overall and disease-specific survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene NCOA3/NCBI:8202 1985 AN5458-1 NCOA3 OVEREXPRESSION NCOA3 NCBI:8202 gene breast cancer DOID:1612 prognostic CIViC:205 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene NCOA3/NCBI:8202 1985 AN5459-1 NEDD9 EXPRESSION NEDD9 NCBI:4739 gene hepatocellular carcinoma DOID:684 prognostic PubMed:26893853 IHC was performed in 123 hepatocellular carcinoma tissues and their adjacent normal liver tissues for protein expression of HEF1 (NEDD9). Overexpression of HEF1 protein was observed in HCC tissue when compared with their adjacent non-malignant liver tissue. High expression of HEF1 correlated with higher advanced tumor, node, metastasis (TNM) stage and vascular invasion (P<0.05). In univariate and multivariate analysis, the expression of HEF1 was identified as an independent prognostic factor (Spearman's rank correlation, Kaplan-Meier plots and Cox regression model). In subgroup analysis, high expression of HEF1 correlated with a poorer prognosis in advanced (TNM III+IV) stages (P<0.05). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene NEDD9/NCBI:4739 1986 AN5459-1 NEDD9 EXPRESSION NEDD9 NCBI:4739 gene hepatocellular carcinoma DOID:684 prognostic CIViC:440 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene NEDD9/NCBI:4739 1986 AN5460-1 NF1 Inactivating Mutation NF1 NCBI:4763 gene cancer DOID:162 risk 21717-4 PubMed:35363510 In this Phase II study, 20 patients harboring activating RAS gene mutations (KRAS = 8, NRAS = 3. HRAS = 1), BRAF V600E mutations, and NF1 inactivating mutations (n=7) were treated with Selumetinib. No objected response was reported in these patients, and the six-month PFS was 15% (95% CI; 4-34). 25% (n=5) of the patients experienced a grade 3 or higher adverse effects, likely associated with selumetinib. Overall, selumetinib had limited efficacy in this cohort. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::inactivating:mutation sequence variation in gene NF1/NCBI:4763 1987 check_entity AN5460-1 NF1 Inactivating Mutation NF1 NCBI:4763 gene cancer DOID:162 risk 21717-4 CIViC:4748 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::inactivating:mutation sequence variation in gene NF1/NCBI:4763 1987 check_entity AN5461-1 NF1 Loss NF1 NCBI:4763 gene malignant peripheral nerve sheath tumor DOID:5940 risk 21717-4 PubMed:24373973 BRD4 inhibition supressess growth and tumorigenesis of NF1-/-, TP53-/- MPNST cells in mouse xenografts assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition NF1 Loss [biomarker_term_in_review] 1988 not_mapped AN5461-1 NF1 Loss NF1 NCBI:4763 gene malignant peripheral nerve sheath tumor DOID:5940 risk 21717-4 CIViC:679 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition NF1 Loss [biomarker_term_in_review] 1988 not_mapped AN5462-1 NF1 Mutation NF1 NCBI:4763 gene cancer DOID:162 risk 21717-4 PubMed:35363510 In this phase II study of the arm E of the NCI-COG pediatric MATCH trial, 20 patients (median age: 14) were treated with Selumetinib. High-grade glioma (n=7) and rhabdomyosarcoma (n=7) were the most common types of cancers in this cohort. There was no objective response (PR or CR), the best overall response being SD, in three patients. The 6-month PFS rate was 15% (95% CI; 4-34). 25% of the patients had grade 3 or higher AEs, possibly attributed to selumetinib treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NF1/NCBI:4763 1989 check_entity AN5462-1 NF1 Mutation NF1 NCBI:4763 gene cancer DOID:162 risk 21717-4 CIViC:4715 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NF1/NCBI:4763 1989 check_entity AN5462-2 NF1 Mutation NF1 NCBI:4763 gene childhood low-grade glioma DOID:0080830 risk 21717-4 PubMed:31151904 In a phase 2 trial, patients with pediatric low-grade glioma after at least one standard therapy were treated with MEK1/2 inhibitor selumetinib. In stratum 1, nine patients with WHO grade I pilocytic astrocytoma harboring KIAA1549-BRAF fusion or BRAF V600E mutation showed tumor response. The response rate was 36% (9/25). In stratum 3, ten patients with neurofibromatosis type 1 associated pediatric low-grade glioma showed tumor response. The response rate was 40% (10/25). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NF1/NCBI:4763 1990 check_entity AN5462-2 NF1 Mutation NF1 NCBI:4763 gene childhood low-grade glioma DOID:0080830 risk 21717-4 CIViC:583 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NF1/NCBI:4763 1990 check_entity AN5462-3 NF1 Mutation NF1 NCBI:4763 gene plexiform neurofibroma DOID:5151 risk 21717-4 PubMed:28029918 Treatment with selumetinib (NCT01362803) resulted in confirmed partial, long term responses in 17 of the 24 children with NF1 associated plexiform fibromas (71%) and decreases from baseline in neurofibroma volume in 12 of 18 mice (67%). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NF1/NCBI:4763 1991 check_entity AN5462-3 NF1 Mutation NF1 NCBI:4763 gene plexiform neurofibroma DOID:5151 risk 21717-4 CIViC:583 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NF1/NCBI:4763 1991 check_entity AN5462-4 NF1 Mutation NF1 NCBI:4763 gene skin melanoma DOID:8923 risk 21717-4 PubMed:23171796 Preclinical study of mouse melanoma in-vitro and in-vivo. In-vitro treament of Braf-mutant melanomas were 10-fold more sensitive to vermurafenib (PLX4032) treatment than Braf/Nf1-mutant melanomas. In vivo treatment of mice with Braf/Nf1-mutant allografts showed less sensitivity to vemurafenib (PLX4032) than the MEK inhibitor, PD0325901. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NF1/NCBI:4763 1992 check_entity AN5462-4 NF1 Mutation NF1 NCBI:4763 gene skin melanoma DOID:8923 risk 21717-4 PubMed:23288408 NF1 was identified in an unbiased RNAi screen as mediator of resistance to BRAF inhibition in BRAF mutant melanoma. Knockdown of NF1 led to PLX4720 resistance in-vitro. MEK inhibition with AZD6244 (selumetinib) had some efficacy but was also less active than in NF1 proficient cells. 4 patients with mutant alleles of NF1 were identified among patients relapsed after vemurafenib. Of these, one was a nonsense mutation (p.R2450*) present in both pretreatment and postrelapse biopsies. The patient had a progression-free survival (PFS) of about 10 weeks. The other NF1 mutations were silent events (patient 15, c.135T>C, patient 45 c.4023G>A, and patient 50 c3018C>T) located within candidate splicing motifs. Patients 15 and 50 exhibited response rates of relatively short duration (10 and 12 weeks, respectively) and the mutations were observed in both the pretreatment and postrelapse biopsies. Patient 45 experienced a PFS of 5 months, and the NF1 mutation was only present in the postrelapse biopsy indicative of acquired resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NF1/NCBI:4763 1992 check_entity AN5462-4 NF1 Mutation NF1 NCBI:4763 gene skin melanoma DOID:8923 risk 21717-4 CIViC:583 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NF1/NCBI:4763 1992 check_entity AN5463-1 NF2 K159fs mutation NF2 NCBI:4771 gene breast cancer DOID:1612 risk 45332-4 PubMed:25878190 23 patients were treated with temsirolimus containing regimens. 1 patient with a complete response >3 years had a K159fs*16 mutation in NF2. 2 patients were tested for NF2 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::k159fs:mutation sequence variation in gene NF2/NCBI:4771 1993 check_entity AN5463-1 NF2 K159fs mutation NF2 NCBI:4771 gene breast cancer DOID:1612 risk 45332-4 CIViC:275 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::k159fs:mutation sequence variation in gene NF2/NCBI:4771 1993 check_entity AN5464-1 NF2 Loss NF2 NCBI:4771 gene thyroid gland carcinoma DOID:3963 risk 45332-4 PubMed:26359368 NF2 loss promotes oncogenic RAS-signaling via YAP-dependent transactivation of RAS and sensitizes to MEK inhibition. The authors demonstrate this in (A) isogenic lines derived from C643 cells (HRASG13R, NF2-WT) modified to stably express shNF2, (B) in set of 7 RAS-mutant thyroid cancer cell lines that differ in their NF2 expression levels, and (C) in a Hras-G12V/Nf2-null mouse model. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition NF2 Loss [biomarker_term_in_review] 1994 not_mapped AN5464-1 NF2 Loss NF2 NCBI:4771 gene thyroid gland carcinoma DOID:3963 risk 45332-4 CIViC:678 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition NF2 Loss [biomarker_term_in_review] 1994 not_mapped AN5465-1 NF2 Y177fs mutation NF2 NCBI:4771 gene peritoneal mesothelioma DOID:1788 risk 45332-4 PubMed:25798586 A frameshift mutation in NF2 at position Y177 was found in a patient who responded poorly to therapy and died within 8 months of diagnosis. Initially treated with 3 cycles of systemic chemotherapy with cisplatin and pemetrexed with modest response, 2 months after cytoreductive surgery the patient had no response to platinum doublet chemotherapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::y177fs:mutation sequence variation in gene NF2/NCBI:4771 1995 check_entity AN5465-1 NF2 Y177fs mutation NF2 NCBI:4771 gene peritoneal mesothelioma DOID:1788 risk 45332-4 CIViC:241 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::y177fs:mutation sequence variation in gene NF2/NCBI:4771 1995 check_entity AN5466-1 NF2 c.1396C>T mutation NF2 NCBI:4771 gene adult spinal cord ependymoma DOID:7788 diagnostic 45332-4 PubMed:21294614 Blood or tumor specimens of 37 unrelated adult patients with ependymomas related to neurofibromatosis Type 2 (NF2) underwent sequencing of the NF2 gene to reveal germline variants. Overall, 64% were found to harbor truncating mutations of NF2, which the authors conclude supports previous reports of truncating mutations in NF2 associate with more severe phenotypes. Three unrelated patients harbored NF2 R466* (c.1396C>T). It's unclear whether these three patients were symptomatic, but none of them underwent surgical resection of the ependymomas during the study period. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.1396c>t:mutation sequence variation in gene NF2/NCBI:4771 1996 check_entity AN5466-1 NF2 c.1396C>T mutation NF2 NCBI:4771 gene adult spinal cord ependymoma DOID:7788 diagnostic 45332-4 CIViC:2871 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.1396c>t:mutation sequence variation in gene NF2/NCBI:4771 1996 check_entity AN5467-1 NFE2L2 Mutation NFE2L2 NCBI:4780 gene lung squamous cell carcinoma DOID:3907 risk PubMed:174406 In an NCI-CTEP phase 2 trial, patients with squamous cell lung carcinoma with NFE2L2 mutations were treated with TORC1/2 inhibitor TAK-228. The response rate was 29% (2/7）and disease control rate was 100%. NFE2L2 mutations included Exon 2 deletion, F37V, D29H, W24C, E79K, G31R, R34G, R34Q, W24R, D77H, and T80R. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NFE2L2/NCBI:4780 1997 check_entity AN5467-1 NFE2L2 Mutation NFE2L2 NCBI:4780 gene lung squamous cell carcinoma DOID:3907 risk CIViC:2618 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NFE2L2/NCBI:4780 1997 check_entity AN5468-1 NOT KIT D816V NR4A2 NCBI:4929 gene systemic mastocytosis DOID:349 risk 34492-9 PubMed:19193436 n this open-label phase II study, 20 patients with systemic mastocytosis (SM) were recruited between 2003-2005. 7/20 patients were KIT D816V mutation-negative, among which one patient achieved objective response and had complete resolution of signs and symptom; with normalization of bone marrow/blood abnormalities and tryptase levels. The patient remains in complete remission after more than 44 months. Moreover, four other patients reported improvement in some of their symptoms but no complete response was recorded. These data support imatinib’s use in SM patients with KIT D816V mutation-negative status. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D816V sequence variation in gene NR4A2/NCBI:4929 1998 check_entity AN5468-1 NOT KIT D816V NR4A2 NCBI:4929 gene systemic mastocytosis DOID:349 risk 34492-9 CIViC:4353 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D816V sequence variation in gene NR4A2/NCBI:4929 1998 check_entity AN5469-1 NOTCH1 Amplification NOTCH1 NCBI:4851 gene colorectal cancer DOID:9256 prognostic;risk 99126-5 PubMed:26152787 NOTCH1 copy-number gain in a patient-derived tumor xenograft model of colorectal cancer, was associated with increased NOTCH1 and JAG1 activity and response to a NOTCH1-targeting antibody (PF-06293622). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene NOTCH1/NCBI:4851 1999 AN5469-1 NOTCH1 Amplification NOTCH1 NCBI:4851 gene colorectal cancer DOID:9256 prognostic;risk 99126-5 CIViC:326 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene NOTCH1/NCBI:4851 1999 AN5470-1 NOTCH1 D1642H mutation NOTCH1 NCBI:4851 gene lung non-small cell carcinoma DOID:3908 prognostic 99126-5 PubMed:20007775 NOTCH1 gain-of-function mutations, including D1642H (called D1643H in publication), have shown to be correlated with poor prognosis in lung cancer. This is in a TP53 wild-type context. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D1642H sequence variation in gene NOTCH1/NCBI:4851 2000 check_entity AN5470-1 NOTCH1 D1642H mutation NOTCH1 NCBI:4851 gene lung non-small cell carcinoma DOID:3908 prognostic 99126-5 CIViC:135 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D1642H sequence variation in gene NOTCH1/NCBI:4851 2000 check_entity AN5471-1 NOTCH1 Loss-of-function NOTCH1 NCBI:4851 gene head and neck squamous cell carcinoma DOID:5520 risk 99126-5 PubMed:24277854 In an evaluation of 96 head and neck squamous cell carcinoma (HNSCC) cell lines, 31 were responsive to LGK974 (PORCN inhibitor). Of 40 cell lines (25 responsive, 15 non-responsive) that were exome sequenced, 6 cell lines had NOTCH1 loss-of-function mutations (N-terminal frameshift/nonsense) and 5/6 cell lines that had NOTCH1 mutations were susceptible to LGK974 (PORCN inhibitor). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition NOTCH1 Loss-of-function [biomarker_term_in_review] 2001 not_mapped AN5471-1 NOTCH1 Loss-of-function NOTCH1 NCBI:4851 gene head and neck squamous cell carcinoma DOID:5520 risk 99126-5 CIViC:597 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition NOTCH1 Loss-of-function [biomarker_term_in_review] 2001 not_mapped AN5472-1 NOTCH1 Mutation NOTCH1 NCBI:4851 gene chronic lymphocytic leukemia DOID:1040 prognostic 99126-5 PubMed:23086750 In the randomized UK LRF CCL4 phase 3 trial comparing first-line treatment with chlorambucil, fludarabine, or fludarabine plus cyclophosphamide, univariate analysis of patients with NOTCH1 mutations (within amino acids 2405-2525, a 399bp region of the PEST domain) demonstrated poorer overall survival (54.8 vs 74.6 months, P=0.02) and progression free survival (22 vs 26.4 months, P=0.02) compared to patients with wild-type NOTCH1. Progression-free survival was not significant (P = 0.21), however, overall survival remained significant (P = 0.03) under multivariate analysis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NOTCH1/NCBI:4851 2002 check_entity AN5472-1 NOTCH1 Mutation NOTCH1 NCBI:4851 gene chronic lymphocytic leukemia DOID:1040 prognostic 99126-5 PubMed:24943832 In a multivariate analysis of 774 CLL patients, NOTCH1 mutations were not significantly correlated with shorter time to first treatment (HR=1.305; 95% CI=0.923-1.847). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NOTCH1/NCBI:4851 2002 check_entity AN5472-1 NOTCH1 Mutation NOTCH1 NCBI:4851 gene chronic lymphocytic leukemia DOID:1040 prognostic 99126-5 PubMed:26837699 In a study of 406 previously untreated CLL cases, a multivariate analysis indicated clonal NOTCH1 mutations (N=55) were significantly associated with reduced overall survival (HR: 1.5; 95%CI: 1.13-1.99; P = 0.0049). Subclonal mutations (VAF <12%) were not associated with reduced OS (N=29, P=0.94, univariate analysis). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NOTCH1/NCBI:4851 2002 check_entity AN5472-1 NOTCH1 Mutation NOTCH1 NCBI:4851 gene chronic lymphocytic leukemia DOID:1040 prognostic 99126-5 CIViC:206 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NOTCH1/NCBI:4851 2002 check_entity AN5472-2 NOTCH1 Mutation NOTCH1 NCBI:4851 gene mantle cell lymphoma DOID:0050746 prognostic 99126-5 PubMed:22210878 14 out of 121 patient samples contained mutations in NOTCH1. Those with mutations had worse overall survival than wild-type (median OS, 1.43 years vs. 3.86 years). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NOTCH1/NCBI:4851 2003 check_entity AN5472-2 NOTCH1 Mutation NOTCH1 NCBI:4851 gene mantle cell lymphoma DOID:0050746 prognostic 99126-5 CIViC:206 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NOTCH1/NCBI:4851 2003 check_entity AN5473-1 NOTCH1 P2514FS mutation NOTCH1 NCBI:4851 gene chronic lymphocytic leukemia DOID:1040 prognostic 99126-5 PubMed:21670202 In a cohort of 120 patients with chronic lymphoytic leukemia, those with P2515 frameshift deletions in NOTCH1 at diagnosis had worse overall and treatment free survival. NOTCH1 mutations were also found to be an independent poor predictor of survival regardless of TP53 and IGHV status. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::p2514fs:mutation sequence variation in gene NOTCH1/NCBI:4851 2004 check_entity AN5473-1 NOTCH1 P2514FS mutation NOTCH1 NCBI:4851 gene chronic lymphocytic leukemia DOID:1040 prognostic 99126-5 PubMed:22077063 NOTCH1 mutations were found to be associated with worse overall survival (3.77-fold increase in the hazard of death, P < .001) in a series of 309 newly diagnosed CLL and confirmed in an additional set of 230 patients. NOTCH1 mutations were mostly represented (26/34, 76.5%) by a recurrent 2-bp frameshift deletion (c.7544_7545delCT), with the remaining being other frameshift deletions or insertions. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::p2514fs:mutation sequence variation in gene NOTCH1/NCBI:4851 2004 check_entity AN5473-1 NOTCH1 P2514FS mutation NOTCH1 NCBI:4851 gene chronic lymphocytic leukemia DOID:1040 prognostic 99126-5 CIViC:207 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::p2514fs:mutation sequence variation in gene NOTCH1/NCBI:4851 2004 check_entity AN5474-1 NOTCH1 R2327W mutation NOTCH1 NCBI:4851 gene lung non-small cell carcinoma DOID:3908 prognostic 99126-5 PubMed:20007775 NOTCH1 gain-of-function mutations, including R2327W (called R2328W in publication), have shown to be correlated to poor prognosis in lung cancer. This is in a TP53 wild-type context. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R2327W sequence variation in gene NOTCH1/NCBI:4851 2005 check_entity AN5474-1 NOTCH1 R2327W mutation NOTCH1 NCBI:4851 gene lung non-small cell carcinoma DOID:3908 prognostic 99126-5 CIViC:136 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R2327W sequence variation in gene NOTCH1/NCBI:4851 2005 check_entity AN5475-1 NOTCH1 S2275FS mutation NOTCH1 NCBI:4851 gene lung non-small cell carcinoma DOID:3908 prognostic 99126-5 PubMed:20007775 NOTCH1 gain-of-function mutations, including S2275fs, have shown to be correlated to poor prognosis in lung cancer. This is in a TP53 wild-type context. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::s2275fs:mutation sequence variation in gene NOTCH1/NCBI:4851 2006 check_entity AN5475-1 NOTCH1 S2275FS mutation NOTCH1 NCBI:4851 gene lung non-small cell carcinoma DOID:3908 prognostic 99126-5 CIViC:138 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::s2275fs:mutation sequence variation in gene NOTCH1/NCBI:4851 2006 check_entity AN5476-1 NOTCH1 V2444FS mutation NOTCH1 NCBI:4851 gene lung non-small cell carcinoma DOID:3908 prognostic 99126-5 PubMed:20007775 NOTCH1 gain-of-function mutations, including V2444fs, have shown to be correlated to poor prognosis in lung cancer. This is in a TP53 wild-type context. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::v2444fs:mutation sequence variation in gene NOTCH1/NCBI:4851 2007 check_entity AN5476-1 NOTCH1 V2444FS mutation NOTCH1 NCBI:4851 gene lung non-small cell carcinoma DOID:3908 prognostic 99126-5 CIViC:137 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::v2444fs:mutation sequence variation in gene NOTCH1/NCBI:4851 2007 check_entity AN5477-1 NPM1 EXON 12 MUTATION NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 54448-6 PubMed:16455956 NPM1 mutations were not associated with the M3 acute myeloid leukemia FAB subtype (0/55). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12:mutation sequence variation in gene NPM1/NCBI:4869 2008 check_entity AN5477-1 NPM1 EXON 12 MUTATION NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 54448-6 PubMed:16076867 NPM1 mutations were not associated with the M2 FAB subtype of acute myeloid leukemia. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12:mutation sequence variation in gene NPM1/NCBI:4869 2008 check_entity AN5477-1 NPM1 EXON 12 MUTATION NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 54448-6 PubMed:19357394 AML with mutated NPM1 is a provisional entity in the World Health Organization (WHO) classification of acute myeloid leukemia (AML). This mutation should be tested for in clinical trials and is recommended for testing in patients with cytogentically normal AML. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12:mutation sequence variation in gene NPM1/NCBI:4869 2008 check_entity AN5477-1 NPM1 EXON 12 MUTATION NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 54448-6 PubMed:17957027 NPM1 mutations were associated with de novo AML as well as M4 and M5 FAB subtypes. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12:mutation sequence variation in gene NPM1/NCBI:4869 2008 check_entity AN5477-1 NPM1 EXON 12 MUTATION NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 54448-6 PubMed:19059939 NPM1 mutations were associated with normal karyotype in older (>60) patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12:mutation sequence variation in gene NPM1/NCBI:4869 2008 check_entity AN5477-1 NPM1 EXON 12 MUTATION NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 54448-6 PubMed:19965647 ATRA treatment plus chemotherapy (daunorubicin, Ara-C, and thioguanine, N=113) did not effect overall survival in patients <60 years old with NPM1 mutation regardless of FLT3-ITD status compared to chemotherapy alone (N=94). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12:mutation sequence variation in gene NPM1/NCBI:4869 2008 check_entity AN5477-1 NPM1 EXON 12 MUTATION NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 54448-6 PubMed:22417203 Young patients (18-60) with NPM1 mutations had improved overall survival following high-dose versus standard dose daunorubicin (p=0.01) in univariate analysis. However, the adjusted p-value for multiple testing is 0.11. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12:mutation sequence variation in gene NPM1/NCBI:4869 2008 check_entity AN5477-1 NPM1 EXON 12 MUTATION NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 54448-6 PubMed:24797300 For patients with NPM1 mutation that achieved CR following induction therapy, relapse-free survival was improved following treatment with valproic acid. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12:mutation sequence variation in gene NPM1/NCBI:4869 2008 check_entity AN5477-1 NPM1 EXON 12 MUTATION NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 54448-6 PubMed:21719597 NSC348884 combined with ATRA treatment induces apoptosis in primary AML cells harboring mutant NPM1 but not in cells with wildtype NPM1 or both mutant NPM1 and FLT3-ITD. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12:mutation sequence variation in gene NPM1/NCBI:4869 2008 check_entity AN5477-1 NPM1 EXON 12 MUTATION NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 54448-6 PubMed:24927407 CD33 and CD123 expression was significantly increased in patients with NPM1 mutation with FLT3-ITD, indicating these patients may respond to combined anti-CD33 and anti-CD123 therapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12:mutation sequence variation in gene NPM1/NCBI:4869 2008 check_entity AN5477-1 NPM1 EXON 12 MUTATION NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 54448-6 PubMed:15659725 Cytoplasmic localization of NPM in AML patients was an independent prognositic factor associated with complete remission in response to induction therapy in a multivariate analysis (p=0.019) but not in a univariate analysis (p=0.07). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12:mutation sequence variation in gene NPM1/NCBI:4869 2008 check_entity AN5477-1 NPM1 EXON 12 MUTATION NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 54448-6 PubMed:19047294 Normal karyotype patients with NPM1 mutation and without FLT3-ITD had improved overall and relapse-free survival, complete remission rates and remission duration compared to all other combinations of mutants. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12:mutation sequence variation in gene NPM1/NCBI:4869 2008 check_entity AN5477-1 NPM1 EXON 12 MUTATION NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 54448-6 PubMed:24855211 NPM1 mutation (N=724) was associated with higher complete remission rates (92% vs 82%; P < 0.0001), lower cumulative incidence of relapse (42% vs 58%; P < 0.0001) and higher overall survival (48% vs 27%; P < .0001) than NPM1 wildtype status (N=885) in intermediate risk, young adult AML patients (median age 46 years). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12:mutation sequence variation in gene NPM1/NCBI:4869 2008 check_entity AN5477-1 NPM1 EXON 12 MUTATION NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 54448-6 PubMed:22430270 NPM1 mutation was associated with increased overall, event-free and relapse-free survival and remission after induction therapy in the entire cohort and in the cytogenetically normal subset of patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12:mutation sequence variation in gene NPM1/NCBI:4869 2008 check_entity AN5477-1 NPM1 EXON 12 MUTATION NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 54448-6 PubMed:18450602 In young patients (age 16-60) with previously untreated, cytogenetically normal acute myeloid leukemia, NPM1 mutation without FLT3-ITD was significantly associated with complete remission in multivariate analysis (odds ratio, 1.48; 95% CI, 1.21 to 1.80). Multivariate analysis was performed on all patients that were evaluated for a mutation in at least 1 gene (CEBPA, FLT3-ITD or NPM1) totaling 693/872 patients in the study. 130 patients had NPM1 mutations without FLT3-ITD. NPM1 mutations were evaluated in 570 patients (310 mutated). FLT3-ITD was evaluated in 531 patients (164 mutated). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12:mutation sequence variation in gene NPM1/NCBI:4869 2008 check_entity AN5477-1 NPM1 EXON 12 MUTATION NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 54448-6 PubMed:20026798 NPM1 mutations were associated with increased complete remission rates as well as longer overall disease free survival in normal karyotype AML patients >59 years old, particularly in those >69 years old. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12:mutation sequence variation in gene NPM1/NCBI:4869 2008 check_entity AN5477-1 NPM1 EXON 12 MUTATION NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 54448-6 PubMed:16051734 Younger (16-60), normal karyotype AML patients with Exon 12 NPM1 mutation and without FLT3-ITD have increased overall survival (N=74, P = .001), relapse-free survival (N=86, P < .001) and response to induction chemotherapy. Multivariate analysis identified NPM1 mutation in the absence of FLT3-ITD as a prognostic marker for the achievement of CR (P=0.004). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12:mutation sequence variation in gene NPM1/NCBI:4869 2008 check_entity AN5477-1 NPM1 EXON 12 MUTATION NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 54448-6 PubMed:19587375 Monitoring NPM1 mutation by cDNA-based RT-PCR effectively predicted relapse in 62/93 patients by >1 log increase in NPM1 levels (N=57) or lack of reduction in NPM1 levels following first line therapy (N=15). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12:mutation sequence variation in gene NPM1/NCBI:4869 2008 check_entity AN5477-1 NPM1 EXON 12 MUTATION NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 54448-6 PubMed:24859829 TET2 mutation reduces overall survival of normal karyotype patients with either an NPM1 mutation or NPM1 mutation without FLT3-ITD. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12:mutation sequence variation in gene NPM1/NCBI:4869 2008 check_entity AN5477-1 NPM1 EXON 12 MUTATION NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 54448-6 PubMed:26789727 Peripheral blood from NPM1 mutated AMLs was assessed for NPM1 mutation status at multiple time points using RT-qPCR with primers designed to amplify different mutant NPM1 transcripts. The test development cohort consisted of 194 cases and an independent validation cohort consisted of 91 cases. Persistence of NPM1-mutated transcripts in blood was present in 15% of the patients after the second chemotherapy cycle. This persistence was associated with a greater risk of relapse after 3 years of follow-up than was an absence of such transcripts (82% vs. 30%; hazard ratio, 4.80; 95% confidence interval [CI], 2.95 to 7.80; P<0.001) and a lower rate of survival (24% vs. 75%; hazard ratio for death, 4.38; 95% CI, 2.57 to 7.47; P<0.001). The presence of minimal residual disease was the only independent prognostic factor for death in multivariate analysis (hazard ratio, 4.84; 95% CI, 2.57 to 9.15; P<0.001). On sequential monitoring of minimal residual disease, relapse was reliably predicted by a rising level of NPM1-mutated transcripts. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12:mutation sequence variation in gene NPM1/NCBI:4869 2008 check_entity AN5477-1 NPM1 EXON 12 MUTATION NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 54448-6 PubMed:16046528 In normal karyotype patients with AML (15-65 years old), complete remission rates and overall, event-free and relapse-free survival were not different for patients harboring NPM1 exon 12 mutations (N=50) than those wildtype for NPM1 (N=56). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12:mutation sequence variation in gene NPM1/NCBI:4869 2008 check_entity AN5477-1 NPM1 EXON 12 MUTATION NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic;risk 54448-6 CIViC:86 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:12:mutation sequence variation in gene NPM1/NCBI:4869 2008 check_entity AN5478-1 NPM1 W288FS mutation NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;risk 54448-6 PubMed:21067377 No NPM1 mutations were identified in patients with favorable risk cytogenetics (79/215 patients). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::w288fs:mutation sequence variation in gene NPM1/NCBI:4869 2009 check_entity AN5478-1 NPM1 W288FS mutation NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;risk 54448-6 PubMed:21719597 NSC348884 induced apoptosis in OPI-AML3 cells harboring an NPM1 mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::w288fs:mutation sequence variation in gene NPM1/NCBI:4869 2009 check_entity AN5478-1 NPM1 W288FS mutation NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;risk 54448-6 PubMed:15659725 NPM1 mutation (Type A, W288fs) causes cytoplasmic localization of NPM when transfected into a non-hematopoietic cell line (293T cells). Cytoplasmic localization of NPM in AML patients was associated with good response to induction therapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::w288fs:mutation sequence variation in gene NPM1/NCBI:4869 2009 check_entity AN5478-1 NPM1 W288FS mutation NPM1 NCBI:4869 gene acute myeloid leukemia DOID:9119 diagnostic;risk 54448-6 CIViC:87 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::w288fs:mutation sequence variation in gene NPM1/NCBI:4869 2009 check_entity AN5479-1 NQO1 EXPRESSION NQO1 NCBI:1728 gene lung cancer DOID:1324 risk PubMed:21964527 Higher expression of NQO1 was correlated with decreased cytotoxicity of amrubicin (amrubicinol is the active metabolite) in 27 NSCLC and SCLC cell lines. siRNA knockdown of NQO1 (in two cell lines) increased amrubicinol cytotoxicity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene NQO1/NCBI:1728 2010 AN5479-1 NQO1 EXPRESSION NQO1 NCBI:1728 gene lung cancer DOID:1324 risk CIViC:397 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene NQO1/NCBI:1728 2010 AN5480-1 NQO1 P187S mutation NQO1 NCBI:1728 gene lung cancer DOID:1324 risk PubMed:21964527 The presence of NQO1 C609T SNP (rs1800566) was associated with decreased protein expression and higher amrubicin sensitivity in 29 NSCLC and SCLC cell lines. 15 of these cell lines were genotyped for C609T (only 3 were T/T, and the rest were C/C or C/T). Cell lines with the T/T genotype had lower expression of NQ01 and greater response to amrubicinol. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P187S sequence variation in gene NQO1/NCBI:1728 2011 check_entity AN5480-1 NQO1 P187S mutation NQO1 NCBI:1728 gene lung cancer DOID:1324 risk CIViC:398 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P187S sequence variation in gene NQO1/NCBI:1728 2011 check_entity AN5481-1 NRAS G12 mutation NRAS NCBI:4893 gene acute myeloid leukemia DOID:9119 prognostic 21719-0 PubMed:16434492 NRAS mutation status does not impact overall, event-free or disease-free survival in patients with AML. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12 sequence variation in gene NRAS/NCBI:4893 2012 check_entity AN5481-1 NRAS G12 mutation NRAS NCBI:4893 gene acute myeloid leukemia DOID:9119 prognostic 21719-0 CIViC:92 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12 sequence variation in gene NRAS/NCBI:4893 2012 check_entity AN5482-1 NRAS G12/G13 mutation NRAS NCBI:4893 gene acute myeloid leukemia DOID:9119 prognostic 21719-0 PubMed:27276561 Patients with a triple mutation of NPM1, DNMT3A, and NRAS (G12/13) (three-way interaction p=0.04) showed a relatively benign prognosis with an 8-year survival rate of 75% and a 10-year survival rate of 55%. Conversely, patients with a concomitant NPM1/DNMT3A co-mutation, in the absence of an NRAS (G12/13) mutation, showed a clinically unfavorable 10-year survival rate of 30%. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::g12/g13:mutation sequence variation in gene NRAS/NCBI:4893 2013 check_entity AN5482-1 NRAS G12/G13 mutation NRAS NCBI:4893 gene acute myeloid leukemia DOID:9119 prognostic 21719-0 CIViC:592 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::g12/g13:mutation sequence variation in gene NRAS/NCBI:4893 2013 check_entity AN5483-1 NRAS G12C mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 risk 21719-0 PubMed:20619739 Two patients participating in a large retrospective trial of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored NRAS G12C and were wild type for KRAS, PIK3CA, and BRAF. Both experienced stable disease, which the authors classified as non-response. The two patients whose tumors harbored NRAS G12C included a 63 year old female treated with cetuximab and irinotecan as a 3rd line treatment who had PFS of 34 weeks and OS of 55 weeks; and a 38 year old female treated with cetuximab, oxaliplatin and 5FU as a 2nd line therapy who had PFS of 12 weeks. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12C sequence variation in gene NRAS/NCBI:4893 2014 check_entity AN5483-1 NRAS G12C mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 risk 21719-0 CIViC:871 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12C sequence variation in gene NRAS/NCBI:4893 2014 check_entity AN5484-1 NRAS G12D mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 risk 21719-0 PubMed:20619739 One patient participating in a large retrospective trial of cetuximab in metastatic, treatment refractory colorectal cancer had a tumor which harbored NRAS G12D and was wild type for KRAS, PIK3CA, and BRAF. This patient was a 64 year old male treated with cetuximab and irinotecan as 5th line therapy who experienced stable disease and had PFS of 64 weeks and OS of 84 weeks. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene NRAS/NCBI:4893 2015 check_entity AN5484-1 NRAS G12D mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 risk 21719-0 PubMed:25666295 In a retrospective study of 148 treatment naive metastatic colorectal cancer patients, patients with RAS mutations (n=10), including KRAS A146T, KRAS G13D, NRAS G12D and NRAS Q179*, treated with FOLFOX4 plus cetuximab were associated with decreased overall survival (16.3mo vs. 28.5mo, HR:0.43, 95% CI:0.20-0.89, P=0.020) and decreased progression free survival (7.2mo vs. 9.7mo, HR:0.56, 95% CI:0.27-1.16, P=0.11), as compared to patients with wild-type KRAS and NRAS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene NRAS/NCBI:4893 2015 check_entity AN5484-1 NRAS G12D mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 risk 21719-0 CIViC:852 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G12D sequence variation in gene NRAS/NCBI:4893 2015 check_entity AN5485-1 NRAS G13D mutation NRAS NCBI:4893 gene melanoma DOID:1909 risk 21719-0 PubMed:18375819 Likely due to increased reliance of mutant NRAS on HSP90 for stabilization, inhibition of HSP90 by 17-AAG was shown to be effective in a patient with metastatic malignant melanoma with an NRAS G13D mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13D sequence variation in gene NRAS/NCBI:4893 2016 check_entity AN5485-1 NRAS G13D mutation NRAS NCBI:4893 gene melanoma DOID:1909 risk 21719-0 CIViC:93 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13D sequence variation in gene NRAS/NCBI:4893 2016 check_entity AN5486-1 NRAS G13R mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 risk 21719-0 PubMed:20619739 One patient participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had a tumor which harbored NRAS G13R, was wildtype for KRAS, BRAF and PIK3CA, and had individual response data. This patient was was a 68 year old male treated with cetuximab + irinotecan as 3rd line therapy who experienced stable disease (PFS: 18 weeks; OS: 34 weeks). Authors considered stable disease as both clinical benefit and non response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13R sequence variation in gene NRAS/NCBI:4893 2017 check_entity AN5486-1 NRAS G13R mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 risk 21719-0 CIViC:870 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G13R sequence variation in gene NRAS/NCBI:4893 2017 check_entity AN5487-1 NRAS Mutation NRAS NCBI:4893 gene acute myeloid leukemia DOID:9119 prognostic 21719-0 PubMed:15951308 The presence of NRAS mutation in AML patients does not impact diease prognosis (resistant disease, disease-free survival, complete remission rate, relapse rate, induction death). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2018 check_entity AN5487-1 NRAS Mutation NRAS NCBI:4893 gene acute myeloid leukemia DOID:9119 prognostic 21719-0 CIViC:208 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2018 check_entity AN5487-2 NRAS Mutation NRAS NCBI:4893 gene cancer DOID:162 risk 21719-0 PubMed:25504439 Preclinical study in 16 NRAS mutant cell lines (melanoma, lung carcinoma, neuroblastoma with various Q61, G13, G12 mutations). The combination of metformin and trametinib shown synergistic effects in most tested cell lines (no antagonistic effects observed) and a melanoma xenograft model. Metformin-induced PI3K pathway suppression was identified as a potential mechanism. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2019 check_entity AN5487-2 NRAS Mutation NRAS NCBI:4893 gene cancer DOID:162 risk 21719-0 PubMed:33637626 In this NCI-MATCH trial, 47 patients harboring codon 12, 13, or 61 NRAS mutated refractory solid tumors were treated with binimetinib. Of the 47 patients, >50% of the patients had metastatic colorectal adenocarcinoma (n=24). Around 30% of the the cohort had to discontinue due to binimetinib associated toxicity. The ORR was 2.1% (90% CI; 0.1-9.7), the 6-month PFS was 29.2% (90% CI; 19.4-44.0), the OS was 10.5 months (95% CI; 5.3-13.2), and the PFS was 3.5 months (95% CI; 1.8-5.8). Additionally, it was noted that patients with codon 61 mutated tumors had longer OS and PFS, compared to those with codon 12 or 13 mutated tumors. Overall, no appreciable antitumor activity was reported. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2019 check_entity AN5487-2 NRAS Mutation NRAS NCBI:4893 gene cancer DOID:162 risk 21719-0 PubMed:35363510 In this phase II study of the arm E of the NCI-COG pediatric MATCH trial, 20 patients (median age: 14) were treated with Selumetinib. High-grade glioma (n=7) and rhabdomyosarcoma (n=7) were the most common types of cancers in this cohort. There was no objective response (PR or CR), the best overall response being SD, in three patients. The 6-month PFS rate was 15% (95% CI; 4-34). 25% of the patients had grade 3 or higher AEs, possibly attributed to selumetinib treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2019 check_entity AN5487-2 NRAS Mutation NRAS NCBI:4893 gene cancer DOID:162 risk 21719-0 CIViC:208 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2019 check_entity AN5487-2 NRAS Mutation NRAS NCBI:4893 gene cancer DOID:162 risk 21719-0 CIViC:4715 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2019 check_entity AN5487-2 NRAS Mutation NRAS NCBI:4893 gene cancer DOID:162 risk 21719-0 CIViC:4748 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2019 check_entity AN5487-3 NRAS Mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 prognostic;risk 21719-0 PubMed:24666267 Patients with colorectal cancer harboring NRAS mutation have poorer survival outcome and worse prognosis than patients with wildtype NRAS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2020 check_entity AN5487-3 NRAS Mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 prognostic;risk 21719-0 PubMed:22586653 A cohort of patient-derived xenografts (PDX) from 85 patients with metastatic colorectal cancer was created. PDX were treated with cetuximab and mechanisms of resistance investigated. None of the xenografts harboring KRAS (N=18), NRAS (N=7) or BRAF (N=3) mutations showed a response to cetuximab whereas 1 out of 4 xenografts with a PIK3CA mutation responded to cetuximab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2020 check_entity AN5487-3 NRAS Mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 prognostic;risk 21719-0 PubMed:20619739 This was a retrospective study of 605 patients with metastatic, chemotherapy refractory colorectal cancer treated with cetuximab + chemotherapy. Patients with KRAS wildtype, NRAS assessable tumors, and individual response data (n=301) were genotyped for NRAS mutations. Patients harboring NRAS mutant tumors (n=13) had a significantly lower response rate than did patients with wildtype NRAS (n=289; 1/13 [7.7%] vs 110/289 [77.9%]; p =.013). However, there was no significant difference between patients with mutant or wildtype NRAS in disease control rate, progression free survival, or overall survival. Authors note that their small sample size of patients with NRAS mutant tumors made it difficult to assess the effect of NRAS mutation on survival thus the large confidence intervals. Authors further note that the close relationship between KRAS and NRAS, and the lack of NRAS response to another EGFR inhibitor (panitumumab) support the inclusion of NRAS genotyping prior to cetuximab treatment. Authors suggest screening for mutations in the following gene order: KRAS, BRAF, NRAS, PIK3CA exon 21 (listed as PIK3CA exon 20 in the source). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2020 check_entity AN5487-3 NRAS Mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 prognostic;risk 21719-0 PubMed:28275037 NCCN guidelines indicate colorectal cancer patients with NRAS mutations should not be treated with EGFR inhibitors cetuximab or panitumumab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2020 check_entity AN5487-3 NRAS Mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 prognostic;risk 21719-0 CIViC:208 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2020 check_entity AN5487-4 NRAS Mutation NRAS NCBI:4893 gene melanoma DOID:1909 prognostic;risk 21719-0 PubMed:22180178 In patients with stage IV melanoma, NRAS mutation was associated with reduced median survival compared to patients with wildtype NRAS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2021 check_entity AN5487-4 NRAS Mutation NRAS NCBI:4893 gene melanoma DOID:1909 prognostic;risk 21719-0 PubMed:24947927 Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655). Among 8 patients with NRAS mutated melanoma, 3 experienced clinical benefit: 2 stable disease and 1 partial response (1 Patient received study treatment for 323 days). Of 10 NRAS wt patients, 4 experienced clinical benefit. Authors note that RO4987655 demonstrates clinical efficacy in BRAF wildtype melanomas with NRAS mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2021 check_entity AN5487-4 NRAS Mutation NRAS NCBI:4893 gene melanoma DOID:1909 prognostic;risk 21719-0 PubMed:22805292 Phase 1 trial in 97 patients with melanoma (81 cutaneous or unknown, 16 uveal). Seven patients were found to harbor an NRAS mutation and two of them experienced stable disease (one 48 weeks on treatment). Patients with concurrent BRAFV600wt/NRASwt (n=20) had a trend of higher response rates (20%) than BRAFV600wt/NRAS-mutant patients (n=11; RR=0%; p=0.27), as well as a trend of higher percentage of patients on study at Week 24 or at 1 year (40% vs. 18% [p=0.26] and 30% vs. 0% [p=0.07], respectively). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2021 check_entity AN5487-4 NRAS Mutation NRAS NCBI:4893 gene melanoma DOID:1909 prognostic;risk 21719-0 PubMed:23431193 In six NRAS mutant melanoma cell lines, concomitant use of MEK inhibitor and PI3K/mTOR inhibitor resulted in greater decrease in cell viability than either alone, with the synergistic effect being marked in 4/6 cell lines. MEK inhibitor JTP-74057 and PI3K/mTOR inhibitor GSK2126458 together induced synergistic increase in apoptotic Annexin V+/PI+ cells in these cell lines. Tumor xenografts in nude mice were established with 5 of the 6 cell lines. Effects of single agent treatment with JTP-74057 or GSK2126458 ranged from minor inhibition to tumor stasis, while dual inhibitor treatment showed synergistic effects in each case, with marked tumor reductions in 2/5 cases and the authors report one compete response in a MaMel301 cell line xenograft mouse. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2021 check_entity AN5487-4 NRAS Mutation NRAS NCBI:4893 gene melanoma DOID:1909 prognostic;risk 21719-0 PubMed:24588908 In a panel of 7 NRAS mutant melanoma cell lines, all 7 were found to be sensitive to the MEK inhibitor MEK162, whereas 3 of 5 melanoma cell lines that were wild type for BRAF and NRAS were not sensitive to MEK162. In further tests using two of the seven NRAS mutant cell lines (YUDOSO Q16K/wt and YUKIM Q16R), colony forming capacity was reduced with increased MEK162 treatment, and MEK162 induced apoptotic markers in these cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2021 check_entity AN5487-4 NRAS Mutation NRAS NCBI:4893 gene melanoma DOID:1909 prognostic;risk 21719-0 PubMed:24265155 In a retrospective study of 44 relapsed melanoma patients harboring BRAF V600E or V600K (known BRAF inhibitor sensitizing mutations), MAPK pathway reactivation mechanisms were implicated in acquired resistance to BRAF inhibitor (vemurafenib or dabrafenib) monotherapy. The following MAPK pathway variants were found in progressive tumors with patient matched baseline tumors (some patients donated samples from multiple geographically/temporally distinct progressive tumors): NRAS mutations (G12D, G12R, G13R, Q61K, Q61R, Q61L) in 13/71 (18%) of progressive tumors, KRAS mutations (G12C, G12R, Q61H) in 5/71 (7%) of progressive tumors, mutant BRAF amplification (2-15 fold or 4-75 copies) in 11/57 (19%) of progressive tumors, mutant BRAF alternative splice variants (novel exon boundaries between 1/9, 1/11, 3/9) in 6/48 (13%) of progressive tumor RNA. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2021 check_entity AN5487-4 NRAS Mutation NRAS NCBI:4893 gene melanoma DOID:1909 prognostic;risk 21719-0 CIViC:208 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2021 check_entity AN5487-5 NRAS Mutation NRAS NCBI:4893 gene multiple myeloma DOID:9538 prognostic 21719-0 PubMed:18528420 In patients with multiple myeloma, the presence of a mutation in NRAS was not significantly associated with progression-free or overall survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2022 check_entity AN5487-5 NRAS Mutation NRAS NCBI:4893 gene multiple myeloma DOID:9538 prognostic 21719-0 CIViC:208 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2022 check_entity AN5487-6 NRAS Mutation NRAS NCBI:4893 gene skin melanoma DOID:8923 risk 21719-0 PubMed:25542057 Phase 1 trial of trametinib and docetaxel in patients with advanced melanoma lacking BRAF V600 mutations. 15 patients were enrolled (14 BRAF wt). Six patients had a partial response, including four out of eight patients with NRAS mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2023 check_entity AN5487-6 NRAS Mutation NRAS NCBI:4893 gene skin melanoma DOID:8923 risk 21719-0 PubMed:23414587 Phase II study in 71 patients with NRAS or BRAF V600 mutant melanoma treated with MEK162. Six (20%) of 30 patients with NRAS-mutated melanoma had a partial response (three confirmed). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2023 check_entity AN5487-6 NRAS Mutation NRAS NCBI:4893 gene skin melanoma DOID:8923 risk 21719-0 PubMed:24950457 Preclinical study in melanoma cell lines. Cell lines (2-5/assay) with NRAS mutation were more sensitive to Amuvatinib (inhibitor targets multiple tyrosine kinases) than BRAF mutant cell lines in growth inhibition, tyrosine phosphorylation inhibition, cell cycle and apoptotic (Annexin V) assays. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2023 check_entity AN5487-6 NRAS Mutation NRAS NCBI:4893 gene skin melanoma DOID:8923 risk 21719-0 PubMed:26987942 Inhibition of CDK4 and 6, regulators of the G1/S cell cycle checkpoint, arrests the cell cycle in the G1 phase, suppresses DNA synthesis, and inhibits cancer cell growth. There is an ongoing phase 1/2 trial of binimetinib with the CDK4/6 inhibitor ribociclib (LEE011) in mutant NRAS melanoma patients (NCT01781572). Early results from the 21 evaluable patients were very promising, with 7 patients achieving a partial response (33%) and 11 patients with stable disease (52%) assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2023 check_entity AN5487-6 NRAS Mutation NRAS NCBI:4893 gene skin melanoma DOID:8923 risk 21719-0 PubMed:28284557 NEMO is an ongoing, randomised, open-label phase 3 study of patients with advanced, unresectable, AJCC IIIC/IV NRAS-mutant melanoma. 402 patients that were previously untreated or progressed on or after previous immunotherapy were randomised to receive either binimetinib (269) or dacarbazine (133). The study's primary endpoint was progression free survival. Median follow-up was 1.7 months (IQR 1.4-4.1). Median progression-free survival was 2.8 months (95% CI 2.8-3.6) in the binimetinib group and 1.5 months (1.5-1.7) in the dacarbazine group, demonstrating improved progression-free survival of binimetinib compared with dacarbazine. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2023 check_entity AN5487-6 NRAS Mutation NRAS NCBI:4893 gene skin melanoma DOID:8923 risk 21719-0 CIViC:208 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NRAS/NCBI:4893 2023 check_entity AN5488-1 NRAS Q179X mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 risk 21719-0 PubMed:25666295 In a retrospective study of 148 treatment naive metastatic colorectal cancer patients, patients with RAS mutations (n=10), including KRAS A146T, KRAS G13D, NRAS G12D and NRAS Q179*, treated with FOLFOX4 plus cetuximab were associated with decreased overall survival (16.3mo vs. 28.5mo, HR:0.43, 95% CI:0.20-0.89, P=0.020) and decreased progression free survival (7.2mo vs. 9.7mo, HR:0.56, 95% CI:0.27-1.16, P=0.11), as compared to patients with wild-type KRAS and NRAS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q179X sequence variation in gene NRAS/NCBI:4893 2024 check_entity AN5488-1 NRAS Q179X mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 risk 21719-0 CIViC:1562 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q179X sequence variation in gene NRAS/NCBI:4893 2024 check_entity AN5489-1 NRAS Q61 mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 risk 21719-0 PubMed:20619739 Chemotherapy-refractory patients with KRAS wt metastatic colorectal cancer harboring NRAS mutation (primarily Q61, n=10) have a significantly lower response rate to cetuximab than patients wildtype for NRAS (7.1% [1/14] vs 38.1% [110/289]). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61 sequence variation in gene NRAS/NCBI:4893 2025 check_entity AN5489-1 NRAS Q61 mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 risk 21719-0 CIViC:94 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61 sequence variation in gene NRAS/NCBI:4893 2025 check_entity AN5489-2 NRAS Q61 mutation NRAS NCBI:4893 gene melanoma DOID:1909 diagnostic;risk 21719-0 PubMed:23861977 Melanoma associated with NRAS Q61 mutation was more often associated with those at the extremity than those at the trunk. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61 sequence variation in gene NRAS/NCBI:4893 2026 check_entity AN5489-2 NRAS Q61 mutation NRAS NCBI:4893 gene melanoma DOID:1909 diagnostic;risk 21719-0 PubMed:23569304 Vemurafenib resistance is associated with gain of Q61 mutation in NRAS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61 sequence variation in gene NRAS/NCBI:4893 2026 check_entity AN5489-2 NRAS Q61 mutation NRAS NCBI:4893 gene melanoma DOID:1909 diagnostic;risk 21719-0 CIViC:94 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61 sequence variation in gene NRAS/NCBI:4893 2026 check_entity AN5489-3 NRAS Q61 mutation NRAS NCBI:4893 gene skin melanoma DOID:8923 risk 21719-0 PubMed:23414587 Phase 2 study of MEK162 in patients with advanced melanoma and NRAS or BRAF mutation. 71 patients were enrolled, 6/30 patients with NRAS mutation had a partial response (Gln61Leu 1 Patient, Gln61Lys 9 Patients, Gln61Arg 15 Patients). Another 13 patients had stable disease (63% disease control rate). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61 sequence variation in gene NRAS/NCBI:4893 2027 check_entity AN5489-3 NRAS Q61 mutation NRAS NCBI:4893 gene skin melanoma DOID:8923 risk 21719-0 PubMed:18390968 Phase 1 trial in 57 patients with advanced cancers treated with selumetinib. 4 melanoma patients had NRAS Q61 mutations. One patient with NRAS mutation had 70% tumor shrinkage after three cycles of selumetinib (AZD6244) but developed symptomatic brain metastases before confirmatory scans could be performed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61 sequence variation in gene NRAS/NCBI:4893 2027 check_entity AN5489-3 NRAS Q61 mutation NRAS NCBI:4893 gene skin melanoma DOID:8923 risk 21719-0 CIViC:94 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61 sequence variation in gene NRAS/NCBI:4893 2027 check_entity AN5489-4 NRAS Q61 mutation NRAS NCBI:4893 gene thyroid gland follicular carcinoma DOID:3962 prognostic 21719-0 PubMed:22650231 In patients with follicular thyroid carcinoma, those with mutations in NRAS at codon 61 did not have significantly different overall survival than patients with wild-type NRAS (p=0.36). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61 sequence variation in gene NRAS/NCBI:4893 2028 check_entity AN5489-4 NRAS Q61 mutation NRAS NCBI:4893 gene thyroid gland follicular carcinoma DOID:3962 prognostic 21719-0 PubMed:25448848 Follicular thyroid cancers harboring RAS mutations have limited aggressiveness in the absence of TERT mutations. 2/2 follicular thyroid cancer patients with co-mutations in NRAS (10 Q61R and 1 Q61K) or HRAS (2 Q61R and 1 Q61K) and TERT promoter mutations had persistent or recurrent disease compared to 1/11 patients with only a RAS mutation (100% vs 8%, P=0.03). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61 sequence variation in gene NRAS/NCBI:4893 2028 check_entity AN5489-4 NRAS Q61 mutation NRAS NCBI:4893 gene thyroid gland follicular carcinoma DOID:3962 prognostic 21719-0 CIViC:94 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61 sequence variation in gene NRAS/NCBI:4893 2028 check_entity AN5490-1 NRAS Q61H mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 risk 21719-0 PubMed:20619739 One patient participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had a tumor which harbored NRAS Q61H was wildtype for KRAS, BRAF and PIK3CA. This patient was was a 73 year old male treated with cetuximab and irinotecan as 4th line therapy who experienced progressive disease and had PFS of 10 weeks and OS of 36 weeks. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61H sequence variation in gene NRAS/NCBI:4893 2029 check_entity AN5490-1 NRAS Q61H mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 risk 21719-0 CIViC:867 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61H sequence variation in gene NRAS/NCBI:4893 2029 check_entity AN5491-1 NRAS Q61K mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 risk 21719-0 PubMed:20619739 Four patients participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored NRAS Q61K and were wildtype for KRAS, BRAF and PIK3CA. One patient experienced partial response and three patients experienced progressive disease. The four patients whose tumors harbored NRAS Q61K included an 80 year old male treated with cetuximab and irinotecan as a 3rd line treatment who experienced progressive disease and had PFS of 6 weeks and OS of 43 weeks; a 51 year old male treated with cetuximab and ironotecan as a 3rd line therapy who experienced a partial response and had PFS of 24 weeks and OS of 54 weeks; a 64 year old male treated with cetuximab and ironotecan as a 5th line therapy who experienced progressive disease and had PFS of 8 weeks and OS of 33 weeks; and a 65 year old female treated with cetuximab, oxaliplatin and 5FU as a 2nd line therapy who experienced progressive disease and had PFS of 31 weeks and OS of 50 weeks. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61K sequence variation in gene NRAS/NCBI:4893 2030 check_entity AN5491-1 NRAS Q61K mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 risk 21719-0 PubMed:22392911 In 28 out of 40 (70%) metastatic colorectal cancer tumors harboring mutations in KRAS, NRAS, BRAF, or PIK3CA and implanted into mice, the therapeutic combination of the MEK inhibitor AZD6244 and the PI3K/mTor inhibitor BEZ235 resulted in disease stabilization. Mean tumor growth was lower in the tumors treated with AZD6244+ BEZ235 (+77% vs. +267%, P=1E-6) compared to AZD6244 alone and (+77% vs. +222%, P=0.0014) BEZ235 alone. NRAS mutations were in 4/40 tumors (three Q61K, one G12D). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61K sequence variation in gene NRAS/NCBI:4893 2030 check_entity AN5491-1 NRAS Q61K mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 risk 21719-0 CIViC:423 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61K sequence variation in gene NRAS/NCBI:4893 2030 check_entity AN5491-2 NRAS Q61K mutation NRAS NCBI:4893 gene lung non-small cell carcinoma DOID:3908 risk 21719-0 PubMed:23515407 Of the 4,562 patients with lung cancers, 30 showed NRAS mutations, which corresponded to 9 different amino acid substitutions. Cell lines were developed for 6 of these mutations (one harboring Q61L, two Q61R, and three Q61K mutations) and 5/6 were sensitive to MEK inhibitors selumetinib and trametinib. One Q61K line was not sensitive to these inhibitors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61K sequence variation in gene NRAS/NCBI:4893 2031 check_entity AN5491-2 NRAS Q61K mutation NRAS NCBI:4893 gene lung non-small cell carcinoma DOID:3908 risk 21719-0 CIViC:423 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61K sequence variation in gene NRAS/NCBI:4893 2031 check_entity AN5491-3 NRAS Q61K mutation NRAS NCBI:4893 gene neuroblastoma DOID:769 risk 21719-0 PubMed:26821351 In-vitro study in 5 neuroblastoma cell lines (2 with NRAS Q61K mutation). The combination of mTOR and MEK Inhibitors synergistically blocked cell growth in NRAS mutant but not wild type cell lines. Single agent MEK inhibition (AZD6244/selumetinib, MEK162 or PD0325901) and single agent mTOR inhibition (Everolimus or AZD8055) also blocked cell growth in NRAS mutant cell lines, whereas single agent PI3K inhibitors or MEK Inhibitors in combination with PIK3CA/AKT inhibitors did not show synergistic effects. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61K sequence variation in gene NRAS/NCBI:4893 2032 check_entity AN5491-3 NRAS Q61K mutation NRAS NCBI:4893 gene neuroblastoma DOID:769 risk 21719-0 CIViC:423 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61K sequence variation in gene NRAS/NCBI:4893 2032 check_entity AN5491-4 NRAS Q61K mutation NRAS NCBI:4893 gene ovary serous adenocarcinoma DOID:5744 risk 21719-0 PubMed:30809568 One 56 year old female with advanced recurrent low grade serous ovarian cancer with NRAS Q61K mutation had a partial response to trametinib, with short follow-up. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61K sequence variation in gene NRAS/NCBI:4893 2033 check_entity AN5491-4 NRAS Q61K mutation NRAS NCBI:4893 gene ovary serous adenocarcinoma DOID:5744 risk 21719-0 CIViC:423 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61K sequence variation in gene NRAS/NCBI:4893 2033 check_entity AN5491-5 NRAS Q61K mutation NRAS NCBI:4893 gene skin melanoma DOID:8923 risk 21719-0 PubMed:22194965 Preclinical study in melanoma cell lines. NRAS Q61K, in addition to the BRAF V600E mutation was associated with resistance to vemurafenib but sensitivity to AZD6244 (selumetinib) in vitro in the acquired resistant cell line M249-AR4 and in the patient-derived acquired resistant cell line M376. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61K sequence variation in gene NRAS/NCBI:4893 2034 check_entity AN5491-5 NRAS Q61K mutation NRAS NCBI:4893 gene skin melanoma DOID:8923 risk 21719-0 CIViC:423 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61K sequence variation in gene NRAS/NCBI:4893 2034 check_entity AN5492-1 NRAS Q61L mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 risk 21719-0 PubMed:20619739 Two patients participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored NRAS Q61L and were wildtype for KRAS, BRAF and PIK3CA. Both patients experienced stable disease, which the authors classified as non-response. The two patients whose tumors harbored NRAS Q61L included a 53 year old female treated with cetuximab and irinotecan as a 6th line treatment who had PFS of 12 weeks and OS of 25 weeks; and a 64 year old female treated with cetuximab and ironotecan as a 3rd line therapy who had PFS of 12 weeks and OS of 46 weeks. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61L sequence variation in gene NRAS/NCBI:4893 2035 check_entity AN5492-1 NRAS Q61L mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 risk 21719-0 CIViC:95 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61L sequence variation in gene NRAS/NCBI:4893 2035 check_entity AN5492-2 NRAS Q61L mutation NRAS NCBI:4893 gene melanoma DOID:1909 risk 21719-0 PubMed:21576590 In a melanoma patient with NRAS Q61L mutation, treatment with temozolomide resulted in disease free survival of 14 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61L sequence variation in gene NRAS/NCBI:4893 2036 check_entity AN5492-2 NRAS Q61L mutation NRAS NCBI:4893 gene melanoma DOID:1909 risk 21719-0 CIViC:95 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61L sequence variation in gene NRAS/NCBI:4893 2036 check_entity AN5493-1 NRAS Q61R mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 risk 21719-0 PubMed:20619739 Five patients participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored NRAS Q61R and were wildtype for KRAS, BRAF and PIK3CA. Overall, one patient experienced stable disease, and the other four experienced progressive disease.The five patients whose tumors harbored NRAS Q61R included a 65 year old male treated with cetuximab monotherapy as a 3rd line treatment who experienced progressive disease and had PFS of 6 weeks and OS of 41 weeks; a 47 year old female treated with cetuximab and ironotecan as a 5th line therapy who experienced progressive disease and had PFS of 4 weeks and OS of 10 weeks; a 60 year old female treated with cetuximab and ironotecan as a 3rd line therapy who experienced stable disease and had PFS of 24 weeks and OS of 38 weeks; a 47 year old female treated with cetuximab and ironotecan as a 3rd line therapy who experienced progressive disease and had PFS of 14 weeks and OS of 18 weeks; and a 77 year old male treated with cetuximab monotherapy as a 1st line therapy who experienced progressive disease and had PFS of 7 weeks and OS of 67 weeks. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61R sequence variation in gene NRAS/NCBI:4893 2037 check_entity AN5493-1 NRAS Q61R mutation NRAS NCBI:4893 gene colorectal cancer DOID:9256 risk 21719-0 CIViC:96 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61R sequence variation in gene NRAS/NCBI:4893 2037 check_entity AN5493-2 NRAS Q61R mutation NRAS NCBI:4893 gene melanoma DOID:1909 risk 21719-0 PubMed:21576590 In a melanoma patient with Q61R mutation, treatment with temozolomide resulted in overall survival of 16 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61R sequence variation in gene NRAS/NCBI:4893 2038 check_entity AN5493-2 NRAS Q61R mutation NRAS NCBI:4893 gene melanoma DOID:1909 risk 21719-0 CIViC:96 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q61R sequence variation in gene NRAS/NCBI:4893 2038 check_entity AN5494-1 NRG1 APP::NRG1 mutation NRG1 NCBI:3084 gene pancreatic ductal adenocarcinoma DOID:3498 risk PubMed:31068372 Whole genome sequencing and transcriptomic analysis were performed on 47 advanced PDAC patients. 3/47 patients were KRAS wildtype and all three of these cases harbored a NRG1 fusion. In a 54-year-old with metastatic PDAC, a complex rearrangement involving the insertion of exons 6 and 7 of NRG1 between exons 15 and 16 of APP was found. This in-frame fusion resulted in the preservation and increased expression of the EGF-like domain of NRG1, which is required for HER-family kinase activation. Treatment with afatinib resulted in the resolution of multiple metastases and imaging showed ongoing response 5 months after treatment initiation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::APP::NRG1 sequence variation in gene NRG1/NCBI:3084 2039 check_entity AN5494-1 NRG1 APP::NRG1 mutation NRG1 NCBI:3084 gene pancreatic ductal adenocarcinoma DOID:3498 risk CIViC:2641 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::APP::NRG1 sequence variation in gene NRG1/NCBI:3084 2039 check_entity AN5495-1 NRG1 ATP1B1::NRG1 mutation NRG1 NCBI:3084 gene cholangiocarcinoma DOID:4947 risk PubMed:28950338 In a single patient with presumed cholangiocarcinoma a novel ATP1B1-NRG1 gene fusion was detected. Integrative genome analysis was used to assess the potential functional significance of the gene fusion, prioritizing a therapeutic strategy targeting the HER-family of growth factor receptors with afatinib. This patient was treated with the pan HER-family kinase inhibitor afatinib and displayed significant and durable response to treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ATP1B1::NRG1 sequence variation in gene NRG1/NCBI:3084 2040 check_entity AN5495-1 NRG1 ATP1B1::NRG1 mutation NRG1 NCBI:3084 gene cholangiocarcinoma DOID:4947 risk CIViC:2054 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ATP1B1::NRG1 sequence variation in gene NRG1/NCBI:3084 2040 check_entity AN5495-2 NRG1 ATP1B1::NRG1 mutation NRG1 NCBI:3084 gene pancreatic ductal adenocarcinoma DOID:3498 risk PubMed:31068372 Whole genome sequencing and transcriptomic analysis were performed on 47 advanced PDAC patients. 3/47 patients were KRAS wildtype and all three of these cases harbored a NRG1 fusion. A 59-year-old metastatic PDAC patient harbored an in-frame fusion of exon 3 of ATP1B1 with exon 2 of NRG1 and no other observed clinically relevant small mutations. Compared to this PDAC cohort, significant overexpression of NRG1 (exons 2-7) was observed in the tumor. Of note, the EGF-like domain of NRG1 (exons 6 & 7), which is required for HER-family kinase activation, is preserved in the fusion. Treatment with afatinib resulted in significant clinical response as measured by imaging, as well as a drastic reduction in CA19-9 levels. Disease progression was noted 5.5 months after treatment initiation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ATP1B1::NRG1 sequence variation in gene NRG1/NCBI:3084 2041 check_entity AN5495-2 NRG1 ATP1B1::NRG1 mutation NRG1 NCBI:3084 gene pancreatic ductal adenocarcinoma DOID:3498 risk CIViC:2054 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ATP1B1::NRG1 sequence variation in gene NRG1/NCBI:3084 2041 check_entity AN5496-1 NRG1 Expression NRG1 NCBI:3084 gene cancer DOID:162 risk PubMed:25542901 This screening study in various tumor xenografts identified NRG1 expression to correlate with sensivity to ERBB3 inhibitory antibody AV-203. ERBB3 expression was not predictive of response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene NRG1/NCBI:3084 2042 AN5496-1 NRG1 Expression NRG1 NCBI:3084 gene cancer DOID:162 risk CIViC:310 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene NRG1/NCBI:3084 2042 AN5496-2 NRG1 Expression NRG1 NCBI:3084 gene colorectal cancer DOID:9256 risk PubMed:21900593 NRG1 upregulation or ERBB2 amplification were the main causes of resistance to cetuximab in-vivo and in-vitro in this study. Inhibition of ERBB2/ERBB3 signaling restored cetuximab sensitivity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene NRG1/NCBI:3084 2043 AN5496-2 NRG1 Expression NRG1 NCBI:3084 gene colorectal cancer DOID:9256 risk CIViC:310 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene NRG1/NCBI:3084 2043 AN5496-3 NRG1 Expression NRG1 NCBI:3084 gene head and neck squamous cell carcinoma DOID:5520 risk PubMed:21840482 In non-HER2 amplified cell lines, sensitivity to HER2 kinase inhibitor lapatinib was found mainly in cell-lines with elevated NRG1 expression and HER3 activation. This aberration was mainly identified in head and neck cancer cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene NRG1/NCBI:3084 2044 AN5496-3 NRG1 Expression NRG1 NCBI:3084 gene head and neck squamous cell carcinoma DOID:5520 risk CIViC:310 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene NRG1/NCBI:3084 2044 AN5496-4 NRG1 Expression NRG1 NCBI:3084 gene lung non-small cell carcinoma DOID:3908 risk PubMed:23390248 In-vivo studies of residual NSCLC tumors (xenografts of 5 cell lines) after chemotherapy found increased EGFR-family signaling and NRG1 expression. NRG1 inhibition (YW538.24.71 antibody) led to decreased tumor growth and enhanced magnitude and response to chemotherapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene NRG1/NCBI:3084 2045 AN5496-4 NRG1 Expression NRG1 NCBI:3084 gene lung non-small cell carcinoma DOID:3908 risk PubMed:26137564 In this phase-2 study, 215 patients were randomized to either erlotinib and placebo or erlotinib and HER3 monoclonal antibody patritumab. HRG (NRG1) expression was retrospectively defined as predictive biomarker but prospectively assessed in 102 patients before unblinding. NRG1-high groups demonstrated clinical benefit from additional patritumab with hazard ratios of 0.37 (P = 0.0283) and 0.29 (P = 0.0027) in the high- and low-dose patritumab arms, respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene NRG1/NCBI:3084 2045 AN5496-4 NRG1 Expression NRG1 NCBI:3084 gene lung non-small cell carcinoma DOID:3908 risk CIViC:310 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene NRG1/NCBI:3084 2045 AN5496-5 NRG1 Expression NRG1 NCBI:3084 gene ovarian cancer DOID:2394 risk PubMed:20227043 An NRG1-ERBB3 autocrine signal-transducing loop was identified in a subset of ovarian cancers and cell lines. Disruption of this loop led to decreased cell-growth in-vitro and prolonged survival in-vivo. An ERBB3 directed antibody (MM-121) inhibited tumor-growth in-vivo. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene NRG1/NCBI:3084 2046 AN5496-5 NRG1 Expression NRG1 NCBI:3084 gene ovarian cancer DOID:2394 risk CIViC:310 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene NRG1/NCBI:3084 2046 AN5497-1 NRG1 Fusion NRG1 NCBI:3084 gene mucinous adenocarcinoma DOID:3030 risk PubMed:29610121 One patient with an NRG1-rearranged invasive mucinous adenocarcinomas (IMAs) of the lung had a response with an anti-ERBB3 monoclonal antibody (GSK2849330). No response was achieved with afatinib in four NRG1-rearranged IMA patients (including the index patient post-GSK2849330). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene NRG1/NCBI:3084 2047 check_entity AN5497-1 NRG1 Fusion NRG1 NCBI:3084 gene mucinous adenocarcinoma DOID:3030 risk CIViC:2162 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene NRG1/NCBI:3084 2047 check_entity AN5497-2 NRG1 Fusion NRG1 NCBI:3084 gene pancreatic adenocarcinoma DOID:4074 risk PubMed:29802158 In patients with KRAS wild-type (KRASwt) tumors druggable gene fusions have been identified. These alterations included recurrent NRG1 rearrangements predicted to drive PDAC development through aberrant ERBB receptor-mediated signaling, and pharmacologic ERBB inhibition resulted in clinical improvement and remission of liver metastases in two patients with NRG1-rearranged tumors that had proved resistant to standard treatment. One patient (30) was treated with afatinib monotherapy and showed improvement at 7 weeks, followed by progression at 3 months after necessary dose reduction. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene NRG1/NCBI:3084 2048 check_entity AN5497-2 NRG1 Fusion NRG1 NCBI:3084 gene pancreatic adenocarcinoma DOID:4074 risk CIViC:2162 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene NRG1/NCBI:3084 2048 check_entity AN5498-1 NRG1 SDC4::NRG1 mutation NRG1 NCBI:3084 gene lung adenocarcinoma DOID:3910 risk PubMed:28950338 In patient with lung adenocarcinoma an SDC4-NRG1 gene fusion was detected. Integrative genome analysis was used to assess the potential functional significance of the detected gene fusion, prioritizing therapeutic strategies targeting the HER-family of growth factor receptors. This patient was treated with the pan HER-family kinase inhibitor afatinib and displayed a significant and durable response to treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SDC4::NRG1 sequence variation in gene NRG1/NCBI:3084 2049 check_entity AN5498-1 NRG1 SDC4::NRG1 mutation NRG1 NCBI:3084 gene lung adenocarcinoma DOID:3910 risk CIViC:2055 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SDC4::NRG1 sequence variation in gene NRG1/NCBI:3084 2049 check_entity AN5499-1 NRG1 SLC3A2::NRG1 mutation NRG1 NCBI:3084 gene lung adenocarcinoma DOID:3910 prognostic PubMed:27626312 13 patients with invasive mucinous adenocarcinoma of the lung from a cohort of 59 were found to be SLC3A2-NRG1 fusion positive. Survival was assessed according to the presence of the NRG1 fusion, which included 13 SLC3A2-NRG1 and 3 CD74-NRG1 fusions. NRG1 fusions positive patients demonstrated inferior overall survival (OS; P=0.019) and disease-free survival (DFS; P=0.113) compared with those without NRG1 fusion. To exclude the impact of stage on survival OS and DFS was compared only in patients with stage I disease. Patients with NRG1 fusions showed significantly inferior OS (P=0.009) and DFS (P=0.013) compared to those without NRG1 fusions. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SLC3A2::NRG1 sequence variation in gene NRG1/NCBI:3084 2050 check_entity AN5499-1 NRG1 SLC3A2::NRG1 mutation NRG1 NCBI:3084 gene lung adenocarcinoma DOID:3910 prognostic CIViC:2042 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SLC3A2::NRG1 sequence variation in gene NRG1/NCBI:3084 2050 check_entity AN5500-1 NT5C2 D407A mutation NT5C2 NCBI:22978 gene T-cell acute lymphoblastic leukemia DOID:5603 risk PubMed:23377281 CCRF-CEM and to a lesser extent CUTLL1 T-ALL cell lines expressing the NT5C2 D407A mutation had increased resistance to 6-mercaptopurine and 6-thioguanine treatment than cells expressing wildtype NT5C2. Consistent with this, isolated mutant proteins also showed increased enzyme activity compared to wildtype protein. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D407A sequence variation in gene NT5C2/NCBI:22978 2051 check_entity AN5500-1 NT5C2 D407A mutation NT5C2 NCBI:22978 gene T-cell acute lymphoblastic leukemia DOID:5603 risk CIViC:236 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D407A sequence variation in gene NT5C2/NCBI:22978 2051 check_entity AN5501-1 NT5C2 K359Q mutation NT5C2 NCBI:22978 gene acute lymphoblastic leukemia DOID:9952 prognostic PubMed:23377281 The K359Q somatic mutation was significantly correlated with early disease recurrence and relapse in 103 T-cell ALL regardless of treatment course. The data was obtained from Berlin Frankfurt Münster Clinical Trials. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K359Q sequence variation in gene NT5C2/NCBI:22978 2052 check_entity AN5501-1 NT5C2 K359Q mutation NT5C2 NCBI:22978 gene acute lymphoblastic leukemia DOID:9952 prognostic CIViC:235 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K359Q sequence variation in gene NT5C2/NCBI:22978 2052 check_entity AN5501-2 NT5C2 K359Q mutation NT5C2 NCBI:22978 gene T-cell acute lymphoblastic leukemia DOID:5603 risk PubMed:23377281 CCRF-CEM and to a lesser extent CUTLL1 T-ALL cell lines expressing the NT5C2 K359Q mutation had increased resistance to 6-mercaptopurine and 6-thioguanine treatment than cells expressing wildtype NT5C2. Consistent with this, isolated mutant proteins also showed increased enzyme activity compared to wildtype proteins. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K359Q sequence variation in gene NT5C2/NCBI:22978 2053 check_entity AN5501-2 NT5C2 K359Q mutation NT5C2 NCBI:22978 gene T-cell acute lymphoblastic leukemia DOID:5603 risk CIViC:235 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K359Q sequence variation in gene NT5C2/NCBI:22978 2053 check_entity AN5502-1 NT5C2 Mutation NT5C2 NCBI:22978 gene childhood acute lymphocytic leukemia DOID:0080144 prognostic PubMed:23377183 Within a cohort of 71 pediatric B-ALL relapse cases, all 7 patients with NT5C2 mutations detected at relapse demonstrated early relapse (<36 months from initial diagnosis) with a median time to relapse of 516 days versus a 930-day median time to relapse for the 64 patients wild type for NT5C2 (p=.03). Patients were derived from the Children's Oncology Group (COG), but Individual patient treatment regimens were not given. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NT5C2/NCBI:22978 2054 check_entity AN5502-1 NT5C2 Mutation NT5C2 NCBI:22978 gene childhood acute lymphocytic leukemia DOID:0080144 prognostic CIViC:2767 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene NT5C2/NCBI:22978 2054 check_entity AN5503-1 NT5C2 R238W mutation NT5C2 NCBI:22978 gene childhood acute lymphocytic leukemia DOID:0080144 prognostic;risk PubMed:23377183 Lentiviral-mediated overexpression of NT5C2 R238W in Reh cells resulted in significant resistance against thiopurines (mercaptopurine and thioguanine) versus wildtype and GFP controls, as indicated by reduced apoptosis. Compared to controls, overexpression cells also displayed reduced intercellular thioguanoside nucleotides after 24 hours of drug exposure, as measured by HPLC. Additionally, recombinant protein expression of R238W led to increased 5’ nucleotidase activity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R238W sequence variation in gene NT5C2/NCBI:22978 2055 check_entity AN5503-1 NT5C2 R238W mutation NT5C2 NCBI:22978 gene childhood acute lymphocytic leukemia DOID:0080144 prognostic;risk CIViC:2765 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R238W sequence variation in gene NT5C2/NCBI:22978 2055 check_entity AN5504-1 NT5C2 R367Q mutation NT5C2 NCBI:22978 gene childhood acute lymphocytic leukemia DOID:0080144 risk PubMed:23377183 71 Childhood B-cell acute lymphocytic leukemia relapse patients had their diagnosis and relapse samples sequenced for NT5C2 mutations. Sequencing revealed an early relapse case with NT5C2 R367Q enriched to a variant allele frequency (VAF) of 25% at relapse and only a VAF of .02% at diagnosis. R367Q could drive clonal outgrowth through the promotion of drug resistance, specifically to thiopurines, which are a staple of ALL maintenance therapy that are administered daily. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R367Q sequence variation in gene NT5C2/NCBI:22978 2056 check_entity AN5504-1 NT5C2 R367Q mutation NT5C2 NCBI:22978 gene childhood acute lymphocytic leukemia DOID:0080144 risk CIViC:234 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R367Q sequence variation in gene NT5C2/NCBI:22978 2056 check_entity AN5504-2 NT5C2 R367Q mutation NT5C2 NCBI:22978 gene T-cell acute lymphoblastic leukemia DOID:5603 risk PubMed:23377281 CCRF-CEM and to a lesser extent CUTLL1 T-ALL cell lines expressing the NT5C2 R367Q mutation had increased resistance to 6-mercaptopurine and 6-thioguanine treatment than cells expressing wildtype NT5C2. Consistent with this, isolated mutant proteins also showed increased enzyme activity compared to wildtype proteins. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R367Q sequence variation in gene NT5C2/NCBI:22978 2057 check_entity AN5504-2 NT5C2 R367Q mutation NT5C2 NCBI:22978 gene T-cell acute lymphoblastic leukemia DOID:5603 risk CIViC:234 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R367Q sequence variation in gene NT5C2/NCBI:22978 2057 check_entity AN5505-1 NT5C2 S445F mutation NT5C2 NCBI:22978 gene childhood acute lymphocytic leukemia DOID:0080144 prognostic;risk PubMed:23377183 Lentiviral-mediated overexpression of NT5C2 S445F in Reh cells resulted in significant resistance against thiopurines (mercaptopurine and thioguanine) versus wildtype and GFP controls, as indicated by reduced apoptosis. Compared to controls, overexpression cells also displayed reduced intercellular thioguanoside nucleotides after 24 hours of drug exposure, as measured by HPLC. Additionally, recombinant protein expression of S445F led to increased 5’ nucleotidase activity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S445F sequence variation in gene NT5C2/NCBI:22978 2058 check_entity AN5505-1 NT5C2 S445F mutation NT5C2 NCBI:22978 gene childhood acute lymphocytic leukemia DOID:0080144 prognostic;risk CIViC:2766 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S445F sequence variation in gene NT5C2/NCBI:22978 2058 check_entity AN5506-1 NT5E Overexpression NT5E NCBI:4907 gene colorectal cancer DOID:9256 risk PubMed:25520391 CD73 high expression was identified as a potential marker of improved PFS from cetuximab treatment in patients with metastatic CRC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene NT5E/NCBI:4907 2059 AN5506-1 NT5E Overexpression NT5E NCBI:4907 gene colorectal cancer DOID:9256 risk CIViC:286 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene NT5E/NCBI:4907 2059 AN5507-1 NTRK1 Amplification NTRK1 NCBI:4914 gene cancer DOID:162 risk PubMed:28183697 Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two phase I studies in patients with advanced or metastatic solid tumors, including CNS disease. Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. No objective responses (per RECIST v1.1) were observed in patients whose tumors did not harbor gene fusions involving NTRK1/2/3, ROS1, or ALK, with the exception of 1 patient with an ALKF1245V mutant neuroblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene NTRK1/NCBI:4914 2060 AN5507-1 NTRK1 Amplification NTRK1 NCBI:4914 gene cancer DOID:162 risk PubMed:30624546 In a phase I study of larotrectinib in 67 patients with solid tumours, 8 patients were recorded as having objective response. 7 of these harboured NTRK fusions, and one had a NTRK1 amplification. This patient's tumour had a size reduction measured as 45% and a response duration of 3.7 months. It is not stated in the publication whether a survey of amplification status in other patients in the study was done. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene NTRK1/NCBI:4914 2060 AN5507-1 NTRK1 Amplification NTRK1 NCBI:4914 gene cancer DOID:162 risk CIViC:1254 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene NTRK1/NCBI:4914 2060 AN5508-1 NTRK1 DDR2::NTRK1 mutation NTRK1 NCBI:4914 gene melanoma DOID:1909 risk PubMed:29683819 In this study we report that nonspitzoid metastasizing melanomas of adults may also harbor NTRK fusions and that NTRK expression can be immunohistochemically detected in these tumors. Of 751 melanomas analyzed by next-generation sequencing, 4 metastatic melanomas were identified with NTRK fusions, 3 involving NTRK1 (TRIM63, DDR2, and GON4L), 1 involving NTRK2 (TRAF2). All tumors were cytologically characterized by the presence of large epithelioid melanocytes and were immunoreactive with anti-Trk antibody. The NTRK1-DDR2 fusion occurred in a 55 yo woman with a nodular melanoma. Her primary tumor was umbilical with a metastasis to the colon. NF1 truncation and RAC1 p295 were identified as co-occurring melanoma drivers in this patient. Thus, the presence of an NTRK family fusion in nonspitzoid metastasizing melanomas of adults may provide a therapeutic opportunity for NTRK inhibitors such as larotrectinib in a small subset of patients with metastatic melanoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::DDR2::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2061 check_entity AN5508-1 NTRK1 DDR2::NTRK1 mutation NTRK1 NCBI:4914 gene melanoma DOID:1909 risk CIViC:2267 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::DDR2::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2061 check_entity AN5509-1 NTRK1 ETV6::NTRK1 mutation NTRK1 NCBI:4914 gene cancer DOID:162 risk PubMed:26884591 BaF3 cells were transduced with a number of NTRK fusions. IC50 values were measured following treatment with entrectinib: TPM3-NTRK1 (2.5nM), LMNA-NTRK1 (1.4nM), ETV6-NTRK1 (2.5nM), VCL-NTRK2 (4.3nM), AFAP1-NTRK2 (2.7nM), ETV6-NTRK2 (4.5nM), ETV6-NTRK3 (3.8nM), and control (>1000nM). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2062 check_entity AN5509-1 NTRK1 ETV6::NTRK1 mutation NTRK1 NCBI:4914 gene cancer DOID:162 risk CIViC:3568 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2062 check_entity AN5510-1 NTRK1 Fusion NTRK1 NCBI:4914 gene cancer DOID:162 risk PubMed:28183697 in two phase I studies in patients with advanced or metastatic solid tumors, including patients with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene NTRK1/NCBI:4914 2063 check_entity AN5510-1 NTRK1 Fusion NTRK1 NCBI:4914 gene cancer DOID:162 risk PubMed:26603524 Results from a phase I study show that the TRK inhibitor LOXO-101 is well tolerated and effective, with patients whose tumors bear NTRK fusions responding well and durably to this targeted therapy. This publication reported results from an AACR meeting for an ongoing study that had enrolled six patients with NTRK fusions, three of whom could be evaluated at the time. Each had a different, heavily pretreated advanced disease: soft-tissue sarcoma; gastrointestinal stromal tumor (GIST); and MASC. All three patients experienced partial responses by 3-4 months with resolution of key tumour-related symptoms within two weeks. One of three patients experienced near-complete response by 8 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene NTRK1/NCBI:4914 2063 check_entity AN5510-1 NTRK1 Fusion NTRK1 NCBI:4914 gene cancer DOID:162 risk PubMed:31838007 Describes a meta-analysis of three separate phase I or II trials: ALKA-372-001, STARTRK-1, and STARTRK-2. All of these evaluate entrectinib in NTRK fusion-positive solid tumours. 31/54 had objective response (57%; 95% CI 43·2–70·8), including 4 CR and 27 PR. 9 had SD. Response by NTRK gene type: 13/22 NTRK1 fusions [59%; 95% CI 36·4–79·3], 18/31 NTRK3 fusions [58%; 39·1–75·5], and 0/1 NTRK2 fusion. Most frequent tumour types were sarcoma, NSCLC, salivary, breast, thyroid, colorectal. Most common fusions were ETV6-NTRK3 (25), TPM3-NTRK1 (4) and TPR-NTRK1 (4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene NTRK1/NCBI:4914 2063 check_entity AN5510-1 NTRK1 Fusion NTRK1 NCBI:4914 gene cancer DOID:162 risk CIViC:415 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene NTRK1/NCBI:4914 2063 check_entity AN5510-1 NTRK1 Fusion NTRK1 NCBI:4914 gene cancer DOID:162 risk PubMed:29466156 This was a Phase 1/2 study of 55 patients from 4 months to 76 years old with TRK-fusion positive tumors given NTRK inhibitor Larotrectinib. Patients had 17 unique NTRK fusion types. Patient overall response rate was 75% according to independent review and 80% according to investigator assessment. Authors state that Larotrectinib had durable anti tumor activity regardless of age or tumor type. 17/23 patients with NTRK1-fusion showed maximum percent change in tumor size between -30% and -100%. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene NTRK1/NCBI:4914 2063 check_entity AN5510-2 NTRK1 Fusion NTRK1 NCBI:4914 gene colorectal cancer DOID:9256 risk PubMed:26716414 NTRK1 fusions (one LMNA-NTRK1 and two TPM3-NTRK1) were identified in 2% of Korean colorectal cancer patients (147 patients). TrkA (NTRK1) protein expression was associated with presence of NTRK1 gene fusion. These fusions were mutually exclusive with other oncogenic drivers and showed in-vitro sensitivity to TrkA Inhibitor ARRY470 (Larotrectinib) (one cell line with fusion (KM12), one control cell line). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene NTRK1/NCBI:4914 2064 check_entity AN5510-2 NTRK1 Fusion NTRK1 NCBI:4914 gene colorectal cancer DOID:9256 risk CIViC:415 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene NTRK1/NCBI:4914 2064 check_entity AN5510-3 NTRK1 Fusion NTRK1 NCBI:4914 gene lung adenocarcinoma DOID:3910 risk PubMed:24162815 Two patients were found to harbor gene fusions maintaining the kinase domain of NTRK1 (3' partner), specifically: MPRIP-NTRK1 and CD74-NTRK1. Both of these fusions lead to constitutive kinase activity and were found to be oncogenic. Treatment of cells expressing NTRK1 fusions with inhibitors of TRKA kinase activity (ARRY-470, CEP-701 and, to a lesser extent, crizotinib) inhibited autophosphorylation of TRKA and cell growth. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene NTRK1/NCBI:4914 2065 check_entity AN5510-3 NTRK1 Fusion NTRK1 NCBI:4914 gene lung adenocarcinoma DOID:3910 risk CIViC:415 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene NTRK1/NCBI:4914 2065 check_entity AN5510-4 NTRK1 Fusion NTRK1 NCBI:4914 gene sarcoma DOID:1115 risk PubMed:29606586 In a Phase 1/2 study involving 15 pediatric patients with infantile fibrosarcoma or soft tissue sarcoma, 8 patients had NTRK1 fusions. The patients were administered Larotrectinib, and 7 out of 8 patients showed objective response, with 2 complete and 5 partial responses. The patient without objective response had soft tissue sarcoma, and showed stable disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene NTRK1/NCBI:4914 2066 check_entity AN5510-4 NTRK1 Fusion NTRK1 NCBI:4914 gene sarcoma DOID:1115 risk CIViC:415 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene NTRK1/NCBI:4914 2066 check_entity AN5511-1 NTRK1 G595R mutation NTRK1 NCBI:4914 gene lung non-small cell carcinoma DOID:3908 risk PubMed:30624546 A 29-year-old male with NTRK-fusion positive NSCLC demonstrated initial response to Larotrectinib but progressed after devloping solvent-front (TRKA G595R) and xDFG (TRKA G667S) mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G595R sequence variation in gene NTRK1/NCBI:4914 2067 check_entity AN5511-1 NTRK1 G595R mutation NTRK1 NCBI:4914 gene lung non-small cell carcinoma DOID:3908 risk CIViC:4177 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G595R sequence variation in gene NTRK1/NCBI:4914 2067 check_entity AN5512-1 NTRK1 G667S mutation NTRK1 NCBI:4914 gene lung non-small cell carcinoma DOID:3908 risk PubMed:30624546 A 29-year-old male with NTRK-fusion positive NSCLC demonstrated initial response to Larotrectinib but progressed after devloping solvent-front (TRKA G595R) and xDFG (TRKA G667S) mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G667S sequence variation in gene NTRK1/NCBI:4914 2068 check_entity AN5512-1 NTRK1 G667S mutation NTRK1 NCBI:4914 gene lung non-small cell carcinoma DOID:3908 risk CIViC:4177 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G667S sequence variation in gene NTRK1/NCBI:4914 2068 check_entity AN5513-1 NTRK1 GON4L::NTRK1 mutation NTRK1 NCBI:4914 gene melanoma DOID:1909 risk PubMed:29683819 In this study we report that nonspitzoid metastasizing melanomas of adults may also harbor NTRK fusions and that NTRK expression can be immunohistochemically detected in these tumors. Of 751 melanomas analyzed by next-generation sequencing, 4 metastatic melanomas were identified with NTRK fusions, 3 involving NTRK1 (TRIM63, DDR2, and GON4L), 1 involving NTRK2 (TRAF2). All tumors were cytologically characterized by the presence of large epithelioid melanocytes and were immunoreactive with anti-Trk antibody. The NTRK1-GON4L fusion occurred in a 36 yo woman with a nodular melanoma. Her primary tumor was on her back with a metastasis to the duodenum. NRAS Q61L was identified as a co-occurring melanoma driver in this patient. Thus, the presence of an NTRK family fusion in nonspitzoid metastasizing melanomas of adults may provide a therapeutic opportunity for NTRK inhibitors such as larotrectinib in a small subset of patients with metastatic melanoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::GON4L::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2069 check_entity AN5513-1 NTRK1 GON4L::NTRK1 mutation NTRK1 NCBI:4914 gene melanoma DOID:1909 risk CIViC:2268 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::GON4L::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2069 check_entity AN5514-1 NTRK1 LMNA::NTRK1 G595R NTRK1 NCBI:4914 gene colorectal adenocarcinoma DOID:0050861 risk PubMed:26546295 A gene fusion between exon 10 of NTRK1 and exon 11 of the LMNA genes was observed in a patient with metastatic colorectal cancer after therapy with first-line FOLFOX, second-line FOLFIRI/cetuximab, and third-line irinotecan. The patient treated in a clinical trial with pan-TRK kinase inhibitor entrectinib. Treatment was well tolerated and led to a partial response (PR) with 30% tumor shrinkage of multiple liver metastases. Clinical response lasted 4 months. Longitudinal analysis of ctDNA in plasma samples revealed a p.G595R- and p.G667C mutation in NTRK1 that were absent before treatment initiation but emerged 4 weeks upon initiation of treatment with entrectinib. These mutations were also validated using xenograft, in vitro and 3D-modeling. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G595R sequence variation in gene NTRK1/NCBI:4914 2070 check_entity AN5514-1 NTRK1 LMNA::NTRK1 G595R NTRK1 NCBI:4914 gene colorectal adenocarcinoma DOID:0050861 risk CIViC:1256 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G595R sequence variation in gene NTRK1/NCBI:4914 2070 check_entity AN5515-1 NTRK1 LMNA::NTRK1 G667C NTRK1 NCBI:4914 gene colorectal adenocarcinoma DOID:0050861 risk PubMed:26546295 A gene fusion between exon 10 of NTRK1 and exon 11 of the LMNA genes was observed in a patient with metastatic colorectal cancer after therapy with first-line FOLFOX, second-line FOLFIRI/cetuximab, and third-line irinotecan. The patient treated in a clinical trial with pan-TRK kinase inhibitor entrectinib. Treatment was well tolerated and led to a partial response (PR) with 30% tumor shrinkage of multiple liver metastases. Clinical response lasted 4 months. Longitudinal analysis of ctDNA in plasma samples revealed a p.G595R- and p.G667C mutation in NTRK1 that were absent before treatment initiation but emerged 4 weeks upon initiation of treatment with entrectinib. These mutations were also validated using xenograft, in vitro and 3D-modeling. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G667C sequence variation in gene NTRK1/NCBI:4914 2071 check_entity AN5515-1 NTRK1 LMNA::NTRK1 G667C NTRK1 NCBI:4914 gene colorectal adenocarcinoma DOID:0050861 risk CIViC:1256 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G667C sequence variation in gene NTRK1/NCBI:4914 2071 check_entity AN5516-1 NTRK1 LMNA::NTRK1 mutation NTRK1 NCBI:4914 gene cancer DOID:162 risk PubMed:30624546 One patient was identified with a LMNA-NTRK1 positive tumor in this Phase I study (NCT02122913), which involved 70 heavily pretreated patients with a median age of 59.5 years, with multiple solid tumor types. A total of eight patients had NTRK fusions, and by independent radiology review, all patients with TRK fusion were considered to have had an objective response. The average time on treatment was 28.4 months for patients with NTRK fusion cancer, compared to 1.8 months for those without an NTRK fusion. Authors concluded that NTRK fusions may represent tissue and age agnostic oncogenic drivers, and that Larotrectinib was well tolerated in the patients and demonstrated activity in all tumors with NTRK fusions. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::LMNA::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2072 check_entity AN5516-1 NTRK1 LMNA::NTRK1 mutation NTRK1 NCBI:4914 gene cancer DOID:162 risk PubMed:26884591 BaF3 cells were transduced with a number of NTRK fusions. IC50 values were measured following treatment with entrectinib: TPM3-NTRK1 (2.5nM), LMNA-NTRK1 (1.4nM), ETV6-NTRK1 (2.5nM), VCL-NTRK2 (4.3nM), AFAP1-NTRK2 (2.7nM), ETV6-NTRK2 (4.5nM), ETV6-NTRK3 (3.8nM), and control (>1000nM). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::LMNA::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2072 check_entity AN5516-1 NTRK1 LMNA::NTRK1 mutation NTRK1 NCBI:4914 gene cancer DOID:162 risk CIViC:1252 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::LMNA::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2072 check_entity AN5516-2 NTRK1 LMNA::NTRK1 mutation NTRK1 NCBI:4914 gene colorectal adenocarcinoma DOID:0050861 risk PubMed:26546295 A gene fusion between exon 11 of LMNA and exon 10 of NTRK1 was observed in a patient with metastatic colorectal cancer after therapy with first-line FOLFOX, second-line FOLFIRI/cetuximab, and third-line irinotecan. The patient treated in a clinical trial with pan-TRK kinase inhibitor entrectinib. Treatment was well tolerated and led to a partial response (PR) with 30% tumor shrinkage of multiple liver metastases. Clinical response lasted 4 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::LMNA::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2073 check_entity AN5516-2 NTRK1 LMNA::NTRK1 mutation NTRK1 NCBI:4914 gene colorectal adenocarcinoma DOID:0050861 risk CIViC:1252 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::LMNA::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2073 check_entity AN5516-3 NTRK1 LMNA::NTRK1 mutation NTRK1 NCBI:4914 gene colorectal cancer DOID:9256 risk PubMed:26563355 After disease progression with no objective response to therapy, a 75-year-old with metastatic colorectal cancer that spread to the liver displayed elevated NTRK1 expression in both primary tumor and liver metastasis as measured by immunohistochemistry. FISH of the tumor and patient derived xenograft indicated NTRK1 involvement. 5’RACE PCR discovered a novel LMNA-NTRK1 fusion (exon 11 & exon 10), which resulted in the expression of two different fusion splice transcripts (exons 1-10 with exons 10-16 and exons 1-11 with exons 10-16). Fusion expression of both transcripts was confirmed by western blot, and Sanger sequencing revealed the fusion to be in-frame with the kinase domain intact. After 4 weeks of treatment with Entrectinib, CT scan revealed the patient showed a partial response with a 30% reduction of target lesions. This response was maintained for 5 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::LMNA::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2074 check_entity AN5516-3 NTRK1 LMNA::NTRK1 mutation NTRK1 NCBI:4914 gene colorectal cancer DOID:9256 risk CIViC:1252 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::LMNA::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2074 check_entity AN5516-4 NTRK1 LMNA::NTRK1 mutation NTRK1 NCBI:4914 gene congenital fibrosarcoma DOID:8418 risk PubMed:30709876 A mass found at birth in a patient’s left arm became enlarged at age 2 and was resected and characterized as a high-grade spindle cell sarcoma. FISH and RT-PCR did not detect any common sarcoma translocations. A recurrence and a new mass formed after 4 months of therapy, so amputation was performed. Metastatic high-grade sarcoma appeared in the lungs 4 months later followed by multiple recurrences 10 months after treatment. Whole exome and transcriptome sequencing of diagnosis and normal samples were performed and the in-frame LMNA-NTRK1 fusion (exon 2 & exon 10) with the kinase domain intact was discovered. Treatment with Crizotinib was started and a chest CT after 2 months revealed partial response. After 22 months of therapy, chest CT revealed a complete response of lung nodules, which has been sustained >18 months beyond the conclusion of treatment at 31 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::LMNA::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2075 check_entity AN5516-4 NTRK1 LMNA::NTRK1 mutation NTRK1 NCBI:4914 gene congenital fibrosarcoma DOID:8418 risk CIViC:1252 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::LMNA::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2075 check_entity AN5516-5 NTRK1 LMNA::NTRK1 mutation NTRK1 NCBI:4914 gene lipofibromatosis-like neural tumor DOID:0080894 diagnostic;risk PubMed:29892662 A 14-month-old boy presented with a slow-growing, asymptomatic back plaque, which was biopsied and found to have S100 positivity, sparse CD34 staining, and no significant mitotic activity, nuclear pleomorphism, or necrosis. IHC detected cytoplasmic expression of NTRK1 and FISH detected the LMNA::NTRK1 fusion. Based on these findings the authors conclude this is patient has a lipofibromatosis-like neural tumor (LPF-NT). The patient was treated with wide local excision and has developed no complications or evidence of recurrence with 6 months of follow-up time. LPF-NT is rare, with 14 cases previously reported, and this patient was the first report of this diagnosis in infancy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::LMNA::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2076 check_entity AN5516-5 NTRK1 LMNA::NTRK1 mutation NTRK1 NCBI:4914 gene lipofibromatosis-like neural tumor DOID:0080894 diagnostic;risk PubMed:32519338 A 31-year-old female presented with a pigmented nodule on her scalp that enlarged in size over a 2-year period. Biopsy demonstrated a fascicular proliferation of bland spindle cells within the dermis and subcutaneous tissue and was found in adipose tissue in a “honeycomb pattern.” Immunohistochemical staining revealed the spindle cells were positive for CD34 and S-100 protein and were negative for SOX10. FISH was negative for PDGFB rearrangement. The spindle cells were positive for pan-NTRK by IHC and targeted RNA sequencing revealed the LMNA::NTRK1 e2::e10 fusion. The patient’s tumor was completely excised, and no evidence of recurrence or metastatic disease was found at 24-month follow-up. The authors indicate the tumor analyses demonstrate a diagnosis of a NTRK-rearranged LPF-NT with unusual histopathological findings that include lymphoid aggregates and pigmented dendritic melanocytes. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::LMNA::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2076 check_entity AN5516-5 NTRK1 LMNA::NTRK1 mutation NTRK1 NCBI:4914 gene lipofibromatosis-like neural tumor DOID:0080894 diagnostic;risk PubMed:32782782 A 21-year-old man demonstrated intermittent abdominal pain, and a CT scan revealed an abnormal paraspinal lesion. Biopsy revealed a spindle cell mesenchymal tumor with monotonous, bland spindle cells mixed with fat and blood vessels. IHC was positive for CD34, S-100, and pan-TRK and negative for Sox10. Due to the unusual tumor location, an anchored multiplex PCR-based targeted next-generation sequencing (NGS) RNA fusion panel was used and detected a predicted in-frame LMNA::NTRK1 (e2:e11) that retains the NTRK1 tyrosine kinase domain. This fusion was confirmed by RT-PCT and Sanger. The author’s reclassified their diagnosis to an S-100 positive LPF-NT of the spine based on the identification of the fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::LMNA::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2076 check_entity AN5516-5 NTRK1 LMNA::NTRK1 mutation NTRK1 NCBI:4914 gene lipofibromatosis-like neural tumor DOID:0080894 diagnostic;risk CIViC:1252 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::LMNA::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2076 check_entity AN5516-6 NTRK1 LMNA::NTRK1 mutation NTRK1 NCBI:4914 gene sarcoma DOID:1115 risk PubMed:26216294 LOXO-101 is an orally administered inhibitor of the TRK kinase and is highly selective only for the TRK family of receptors. The tumor of a 41-year-old woman with soft-tissue sarcoma metastatic to the lung was found to harbor an in-frame LMNA-NTRK1 (exon 2 & exon 11) gene fusion encoding a functional LMNA-TRKA fusion oncoprotein. This patient's tumors underwent rapid and substantial tumor regression, with an accompanying improvement in pulmonary dyspnea, oxygen saturation, and plasma tumor markers. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::LMNA::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2077 check_entity AN5516-6 NTRK1 LMNA::NTRK1 mutation NTRK1 NCBI:4914 gene sarcoma DOID:1115 risk PubMed:29606586 One Patient with soft tissue sarcoma and a NTRK1-LMNA fusion had a partial response with larotrectinib. Treatment was done within a multicentre, open-label, phase 1/2 study and enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumours or CNS tumours that had relapsed, progressed, or were non-responsive to available therapies regardless of TRK fusion Status. In total, 24 patients (n=17 with tumours harbouring TRK fusions, n=7 without a documented TRK fusion) were enrolled. Among the fusion-positive patients, eight (47%) had infantile fibrosarcoma, seven (41%) had other soft tissue sarcomas, and two (12%) had papillary thyroid cancer. 14 (93%) of 15 patients with TRK fusion-positive cancers achieved an objective response; the remaining patient had tumour regression that did not meet the criteria for objective response. None of the seven patients with TRK fusion-negative cancers had an objective response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::LMNA::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2077 check_entity AN5516-6 NTRK1 LMNA::NTRK1 mutation NTRK1 NCBI:4914 gene sarcoma DOID:1115 risk CIViC:1252 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::LMNA::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2077 check_entity AN5516-7 NTRK1 LMNA::NTRK1 mutation NTRK1 NCBI:4914 gene spindle cell sarcoma DOID:4235 risk PubMed:32050835 A 40-year-old patient with a left calf mass revealed by biopsy to be a low grade myxoid spindle cell carcinoma underwent surgery and radiotherapy. Over a 5-year period, the patient experienced 3 lung metastases, which were all resected. At year 6, unresectable metastases were found in the lungs and lymph nodes. FISH and targeted next generation RNA sequencing of an earlier lung metastasis revealed and confirmed an in-frame LMNA-NTRK1 fusion (exon 2 & exon 10) with the kinase domain intact. TRK inhibitor was administered and PET-CT scan revealed near complete response and no new lesions 1 year later. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::LMNA::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2078 check_entity AN5516-7 NTRK1 LMNA::NTRK1 mutation NTRK1 NCBI:4914 gene spindle cell sarcoma DOID:4235 risk CIViC:1252 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::LMNA::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2078 check_entity AN5516-8 NTRK1 LMNA::NTRK1 mutation NTRK1 NCBI:4914 gene spitzoid melanoma DOID:0070326 diagnostic;risk PubMed:24445538 The in-frame LMNA-NTRK1 fusion (exon 2 & exon 11) with intact kinase domain was found and confirmed by next generation sequencing, RT-PCR, FISH, and/or immunohistochemistry in 3 Spitz neoplasm cases. Compared to controls (wildtype NTRK1 overexpression and GFP), lentiviral mediated overexpression of LMNA-NTRK1 in mouse melanocyte cells (melan-a) displayed increased phosphorylation of the fusion and downstream kinase targets, as assessed by Western Blot. Treatment with the NTRK1 inhibitor, AZ-23, quenched fusion and pathway activation. Additionally, injection of LMNA-NTRK1 melan-a cells into immunocompromised mice resulted in the rapid growth of tumors at the injection site within 40 days. Similar results were observed in mice injected with melan-a cells overexpressing NRAS G12V or HRAS G12V, but no tumors were observed in mice injected with GFP control melan-a cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::LMNA::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2079 check_entity AN5516-8 NTRK1 LMNA::NTRK1 mutation NTRK1 NCBI:4914 gene spitzoid melanoma DOID:0070326 diagnostic;risk CIViC:1252 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::LMNA::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2079 check_entity AN5517-1 NTRK1 Overexpression NTRK1 NCBI:4914 gene neuroblastoma DOID:769 prognostic PubMed:8441429 A high level of expression of the TRK proto-oncogene in a neuroblastoma is strongly predictive of a favorable outcome. A tumor with a functional nerve growth factor receptor may be dependent on the neurotrophin nerve growth factor for survival and may regress in its absence. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene NTRK1/NCBI:4914 2080 AN5517-1 NTRK1 Overexpression NTRK1 NCBI:4914 gene neuroblastoma DOID:769 prognostic CIViC:834 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene NTRK1/NCBI:4914 2080 AN5518-1 NTRK1 PDE4DIP::NTRK1 mutation NTRK1 NCBI:4914 gene sarcoma DOID:1115 risk PubMed:29606586 One Patient with soft tissue sarcoma and a NTRK1-PDE4DIP fusion was treated with larotrectinib and exhibited a partial response. Treatment was done within a multicentre, open-label, phase 1/2 study and enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumours or CNS tumours that had relapsed, progressed, or were non-responsive to available therapies regardless of TRK fusion Status. In total, 24 patients (n=17 with tumours harbouring TRK fusions, n=7 without a documented TRK fusion) were enrolled. Among the fusion-positive patients, eight (47%) had infantile fibrosarcoma, seven (41%) had other soft tissue sarcomas, and two (12%) had papillary thyroid cancer. 14 (93%) of 15 patients with TRK fusion-positive cancers achieved an objective response; the remaining patient had tumour regression that did not meet the criteria for objective response. None of the seven patients with TRK fusion-negative cancers had an objective response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PDE4DIP::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2081 check_entity AN5518-1 NTRK1 PDE4DIP::NTRK1 mutation NTRK1 NCBI:4914 gene sarcoma DOID:1115 risk PubMed:30204247 In a pediatric phase 1 trial (NCT02637687), a boy aged 15 months with soft tissue sarcoma of the right upper thigh harbored the PDE4DIP-NTRK1 fusion. After resection and the failure of initial chemotherapy, Larotrectinib reduced tumor size by 37% after 2 cycles and 64% after 6 cycles. An R2 resection was performed and Larotrectinib again reduced tumor progression. A second R2 resection was followed by adjuvant radiotherapy and Larotrectinib cycles and the patient remained in complete response at the time of the last follow-up. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PDE4DIP::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2081 check_entity AN5518-1 NTRK1 PDE4DIP::NTRK1 mutation NTRK1 NCBI:4914 gene sarcoma DOID:1115 risk CIViC:2165 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PDE4DIP::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2081 check_entity AN5519-1 NTRK1 SCP2::NTRK1 mutation NTRK1 NCBI:4914 gene breast cancer DOID:1612 risk PubMed:32348852 Of the 4854 Breast Cancer patients analyzed by Memorial Sloan Kettering-IMPACT targeted DNA sequencing and MSK-Fusion targeted RNA-seq, fusions were detected in 27 patients. One of these patients was a 49 year-old that harbored the SCP2::NTRK1 e13::e11 fusion with the NTRK tyrosine kinase domain intact in their lymph node metastasis that arose post endocrine therapy (tamoxifen and letrozole), which was detected by MSK-IMPACT and MSK-Fusion. The patient’s diagnosis sample was negative for the fusion as determined by negative FISH and Pan-TRK immunohistochemical staining. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SCP2::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2082 check_entity AN5519-1 NTRK1 SCP2::NTRK1 mutation NTRK1 NCBI:4914 gene breast cancer DOID:1612 risk PubMed:33002320 A breast cancer patient harbored the SCP2::NTRK1 fusion. This report demonstrated positive pan-tyrosine receptor kinase (TRK) immunohistochemical staining in a core-needle biopsy taken from the patient post-endocrine therapy. The fusion contained the tyrosine kinase domain of NTRK1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SCP2::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2082 check_entity AN5519-1 NTRK1 SCP2::NTRK1 mutation NTRK1 NCBI:4914 gene breast cancer DOID:1612 risk CIViC:4121 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SCP2::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2082 check_entity AN5520-1 NTRK1 SQSTM1::NTRK1 mutation NTRK1 NCBI:4914 gene congenital fibrosarcoma DOID:8418 risk PubMed:29606586 One patient with infantile fibrosarcoma and a NTRK1-SQSTM1 fusion was treated with larotrectinib and exhibited a partial response. Treatment was done within a multicentre, open-label, phase 1/2 study and enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumours or CNS tumours that had relapsed, progressed, or were non-responsive to available therapies regardless of TRK fusion Status. In total, 24 patients (n=17 with tumours harbouring TRK fusions, n=7 without a documented TRK fusion) were enrolled. Among the fusion-positive patients, eight (47%) had infantile fibrosarcoma, seven (41%) had other soft tissue sarcomas, and two (12%) had papillary thyroid cancer. 14 (93%) of 15 patients with TRK fusion-positive cancers achieved an objective response; the remaining patient had tumour regression that did not meet the criteria for objective response. None of the seven patients with TRK fusion-negative cancers had an objective response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SQSTM1::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2083 check_entity AN5520-1 NTRK1 SQSTM1::NTRK1 mutation NTRK1 NCBI:4914 gene congenital fibrosarcoma DOID:8418 risk PubMed:30204247 In a pediatric phase 1 trial (NCT02637687), a 2 year old with infantile fibrosarcoma of the shoulder harbored the SQSTM1-NTRK1 fusion. After two surgical resections and multiple rounds of chemotherapy, Larotrectinib treatment resulted in 93% tumour reduction. An R1 resection was performed followed by adjuvant Larotrectinib. The patient remained on Larotrectinib without evidence of disease progression at the time of last follow-up. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SQSTM1::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2083 check_entity AN5520-1 NTRK1 SQSTM1::NTRK1 mutation NTRK1 NCBI:4914 gene congenital fibrosarcoma DOID:8418 risk CIViC:778 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SQSTM1::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2083 check_entity AN5520-2 NTRK1 SQSTM1::NTRK1 mutation NTRK1 NCBI:4914 gene lung non-small cell carcinoma DOID:3908 risk PubMed:26565381 In 1378 cases of NSCLC screened for NTRK1 rearrangements, 2 were identified (frequency 0.1%). One patient with SQSTM1-NTRK1 was treated with entrectinib in a phase 1 study. The patient had resolution of prior dyspnea and pain within 3 weeks. CT scans showed a partial response and complete resolution of brain metastases. The patient has continued treatment for over 6 months with ongoing PR. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SQSTM1::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2084 check_entity AN5520-2 NTRK1 SQSTM1::NTRK1 mutation NTRK1 NCBI:4914 gene lung non-small cell carcinoma DOID:3908 risk PubMed:28183697 Two phase I studies in patients with advanced or metastatic solid tumors, including patients with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SQSTM1::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2084 check_entity AN5520-2 NTRK1 SQSTM1::NTRK1 mutation NTRK1 NCBI:4914 gene lung non-small cell carcinoma DOID:3908 risk CIViC:778 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SQSTM1::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2084 check_entity AN5521-1 NTRK1 TPM3::NTRK1 mutation NTRK1 NCBI:4914 gene cancer DOID:162 risk PubMed:26884591 BaF3 cells transduced with a number of NTRK fusions were sensitive to entrectinib. IC50 values were measured following treatment with entrectinib: TPM3-NTRK1 (2.5nM), LMNA-NTRK1 (1.4nM), ETV6-NTRK1 (2.5nM), VCL-NTRK2 (4.3nM), AFAP1-NTRK2 (2.7nM), ETV6-NTRK2 (4.5nM), ETV6-NTRK3 (3.8nM), and control (>1000nM). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::TPM3::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2085 check_entity AN5521-1 NTRK1 TPM3::NTRK1 mutation NTRK1 NCBI:4914 gene cancer DOID:162 risk CIViC:2861 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::TPM3::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2085 check_entity AN5521-2 NTRK1 TPM3::NTRK1 mutation NTRK1 NCBI:4914 gene sarcoma DOID:1115 risk PubMed:29606586 Four patients with infantile fibrosarcoma and soft tissue sarcoma and a TPM3::NTRK1 fusion were treated with larotrectinib. Two had a partial, and two had a complete response. Treatment was done within a multicentre, open-label, phase 1/2 study and enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumours or CNS tumours that had relapsed, progressed, or were non-responsive to available therapies regardless of TRK fusion Status. In total, 24 patients (n=17 with tumours harbouring TRK fusions, n=7 without a documented TRK fusion) were enrolled. Among the fusion-positive patients, eight (47%) had infantile fibrosarcoma, seven (41%) had other soft tissue sarcomas, and two (12%) had papillary thyroid cancer. 14 (93%) of 15 patients with TRK fusion-positive cancers achieved an objective response; the remaining patient had tumour regression that did not meet the criteria for objective response. None of the seven patients with TRK fusion-negative cancers had an objective response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::TPM3::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2086 check_entity AN5521-2 NTRK1 TPM3::NTRK1 mutation NTRK1 NCBI:4914 gene sarcoma DOID:1115 risk CIViC:2861 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::TPM3::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2086 check_entity AN5521-3 NTRK1 TPM3::NTRK1 mutation NTRK1 NCBI:4914 gene spindle cell sarcoma DOID:4235 risk PubMed:30204247 In a pediatric phase 1 trial (NCT02637687), a 12-year-old boy with TPM3-NTRK1 fusion was treated with Larotrectinib as first line treatment as no standard treatment options were available. Following a significant tumor burden reduction of 31%, he underwent surgical resection, with R0 resection and no evidence for tumor recurrence at the time of last follow-up (>7 months). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::TPM3::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2087 check_entity AN5521-3 NTRK1 TPM3::NTRK1 mutation NTRK1 NCBI:4914 gene spindle cell sarcoma DOID:4235 risk CIViC:2861 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::TPM3::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2087 check_entity AN5522-1 NTRK1 TRIM63::NTRK1 mutation NTRK1 NCBI:4914 gene melanoma DOID:1909 risk PubMed:29683819 In this study we report that nonspitzoid metastasizing melanomas of adults may also harbor NTRK fusions and that NTRK expression can be immunohistochemically detected in these tumors. Of 751 melanomas analyzed by next-generation sequencing, 4 metastatic melanomas were identified with NTRK fusions, 3 involving NTRK1 (TRIM63, DDR2, and GON4L), 1 involving NTRK2 (TRAF2). All tumors were cytologically characterized by the presence of large epithelioid melanocytes and were immunoreactive with anti-Trk antibody. The NTRK1-TRIM63 fusion occurred in a 63 yo man with a nodular melanoma with the primary tumor on the shin and skin and lymph node metastases. No known melanoma drivers were identified as co-occurring in this patient. Thus, the presence of an NTRK family fusion in nonspitzoid metastasizing melanomas of adults may provide a therapeutic opportunity for NTRK inhibitors such as larotrectinib in a small subset of patients with metastatic melanoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::TRIM63::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2088 check_entity AN5522-1 NTRK1 TRIM63::NTRK1 mutation NTRK1 NCBI:4914 gene melanoma DOID:1909 risk CIViC:2266 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::TRIM63::NTRK1 sequence variation in gene NTRK1/NCBI:4914 2088 check_entity AN5523-1 NTRK2 AFAP1::NTRK2 mutation NTRK2 NCBI:4915 gene cancer DOID:162 risk PubMed:26884591 fusions. IC50 values were measured following treatment with entrectinib: TPM3-NTRK1 (2.5nM), LMNA-NTRK1 (1.4nM), ETV6-NTRK1 (2.5nM), VCL-NTRK2 (4.3nM), AFAP1-NTRK2 (2.7nM), ETV6-NTRK2 (4.5nM), ETV6-NTRK3 (3.8nM), and control (>1000nM). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::AFAP1::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2089 check_entity AN5523-1 NTRK2 AFAP1::NTRK2 mutation NTRK2 NCBI:4915 gene cancer DOID:162 risk CIViC:3570 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::AFAP1::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2089 check_entity AN5524-1 NTRK2 ETV6::NTRK2 mutation NTRK2 NCBI:4915 gene acute myeloid leukemia DOID:9119 risk PubMed:29920189 Rearrangements involving the neurotrophic receptor kinase genes (NTRK1, NTRK2, and NTRK3; hereafter referred to as TRK) produce oncogenic fusions in a wide variety of cancers in adults and children. In this manuscript, TRK fusions were screened for in 7,311 patients with a variety of hematologic malignancies. Overall, 8 TRK-fusions were identified including 1 ETV6-NTRK2 fusion in a patient with acute myeloid leukemia (AML) Treatment with TRK-Inhibitor larotrectinib led to a partial Response in an AML patient with ETV6-NTRK2 fusion after sucessful xenograft studies. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2090 check_entity AN5524-1 NTRK2 ETV6::NTRK2 mutation NTRK2 NCBI:4915 gene acute myeloid leukemia DOID:9119 risk CIViC:2269 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2090 check_entity AN5524-2 NTRK2 ETV6::NTRK2 mutation NTRK2 NCBI:4915 gene cancer DOID:162 risk PubMed:26884591 BaF3 cells were transduced with a number of NTRK fusions. IC50 values were measured following treatment with entrectinib in cell viability assays: TPM3-NTRK1 (2.5nM), LMNA-NTRK1 (1.4nM), ETV6-NTRK1 (2.5nM), VCL-NTRK2 (4.3nM), AFAP1-NTRK2 (2.7nM), ETV6-NTRK2 (4.5nM), ETV6-NTRK3 (3.8nM), and control (>1000nM). The authors conclude that entrectinib has potent in vitro activity against multiple NTRK fusions including ETV6-NTRK2. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2091 check_entity AN5524-2 NTRK2 ETV6::NTRK2 mutation NTRK2 NCBI:4915 gene cancer DOID:162 risk CIViC:2269 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2091 check_entity AN5525-1 NTRK2 Fusion NTRK2 NCBI:4915 gene cancer DOID:162 risk PubMed:32105622 A pooled analysis of three phase 1/2 clinical trials investigating the efficacy and safety of larotrectinib in 159 NTRK fusion positive solid tumor patients (1 month - 84 years old) confirmed larotrectinib to be effective and safe in these patients. NTRK2 fusions were found in 4 of the 159 patients. Two cases NTRK2 fusion cases were shown to have reduction in tumor size with another tumor showing only minor growth. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene NTRK2/NCBI:4915 2092 check_entity AN5525-1 NTRK2 Fusion NTRK2 NCBI:4915 gene cancer DOID:162 risk CIViC:2509 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene NTRK2/NCBI:4915 2092 check_entity AN5525-1 NTRK2 Fusion NTRK2 NCBI:4915 gene cancer DOID:162 risk PubMed:31838007 54 patients aged 18 or older with metastatic or locally advanced NTRK-fusion positive solid tumours (including ten tumour types and 19 unique histologies) were enrolled in one of three phase 1 or 2 trials (ALKA-372–001, STARTRK-1, and STARTRK-2). The patients were administered a 600 mg dose of entrectinib orally daily, with the primary endpoints being the proportion of patient with an objective response and the median duration of response. 31 of the 54 patients had an objective response (95% CI: 43.2–70.8), four of which were complete responses. The median duration of the response was 10 months (95% CI: 7.1 to not estimable). The most common fusions were ETV6-NTRK3 (n = 25), TPM3-NTRK1 (n = 4) and TPR-NTRK1 (n = 4), and only one patient had an NRTK2 fusion (SQSTM1-NTRK2) assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene NTRK2/NCBI:4915 2092 check_entity AN5526-1 NTRK2 KANK1::NTRK2 mutation NTRK2 NCBI:4915 gene anaplastic ependymoma DOID:5889 risk PubMed:34651095 An MRI in a previously healthy 6-year-old boy now presenting with neurologic abnormalities and seizers revealed a mass obstructing the foramen of Monro and diffuse leptomeningeal dissemination. The primary tumor was resected and subsequent radiation therapy resulted in moderate cognitive and motor improvements. Seven months later, an MRI detected a recurrence, which led to tumor molecular profiling of patient DNA and RNA. RNA analysis discovered and confirmed an in-frame KANK1::NTRK2 e3::ex16 fusion, which was predicted to preserve NTRK2’s tyrosine kinase domain. The patient was started on larotrectinib and within 2 weeks demonstrated cognitive and motor improvements. After 2 months of therapy, an MRI showed significant tumor response and by 4 months cognition and memory were near-baseline. Overall, larotrectinib resulted in both sustained clinical and radiographic response through 10 months of treatment with no related toxicity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KANK1::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2093 check_entity AN5526-1 NTRK2 KANK1::NTRK2 mutation NTRK2 NCBI:4915 gene anaplastic ependymoma DOID:5889 risk CIViC:3027 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KANK1::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2093 check_entity AN5526-2 NTRK2 KANK1::NTRK2 mutation NTRK2 NCBI:4915 gene brain glioblastoma multiforme DOID:3073 risk PubMed:31375766 From a retrospective review of 38,095 tumor samples from 33,997 patients that underwent fusion screening at Memorial Sloan Kettering Cancer Center, 87 tumors were found to be positive for an NTRK1, NTRK2, or NTRK3 fusion. One positive patient with Glioblastoma Multiforme had an in-frame KANK1::NTRK2 (e11::e14) fusion that was not detected by MSK-IMPACT, but was found with the RNA Archer screen. Detection of this fusion was positive in the cytoplasm by Pan-Trk immunohistochemical staining. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KANK1::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2094 check_entity AN5526-2 NTRK2 KANK1::NTRK2 mutation NTRK2 NCBI:4915 gene brain glioblastoma multiforme DOID:3073 risk CIViC:3027 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KANK1::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2094 check_entity AN5526-3 NTRK2 KANK1::NTRK2 mutation NTRK2 NCBI:4915 gene glioblastoma DOID:3068 risk PubMed:34041811 An MRI of 26-year-old man presenting with motor weakness and language difficultly revealed a lesion in the left frontal lobe that extended across the corpus callosum. Histologic analysis of the biopsy characterized the lesion as a glioblastoma wildtype for IDH and was negative for EGFR and MET amplification based on FISH. The biopsy material was analyzed with a DNA based genotyping panel and RNA-based NGS assay. The latter detected a KANK1::NTRK2 e4::e16 fusion that was confirmed by FISH. Following the partial resection of the tumor and six weeks of concurrent temozolomide and radiation therapy, an MRI revealed enhancement of the remaining tumor with no significant disease progression. Larotrectinib (100mg) was administered and after 49 days an MRI displayed significant treatment response as the lesion shrunk (25mm to <10mm) and the patient demonstrated slight motor improvements. By day 106 of Larotrectinib treatment, disease progression was evident. However, molecular analysis of a rebiopsy revealed KANK1::NTRK2 was no longer detectable, but a minor subclone at diagnosis with PDGFRA amplification was driving disease progression. Therefore, the authors conclude the KANK1::NTRK2 clones were effectively targeted by Larotrectinib treatment over several months resulting in a robust clinical response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KANK1::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2095 check_entity AN5526-3 NTRK2 KANK1::NTRK2 mutation NTRK2 NCBI:4915 gene glioblastoma DOID:3068 risk CIViC:3027 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KANK1::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2095 check_entity AN5526-4 NTRK2 KANK1::NTRK2 mutation NTRK2 NCBI:4915 gene pilocytic astrocytoma DOID:4851 diagnostic PubMed:29804288 A case report showing a two-year-old girl with an unusual pilocytic astrocytoma (PA) with both classic- and anaplastic- appearing tumors. A custom NGS panel identified a novel KANK1-NTRK2 fusion in both the classic and anaplastic regions. The KANK1-NTRK2 fusion was also detected in the resected recurrence, which was histologically similar to the initial anaplastic region. The KIAA1549-BRAF fusion, the most common genetic alteration in PA, was absent in this case. Different from previously known mechanisms underlying the progression to anaplastic PA, this case lacks NF1 alterations and is radiation-naïve. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KANK1::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2096 check_entity AN5526-4 NTRK2 KANK1::NTRK2 mutation NTRK2 NCBI:4915 gene pilocytic astrocytoma DOID:4851 diagnostic CIViC:3027 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KANK1::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2096 check_entity AN5526-5 NTRK2 KANK1::NTRK2 mutation NTRK2 NCBI:4915 gene sarcoma DOID:1115 risk PubMed:34464935 In a further investigation of non-traditional sarcoma cases, a 41-year-old man was thought to have a malignant peripheral nerve sheath tumor (MPNST) in the neck and spinal cord, but large rhabdoid/epithelioid cell morphology and retained H3K27Me3. Metastatic lesions were found in the lung and spine. Pan-TRK immunostain was positive and RNA NGS detected a KANK1::NTRK2 fusion. The authors state this is the first report of a KANK1::NTRK2 fusion in a sarcoma, which seems to forecast high-grade morphology and behavior. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KANK1::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2097 check_entity AN5526-5 NTRK2 KANK1::NTRK2 mutation NTRK2 NCBI:4915 gene sarcoma DOID:1115 risk CIViC:3027 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KANK1::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2097 check_entity AN5527-1 NTRK2 QKI::NTRK2 mutation NTRK2 NCBI:4915 gene malignant astrocytoma DOID:3069 risk PubMed:27402815 Authors demonstrated that a flag-tagged QKI::NTRK2 (e6::e16) fusion was able to transform Ink4a−/−/Arf−/− astrocytes, and these cells induced astrocytomas when injected intracranially into mice. QKI::NTRK2 resulted in an increase in phospho-STAT3 and the downstream target Ccl2 suggesting oncogenicity is mediated through STAT3 signaling. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::QKI::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2098 check_entity AN5527-1 NTRK2 QKI::NTRK2 mutation NTRK2 NCBI:4915 gene malignant astrocytoma DOID:3069 risk CIViC:4564 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::QKI::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2098 check_entity AN5527-2 NTRK2 QKI::NTRK2 mutation NTRK2 NCBI:4915 gene low grade glioma DOID:0080829 risk PubMed:31375766 From a retrospective review of 38,095 tumor samples from 33,997 patients that underwent fusion screening at Memorial Sloan Kettering Cancer Center, 87 tumors were found to be positive for an NTRK1, NTRK2, or NTRK3 fusion.  One glioma patient (cBioPortal patient ID: P‐0032222) contained a QKI::NTRK2 (e6::e15) fusion that was detected by an RNA Archer assay and was positive by a NTRK IHC assay. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::QKI::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2099 check_entity AN5527-2 NTRK2 QKI::NTRK2 mutation NTRK2 NCBI:4915 gene low grade glioma DOID:0080829 risk CIViC:4564 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::QKI::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2099 check_entity AN5527-3 NTRK2 QKI::NTRK2 mutation NTRK2 NCBI:4915 gene pilocytic astrocytoma DOID:4851 risk PubMed:23817572 'Whole genome sequencing of 96 pilocytic astrocytomas by the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project identified QKI::NTRK2 (e6::e16) fusions in 2 cases (5 yo & 12 yo males). Both contained a fusion between exons 1-6 of QKI including a Qua1 dimerization domain and exons 16-21 of NTRK2 which encompasses the kinase domain. The QKI dimerization domain is predicted to induce ligand-independent dimerization and activation of the NTRK2 kinase.''' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::QKI::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2100 check_entity AN5527-3 NTRK2 QKI::NTRK2 mutation NTRK2 NCBI:4915 gene pilocytic astrocytoma DOID:4851 risk CIViC:4564 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::QKI::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2100 check_entity AN5527-4 NTRK2 QKI::NTRK2 mutation NTRK2 NCBI:4915 gene polymorphous low grade neuroepithelial tumour of the young DOID:0081305 risk PubMed:34363682 Molecular profiling of 13 patients with polymorphous low-grade neuroepithelial tumor of the young (PLNTY) at Mayo Clinic, identified 1 patient (15 yo female) with a QKI::NTRK2 (e6::e15) fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::QKI::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2101 check_entity AN5527-4 NTRK2 QKI::NTRK2 mutation NTRK2 NCBI:4915 gene polymorphous low grade neuroepithelial tumour of the young DOID:0081305 risk CIViC:4564 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::QKI::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2101 check_entity AN5528-1 NTRK2 STRN::NTRK2 mutation NTRK2 NCBI:4915 gene sarcoma DOID:1115 risk PubMed:29606586 One Patient with soft tissue sarcoma and a STRN-NTRK2 fusion had a partial Response with larotrectinib. Treatment was done within a multicentre, open-label, phase 1/2 study and enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumours or CNS tumours that had relapsed, progressed, or were non-responsive to available therapies regardless of TRK fusion Status. In total, 24 patients (n=17 with tumours harbouring TRK fusions, n=7 without a documented TRK fusion) were enrolled. Among the fusion-positive patients, eight (47%) had infantile fibrosarcoma, seven (41%) had other soft tissue sarcomas, and two (12%) had papillary thyroid cancer. 14 (93%) of 15 patients with TRK fusion-positive cancers achieved an objective response; the remaining patient had tumour regression that did not meet the criteria for objective response. None of the seven patients with TRK fusion-negative cancers had an objective response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::STRN::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2102 check_entity AN5528-1 NTRK2 STRN::NTRK2 mutation NTRK2 NCBI:4915 gene sarcoma DOID:1115 risk CIViC:2163 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::STRN::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2102 check_entity AN5529-1 NTRK2 VCL::NTRK2 mutation NTRK2 NCBI:4915 gene cancer DOID:162 risk PubMed:26884591 BaF3 cells were transduced with a number of NTRK fusions. IC50 values were measured following treatment with entrectinib: TPM3-NTRK1 (2.5nM), LMNA-NTRK1 (1.4nM), ETV6-NTRK1 (2.5nM), VCL-NTRK2 (4.3nM), AFAP1-NTRK2 (2.7nM), ETV6-NTRK2 (4.5nM), ETV6-NTRK3 (3.8nM), and control (>1000nM). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::VCL::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2103 check_entity AN5529-1 NTRK2 VCL::NTRK2 mutation NTRK2 NCBI:4915 gene cancer DOID:162 risk CIViC:3569 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::VCL::NTRK2 sequence variation in gene NTRK2/NCBI:4915 2103 check_entity AN5530-1 NTRK3 Amplification NTRK3 NCBI:4916 gene cancer DOID:162 risk PubMed:28183697 Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two phase I studies in patients with advanced or metastatic solid tumors, including CNS disease. Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. No objective responses (per RECIST v1.1) were observed in patients whose tumors did not harbor gene fusions involving NTRK1/2/3, ROS1, or ALK, with the exception of 1 patient with an ALKF1245V mutant neuroblastoma. Only 9 of 119 patients had NTRK Amplifications. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene NTRK3/NCBI:4916 2104 AN5530-1 NTRK3 Amplification NTRK3 NCBI:4916 gene cancer DOID:162 risk CIViC:1255 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene NTRK3/NCBI:4916 2104 AN5531-1 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene cervical carcinosarcoma DOID:4112 risk PubMed:35572973 A 33-year-old Han Chinese woman has been associated with an NTRK fusion cervical sarcoma which was positive for Pan-TRK by immunohistochemistry (IHC) analysis. However, FISH for NTRK1 was negative. The tumor resection was performed by hysterectomy, bilateral salpingo-oophorectomy, pelvic lymph node dissection, and partial vaginal resection. No evidence of lymph node metastasis was noted. Patient underwent 6 course adjuvant chemotherapy. On a follow-up visit after two months from her last follow up a mass in the right trigeminal nerve area was detected. This was morphologically confirmed as spindle cell sarcoma. NGS and IHC on this tumor specimen confirmed EML4-NTRK3 (e2-e14) fusion and pan-TRK positive, respectively. Tumor recurrence and invasion was noted one month later with a mass protruding from the vaginal external orifice. The mass was resected, and this specimen was positive for Pan-TRK by IHC. The patient passed away (14 months after diagnosis) before being enrolled in the TRK inhibitor clinical trial. The authors of this paper reported this as a first cervical sarcoma case with TRK fusion from a Chinese institution. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2105 check_entity AN5531-1 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene cervical carcinosarcoma DOID:4112 risk CIViC:4167 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2105 check_entity AN5531-2 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene colon adenocarcinoma DOID:234 risk PubMed:31375766 From a retrospective review of 38,095 tumor samples from 33,997 patients using DNA sequencing (MSK-IMPACT) and RNA sequencing (MSK-Fusion panel) identified 87 tumors with NTRK1-3 fusions. Two cases of Colon Adenocarcinoma had an in-frame EML4::NTRK3 (e2::e14) fusion that was not detected by MSK-IMPACT but was found with the MSK-Fusion assay. Detection of this fusion was positive in one of this case by pan-Trk immunohistochemistry. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2106 check_entity AN5531-2 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene colon adenocarcinoma DOID:234 risk CIViC:4167 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2106 check_entity AN5531-3 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene colon cancer DOID:219 risk PubMed:28512242 From whole exome sequencing of 278 primary colon tumors with stage I-III, 2.5% carried gene fusion. 1.5% of these were positive for kinase fusions including BRAF, NTRK3 and RET gene fusions. These gene fusions were verified by RT-PCR. One positive patient with colon cancer had an in-frame EML4::NTRK3 (e2-e14) fusion. Molecular effects of EML4::NTRK3 fusion gene was assessed using HEK293T cells or NIH-3T3-A14 cells transfected with pBABE constructs containing fusion gene and co-transfected with constructs encoding either MYC-tagged ERK1 or GFP-tagged AKT. Western blot results showed EML4::NTRK3 fusion induces ERK1 and AKT phosphorylation confirming EML4::NTRK3 affects oncogenic pathways such as MAPK/ERK signaling pathway. However similar activation was not observed in the truncated form of the fusion gene or the wild type NTRK3 constructs. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2107 check_entity AN5531-3 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene colon cancer DOID:219 risk CIViC:4167 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2107 check_entity AN5531-4 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene congenital fibrosarcoma DOID:8418 diagnostic;risk PubMed:27148571 A novel EML4::NTRK3 fusion was identified in a 9-month-old male with a recurrent congenital fibrosarcoma. The in-frame fusion transcript contained exons 1-2 of EML4 fused to exon 14 of NTRK3 which is predicted to include the entire intact NTRK3 kinase domain. The fusion transcript was cloned through RT-PCR from the patient’s pulmonary tissue and stably transduced with lentivirus into NIH-3T3 cells. These fusion expressing cells demonstrated in vitro anchorage independent growth in a soft agar assay after 21 days. These cell lines also generated large tumors when injected subcutaneously into the flanks of mice after 18 days with tumors exhibiting histology similar to congenital fibrosarcoma. NIH-3T3 cells with only empty vector generated no colonies in the soft agar assay and no tumors in mice. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2108 check_entity AN5531-4 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene congenital fibrosarcoma DOID:8418 diagnostic;risk PubMed:29099503 To determine if EML4::NTRK3 fusions were recurrent in tumors types known to harbor ETV6::NTRK3 fusions, the authors screened 63 cases with varying diagnoses (infantile fibrosarcoma, congenital mesoblastic nephroma, mammary analog secretory carcinoma and secretory breast carcinoma). A novel NTRK3 break-apart probe set detected an NTRK3 rearrangement in 34/58 cases tested, including 25/26 infantile fibrosarcomas. In 46 cases tested, a novel EML4::NTRK3 dual fusion FISH probe set detected the fusion in 1 infantile fibrosarcoma case (case 58; 1 years old) known to harbor the EML4::NTRK3 fusion and a new case (case 3; 7 months), both with histology typical for what is observed in ETV6::NTRK3 infantile fibrosarcoma. The probe did not detect the fusion in any case known to have an ETV6::NTRK3 fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2108 check_entity AN5531-4 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene congenital fibrosarcoma DOID:8418 diagnostic;risk CIViC:4167 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2108 check_entity AN5531-5 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene congenital mesoblastic nephroma DOID:4773 diagnostic PubMed:29099503 To determine if EML4::NTRK3 fusions were recurrent in tumors known to harbor ETV6::NTRK3 fusions, the authors screened 63 cases with varying diagnoses (infantile fibrosarcoma, congenital mesoblastic nephroma, mammary analog secretory carcinoma and secretory breast carcinoma). A novel NTRK3 break-apart probe set detected an NTRK3 rearrangement in 34/58 cases tested, including 7/18 congenital mesoblastic nephromas. In 46 cases tested, a novel EML4::NTRK3 dual fusion FISH probe set detected the fusion in one congenital mesoblastic nephroma case with histology typical for what is observed in ETV6::NTRK3 congenital mesoblastic nephroma (case 41; 6 days old). The probe did not detect the fusion in any case know to have an ETV6::NTRK3 fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2109 check_entity AN5531-5 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene congenital mesoblastic nephroma DOID:4773 diagnostic CIViC:4167 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2109 check_entity AN5531-6 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene glioblastoma DOID:3068 risk PubMed:31375766 From a retrospective review of 38,095 tumor samples from 33,997 patients using DNA sequencing (MSK-IMPACT) and RNA sequencing (MSK-Fusion panel) identified 87 tumors with NTRK1-3 fusions. One case of Glioblastoma had an in-frame EML4::NTRK3 (e2::e14) fusion that was not detected by MSK-IMPACT but was found with the MSK-Fusion assay. Detection of this fusion was positive by pan-Trk immunohistochemistry. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2110 check_entity AN5531-6 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene glioblastoma DOID:3068 risk CIViC:4167 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2110 check_entity AN5531-7 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene high grade glioma DOID:3070 risk PubMed:33403813 A 7 month old male had a large cystic mass in his brain surgically resected. Pathological analysis determined the mass to be an infantile high-grade glioma and transcriptome sequencing of the tumor RNA found the tumor harbored an EML4::NTRK3 fusion. The patient then went through four cycles of chemotherapy, but imaging taken two months later revealed no change in tumor size. The patient was treated with Larotrectinib (100 mg/m2/dose BID) and an MRI two months later demonstrated a significant decrease of his tumor. The patient (now 17 months old) continues on twice daily larotrectinib and shows no signs of progression after 10 months of treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2111 check_entity AN5531-7 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene high grade glioma DOID:3070 risk CIViC:4167 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2111 check_entity AN5531-8 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene lung adenocarcinoma DOID:3910 risk PubMed:36419889 A 45-year-old non-smoking female patient was diagnosed with a stage IV lung adenocarcinoma and magnetic resonance imaging showed multiple brain metastases. Targeted NGS analysis on the pleural biopsy using the Oncomine Comprehensive Assay v3 panel identified the EML4::NTRK3 (e2::e14) fusion. This fusion was confirmed by both fluorescence in situ hybridization (FISH) analysis, using NTRK3 and EML4 Dual Color Break Apart probes and panTRK antibody IHC staining. Entrectinib was started and two months later PET scan and brain MR revealed partial response. After 5 months of treatment, complete response was observed in the lungs and brain. As of publication, the patient was still being treated with entrectinib, and their most recent PET and MR scan taken 1 year and 5 months into treatment demonstrated maintained complete response in the brain and lungs. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2112 check_entity AN5531-8 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene lung adenocarcinoma DOID:3910 risk CIViC:4167 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2112 check_entity AN5531-9 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene lung non-small cell carcinoma DOID:3908 risk PubMed:34625502 The paper mentions a 43-year-old-male with an EML4::NTRK3 rearrangement in metastatic non-small cell lung cancer initially treated with carboplatin/paclitaxel chemotherapy. Upon identification of an EML4::NTRK3 fusion, the patient was treated with the NTRK inhibitor entrectinib for 12 months with a partial response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2113 check_entity AN5531-9 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene lung non-small cell carcinoma DOID:3908 risk CIViC:4167 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2113 check_entity AN5531-9 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene lung non-small cell carcinoma DOID:3908 risk CIViC:4596 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2113 check_entity AN5531-10 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene pancreatic ductal adenocarcinoma DOID:3498 risk PubMed:34583947 Whole genome sequencing and RNAseq were performed on 400 patients with resected or locally advanced/metastatic Pancreatic Ductal Adenocarcinoma (PDAC). Immunohistochemistry (IHC) analysis was performed in a subset of these patients. Two adult cases of PDAC were identified with an in-frame EML4::NTRK3 (e6-e14) fusion. This fusion was further confirmed by RT-PCR and Sanger sequencing. Pan-Trk IHC was positive for this fusion. In one case, the fusion was found postmortem. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2114 check_entity AN5531-10 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene pancreatic ductal adenocarcinoma DOID:3498 risk CIViC:4167 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2114 check_entity AN5531-11 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene thyroid gland carcinoma DOID:3963 risk PubMed:31375766 From a retrospective review of 38,095 tumor samples from 33,997 patients using DNA sequencing (MSK-IMPACT) and RNA sequencing (MSK-Fusion panel) identified 87 tumors with NTRK1-3 fusions. One case of poorly differentiated thyroid carcinoma had an in-frame EML4::NTRK3 (e2::e14) fusion that was not detected by MSK-IMPACT but was found with the MSK-Fusion assay. Detection of this fusion was positive by pan-Trk immunohistochemistry. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2115 check_entity AN5531-11 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene thyroid gland carcinoma DOID:3963 risk CIViC:4167 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2115 check_entity AN5531-12 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene thyroid gland papillary carcinoma DOID:3969 risk PubMed:32457407 Of 351 primary thyroid carcinoma patients assessed by targeted gene rearrangement next-generation assay, 11 cases (3.1%) had NTRK rearrangement. Only one case of EML4::NTRK3 fusion (e2,e13) with an intact kinase domain was detected in an intracranial metastatic thyroid carcinoma. This patient underwent a total thyroidectomy and radioactive iodine (RAI) treatment at initial diagnosis. However, disease persisted and after three decades brain metastasis occurred. NTRK inhibitor therapy was given which showed a 69.7% decrease in disease burden following 34 cycles of entrectinib (400 mg daily) with mild side effects. pTERT C228T mutation and the frameshift MEN1 deletion cooccurred with EML4::NTRK3 fusion and both did not confer to entrectinib resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2116 check_entity AN5531-12 NTRK3 EML4::NTRK3 mutation NTRK3 NCBI:4916 gene thyroid gland papillary carcinoma DOID:3969 risk CIViC:4167 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EML4::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2116 check_entity AN5532-1 NTRK3 ETV6::NTRK3 G623R NTRK3 NCBI:4916 gene mammary analogue secretory carcinoma DOID:0080808 risk PubMed:26884591 Case report of a patient with mammary analogue secretory carcinoma (MASC) harboring an etv6-ntrk3 fusion. The patient was treated with entrectinib and exhibited a partial response for 7 months followed by disease progression. A NTRK3 exon 16 G623R (c.1867G>A) mutation was identified in the progressive tumor. Cell line and structural models revealed that this mutation conferred relative resistance to entrectinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G623R sequence variation in gene NTRK3/NCBI:4916 2117 check_entity AN5532-1 NTRK3 ETV6::NTRK3 G623R NTRK3 NCBI:4916 gene mammary analogue secretory carcinoma DOID:0080808 risk CIViC:783 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G623R sequence variation in gene NTRK3/NCBI:4916 2117 check_entity AN5533-1 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene acute myeloid leukemia DOID:9119 risk PubMed:29237803 Two AML cell lines, IMS-M2 and M0-91, with the ETV6-NTRK3 fusion were treated with entrectinib. Sequencing of these cell lines found no other driver mutations in 265 other cancer genes suggesting the ETV6-NTRK3 fusion is the oncogenic driver. The IC50 for the IMS-M2 and M0-91 cell lines was 0.47 and 0.65 nmol/L, respectively. Mouse xenografts treated with entrectinib at 10 or 30 mg/kg had complete remission while treatment with 3 mg/kg caused significant reduction in tumor growth. Testing of the bone marrow of IMS-M2 xenografts after 3 weeks of treatment found no human CD45-positive cells in the 3, 10, and 30 mg/kg treatment groups; all vehicle treated mice had some human CD45-positive cells in their bone marrow. Zebrafish xenotransplantation of M0-91 cells were sensitive to entrectinib treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2118 check_entity AN5533-1 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene acute myeloid leukemia DOID:9119 risk CIViC:779 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2118 check_entity AN5533-2 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk PubMed:29880614 Both in vivo and in vitro models demonstrated Larotrectinib was an effective treatment against cells harboring ETV6-NTRK3. In YFP-luciferase PDX mice from a 16-year-old with Ph-like B-ALL, flow cytometry indicated the absence of leukemic cells in the bone marrow (p<.0001), peripheral blood (p=.0018), and spleen (p=.0001) after 6 weeks of Larotrectinib (n=10) compared to vehicle treated mice (n=10). Treated mice also had lower splenic weight (p<.001) and the absence of leukemia burden in the bone marrow and central nervous system as determined by histopathology. In 2 mice, leukemic burden increased while Larotrectinib was paused from weeks 6-25. Upon the reintroduction of treatment for 4 weeks, leukemic burden was lowered. Conditional knock-in Etv6-NTRK CD19-Cre cells isolated from bone marrow and cultured ex vivo were highly sensitive to serial dilutions of Larotrectinib. After 48 hours of Larotrectinib exposure, Ba/F3 cells stably expressing ETV6-NTRK3 demonstrated a response with an IC50 of 17.0nM (viability measured by CellTiter blue). Finally, Larotrectinib was 1000x more potent against 3 human cancer cell lines with an NTRK fusion versus the 76 with other alterations. The most sensitive was an AML cell line (M0-91) with an ETV6-NTRK3 fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2119 check_entity AN5533-2 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk PubMed:31905241 Case report of a 61-year-old man with B-ALL. An initial analysis detected the ETV6-NTRK3 fusion and a NRASGly12Asp mutation. Initial therapies included chemotherapy and CAR-T infusion. Relapse 6 weeks after initial complete response to these therapies found a large increase in fusion transcripts and NTRK3 rearrangements were detectable by FISH in 50/50 blast nuclei whereas NRAS mutations were no longer detectable. The patient was treated with oral monotherapy larotrectinib (100mg twice per day). After 4 days on treatment peripheral blood blasts became undetectable; after 6 days on treatment lymphadenopathy and leukemia cutis resolved and a biopsy revealed an ablated bone marrow with only a few scattered blasts. The patient experienced clinical benefit with no apparent side effects during 42 days of larotrectinib treatment, however, patient eventually succumbed to multifocal angioinvasive aspergillosis because of insufficient recovery of normal hematopoiesis. Later sequencing of the NTRK3 kinase domain did not detect any larotrectinib resistance mutations (p.G623R, p.G696A). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2119 check_entity AN5533-2 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk PubMed:31725893 All lines of conventional therapy (including allogeneic HSCT, blinatumomab, and CAR T cells) were inefficient for a 6-year-old boy with B-cell ALL and CNS infiltration (National Cancer Institute high risk). Conventional cytogenetics, FISH, and an Abbott break-apart probe of a peripheral blood sample collected at diagnosis revealed an unbalance translocation of the ETV6 locus. The patient relapsed twice and RNA sequencing of the initial diagnosis sample revealed a cytogenetically cryptic ETV6-NTRK3 fusion. Treatment with larotrectinib was initiated in combination with etoposide and methotrexate resulted in molecular remission in 66 days in bone marrow and CNS. A third relapse occurred 45 days after Larotrectinib was paused for CAR-T infusions. Larotrectinib was resumed with a dosage increase and again achieved sustained undetectable minimal residual disease after 66 days, and displayed molecular remission through 39 days. The authors suggest larotrectinib as a potential effective treatment for B-cell ALL patients harboring ETV6-NTRK3, including those with CNS infiltration. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2119 check_entity AN5533-2 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk CIViC:779 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2119 check_entity AN5533-3 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene breast secretory carcinoma DOID:4922 diagnostic;risk PubMed:29623306 Shukla et al report on a remarkable case study of a 14 year old pediatric patient with refractory secretory breast carcinoma first presenting as a fibroadenoma at 8 yo. Over the next years, she experienced recurrence, multiple rounds of chemotherapy and metastasis -- until her case was presented at a virtual multidisciplinary tumor board organized by the Global Cancer Institute which recommended testing for ETV6-NTRK3 fusion. This fusion was confirmed by RNA-seq, targeted DNA and WGS sequencing as well as immunohistochemistry staining with a TRK antibody. The patient was treated with LOXO-101 (larotrectinib) in a single patient use protocol. Within two months, she experienced near complete resolution of a 10.4 × 8.5 cm fungating chest mass with multiple satellite lesions (See Figure 2). The authors note that TERT promoter mutation and a reciprocal inversion including CDKN2A were also identified, but given what is known about LOXO-101 and ETV6-NTRK3, they infer ETV6-NTRK3 fusion as the primary mitogenic driver in this patient. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2120 check_entity AN5533-3 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene breast secretory carcinoma DOID:4922 diagnostic;risk PubMed:15101049 In developing a FISH assay to detect ETV6::NTRK3 fusions, the authors found 3 of 4 secretary breast carcinomas were positive for the fusion. In a subsequent analysis of an invasive breast carcinoma tissue microarray, only 1 of 202 samples showed evidence of a fusion and this tumor was found to have histology consistent with a secretory carcinoma. None of the fusion-negative samples had secretory carcinoma histology. This suggests the ETV6::NTRK3 fusion is specific for secretory type of invasive breast carcinomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2120 check_entity AN5533-3 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene breast secretory carcinoma DOID:4922 diagnostic;risk PubMed:12450792 12 of 13 (92%) secretory breast carcinomas were found to have ETV6::NTRK3 fusions by RT-PCR and/or FISH whereas other infiltrating ductal carcinomas were negative for the fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2120 check_entity AN5533-3 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene breast secretory carcinoma DOID:4922 diagnostic;risk PubMed:28548128 9 of 9 breast secretory carcinomas were found to have ETV6:NTRK3 fusions, a basal-like phenotype, and no additional pathogenic aberrations in genes commonly mutated in breast cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2120 check_entity AN5533-3 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene breast secretory carcinoma DOID:4922 diagnostic;risk CIViC:779 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2120 check_entity AN5533-4 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene cancer DOID:162 risk PubMed:30624546 In this phase 1 dose-escalation study seventy patients with metastatic solid tumours were enrolled. Eight patient tumours were found to harbour NTRK gene fusions, six of which were ETV6-NTRK3. Treatment with larotrectinib resulted in reduced tumour burden for all patients with NTRK fusions. The average time on treatment was 28.4 months for patients with NTRK fusion cancer, compared to 1.8 months for those without an NTRK fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2121 check_entity AN5533-4 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene cancer DOID:162 risk CIViC:779 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2121 check_entity AN5533-5 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene congenital fibrosarcoma DOID:8418 diagnostic;risk PubMed:29606586 Four out of six patients with infantile fibrosarcoma and a ETV6-NTRK3 fusion had a partial response, the remaining two had a complete response with larotrectinib. Treatment was done within a multicentre, open-label, phase 1/2 study and enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumours or CNS tumours that had relapsed, progressed, or were non-responsive to available therapies regardless of TRK fusion Status. In total, 24 patients (n=17 with tumours harbouring TRK fusions, n=7 without a documented TRK fusion) were enrolled. Among the fusion-positive patients, eight (47%) had infantile fibrosarcoma, seven (41%) had other soft tissue sarcomas, and two (12%) had papillary thyroid cancer. 14 (93%) of 15 patients with TRK fusion-positive cancers achieved an objective response; the remaining patient had tumour regression that did not meet the criteria for objective response. None of the seven patients with TRK fusion-negative cancers had an objective response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2122 check_entity AN5533-5 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene congenital fibrosarcoma DOID:8418 diagnostic;risk PubMed:27093299 Nagasubramanian et al reports on a case of refractory infantile fibrosarcoma (IFS) with constitutive activation of the tropomyosin‐related kinase (TRK) signaling pathway from an ETS variant gene 6–neurotrophin 3 receptor gene (ETV6–NTRK3) gene fusion. The patient was diagnosed with IFS at 6 months of age. At 16 months the patient enrolled in a pediatric Phase 1 trial of LOXO‐101 (Larotrectinib, ARRY-470), an experimental, highly selective inhibitor of TRK. The patient experienced a rapid, radiographic response, demonstrating the potential for LOXO‐101 to provide benefit for IFS harboring NTRK gene fusions. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2122 check_entity AN5533-5 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene congenital fibrosarcoma DOID:8418 diagnostic;risk PubMed:30204247 In a pediatric phase 1 trial (NCT02637687) after initial chemotherapy failure, two ETV6-NTRK3 positive children (2 year old and 5 month old) were treated with Larotrectinib, resulting in reduced tumor burden (4 cycles showed ~50% reduction). Treatment was followed up by surgical resection resulting in a disease-free status at the time of last follow-up (>1 year). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2122 check_entity AN5533-5 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene congenital fibrosarcoma DOID:8418 diagnostic;risk PubMed:9462753 This is the first study showing the ETV6-NTRK3 gene fusion in congenital fibrosarcoma (CFS). Using cytogenetic and FISH analyses, a novel t(12;15)(p13;q25) rearrangement was identified in CFS cases (3 of 4, including 1 case likely presenting overgrowth of normal fibroblasts). Mapping of breakpoints and mRNA analysis revealed that the translocation gives rise to the ETV6-NTRK3 fusion transcript, consisting of the HLH dimerization domain of ETV6 fused to the kinase domain of NTRK3. This aberration was absent in adult-type fibrosarcoma (ATFS, 2 cases) and infantile fibromatosis (IFB, 15 cases). This is the first study describing the involvement of NTRK proteins in human oncogenesis and ETV6 gene fusion in solid tumors and proposing ETV6-NTRK3 as a diagnostic biomarker for CFS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2122 check_entity AN5533-5 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene congenital fibrosarcoma DOID:8418 diagnostic;risk PubMed:10895816 In this study, a collection of pediatric spindle cell tumors were screened for the ETV6::NTRK3 fusion by RT-PCR. 10 of 11 (91%) cases diagnosed as congenital fibrosarcoma were found to harbor the ETV6::NTRK3 fusion while none of the 51 other malignant or benign spindle cell tumors (including adult-type fibrosarcoma, infantile fibromatosis, myofibromatosis, and more aggressive malignant spindle cell tumors) were positive for this fusion. The authors conclude ETV6::NTRK3 RT-PCR analysis is a reliable and specific modality to aid in the diagnosis of this disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2122 check_entity AN5533-5 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene congenital fibrosarcoma DOID:8418 diagnostic;risk PubMed:11242790 In this study, the ETV6::NTRK3 fusion was detected in 7 of 10 (70%) of congenital fibrosarcomas by RT-PCR but absent in 38 other control spindle cell tumors, including adult-type fibrosarcomas, leiomyosarcomas, malignant fibrous histiocytomas, synovial sarcomas, MPNST, dermatofibrosarcoma protuberans, schwannomas, fibromatosis cases, and nodular fasciitis cases. This demonstrates utility of ETV6::NTRK3 fusion detection in diagnosis of this disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2122 check_entity AN5533-5 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene congenital fibrosarcoma DOID:8418 diagnostic;risk CIViC:779 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2122 check_entity AN5533-6 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene congenital mesoblastic nephroma DOID:4773 diagnostic;risk PubMed:29893456 A 23 month old (at the time of report) male was diagnosed prenatally with Stage II cellular mesoblastic nephroma (MN) on the right kidney, which was surgically removed on the sixth day of life. ETV6::NTRK was found by FISH. At 12 months a lesion on the distal tibia developed. The patient entered the larotrectinib pediatric study NCT02637687 and received eight cycles of therapy without any grade 2 or greater toxicities so far. After this the patient had a full range of motion in the lower extremity and the there was a complete disappearance of the soft-tissue component and a near-complete reconstitution of the cortex of the distal right tibial metastatic focus. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2123 check_entity AN5533-6 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene congenital mesoblastic nephroma DOID:4773 diagnostic;risk PubMed:29286563 A frequent genetic alteration in congenital mesoblastic nephroma is the translocation t(12;15) resulting in a fusion of the ETV6 gene on 12p13 and the NTRK3 gene on 15p15 that occurs almost exclusively in cellular mesoblastic nephroma subtype. In a group of 111 mesoblastic nephroma (MN) samples, 79 were were evaluable by FISH, which consisted of 38 classical MN, 29 cellular MN, and 12 mixed MN samples. 16 of 29 cellular type MN had ETV6::NTRK3 via break apart FISH, while 0/38 classical and 0/12 mixed types were positive. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2123 check_entity AN5533-6 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene congenital mesoblastic nephroma DOID:4773 diagnostic;risk PubMed:27020209 In an analysis of 19 cases of mesoblastic nephroma, the ETV6::NTRK3 fusion was detected in 0 of 5 of the classic mesoblastic nephroma, 8 of 8 (100%) of the cellular mesoblastic nephroma and 5 of 6 (83%) of the mixed mesoblastic nephroma cohorts. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2123 check_entity AN5533-6 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene congenital mesoblastic nephroma DOID:4773 diagnostic;risk PubMed:32590884 In an analysis of 22 cases of mesoblastic nephroma, 4 of 5 (80%) cellular mesoblastic nephromas harbored ETV6::NTRK3, 1 of 5 cellular mesoblastic nephromas harbored a KLHL7::BRAF fusion, 12 of 12 (100%) classic mesoblastic nephromas harbored EGFR ITD, 4 of 5 of mixed histology had EGFR ITD, and 1 of 5 of mixed histology had the ETV6::NTRK3 fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2123 check_entity AN5533-6 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene congenital mesoblastic nephroma DOID:4773 diagnostic;risk CIViC:779 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2123 check_entity AN5533-7 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene mammary analogue secretory carcinoma DOID:0080808 risk PubMed:26884591 Case report of a patient with mammary analogue secretory carcinoma (MASC) harboring an ETV6-NTRK3 fusion. The patient was treated with entrectinib and exhibited a partial response for 7 months followed by disease progression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2124 check_entity AN5533-7 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene mammary analogue secretory carcinoma DOID:0080808 risk CIViC:779 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2124 check_entity AN5533-8 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene thyroid gland papillary carcinoma DOID:3969 prognostic PubMed:26784937 Prasad et al queried the histopathology of 28 Papillary Thyroid Carcinomas (PTCs) from patients ages 6-18 years (20 females, 8 males). None had significant exposure to radiation. 5 / 27 PTCs (18.5%) had NTRK3-ETV6 fusion oncogenes. The authors compare NTRK3-ETV6 (and include 2 other NTRK fusion samples) to PTCs with BRAF(V) (600E) and find they are associated with large size (mean, 2.2 cm vs 1.5 cm, respectively; P = .05), solid and diffuse variants (11 of 13 vs 0 of 13 tumors, respectively; P < .001), and lymphovascular invasion (12 of 13 vs 6 of 13 tumors, respectively; P = .02); The authors conclude that NTRK fusion oncogene PTC presents with more extensive disease and aggressive pathology than BRAF(V) (600E) PTC in the pediatric population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2125 check_entity AN5533-8 NTRK3 ETV6::NTRK3 mutation NTRK3 NCBI:4916 gene thyroid gland papillary carcinoma DOID:3969 prognostic CIViC:779 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ETV6::NTRK3 sequence variation in gene NTRK3/NCBI:4916 2125 check_entity AN5534-1 NTRK3 F617L mutation NTRK3 NCBI:4916 gene gastrointestinal stromal tumor DOID:9253 risk PubMed:30624546 A 58-year-old male with NTRK-fusion positive gastrointestinal stromal tumour (GIST) demonstrated initial response to Larotrectinib but progressed after developing a gatekeeper mutation (TRKC F617L). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F617L sequence variation in gene NTRK3/NCBI:4916 2126 check_entity AN5534-1 NTRK3 F617L mutation NTRK3 NCBI:4916 gene gastrointestinal stromal tumor DOID:9253 risk CIViC:3336 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F617L sequence variation in gene NTRK3/NCBI:4916 2126 check_entity AN5535-1 NTRK3 Fusion NTRK3 NCBI:4916 gene cancer DOID:162 risk PubMed:28183697 in two phase I studies in patients with advanced or metastatic solid tumors, including patients with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene NTRK3/NCBI:4916 2127 check_entity AN5535-1 NTRK3 Fusion NTRK3 NCBI:4916 gene cancer DOID:162 risk PubMed:31838007 Describes a meta-analysis of three separate phase I or II trials: ALKA-372-001, STARTRK-1, and STARTRK-2. All of these evaluate entrectinib in NTRK fusion-positive solid tumours. 31/54 had objective response (57%; 95% CI 43·2–70·8), including 4 CR and 27 PR. 9 had SD. Response by NTRK gene type: 13/22 NTRK1 fusions [59%; 95% CI 36·4–79·3], 18/31 NTRK3 fusions [58%; 39·1–75·5], and 0/1 NTRK2 fusion. Most frequent tumour types were sarcoma, NSCLC, salivary, breast, thyroid, colorectal. Most common fusions were ETV6-NTRK3 (25), TPM3-NTRK1 (4) and TPR-NTRK1 (4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene NTRK3/NCBI:4916 2127 check_entity AN5535-1 NTRK3 Fusion NTRK3 NCBI:4916 gene cancer DOID:162 risk CIViC:1251 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene NTRK3/NCBI:4916 2127 check_entity AN5535-1 NTRK3 Fusion NTRK3 NCBI:4916 gene cancer DOID:162 risk PubMed:29466156 This was a Phase 1/2 study of 55 patients from 4 months to 76 years old with TRK-fusion positive tumors given NTRK inhibitor Larotrectinib. Patients had 17 unique NTRK fusion types. Patient overall response rate was 75% according to independent review and 80% according to investigator assessment. Authors state that Larotrectinib had durable anti tumor activity regardless of age or tumor type. 26/27 patients with NTRK3-fusion showed maximum percent change in tumor size between -30% and -100%. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene NTRK3/NCBI:4916 2127 check_entity AN5536-1 NTRK3 G623R mutation NTRK3 NCBI:4916 gene lung non-small cell carcinoma DOID:3908 risk PubMed:34625502 A 43-year-old-male with an EML4::NTRK3 rearrangement in metastatic non-small cell lung cancer progressed after 12 months treatment with the NTRK inhibitor entrectinib with the emergence of an NTRK3 G623R solvent-front mutation. The patient then received the second generation NTRK inhibitor repotrectinib as part of the phase II TRIDENT-1 (NCT03093116) trial. 50% tumor regression was seen at 4 months and 65% tumor regression after10 months of repotrectinib treatment. At the time of publication, the patient remained on treatment with duration of treatment of 16.4+ months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G623R sequence variation in gene NTRK3/NCBI:4916 2128 check_entity AN5536-1 NTRK3 G623R mutation NTRK3 NCBI:4916 gene lung non-small cell carcinoma DOID:3908 risk CIViC:4596 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G623R sequence variation in gene NTRK3/NCBI:4916 2128 check_entity AN5537-1 NTRK3 NTRK3::SCAPER mutation NTRK3 NCBI:4916 gene meningeal melanocytoma DOID:5900 risk PubMed:31437301 A 4 year old African American girl was seen for a lesion on the scalp. Punch biopsy was done on a largely skin-colored subcutaneous nodule. Subcutaneous nodular aggregations of heavily pigmented epithelioid melanocytes were seen, with melanophages and a small amount of lymphocytes. Proliferation index (Ki-67) was less than 5%. The child was diagnosed with Pigmented epithelioid melanocytoma (PEM), which usually occurs spontaneously as solitary neoplasms in otherwise healthy patients, and rarely spreads beyond the lymph node basin. Comparative genomic hybridization array showed gains and losses at 15q and losses at 17q. The authors note that melanoma often shows three or more segmental amplifications or deletions in reproducible loci, but the alterations in this patient were not commonly seen. A breakpoint was seen in the amplified regions involving the NTRK3 gene with an amplification of 5' end and loss of 3' end and this indicated a possible fusion. Next generation sequencing confirmed the presence of NTRK3 amplification at the 5' end and loss at the 3' end. In addition, an in-frame fusion with NTRK3 at the 5' end was found involving NTRK3 exons 1 to 7 and SCAPER exons 13 to 31 as the 3' partner. This fusion did not include NTRK3 kinase domain (exons 13-18). The tumor was excised with narrow margins and follow up showed no evidence for underlying Carney complex. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::NTRK3::SCAPER sequence variation in gene NTRK3/NCBI:4916 2129 check_entity AN5537-1 NTRK3 NTRK3::SCAPER mutation NTRK3 NCBI:4916 gene meningeal melanocytoma DOID:5900 risk CIViC:4120 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::NTRK3::SCAPER sequence variation in gene NTRK3/NCBI:4916 2129 check_entity AN5538-1 NUP98 NUP98::NSD1 mutation NUP98 NCBI:4928 gene acute myeloid leukemia DOID:9119 prognostic PubMed:21813447 In this study >1000 well-characterized pediatric and adult AML cases were screened using a NUP98/NSD1-specific RT-PCR. In the pediatric cohort (n = 293; age, 0-18 years), NUP98/NSD1 was present in 16.1% of the cases. The authors identified the cytogenetically cryptic NUP98/NSD1 translocation as an independent factor for dismal clinical outcome for both pediatric and adult patients. The remission rate (CR) of NUP98/NSD1-positive cases in the pediatric cohort was 100%, but 10 of the 12 cases relapsed early. The cumulative incidence of nonresponse/relapse (pCIR) at 4 years was 83 ± 13% for NUP98/NSD1-positive versus 45 ± 3% for negative cases (P < .001). NUP98/NSD1 cases had a poor event-free survival (pEFS) and overall survival (pOS) (4-years pEFS, 8 ± 8% vs 46 ± 3%, P < .001; and 4-years pOS, 31 ± 16% vs 64 ± 3%, P = .011 for NUP98/NSD1-positive vs negative cases, respectively). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::NUP98::NSD1 sequence variation in gene NUP98/NCBI:4928 2130 check_entity AN5538-1 NUP98 NUP98::NSD1 mutation NUP98 NCBI:4928 gene acute myeloid leukemia DOID:9119 prognostic CIViC:2466 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::NUP98::NSD1 sequence variation in gene NUP98/NCBI:4928 2130 check_entity AN5539-1 PALB2 Biallelic Inactivation PALB2 NCBI:79728 gene pancreatic cancer DOID:1793 risk 100761-6 PubMed:21135251 In a patient with gemcitabine-refractory pancreatic cancer, a tumor-derived xenograft was found to be responsive to Mitomycin C. After disease progression, the patient was started on a regimen of mitomycin C, and the patient was shown to be asymptomatic after 3 years of follow-up. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PALB2 Biallelic Inactivation [biomarker_term_in_review] 2131 not_mapped AN5539-1 PALB2 Biallelic Inactivation PALB2 NCBI:79728 gene pancreatic cancer DOID:1793 risk 100761-6 CIViC:528 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PALB2 Biallelic Inactivation [biomarker_term_in_review] 2131 not_mapped AN5539-2 PALB2 Biallelic Inactivation PALB2 NCBI:79728 gene prostate cancer DOID:10283 risk 100761-6 PubMed:26510020 From 14 prostate cancer patients (88%) who had a response to olaparib, 7 patients had BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations), 4 of 5 with had ATM aberrations and one had a biallelic inactivation of PALB2 (frameshift mutation and deletion). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PALB2 Biallelic Inactivation [biomarker_term_in_review] 2132 not_mapped AN5539-2 PALB2 Biallelic Inactivation PALB2 NCBI:79728 gene prostate cancer DOID:10283 risk 100761-6 CIViC:528 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PALB2 Biallelic Inactivation [biomarker_term_in_review] 2132 not_mapped AN5540-1 PALB2 L531FS*30 mutation PALB2 NCBI:79728 gene breast cancer DOID:1612 diagnostic 100761-6 PubMed:18628482 Study explored the known PALB2 variant c.1592delT (p.L531C) in the context of breast cancer. The study found that among an augmented cohort of breast cancer patients with the variant, there was a hazard ratio of 6.1 (p=.01). Further there is weak evidence to conclude that breast cancer risk for this variant decreases with age (p=.06). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::l531fs*30:mutation sequence variation in gene PALB2/NCBI:79728 2133 check_entity AN5540-1 PALB2 L531FS*30 mutation PALB2 NCBI:79728 gene breast cancer DOID:1612 diagnostic 100761-6 CIViC:537 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::l531fs*30:mutation sequence variation in gene PALB2/NCBI:79728 2133 check_entity AN5541-1 PALB2 Mutation PALB2 NCBI:79728 gene castration-resistant prostate carcinoma DOID:0080909 risk 100761-6 PubMed:32343890 This randomized, open-label, phase 3 trial evaluated the PARP inhibitor olaparib in 387 men with metastatic castration-resistant prostate cancer (mCRPC) who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). The study found that in men with mCRPC who had somatic or germline deleterious alterations (irrespective of zygosity) in any of the following HRR genes (BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L), olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone (PFS HR 0.49 [0.38, 0.63]). A total of 8 patients had PALB2 mutations, 4 in each arm. Based on the results of this study, on May 19, 2020, the Food and Drug Administration approved olaparib (LYNPARZA) for adult patients with deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC, who have progressed following prior treatment with enzalutamide or abiraterone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PALB2/NCBI:79728 2134 check_entity AN5541-1 PALB2 Mutation PALB2 NCBI:79728 gene castration-resistant prostate carcinoma DOID:0080909 risk 100761-6 CIViC:2628 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PALB2/NCBI:79728 2134 check_entity AN5542-1 PARP1 OVEREXPRESSION PARP1 NCBI:142 gene malignant peripheral nerve sheath tumor DOID:5940 risk PubMed:26650448 The majority of MPNST samples were positive for PARP staining. Overall, moderate to high expression of PARP1 and PARP2 was observed (Table 1)....Overall, treatment continued for 60 d at which point 5 out of 7 mice in the AZD2281 treatment group were alive versus 0 out of 7 mice in the control group (Fig. 4). These results indicated that treatment with AZD2281 significantly increased the survival of mice with metastatic disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene PARP1/NCBI:142 2135 AN5542-1 PARP1 OVEREXPRESSION PARP1 NCBI:142 gene malignant peripheral nerve sheath tumor DOID:5940 risk CIViC:2459 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene PARP1/NCBI:142 2135 AN5543-1 PAX5 P80R mutation PAX5 NCBI:5079 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 diagnostic PubMed:30487223 In a large-scale international study RNA sequencing was performed to delineate the transcriptome landscape of 1,223 B-cell ALL cases. Twenty two cases were found to have P80R misense mutation in the DNA-binding domain of the PAX5 transcription factor gene. The P80R cases had unique expression profile and did not have any other known key driver mutations. The P80R is proposed to define a specific molecular/genetic subtype of B-ALL. . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P80R sequence variation in gene PAX5/NCBI:5079 2136 check_entity AN5543-1 PAX5 P80R mutation PAX5 NCBI:5079 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 diagnostic PubMed:30643249 Integrated genomic analysis was performed for 1,988 childhood and adult B-ALL cases. Forty four cases (2.2%) showed the P80R substitution in the DNA binding domain for the PAX5 transcription factor gene. These cases were characterized by a unique expression profile. In the majority of the cases the mutation was hemizygous or homozygous, owing to deletion of the wild-type PAX5 allele or copy-neutral loss of heterozygosity. In 96% (42 of 44) of cases, the PAK5 P80R was accompanied by RAS and/or JAK-STAT signaling-pathway alterations (such as NRAS, KRAS, PTPN11, NF1, IL7R), thereby suggesting cooperativity between deregulated PAX5 activity and kinase signaling. The PAX5 P80R is proposed to define a distinct subtype of B-ALL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P80R sequence variation in gene PAX5/NCBI:5079 2136 check_entity AN5543-1 PAX5 P80R mutation PAX5 NCBI:5079 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 diagnostic PubMed:30510083 RNA-seq transcriptome analysis in a discovery cohort of 170 B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cases negative for the common classifying cytogenetic aberrations identified several well-defined hierarchical expression clusters. Four clusters corresponded to known oncogenic subtypes, namely ZNF384, ERG/DUX4, BCR::ABL1-like, and KMT2A/MLL-rearranged. An additional cluster comprised 14 cases (8.2%), which lacked any fusion gene. Mutational analysis of RNA-seq data revealed the presence of a unique PAX5 mutation, c.239C>G, p.Pro80Arg (p.P80R), in all cases. In an additional cohort of 419 unselected BCP-ALL cases, PAX5 P80R was identified in 16 (5.3%). The authors conclude that the PAX5 P80R variant, with its distinct transcriptional signature, defines a subtype of BCP-ALL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P80R sequence variation in gene PAX5/NCBI:5079 2136 check_entity AN5543-1 PAX5 P80R mutation PAX5 NCBI:5079 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 diagnostic CIViC:2566 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P80R sequence variation in gene PAX5/NCBI:5079 2136 check_entity AN5544-1 PAX8 Expression PAX8 NCBI:7849 gene female reproductive organ cancer DOID:120 diagnostic PubMed:24800185 The authors explored the viability of PAX8 expression as a biomarker for differentiating mullerian from non-mullerian tumors. 74 tumors (37 Mullerian/37 non-Mullerian) were examined for PAX8 expression via IHC. Of these 29/37 Mullerian and 1/37 non-Mullerian tumors exhibited PAX8 expression. The sensitivity and specificity of using this as a biomarker to differentiate between the two tumor types was 78.4% and 97.3% respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene PAX8/NCBI:7849 2137 AN5544-1 PAX8 Expression PAX8 NCBI:7849 gene female reproductive organ cancer DOID:120 diagnostic CIViC:671 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene PAX8/NCBI:7849 2137 AN5545-1 PAX8 PAX8::PPARG mutation PAX8 NCBI:7849 gene thyroid gland follicular carcinoma DOID:3962 diagnostic PubMed:12727991 PAX8–PPARG gene fusions were found in 12/33 follicular thyroid carcinoma tumor samples, but were rarely found in thyroid Hürthle cell tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PAX8::PPARG sequence variation in gene PAX8/NCBI:7849 2138 check_entity AN5545-1 PAX8 PAX8::PPARG mutation PAX8 NCBI:7849 gene thyroid gland follicular carcinoma DOID:3962 diagnostic CIViC:209 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PAX8::PPARG sequence variation in gene PAX8/NCBI:7849 2138 check_entity AN5546-1 PBK NUCLEAR EXPRESSION PBK NCBI:55872 gene gastric adenocarcinoma DOID:3717 prognostic PubMed:26894977 Microarray expression data from 48 patients with gastric adenocarcinoma were analyzed for genes differentially expressed with regard to overall survival. Upregulation of proteasome subunit beta type 8 (PSMB8) and PDZ binding kinase (PBK) was confirmed by real-time reverse transcription-PCR Analysis. IHC in 385 gastric cancer patients showed that increased nuclear expression of PSMB8 and PBK was correlated with depth of invasion, lymph node metastasis, and lower survival rates (survival duration, months according to nuclear PBK Expression: -, 72.3 ± 1.2; +, 66.2 ± 3.4; ++, 53.1 ± 9.2; P = 0.002). Cytoplasmic staining of PSMB8 and PBK were not statistically significant. In multivariate analysis, nuclear expression of PSMB8 and PBK were not significant predictors of overall survival (P = 0.085, P = 0.083, respectively). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene PBK/NCBI:55872 2139 AN5546-1 PBK NUCLEAR EXPRESSION PBK NCBI:55872 gene gastric adenocarcinoma DOID:3717 prognostic CIViC:435 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene PBK/NCBI:55872 2139 AN5547-1 PBK OVEREXPRESSION PBK NCBI:55872 gene lung non-small cell carcinoma DOID:3908 risk PubMed:26745678 TOPK (PBK) silencing sensitized lung cancer cells to gefitinib in preclinical xenograft models. Over-expression was also associated with resistance in various lung cancer cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene PBK/NCBI:55872 2140 AN5547-1 PBK OVEREXPRESSION PBK NCBI:55872 gene lung non-small cell carcinoma DOID:3908 risk CIViC:344 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene PBK/NCBI:55872 2140 AN5548-1 PBRM1 Mutation PBRM1 NCBI:55193 gene clear cell renal cell carcinoma DOID:4467 prognostic PubMed:23620406 In renal clear cell carcinoma, patients with PBRM1 mutations did not have a significantly different cancer specific survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PBRM1/NCBI:55193 2141 check_entity AN5548-1 PBRM1 Mutation PBRM1 NCBI:55193 gene clear cell renal cell carcinoma DOID:4467 prognostic CIViC:161 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PBRM1/NCBI:55193 2141 check_entity AN5548-2 PBRM1 Mutation PBRM1 NCBI:55193 gene renal cell carcinoma DOID:4450 prognostic PubMed:23333114 In patients with sporatic clear cell renal cell carcinoma, those with mutations in PBRM1 had better overall survival than patients with BAP1 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PBRM1/NCBI:55193 2142 check_entity AN5548-2 PBRM1 Mutation PBRM1 NCBI:55193 gene renal cell carcinoma DOID:4450 prognostic CIViC:161 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PBRM1/NCBI:55193 2142 check_entity AN5549-1 PDCD4 EXPRESSION PDCD4 NCBI:27250 gene lung cancer DOID:1324 risk PubMed:25928036 PDCD4 expression was associated with response to paclitaxel in a retrospective analysis of 77 patients after preclinical validation and mechanistic analysis of the biomarker. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene PDCD4/NCBI:27250 2143 AN5549-1 PDCD4 EXPRESSION PDCD4 NCBI:27250 gene lung cancer DOID:1324 risk CIViC:333 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene PDCD4/NCBI:27250 2143 AN5550-1 PDGFB COL1A1::PDGFB mutation PDGFB NCBI:5155 gene dermatofibrosarcoma protuberans DOID:3507 diagnostic;risk PubMed:29760553 A 37-year-old man presented with dermatofibrosarcoma protuberans (DFSP). Post resection, multiple nodular metastases were found in both lungs and the disease progressed following treatments with cytotoxic agents and microwave ablation. Overexpression of PDGFRB was detected by IHC and a COL1A1-PDGFB fusion was detected by RT-PCR. Increased PDGFRB is activated by the COL1A1-PDGFB fusion product, which promotes the overactivation of downstream PDGFRB signaling pathways. Imatinib treatment failed as stable disease was followed by disease spread and progression. The patient was then treated with a daily oral dose of sunitinib (a multi-tyrosine kinase inhibitor) for 4 consecutive weeks, followed by a 2-week rest period. After 2 months on sunitinib, the patient experienced overall shrinkage of the body’s tumor mass (reduction of tumor in arm and partial response in lung and pancreas metastases). Sunitinib resulted in 9 months of progression free survival and improved quality of life. Ultimately, the disease progressed and the patient died 46 months after diagnosis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::COL1A1::PDGFB sequence variation in gene PDGFB/NCBI:5155 2144 check_entity AN5550-1 PDGFB COL1A1::PDGFB mutation PDGFB NCBI:5155 gene dermatofibrosarcoma protuberans DOID:3507 diagnostic;risk PubMed:17950782 This study analyzed 27 formalin-fixed-paraffin-embedded samples of patients with known dermatofibrosarcoma protuberans (DFSP) using a newly designed multiplex RT-PCR assay. The assay identified COL1A1-PDGFB fusion transcripts in all but one DFSP case, which was consistent with concurrent FISH testing on the same samples. The study concluded that COL1A1-PDGFB rearrangements appear more prevalent in DFSP (96%) than previously reported. The use of sensitive molecular assays for detection of COL1A1-PDGFB fusion may improve diagnosis in cases of atypical, variant, or metastatic DFSP. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::COL1A1::PDGFB sequence variation in gene PDGFB/NCBI:5155 2144 check_entity AN5550-1 PDGFB COL1A1::PDGFB mutation PDGFB NCBI:5155 gene dermatofibrosarcoma protuberans DOID:3507 diagnostic;risk PubMed:17431412 In this study, 57 cases of dermatofibrosarcoma protuberans (DFSP) were evaluated. The COL1A1-PDGFB fusion was detected in 42 (74%) out of the 57 sample after performing targeted PCR amplification and direct sequencing. The 42 samples were then evaluated for PDGFB and PDGFRB gene amplification using qPCR. SYBR green assay was also used to evaluate PDGFB gene amplification in comparison with a reference gene and a normal tissue. PDGFB mRNA expression was detected in all analyzed samples and was significantly higher in tumor cells compared to adjacent normal tissue; as amplification levels (copy number of PDGFB/ copy number of reference gene) varied from 0.6. to 8.3 (mean 2.4) in 42 tumor samples, and from 0.4 to 3.0 (mean 1.2) in 20 adjacent normal tissue samples (P = 0.0002). Moreover, the mRNA expression levels of PDGFB and PDGFRB showed a significant correlation (P < 0.0001). The authors of this study conclude that these results demonstrate the generation of the COL1A1-PDGFB fusion transcript that functions as a ligand for PDGFRB which subsequently activates the downstream PDGFB/PDGFRB signaling pathway involved in tumorigenesis of DFSP. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::COL1A1::PDGFB sequence variation in gene PDGFB/NCBI:5155 2144 check_entity AN5550-1 PDGFB COL1A1::PDGFB mutation PDGFB NCBI:5155 gene dermatofibrosarcoma protuberans DOID:3507 diagnostic;risk CIViC:2841 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::COL1A1::PDGFB sequence variation in gene PDGFB/NCBI:5155 2144 check_entity AN5551-1 PDGFRA Amplification PDGFRA NCBI:5156 gene lung non-small cell carcinoma DOID:3908 risk 71357-8 PubMed:19366796 In a high-throughput cell line screen of 637 cell lines, only 2 sunitinib sensitive cell lines were identified. In the sunitinib-sensitive adenosquamous NSCLC cell line (NCI-H1703), PDGFRA expression was associated with focal PDGFRA gene amplification. This alteration was detected in a small fraction of primary squamous cell NSCLC tumor specimens. Focal amplification of PDGFC, the gene encoding the PDGFR ligand, was also detected. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene PDGFRA/NCBI:5156 2145 AN5551-1 PDGFRA Amplification PDGFRA NCBI:5156 gene lung non-small cell carcinoma DOID:3908 risk 71357-8 CIViC:697 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene PDGFRA/NCBI:5156 2145 AN5552-1 PDGFRA BCR::PDGFRA mutation PDGFRA NCBI:5156 gene B-cell acute lymphoblastic leukemia DOID:0080638 risk 71357-8 PubMed:12944919 A 47-year-old man was diagnosed with pre-B-cell acute lymphoblastic leukemia. FISH and nested PCR revealed the patient had a t(4;22)(q12;11) translocation that created an in-frame BCR-PDGFRA fusion. The constitutively activating coiled-coil domain and serine/threonine kinase encoded by BCR exon 1 fused with exon 13 of PDGFRA, which retained both tyrosine kinase domains. During initial therapy, intensification, and consolidation, hyperleukocytosis persisted. Based on the presence of the BCR-PDGFRA fusion, single agent imatinib (Glivec) was administered. A complete hematological response was observed within 6 weeks as the presence of t(4;22) in the bone marrow went from a 70% down to 15%. However, the patient had a relapse in the central nervous system. Continued treatment with imatinib along with intrathecal chemotherapy achieved a meningeal remission after 2 weeks. According to the authors, this patient’s response implicates PDGFRA as a clinically actionable imatinib target. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::PDGFRA sequence variation in gene PDGFRA/NCBI:5156 2146 check_entity AN5552-1 PDGFRA BCR::PDGFRA mutation PDGFRA NCBI:5156 gene B-cell acute lymphoblastic leukemia DOID:0080638 risk 71357-8 CIViC:2840 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::BCR::PDGFRA sequence variation in gene PDGFRA/NCBI:5156 2146 check_entity AN5553-1 PDGFRA D842I mutation PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 risk 71357-8 PubMed:22745105 In CHO cells with PDGFRA D842I mutation that have shown imatinib resistance, crenolanib was significantly more potent at inhibiting kinase activity than imatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D842I sequence variation in gene PDGFRA/NCBI:5156 2147 check_entity AN5553-1 PDGFRA D842I mutation PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 risk 71357-8 CIViC:98 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D842I sequence variation in gene PDGFRA/NCBI:5156 2147 check_entity AN5554-1 PDGFRA D842V mutation PDGFRA NCBI:5156 gene cancer DOID:162 risk 71357-8 PubMed:14645423 In an in vitro study of imatinib sensitivity, PDGFRA D842V was cloned into a plasmid by site-directed mutagenesis of PDGFRA WT cDNA. Chinese hamster ovary cells were transiently transfected with the plasmid. The cells were treated with control media or media containing various concentrations of imatinib for 90 minutes. Protein lysates from the transfected cells were examined for phosphorylated tyrosine, a measure of PDGFRA activation. Cells expressing PDGFRA D842V required 10-20 fold higher concentrations of imatinib as ligand activated wildtype PDGFRA (IC50: 1-2 umol/L). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D842V sequence variation in gene PDGFRA/NCBI:5156 2148 check_entity AN5554-1 PDGFRA D842V mutation PDGFRA NCBI:5156 gene cancer DOID:162 risk 71357-8 PubMed:18955458 In an in vitro study, Chinese hamster ovary cells expressing PDGFRA D842V mutation demonstrated reduced sensitivity to sunitinib treatment (IC50>1000 vs. IC50<100), compared to Chinese hamster ovary cells expressing wild-type PDGFRA. Sensitivity was determined by assessing PDGFRA auto-phosphorylation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D842V sequence variation in gene PDGFRA/NCBI:5156 2148 check_entity AN5554-1 PDGFRA D842V mutation PDGFRA NCBI:5156 gene cancer DOID:162 risk 71357-8 CIViC:99 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D842V sequence variation in gene PDGFRA/NCBI:5156 2148 check_entity AN5554-2 PDGFRA D842V mutation PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 diagnostic;risk 71357-8 PubMed:15146165 GIST tumors harboring PDGFRA D842V mutation are more likely to be benign than malignant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D842V sequence variation in gene PDGFRA/NCBI:5156 2149 check_entity AN5554-2 PDGFRA D842V mutation PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 diagnostic;risk 71357-8 PubMed:15928335 GIST cancer with D842V mutation is resistant to imatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D842V sequence variation in gene PDGFRA/NCBI:5156 2149 check_entity AN5554-2 PDGFRA D842V mutation PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 diagnostic;risk 71357-8 PubMed:16954519 While cancer with PDGFRA V561D mutation is known to be sensitive to Imatinib, double mutation of V561D and D842V mutants are resistant to imatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D842V sequence variation in gene PDGFRA/NCBI:5156 2149 check_entity AN5554-2 PDGFRA D842V mutation PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 diagnostic;risk 71357-8 PubMed:22745105 In CHO cells with PDGFRA D842V mutation that have shown imatinib resistance, crenolanib was significantly more potent at inhibiting kinase activity than imatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D842V sequence variation in gene PDGFRA/NCBI:5156 2149 check_entity AN5554-2 PDGFRA D842V mutation PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 diagnostic;risk 71357-8 PubMed:12949711 When 293T cells stably transduced with PDGFRA A842V were treated with imatinib, tyrosine phosphorylation was maintained at 1 and 10umol/L concentrations that inhibited phosphorylation of wildtype PDGFRA, consistent with resistance to this inhibitor. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D842V sequence variation in gene PDGFRA/NCBI:5156 2149 check_entity AN5554-2 PDGFRA D842V mutation PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 diagnostic;risk 71357-8 PubMed:26130666 823 patients with GIST under therapy with imatinib were genotyped for this study. 18 patients (2%) with PDGFRA mutations were identified. In D842V-mutant GISTs, PFS (median 3.8 months) and OS (median 25.2 months) were significantly poorer than Non-D842V mutated (PFS median 29.5 months OS median 59.8 months). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D842V sequence variation in gene PDGFRA/NCBI:5156 2149 check_entity AN5554-2 PDGFRA D842V mutation PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 diagnostic;risk 71357-8 PubMed:14645423 This prospective study of 127 patients with metastatic gastrointestinal stromal tumors (GISTs) examined the relationship between kinase (KIT and PDGFRA) genotype and treatment outcome for patients enrolled in a randomized phase II trial of imatinib (CSTI571B 2222). Three patients' GISTs harbored PDGFRA D842V. Two of these patients experienced progressive disease and one was unassessable. The authors conclude that this finding is consistent with the work of others suggesting that PDGFRA D842V is an imatinib resistant variant in GIST. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D842V sequence variation in gene PDGFRA/NCBI:5156 2149 check_entity AN5554-2 PDGFRA D842V mutation PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 diagnostic;risk 71357-8 PubMed:18955458 Patients 29 and 66 from a larger cohort of genotyped patients (n= 78) with imatinib resistant or intolerant gastrointestinal stromal tumors (GISTs) harbored a primary (pre-imatinib treatment) PDGFRA D842V mutation. Following failure of imatinib, the GIST was again genotyped, but no secondary mutations were found. Patients took 50 mg sunitib per day. Patient 29 was on a treatment schedule of two weeks on/two weeks off, and patient 66 was scheduled for four weeks on/two weeks off. Patient 29 experienced stable disease for less than 6 months and patient 66 experienced disease progression. Time to progression was censored at 0.1 weeks for patient 29 and was 10 weeks for patient 66. Overall survival was 99 and censored at 129 weeks for patients 29 and 66. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D842V sequence variation in gene PDGFRA/NCBI:5156 2149 check_entity AN5554-2 PDGFRA D842V mutation PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 diagnostic;risk 71357-8 CIViC:99 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D842V sequence variation in gene PDGFRA/NCBI:5156 2149 check_entity AN5555-1 PDGFRA D842Y mutation PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 risk 71357-8 PubMed:22745105 In CHO cells with PDGFRA D842Y mutation that have shown imatinib resistance, crenolanib was significantly more potent at inhibiting kinase activity than imatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D842Y sequence variation in gene PDGFRA/NCBI:5156 2150 check_entity AN5555-1 PDGFRA D842Y mutation PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 risk 71357-8 CIViC:100 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D842Y sequence variation in gene PDGFRA/NCBI:5156 2150 check_entity AN5556-1 PDGFRA D842_H845DELDIMH PDGFRA NCBI:5156 gene cancer DOID:162 risk 71357-8 PubMed:14645423 In an in vitro study of imatinib sensitivity, PDGFRA D842_H845del was cloned into a plasmid by site-directed mutagenesis of PDGFRA WT cDNA. Chinese hamster ovary cells were transiently transfected with the plasmid. Cells were treated with control media or media containing various concentrations of imatinib for 90 minutes. Protein lysates from the transfected cells were examined for phosphorylated tyrosine, a measure of PDGFRA activation. Cells expressing PDGFRA D842_H845del were as sensitive to imatinib as ligand activated wildtype PDGFRA (IC50: 100-200 nmol/L). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PDGFRA D842_H845DELDIMH [biomarker_term_in_review] 2151 not_mapped AN5556-1 PDGFRA D842_H845DELDIMH PDGFRA NCBI:5156 gene cancer DOID:162 risk 71357-8 CIViC:917 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PDGFRA D842_H845DELDIMH [biomarker_term_in_review] 2151 not_mapped AN5557-1 PDGFRA D842_I843delinsVM PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 risk 71357-8 PubMed:22745105 In CHO cells with PDGFRA DI842-843VM mutation that have shown imatinib resistance, crenolanib was significantly more potent at inhibiting kinase activity than imatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PDGFRA D842_I843delinsVM [biomarker_term_in_review] 2152 not_mapped AN5557-1 PDGFRA D842_I843delinsVM PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 risk 71357-8 CIViC:102 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PDGFRA D842_I843delinsVM [biomarker_term_in_review] 2152 not_mapped AN5558-1 PDGFRA Exon 18 Mutation PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 risk 71357-8 PubMed:18955451 These four patients were part of a larger cohort of 397 patients with incurable (i.e. metastatic or unresectable) CD117-positive Gastrointestinal stromal tumors (GISTs) enrolled in the North American phase III study SWOG S0033/CALGB 150105 who were treated with either 400mg or 800mg of imatinib per day. All four patients' GISTs harbored PDGFRA exon 18 mutatations (one I843_S847delinsM, three D842_H845del). The overall survival was more than 12 months for all four of these patients (mean 40.8 months), which is comparable to patients with WT PDGFRA (49.0months). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:18:mutation sequence variation in gene PDGFRA/NCBI:5156 2153 check_entity AN5558-1 PDGFRA Exon 18 Mutation PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 risk 71357-8 CIViC:2496 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:18:mutation sequence variation in gene PDGFRA/NCBI:5156 2153 check_entity AN5559-1 PDGFRA FIP1L1::PDGFRA T674I PDGFRA NCBI:5156 gene myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1 DOID:0080164 risk 71357-8 PubMed:12660384 A patient treated with imatinib for a FIP1L1-PDGFRA mutation relapsed during treatment. A T674I mutation in the PDGFRA split kinase domain was hypothesized to confer resistance, due to the strong evidence of this fusion in driving myeloproliferative hypereosinophilic syndrome and the contextual similarity to T315I mutations in BCR-ABL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T674I sequence variation in gene PDGFRA/NCBI:5156 2154 check_entity AN5559-1 PDGFRA FIP1L1::PDGFRA T674I PDGFRA NCBI:5156 gene myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1 DOID:0080164 risk 71357-8 PubMed:24407160 Ba/F3 cells expressing two clinically relevant, imatinib-resistant, mutant forms of FIP1L1-PDGFRA, namely T674I and D842V were tested for growth inhibition by 8 PDGFR-blocking TKIs. Strong inhibitory effects on both mutants were seen only with ponatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T674I sequence variation in gene PDGFRA/NCBI:5156 2154 check_entity AN5559-1 PDGFRA FIP1L1::PDGFRA T674I PDGFRA NCBI:5156 gene myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1 DOID:0080164 risk 71357-8 PubMed:21818111 One patient with FIP1L1/PDGFRA-positive CEL was identified as developing secondary resistance to imatinib. A PDGFRA T674I mutation was identified in the tyrosine kinase domain. Salvage therapy with nilotinib and sorafenib each failed in this patient, who was eventually transplanted with an HLA-matched sibling donor. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T674I sequence variation in gene PDGFRA/NCBI:5156 2154 check_entity AN5559-1 PDGFRA FIP1L1::PDGFRA T674I PDGFRA NCBI:5156 gene myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1 DOID:0080164 risk 71357-8 CIViC:573 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T674I sequence variation in gene PDGFRA/NCBI:5156 2154 check_entity AN5560-1 PDGFRA FIP1L1::PDGFRA mutation PDGFRA NCBI:5156 gene acute myeloid leukemia DOID:9119 risk 71357-8 PubMed:21482694 In a preclinical trial, the AML cell line EOL1with the FIP1L1-PDGFRa fusion mutation was treated with the tyrosine kinase inhibitors (TKI) ponatinib, sorafenib, and sunitinib. Ponatinib was similarly effective in the growth inhibition of cells harboring the fusion mutation (IC50=0.5 nmol/L) compared to sorafenib (IC50=0.5 nmol/L) and sunitinib (IC50=3 nmol/L). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FIP1L1::PDGFRA sequence variation in gene PDGFRA/NCBI:5156 2155 check_entity AN5560-1 PDGFRA FIP1L1::PDGFRA mutation PDGFRA NCBI:5156 gene acute myeloid leukemia DOID:9119 risk 71357-8 CIViC:570 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FIP1L1::PDGFRA sequence variation in gene PDGFRA/NCBI:5156 2155 check_entity AN5560-2 PDGFRA FIP1L1::PDGFRA mutation PDGFRA NCBI:5156 gene myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1 DOID:0080164 risk 71357-8 PubMed:14504092 A cohort of seven male patients with myeloproliferative hypereosinophilic syndrome and elevated serum tryptase levels were enrolled in a study of imatinib mesylate therapy. All seven patients demonstrated improvement in clinical symptoms and resolution of laboratory abnormalities and bone marrow pathology in response to treatment. Complete molecular remission of FIP1L1-PDGFRA was observed in 5 of 6 patients tested post-therapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FIP1L1::PDGFRA sequence variation in gene PDGFRA/NCBI:5156 2156 check_entity AN5560-2 PDGFRA FIP1L1::PDGFRA mutation PDGFRA NCBI:5156 gene myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1 DOID:0080164 risk 71357-8 PubMed:12660384 Of eleven patients prospectively accrued with hypereosinophilic syndrome, nine had favorable responses to imatinib that lasted >3 months post-treatment. Of these nine patients, five were found to have a FIP1L1-PDGFRA fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FIP1L1::PDGFRA sequence variation in gene PDGFRA/NCBI:5156 2156 check_entity AN5560-2 PDGFRA FIP1L1::PDGFRA mutation PDGFRA NCBI:5156 gene myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1 DOID:0080164 risk 71357-8 PubMed:24456122 A patient with monoblastic myeloid sarcoma harbouring a PCR confirmed FIP1L1-PDGFRA rearrangement was treated with imatinib monotherapy. The patient demonstrated a durable response (10 wks) while on therapy which was reversed when the patient discontinued treatment. Imatinib therapy was subsequently restarted, with peripheral blood and BM analyses returning to normal after 4 weeks. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FIP1L1::PDGFRA sequence variation in gene PDGFRA/NCBI:5156 2156 check_entity AN5560-2 PDGFRA FIP1L1::PDGFRA mutation PDGFRA NCBI:5156 gene myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1 DOID:0080164 risk 71357-8 PubMed:24407160 In a FIP1L1-PDGFRA positive eosinophil cell line growth-inhibitory effects were seen with all PDGFR-blocking agents, (ponatinib, sorafenib, masitinib, nilotinib, dasatinib, sunitinib, midostaurin) with ponatinib found to be the most potent compound. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FIP1L1::PDGFRA sequence variation in gene PDGFRA/NCBI:5156 2156 check_entity AN5560-2 PDGFRA FIP1L1::PDGFRA mutation PDGFRA NCBI:5156 gene myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1 DOID:0080164 risk 71357-8 CIViC:570 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::FIP1L1::PDGFRA sequence variation in gene PDGFRA/NCBI:5156 2156 check_entity AN5561-1 PDGFRA Fusion PDGFRA NCBI:5156 gene chronic myelomonocytic leukemia DOID:0080188 diagnostic 71357-8 PubMed:27069254 The 2016 World Health Organization guidelines for the classification of myeloid malignancies uses the detection of PCM1-JAK2 or rearrangements involving PDGFRA, PDGFRB, or FGFR1 as recommended exclusion criteria for a diagnosis of chronic myelomonocytic leukemia, particularly in patients with evidence of eosinophilia. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene PDGFRA/NCBI:5156 2157 check_entity AN5561-1 PDGFRA Fusion PDGFRA NCBI:5156 gene chronic myelomonocytic leukemia DOID:0080188 diagnostic 71357-8 CIViC:563 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene PDGFRA/NCBI:5156 2157 check_entity AN5561-2 PDGFRA Fusion PDGFRA NCBI:5156 gene myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1 DOID:0080164 diagnostic 71357-8 PubMed:27069254 The 2016 World Health Organization guidelines for the classification of myeloid malignancies and acute leukemia describes a new class of disease defined by myeloid or lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene PDGFRA/NCBI:5156 2158 check_entity AN5561-2 PDGFRA Fusion PDGFRA NCBI:5156 gene myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1 DOID:0080164 diagnostic 71357-8 CIViC:563 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene PDGFRA/NCBI:5156 2158 check_entity AN5562-1 PDGFRA G853D mutation PDGFRA NCBI:5156 gene melanoma DOID:1909 risk 71357-8 PubMed:24132921 PDGFRA mutations (exon 12, 14, 18) were assessed in 351 melanoma patient samples. 18 different mutations were detected in 4,6% of samples (all without chronic sun-induced damage and mainly in acral and mucosal melanoma, mutually exclusive with KIT). 12 novel missense mutations were tested for functional significance (western blot of autophosphorylation in transduced 293T cell line). Five PDGFRA Mutations (P577S, V658A, R841K, H845Y, and G853D) resulted in strong autophosphorylation of PDGFRA. Crenolanib showed higher potency than imatinib in inhibiting the kinase activity of PDGFRA. Except for the imatinib-resistant V658A mutation, all the other mutations were sensitive to both imatinib and crenolanib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G853D sequence variation in gene PDGFRA/NCBI:5156 2159 check_entity AN5562-1 PDGFRA G853D mutation PDGFRA NCBI:5156 gene melanoma DOID:1909 risk 71357-8 CIViC:839 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G853D sequence variation in gene PDGFRA/NCBI:5156 2159 check_entity AN5563-1 PDGFRA H845Y mutation PDGFRA NCBI:5156 gene melanoma DOID:1909 risk 71357-8 PubMed:24132921 PDGFRA mutations (exon 12, 14, 18) were assessed in 351 melanoma patient samples. 18 different mutations were detected in 4,6% of samples (all without chronic sun-induced damage and mainly in acral and mucosal melanoma, mutually exclusive with KIT). 12 novel missense mutations were tested for functional significance (western blot of autophosphorylation in transduced 293T cell line). Five PDGFRA Mutations (P577S, V658A, R841K, H845Y, and G853D) resulted in strong autophosphorylation of PDGFRA. Crenolanib showed higher potency than imatinib in inhibiting the kinase activity of PDGFRA. Except for the imatinib-resistant V658A mutation, all the other mutations were sensitive to both imatinib and crenolanib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H845Y sequence variation in gene PDGFRA/NCBI:5156 2160 check_entity AN5563-1 PDGFRA H845Y mutation PDGFRA NCBI:5156 gene melanoma DOID:1909 risk 71357-8 CIViC:838 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H845Y sequence variation in gene PDGFRA/NCBI:5156 2160 check_entity AN5564-1 PDGFRA I843DEL PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 risk 71357-8 PubMed:22745105 In CHO cells with the PDGFRA deletion I843 mutation that have shown imatinib sensitivity, crenolanib showed no significant difference from imatinib in kinase activity inhibition. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PDGFRA I843DEL [biomarker_term_in_review] 2161 not_mapped AN5564-1 PDGFRA I843DEL PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 risk 71357-8 PubMed:14645423 15/127 patients with KIT-WT metastatic gastrointestinal stromal tumors were tested for PDGFRA mutations. 6 GISTs harbored PDGFRA mutations. 1 patient had a deletion of I843. CHO cells expressing this variant showed similar sensitivity to imatinib as cells expressing wildtype PDGFRA. 2/3 patients with a mutation determined to be sensitive in vitro achieved partial response on imatinib treatment. It is not noted whether the patient whose GISTs harbored I843del had partial response or progressive disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PDGFRA I843DEL [biomarker_term_in_review] 2161 not_mapped AN5564-1 PDGFRA I843DEL PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 risk 71357-8 CIViC:101 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PDGFRA I843DEL [biomarker_term_in_review] 2161 not_mapped AN5565-1 PDGFRA Mutation PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 risk 71357-8 PubMed:14645423 This prospective study of 127 patients with metastatic gastrointestinal stromal tumors (GISTs) examined the relationship between kinase (KIT and PDGFRA) genotype and treatment outcome for patients enrolled in a randomized phase II trial of imatinib (CSTI571B 2222). Six GISTs harbored PDGFRA mutations, three of which were deemed imatinib-sensitive by the authors: 1 DIMH842-845 deletion, one I843 deletion, and one V561D point mutation. Two of these patients' GISTs experienced partial responses to imatinib and one experienced progressive disease. Overall, the partial response rate of patients with an imatinib sensitive mutation of KIT or PDGFRA was 75.7% (87 of 115 patients), whereas the partial response rate in patients with no kinase mutation or a previously described imatinib resistant mutation was 0% (0 of 12 patients). The authors concluded that PDGFRA gain-of-function mutations may account for imatinib sensivity in some WT KIT GISTs. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PDGFRA/NCBI:5156 2162 check_entity AN5565-1 PDGFRA Mutation PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 risk 71357-8 CIViC:3143 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PDGFRA/NCBI:5156 2162 check_entity AN5566-1 PDGFRA Overexpression PDGFRA NCBI:5156 gene rhabdomyosarcoma DOID:3247 risk 71357-8 PubMed:19366796 A high-throughput screen of 637 cancer cell lines revealed 2 to be sensitive to the multiple tyrosine kinase inhibitor, sunitinib. The most highly sensitive line was A-204, a rhabdomyosarcoma cell line. A-204 was then compared to a panel of 6 other rhabdomyosarcoma cell lines and was the only one of the 7 with detectable PDGFRA protein (Western) and to demonstrate sensitivity to sunitinib. In A-204, no PDGFRA gene amplification was detected by FISH, but qPCR revealed a an increased PDGFRA mRNA expression. Reduction of PDFGRA expression by shRNA decreased cell number similarly to sunitinib treatment. Additionally, targeting the PDGFRA ligand, PDGFC, with shRNA or antibody decreased cell number similarly to sunitinib treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene PDGFRA/NCBI:5156 2163 AN5566-1 PDGFRA Overexpression PDGFRA NCBI:5156 gene rhabdomyosarcoma DOID:3247 risk 71357-8 CIViC:2813 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene PDGFRA/NCBI:5156 2163 AN5567-1 PDGFRA P577S mutation PDGFRA NCBI:5156 gene melanoma DOID:1909 risk 71357-8 PubMed:24132921 PDGFRA mutations (exon 12, 14, 18) were assessed in 351 melanoma patient samples. 18 different mutations were detected in 4,6% of samples (all without chronic sun-induced damage and mainly in acral and mucosal melanoma, mutually exclusive with KIT). 12 novel missense mutations were tested for functional significance (western blot of autophosphorylation in transduced 293T cell line). Five PDGFRA Mutations (P577S, V658A, R841K, H845Y, and G853D) resulted in strong autophosphorylation of PDGFRA. Crenolanib showed higher potency than imatinib in inhibiting the kinase activity of PDGFRA. Except for the imatinib-resistant V658A mutation, all the other mutations were sensitive to both imatinib and crenolanib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P577S sequence variation in gene PDGFRA/NCBI:5156 2164 check_entity AN5567-1 PDGFRA P577S mutation PDGFRA NCBI:5156 gene melanoma DOID:1909 risk 71357-8 CIViC:836 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P577S sequence variation in gene PDGFRA/NCBI:5156 2164 check_entity AN5568-1 PDGFRA R841K mutation PDGFRA NCBI:5156 gene melanoma DOID:1909 risk 71357-8 PubMed:24132921 PDGFRA mutations (exon 12, 14, 18) were assessed in 351 melanoma patient samples. 18 different mutations were detected in 4.6% of samples (all without chronic sun-induced damage and mainly in acral and mucosal melanoma, mutually exclusive with KIT). 12 novel missense mutations were tested for functional significance (western blot of autophosphorylation in transduced 293T cell line). PDGFRA R841K was detected in one sample of mucosal melanoma. In vitro, PDGFRA R841K expressed in IL-3 dependent Ba/F3 cells resulted in strong auto-phosphorylation and cell growth of PDGFRA independent of the presence of IL-3, suggesting oncogenicity. Crenolanib showed higher potency than imatinib in inhibiting the kinase activity of PDGFRA and cell proliferation. The authors concluded that PDGFRA R841K is sensitive to imatinib and crenolanib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R841K sequence variation in gene PDGFRA/NCBI:5156 2165 check_entity AN5568-1 PDGFRA R841K mutation PDGFRA NCBI:5156 gene melanoma DOID:1909 risk 71357-8 CIViC:837 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R841K sequence variation in gene PDGFRA/NCBI:5156 2165 check_entity AN5569-1 PDGFRA TNKS2::PDGFRA mutation PDGFRA NCBI:5156 gene myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1 DOID:0080164 risk 71357-8 PubMed:25658984 A patient harbouring a novel TNKS2–PDGFRA fusion in a myeloid neoplasm with eosinophilia demonstrated a dramatic and durable response upon treatment with Imatinib mono therapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::TNKS2::PDGFRA sequence variation in gene PDGFRA/NCBI:5156 2166 check_entity AN5569-1 PDGFRA TNKS2::PDGFRA mutation PDGFRA NCBI:5156 gene myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1 DOID:0080164 risk 71357-8 CIViC:755 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::TNKS2::PDGFRA sequence variation in gene PDGFRA/NCBI:5156 2166 check_entity AN5570-1 PDGFRA V561A mutation PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 risk 71357-8 PubMed:12949711 293T cells stably transduced with PDGFRA V561A showed constitutive tyrosine phosphorylation in the absense of ligand; however, when treated with imatinib, this phosphorylation was inhibited similarly to that of wildtype PDGFRA, consistent with sensitivity to this inhibitor. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V561A sequence variation in gene PDGFRA/NCBI:5156 2167 check_entity AN5570-1 PDGFRA V561A mutation PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 risk 71357-8 CIViC:243 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V561A sequence variation in gene PDGFRA/NCBI:5156 2167 check_entity AN5571-1 PDGFRA V561D mutation PDGFRA NCBI:5156 gene cancer DOID:162 risk 71357-8 PubMed:14645423 In an in vitro study of imatinib sensitivity, PDGFRA V561D was cloned into a plasmid by site-directed mutagenesis of PDGFRA WT cDNA. Chinese hamster ovary cells were transiently transfected with the plasmid. The cells were treated with control media or media containing various concentrations of imatinib for 90 minutes. Protein lysates from the transfected cells were examined for phosphorylated tyrosine, a measure of PDGFRA activation. Cells expressing PDGFRA V561D were as sensitive to imatinib as ligand activated wildtype PDGFRA (IC50: 100-200 nmol/L). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V561D sequence variation in gene PDGFRA/NCBI:5156 2168 check_entity AN5571-1 PDGFRA V561D mutation PDGFRA NCBI:5156 gene cancer DOID:162 risk 71357-8 PubMed:18955458 In an in vitro study, Chinese hamster ovary cells expressing PDGFRA V561D mutation demonstrated sensitivity to sunitinib treatment (IC50<100), though this sensitivity was indistinguishable from Chinese hamster ovary cells expressing wild-type PDGFRA. Sensitivity was determined by assessing PDGFRA auto-phosphorylation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V561D sequence variation in gene PDGFRA/NCBI:5156 2168 check_entity AN5571-1 PDGFRA V561D mutation PDGFRA NCBI:5156 gene cancer DOID:162 risk 71357-8 CIViC:915 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V561D sequence variation in gene PDGFRA/NCBI:5156 2168 check_entity AN5571-2 PDGFRA V561D mutation PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 risk 71357-8 PubMed:18955451 This case study examines one patient from a larger cohort of 397 patients with incurable (i.e. metastatic or unresectable) CD117-positive Gastrointestinal stromal tumors (GISTs) enrolled in the North American phase III study SWOG S0033/CALGB 150105. Patients in this cohort were treated with either 400mg or 800mg of imatinib per day. This patient's GIST harbored PDGFRA exon 12 V561D. The patient was treated with 800mg of imatinib per day, and had not progressed or died as of 31 months of follow up (vs median TTP of 12.8 months for WT). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V561D sequence variation in gene PDGFRA/NCBI:5156 2169 check_entity AN5571-2 PDGFRA V561D mutation PDGFRA NCBI:5156 gene gastrointestinal stromal tumor DOID:9253 risk 71357-8 CIViC:915 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V561D sequence variation in gene PDGFRA/NCBI:5156 2169 check_entity AN5572-1 PDGFRB EBF1::PDGFRB mutation PDGFRB NCBI:5159 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 risk PubMed:23835704 A 10-year-old boy with B-cell acute lymphoblastic leukemia refractory to conventional chemotherapy and harboring an EBF1-PDGFRB fusion responded to imatinib plus induction chemotherapy (vincristine, daunorubicin, prednisone, and intrathecal methotrexate). Complete remission was achieved with bone marrow MRD of 0.059% by flow cytometry and normal PDGFRB by FISH. Consolidation therapy with cyclophosphamide, cytarabine, mercaptopurine, and imatinib followed and the patient was still in remission 10 months after beginning imatinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EBF1::PDGFRB sequence variation in gene PDGFRB/NCBI:5159 2170 check_entity AN5572-1 PDGFRB EBF1::PDGFRB mutation PDGFRB NCBI:5159 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 risk PubMed:25207766 The EBF1-PDGFRB fusion was detected in leukemia cells of a 7 year old Latino boy who presented with B-ALL and initial WBC of 600,000. He failed to enter remission with 4 drug induction (90% blasts at day 23), and showed testicular involvement. SNP array showed deletion of IKZF1 deletion and gains in 5q32 and 5q33.3 that interrupted the PDGFRB and EBF1 loci, respectively. FISH studies demonstrated an extra PDGFRB signal with suspect EBF1-PDGFRB that needs molecular confirmation. Imatinib, cyclophosphamide and etoposide were commenced with MRD 4.3% after 1 month. Imatinib dose was increased with MRD 0.44% after additional month of treatment. MRD was 0.0226% after two months of dasatinib treatment, and the patient proceeded to matched unrelated donor hematopoietic stem cell transplantation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EBF1::PDGFRB sequence variation in gene PDGFRB/NCBI:5159 2170 check_entity AN5572-1 PDGFRB EBF1::PDGFRB mutation PDGFRB NCBI:5159 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 risk PubMed:32068648 A 9 year old girl with B-lymphoblastic leukemia/ lymphoma (2016 WHO) relapsed 15 months post-maintenance chemotherapy. FISH and genomic analysis detected the EBF1-PDGFRB fusion (exon 11 with Exon14). The patient was treated with induction [fludarabine, idarubicin and cytarabine] therapy followed by additional chemotherapy (cyclophosphamide, adriamycin, vincristine, and dexamethasone followed by high-dose methotrexate and cytarabine) plus tyrosine kinase inhibitor (TKI, imatinib). Imatinib was stopped 10 days before cord blood transplant (CBT) with reduced intensity conditional and re-initiated on day 47 until 12 months post-transplant. The EBF1-PDGFRB transcript level measured using reverse-transcriptase polymerase chain reaction remained below detection limit (<2.5x102 copies/ microgram RNA) for 36 months post CBT. Furthermore, the patient maintained molecular remission during the 24 months post-CBT and the 12 months following completion of TKI administration, based on minimal residual disease (MRD) testing conducted every 6 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EBF1::PDGFRB sequence variation in gene PDGFRB/NCBI:5159 2170 check_entity AN5572-1 PDGFRB EBF1::PDGFRB mutation PDGFRB NCBI:5159 gene B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like DOID:0080650 risk CIViC:531 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EBF1::PDGFRB sequence variation in gene PDGFRB/NCBI:5159 2170 check_entity AN5572-2 PDGFRB EBF1::PDGFRB mutation PDGFRB NCBI:5159 gene childhood B-cell acute lymphoblastic leukemia DOID:0080146 risk PubMed:24186319 A 16-year-old boy with B-cell acute lymphoblastic leukemia refractory to conventional chemotherapy and harboring an IKZF1 deletion (delta 2-7) and a 5q33 microdeletion resulting in an EBF1-PDGFRB fusion responded to continuous imatinib (400 mg/d) during consolidation. Following consolidation therapy that included dexamethasone, vincristine, etoposide, cytarabine, and high-dose methotrexate, MRD declined to 10^-5 and the patient underwent bone marrow transplant. MRD performed at 105 days post-BMT found no detectable blasts with a sensitivity of 10^-5. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EBF1::PDGFRB sequence variation in gene PDGFRB/NCBI:5159 2171 check_entity AN5572-2 PDGFRB EBF1::PDGFRB mutation PDGFRB NCBI:5159 gene childhood B-cell acute lymphoblastic leukemia DOID:0080146 risk PubMed:26872634 Two patients with EBF1-PDGFRB positive pediatric B-ALL were treated with induction/post-induction therapy and Imatinib. Neither patient experienced disease relapse. One patient died of an undefined encephalopathy at 6 mos post-transplant and the other patient was alive in clinical remission at 10 months after diagnosis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EBF1::PDGFRB sequence variation in gene PDGFRB/NCBI:5159 2171 check_entity AN5572-2 PDGFRB EBF1::PDGFRB mutation PDGFRB NCBI:5159 gene childhood B-cell acute lymphoblastic leukemia DOID:0080146 risk CIViC:531 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::EBF1::PDGFRB sequence variation in gene PDGFRB/NCBI:5159 2171 check_entity AN5573-1 PDGFRB Fusion PDGFRB NCBI:5159 gene chronic myelomonocytic leukemia DOID:0080188 diagnostic PubMed:27069254 The 2016 World Health Organization guidelines for the classification of myeloid malignancies uses the detection of PCM1-JAK2 or rearrangements involving PDGFRA, PDGFRB, or FGFR1 as recommended exclusion criteria for a diagnosis of chronic myelomonocytic leukemia, particularly in patients with evidence of eosinophilia. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene PDGFRB/NCBI:5159 2172 check_entity AN5573-1 PDGFRB Fusion PDGFRB NCBI:5159 gene chronic myelomonocytic leukemia DOID:0080188 diagnostic CIViC:564 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene PDGFRB/NCBI:5159 2172 check_entity AN5573-2 PDGFRB Fusion PDGFRB NCBI:5159 gene hematologic cancer DOID:2531 diagnostic PubMed:27069254 The 2016 World Health Organization guidelines for the classification of myeloid malignancies and acute leukemia describes a new class of disease defined by myeloid or lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene PDGFRB/NCBI:5159 2173 check_entity AN5573-2 PDGFRB Fusion PDGFRB NCBI:5159 gene hematologic cancer DOID:2531 diagnostic CIViC:564 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene PDGFRB/NCBI:5159 2173 check_entity AN5573-3 PDGFRB Fusion PDGFRB NCBI:5159 gene myeloproliferative neoplasm DOID:2226 risk PubMed:16960151 Twelve patients with BCR-ABL-negative chronic myeloproliferative disease and reciprocal translocations involving PDGFRB received imatinib for a median of 47 months (range, 0.1-60 months). Eleven had prompt responses, 10 had complete resolution of cytogenetic abnormalities and decrease or disappearance of fusion transcripts as measured by reverse transcriptase-polymerase chain reaction (RT-PCR). Updates were sought from 8 further patients previously described in the literature; prompt responses were described in 7 and persist in 6. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene PDGFRB/NCBI:5159 2174 check_entity AN5573-3 PDGFRB Fusion PDGFRB NCBI:5159 gene myeloproliferative neoplasm DOID:2226 risk CIViC:564 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene PDGFRB/NCBI:5159 2174 check_entity AN5574-1 PDGFRB Overexpression PDGFRB NCBI:5159 gene dermatofibrosarcoma protuberans DOID:3507 risk PubMed:29760553 A 37-year-old man presented with dermatofibrosarcoma protuberans (DFSP). Post resection, multiple nodular metastases were found in both lungs and the disease progressed following treatments with cytotoxic agents and microwave ablation. Overexpression of PDGFRB was detected by IHC and a COL1A1-PDGFB fusion was detected by RT-PCR. Increased PDGFRB is activated by the COL1A1-PDGFB fusion product, which promotes the overactivation of downstream PDGFRB signaling pathways. Imatinib treatment failed as stable disease was followed by disease spread and progression. The patient was then treated with a daily oral dose of sunitinib (a multi-tyrosine kinase inhibitor) for 4 consecutive weeks, followed by a 2-week rest period. After 2 months on sunitinib, the patient experienced overall shrinkage of the body’s tumor mass (reduction of tumor in arm and partial response in lung and pancreas metastases). Sunitinib resulted in 9 months of progression free survival and improved quality of life. Ultimately, the disease progressed and the patient died 46 months after diagnosis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene PDGFRB/NCBI:5159 2175 AN5574-1 PDGFRB Overexpression PDGFRB NCBI:5159 gene dermatofibrosarcoma protuberans DOID:3507 risk CIViC:2842 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene PDGFRB/NCBI:5159 2175 AN5575-1 PGR Expression PGR NCBI:5241 gene breast cancer DOID:1612 prognostic;risk 77117-0 PubMed:16497822 In patients with breast cancer, those with expression of PgR (determined by immunohistochemical staining) had better relapse-free survival than those without expression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene PGR/NCBI:5241 2176 AN5575-1 PGR Expression PGR NCBI:5241 gene breast cancer DOID:1612 prognostic;risk 77117-0 PubMed:23280579 In patients with ER-Positive breast cancer, expression of PgR does not effect the outcome of treatment with tamoxifen. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene PGR/NCBI:5241 2176 AN5575-1 PGR Expression PGR NCBI:5241 gene breast cancer DOID:1612 prognostic;risk 77117-0 PubMed:21422407 Multivariate Cox regression analysis showed no disease free survival benefit for exemestane compared with tamoxifen in either PgR-low (n=984; HR, 0.85; 95% CI, 0.61 to 1.19) or PgR-high (n=3,341; HR, 0.83; 95% CI, 0.65 to 1.05) breast cancer patients (P=.88 for interaction). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene PGR/NCBI:5241 2176 AN5575-1 PGR Expression PGR NCBI:5241 gene breast cancer DOID:1612 prognostic;risk 77117-0 CIViC:210 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene PGR/NCBI:5241 2176 AN5576-1 PIK3CA Amplification PIK3CA NCBI:5290 gene ovary epithelial cancer DOID:2152 risk 60033-8 PubMed:25370471 One platinum-refractory epithelial ovarian cancer patient with PTEN loss and PIK3CA amplification had a partial response on treatment with PI3K inhibitor pictilisib (GDC-0941) in this phase 1 study. A total of 60 patients with advanced solid tumors were enrolled in this study. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene PIK3CA/NCBI:5290 2177 AN5576-1 PIK3CA Amplification PIK3CA NCBI:5290 gene ovary epithelial cancer DOID:2152 risk 60033-8 CIViC:212 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene PIK3CA/NCBI:5290 2177 AN5576-2 PIK3CA Amplification PIK3CA NCBI:5290 gene gastric adenocarcinoma DOID:3717 prognostic 60033-8 PubMed:22292935 In patients with gastric cancer, those with amplification of PIK3CA had shorter overall survival than those without amplification. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene PIK3CA/NCBI:5290 2178 AN5576-2 PIK3CA Amplification PIK3CA NCBI:5290 gene gastric adenocarcinoma DOID:3717 prognostic 60033-8 CIViC:212 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene PIK3CA/NCBI:5290 2178 AN5576-3 PIK3CA Amplification PIK3CA NCBI:5290 gene head and neck squamous cell carcinoma DOID:5520 risk 60033-8 PubMed:26589432 The HNSCC cell line LB771 with PIK3CA amplification was shown to have low antiproliferative IC50 for the p110beta-sparing PI3K inhibitor taselisib. Under increasing taselisib concentrations, reduction in phospho-Akt pro-survival signal was apparent, along with increased levels of pro-apoptotic marker cleaved PARP. A general tendency for taselisib sensitivity to PI3K activation (mutation/amplification) was also seen in a panel of 26 HNSCC cell lines assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene PIK3CA/NCBI:5290 2179 AN5576-3 PIK3CA Amplification PIK3CA NCBI:5290 gene head and neck squamous cell carcinoma DOID:5520 risk 60033-8 PubMed:30683736 In this retrospective study, the impact of nonsteroidal anti-inflammatory drugs (NSAID) on survival in PIK3CA-altered HNSCC patients (N=266) was assessed. 37 of 266 (14%) patients harbored a mutation, 29 of 266 (11%) had only amplification, and 9 patients had both. Among patients with a PIK3CA mutation or amplification, regular NSAID use was significantly associated with disease-specific (HR 0.23, p=0.0032) and overall survival (HR 0.31, p=0.0043). These findings were recreated in a panel of six patient-derived xenograft models, where treatment with NSAIDs (sulindac, Celecoxib or Aspirin) significantly reduced growth rates in PIK3CA mutant, but not wild-type models. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene PIK3CA/NCBI:5290 2179 AN5576-3 PIK3CA Amplification PIK3CA NCBI:5290 gene head and neck squamous cell carcinoma DOID:5520 risk 60033-8 CIViC:212 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene PIK3CA/NCBI:5290 2179 AN5576-4 PIK3CA Amplification PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 PubMed:19010894 HER2-positive breast cancer cell line BT-474 (heterozygous for PIK3CA K111N) was retrovirally transduced with wildtype PIK3CA and treated with trastuzumab. PIK3CA amplification diminished the growth inhibitory effects of trastuzumab monotherapy in comparison to the inhibition of controls without PIK3CA overexpression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene PIK3CA/NCBI:5290 2180 AN5576-4 PIK3CA Amplification PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 CIViC:212 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene PIK3CA/NCBI:5290 2180 AN5576-5 PIK3CA Amplification PIK3CA NCBI:5290 gene melanoma DOID:1909 risk 60033-8 PubMed:24265155 An in vitro study of M229 (a human melanoma cell line) endogenously expressing wildtype PIK3CA and BRAF V600E (a known BRAF inhibitor sensitizing mutation) found that cells induced to stably over-express PIK3CA (via viral transduction with additional copies of wild type PIK3CA) were significantly more resistant to vemurafenib (a BRAFi) than cells transduced with an empty vector (30% vs 20% survival, p < .0001). Though statistics were not provided, it appears that amplification of wildtype PIK3CA confers less resistance than the positive control variant, PIK3CA E545K. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene PIK3CA/NCBI:5290 2181 AN5576-5 PIK3CA Amplification PIK3CA NCBI:5290 gene melanoma DOID:1909 risk 60033-8 CIViC:212 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene PIK3CA/NCBI:5290 2181 AN5576-6 PIK3CA Amplification PIK3CA NCBI:5290 gene stomach carcinoma DOID:5517 risk 60033-8 PubMed:24608574 474 cancer cell lines from the cancer cell line encyclopedia were assessed for response to the PI3Kalpha inhibitor BYL719 (Alpelisib). PIK3CA amplification was significanly associated with BYL719 response. A gastric cancer patient derived xenograft (PDX) was transplanted into two athymic mice and one was treated with BYL719. The untreated PDX grew by over 100 percent while the BYL719 tumor was reduced by 86 percent. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene PIK3CA/NCBI:5290 2182 AN5576-6 PIK3CA Amplification PIK3CA NCBI:5290 gene stomach carcinoma DOID:5517 risk 60033-8 CIViC:212 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene PIK3CA/NCBI:5290 2182 AN5577-1 PIK3CA C420R mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 PubMed:20619739 One patient participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had a tumor which harbored PIK3CA C420R and was wildtype for KRAS, BRAF and NRAS. This patient was was a 60 year old female treated with cetuximab monotherapy as 5th line therapy who experienced partial response and had PFS of 31 weeks and OS of 59 weeks. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C420R sequence variation in gene PIK3CA/NCBI:5290 2183 check_entity AN5577-1 PIK3CA C420R mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 CIViC:905 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C420R sequence variation in gene PIK3CA/NCBI:5290 2183 check_entity AN5577-2 PIK3CA C420R mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 PubMed:20453058 This preclinical study tested the efficacy on several HER2 amplified breast cancer cell lines of GDC-0941 (pictilisib), a selective inhibitor of all four isoforms of class I PI3-kinases at a range of IC50 values. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. Two HER2 amplified breast cancer cell lines harboring PIK3CA C420R were tested for sensitivity to pictilisib. EFM-192A had an IC50 of 0.32uM and JIMT-1 had an IC50 of 0.86uM. Authors note that HER2 amplified cell lines were generally more sensitive, regardless of mutation, to pictilisib than basal-like cell lines (p=0.002). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C420R sequence variation in gene PIK3CA/NCBI:5290 2184 check_entity AN5577-2 PIK3CA C420R mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 PubMed:26920887 As part of a pre-clinical experiment, the efficacy of ado-trastuzumab emtansine (T-DM1) was compared to that of trastuzumab against various HER2 positive cell lines. EFM-192A cell line expressing PIK3CA C420R was associated with similar sensitivity to T-DM1 as PIK3CA wild-type cell line SK-BR-3; substantially reduced cell viability was observed at concentrations > 0.01 ug/mL in both cell lines. Conversely, when treated with trastuzumab, the cell line harboring PIK3CA C420R experienced a smaller reduction in cell viability. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C420R sequence variation in gene PIK3CA/NCBI:5290 2184 check_entity AN5577-2 PIK3CA C420R mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 CIViC:905 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C420R sequence variation in gene PIK3CA/NCBI:5290 2184 check_entity AN5578-1 PIK3CA D350G mutation PIK3CA NCBI:5290 gene melanoma DOID:1909 risk 60033-8 PubMed:24265155 An in vitro study of M229 (a human melanoma cell line) endogenously expressing wildtype PIK3CA and BRAF V600E (a known BRAF inhibitor sensitizing mutation) found that cells virally induced to stably over-express PIK3CA D350G were significantly more resistant to BRAF inhibition by vemurafenib than cells transduced with empty vectors (40% vs 20% survival at the highest concentration, p=.0148). Though statistics were not provided, D350G appears to confer less resistance to vemurafenib than the positive control variant, PIK3CA E545K. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D350G sequence variation in gene PIK3CA/NCBI:5290 2185 check_entity AN5578-1 PIK3CA D350G mutation PIK3CA NCBI:5290 gene melanoma DOID:1909 risk 60033-8 CIViC:1561 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D350G sequence variation in gene PIK3CA/NCBI:5290 2185 check_entity AN5579-1 PIK3CA E542K mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 risk 60033-8 PubMed:21558396 Breast cancer cell lines with E542K/E545K mutations showed increased sensitivity to CH5132799 than cells with wild-type PIK3CA gene. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E542K sequence variation in gene PIK3CA/NCBI:5290 2186 check_entity AN5579-1 PIK3CA E542K mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 risk 60033-8 PubMed:15647370 Rapamycin inhibits transformation induced by mutation in PIK3CA. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E542K sequence variation in gene PIK3CA/NCBI:5290 2186 check_entity AN5579-1 PIK3CA E542K mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 risk 60033-8 PubMed:20453058 This preclinical study tested the efficacy on several breast cancer cell lines of GDC-0941 (pictilisib), which is a selective inhibitor of all four isoforms of class I PI3-kinases over a range of IC50 values. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. KPL-1 is a luminal-like breast cancer cell line harboring PIK3CA E542K, and it had an IC50 of 0.72uM. Authors note that luminal-like cell lines were generally more sensitive, regardless of mutation, to pictilisib than basal-like cell lines (p=0.02). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E542K sequence variation in gene PIK3CA/NCBI:5290 2186 check_entity AN5579-1 PIK3CA E542K mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 risk 60033-8 PubMed:31091374 In a phase 3 trial, 572 patients with hormone receptor positive, HER2 receptor negative advanced breast cancer who previously received endocrine therapy were allocated to alpelisib plus fulvestrant or placebo plus fulvestrant. Patients were enrolled into two cohorts on the basis of tumor-tissue PIK3CA mutation status (N=341). PIK3CA mutation was determined according to the presence or absence of any hot spot mutation in the C2, helical, and kinase domains of PI3K (corresponding to exon 7, 9, and 20, respectively). In the cohort of patients with PIK3CA-mutated cancer, PFS was 11 months in the alpelisib-fulvestrant group, as compared with 5.7 months in the placebo-fulvestrant group (HR 0.65, p<0.001). In the cohort without PIK3CA-mutated cancer, the HR was 0.85. Analyses of PFS according to mutation types showed consistent benefit of treatment with alpelisib–fulvestrant across prespecified subgroups, including E542K (N=60, HR 0.60, 95% CI 0.29-1.23), E545X, and H1047X. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E542K sequence variation in gene PIK3CA/NCBI:5290 2186 check_entity AN5579-1 PIK3CA E542K mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 risk 60033-8 CIViC:103 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E542K sequence variation in gene PIK3CA/NCBI:5290 2186 check_entity AN5579-2 PIK3CA E542K mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 PubMed:26184520 This was a retrospective analysis of genetic markers in 503 metastatic colorectal cancer patients who participated in the CORRECT phase III trial of regorafenib. PIK3CA mutations were identified in the tumors of 84 patients, including 27 with PIK3CA E542K. Authors found a clinical benefit of regorafenib across PIK3CA mutated and wildtype subgroups (progression free survival with regorafenib vs placebo: mutant HR: 0.54, wildtype HR: 0.50, P=0.85). Authors do not provide direct comparison between patients with wildtype and PIK3CA E542K patients. Note that it's unclear how many PIK3CA wildtype patients harbor KRAS mutations, though authors' suggest that regorafenib induces clinical benefit regardless of KRAS or PIK3CA mutation status. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E542K sequence variation in gene PIK3CA/NCBI:5290 2187 check_entity AN5579-2 PIK3CA E542K mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 PubMed:20619739 This was a retrospective study of 691 cetuximab treated patients with metastatic colorectal cancer. Of those, 7 patients harbored PIK3CA E542K (exon 10), were wt for BRAF, NRAS and PIK3CA, and had individual response data. Two patients had partial response, three had stable disease, and two progressed, resulting in a response rate of 2/7 and a clinical benefit rate of 5/7 according to author criteria. Treatments included cetuximab + irinotecan (n=5), cetuximab + FOLFIRI (n=1), and cetuximab monotherapy (n=1). Median PFS was 34 weeks (17-48 weeks), median OS was 46 weeks (27-91 weeks), and median number of previous chemotherapy lines was 2 (0-4). Median age was 59 years old (53-74), and there were 6 females and one male. Using these and data from the larger cohort, authors concluded that PIK3CA exon 10 (listed as exon 9 in source) mutations are associated with weak or no resistance to cetuximab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E542K sequence variation in gene PIK3CA/NCBI:5290 2187 check_entity AN5579-2 PIK3CA E542K mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 CIViC:103 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E542K sequence variation in gene PIK3CA/NCBI:5290 2187 check_entity AN5579-3 PIK3CA E542K mutation PIK3CA NCBI:5290 gene head and neck squamous cell carcinoma DOID:5520 risk 60033-8 PubMed:26787751 Phase 1 study with the dual PI3K/mTOR inhibitor apitolisib. 120 patients were treated at doses between 2 and 70mg. Of the 14 evaluable patients with PIK3CA mutations total, there were 3 PRs (1 confirmed), 8 SD, and 3 PD as best radiological responses. One of the partial responses harbored a PIK3CA E542K mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E542K sequence variation in gene PIK3CA/NCBI:5290 2188 check_entity AN5579-3 PIK3CA E542K mutation PIK3CA NCBI:5290 gene head and neck squamous cell carcinoma DOID:5520 risk 60033-8 CIViC:103 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E542K sequence variation in gene PIK3CA/NCBI:5290 2188 check_entity AN5579-4 PIK3CA E542K mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 PubMed:20453058 This preclinical study tested the efficacy on several breast cancer cell lines of GDC-0941 (pictilisib), a selective inhibitor of all four isoforms of class I PI3-kinases at a range of IC50 values. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. HCC202 is a HER2 positive, ER/PR negative breast cancer cell line harboring PIK3CA E542K, and it had an IC50 of 0.80uM. Authors further note that HER2 amplified cell lines were generally more sensitive, regardless of mutation, to pictilisib than basal-like cell lines (p=0.002). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E542K sequence variation in gene PIK3CA/NCBI:5290 2189 check_entity AN5579-4 PIK3CA E542K mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 CIViC:103 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E542K sequence variation in gene PIK3CA/NCBI:5290 2189 check_entity AN5579-5 PIK3CA E542K mutation PIK3CA NCBI:5290 gene thyroid cancer DOID:1781 risk 60033-8 PubMed:19706758 Preclinical study in thyroid cancer cell lines. 6 cell lines with alterations of the PI3K/Akt pathway were more sensitive to Akt inhibitor perifosine or MTOR inhibitor temsirolimus than 5 cell lines without genetic alterations in the PI3K/Akt pathway. Among the alterations, One cell line harbored a PIK3CA E542K mutation. Transfection of another cell line with this mutation led to lower IC50 values to perifosine and temsirolimus than in a cell line transfected with a control vector assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E542K sequence variation in gene PIK3CA/NCBI:5290 2190 check_entity AN5579-5 PIK3CA E542K mutation PIK3CA NCBI:5290 gene thyroid cancer DOID:1781 risk 60033-8 CIViC:103 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E542K sequence variation in gene PIK3CA/NCBI:5290 2190 check_entity AN5580-1 PIK3CA E545 mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 risk 60033-8 PubMed:31091374 In a phase 3 trial, 572 patients with hormone receptor positive, HER2 receptor negative advanced breast cancer who previously received endocrine therapy were allocated to alpelisib plus fulvestrant or placebo plus fulvestrant. Patients were enrolled into two cohorts on the basis of tumor-tissue PIK3CA mutation status (N=341). PIK3CA mutation was determined according to the presence or absence of any hot spot mutation in the C2, helical, and kinase domains of PI3K (corresponding to exon 7, 9, and 20, respectively). In the cohort of patients with PIK3CA-mutated cancer, PFS was 11 months in the alpelisib-fulvestrant group, as compared with 5.7 months in the placebo-fulvestrant group (HR 0.65, p<0.001). In the cohort without PIK3CA-mutated cancer, the HR was 0.85. Analyses of PFS according to mutation types showed consistent benefit of treatment with alpelisib–fulvestrant across prespecified subgroups, including E542K, E545X (N=105, HR 0.61, 95% CI 0.37-1), and H1047X. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545 sequence variation in gene PIK3CA/NCBI:5290 2191 check_entity AN5580-1 PIK3CA E545 mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 risk 60033-8 CIViC:2632 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545 sequence variation in gene PIK3CA/NCBI:5290 2191 check_entity AN5581-1 PIK3CA E545G mutation PIK3CA NCBI:5290 gene melanoma DOID:1909 risk 60033-8 PubMed:24265155 An in vitro study of M229 (a human melanoma cell line) endogenously expressing wildtype PIK3CA and BRAF V600E (a known BRAF inhibitor sensitizing mutation) found that cells virally induced to stably over-express PIK3CA E545G were significantly more resistant to BRAF inhibition by vemurafenib than cells transduced with an empty vector (50% vs 20% survival at the highest concentration, p < .0001). Though statistics were not provided, E545G appears to confer similar levels of resistance to vemurafenib as the positive control variant, PIK3CA E545K. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545G sequence variation in gene PIK3CA/NCBI:5290 2192 check_entity AN5581-1 PIK3CA E545G mutation PIK3CA NCBI:5290 gene melanoma DOID:1909 risk 60033-8 CIViC:857 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545G sequence variation in gene PIK3CA/NCBI:5290 2192 check_entity AN5582-1 PIK3CA E545K mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 risk 60033-8 PubMed:23888070 PIK3CA E545K mutation increased sensitivity to AKT inhibitor MK-2206 and PI3K inhibitor GDC-0941 in a breast cancer cell line model. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2193 check_entity AN5582-1 PIK3CA E545K mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 risk 60033-8 PubMed:20453058 This preclinical study tested the efficacy on several breast cancer cell lines of GDC-0941 (pictilisib), a selective inhibitor of all four isoforms of class I PI3-kinases over a range of IC50 values. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. MCF7 is a luminal type breast cancer cell line harboring PIK3CA E545K, and it had an IC50 of 0.34uM. To evaluate in vivo efficacy, MCF7 cells were injected in the mammary fat pad of SCID mice and allowed to grow. Mice treated with 100mg/kg pictilisib experienced a 62% tumor reduction, and those treated with 150mg/kg experienced a 70% tumor reduction, with respect to untreated control. Authors note that pictilisib was well tolerated and observed no toxicities or significant weight loss. Authors further note that luminal-like cell lines were generally more sensitive, regardless of mutation, to pictilisib than basal-like (p=0.02). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2193 check_entity AN5582-1 PIK3CA E545K mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 risk 60033-8 CIViC:104 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2193 check_entity AN5582-2 PIK3CA E545K mutation PIK3CA NCBI:5290 gene cancer DOID:162 risk 60033-8 PubMed:26787751 Phase 1 study with the dual PI3K/mTOR inhibitor apitolisib. 120 patients were treated at doses between 2 and 70mg. Of 45 evaluable patients receiving 40mg, two patients with E545K PIK3CA mutation (one head and neck squamous cell carcinoma patient and a patient with ovarian cancer) had unconfirmed partial responses. Of the 14 evaluable patients with PIK3CA mutations total, there were 3 PRs (1 confirmed), 8 SD, and 3 PD as best radiological responses. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2194 check_entity AN5582-2 PIK3CA E545K mutation PIK3CA NCBI:5290 gene cancer DOID:162 risk 60033-8 CIViC:104 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2194 check_entity AN5582-3 PIK3CA E545K mutation PIK3CA NCBI:5290 gene cervical cancer DOID:4362 risk 60033-8 PubMed:27489350 Authors tested various cervical cancer cell lines (CaSki, SiHa and HeLa) for their responses to cisplatin, radiation therapy, and GDC-0941. CaSki cells that are heterozygous for the PIK3CA-E545K mutation were significantly more resistant to cisplatin or cisplatin plus radiation than either HeLa or SiHa cells that express only wild-type PIK3CA. Similarly, HeLa cells engineered to stably express PIK3CA E545K were more resistant to cisplatin or cisplatin plus radiation than cells expressing only wild-type PIK3CA or with PIK3CA depleted. Cells expressing the PIK3CA-E545K mutation also had constitutive PI3K pathway activation and increased cellular migration and each of these phenotypes was reversed by treatment with the PI3K inhibitor GDC-0941 (pictilisib). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2195 check_entity AN5582-3 PIK3CA E545K mutation PIK3CA NCBI:5290 gene cervical cancer DOID:4362 risk 60033-8 CIViC:104 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2195 check_entity AN5582-4 PIK3CA E545K mutation PIK3CA NCBI:5290 gene cervix carcinoma DOID:2893 risk 60033-8 PubMed:27489350 CaSki cells that are heterozygous for the PIK3CA-E545K mutation are more resistant to cisplatin or cisplatin plus radiation than either HeLa or SiHa cells that express only wild-type PIK3CA. Similarly, HeLa cells engineered to stably express PIK3CA-E545K were more resistant to cisplatin or cisplatin plus radiation than cells expressing only wild-type PIK3CA or with PIK3CA depleted. Cells expressing the PIK3CA-E545K mutation also had constitutive PI3K pathway activation and increased cellular migration and each of these phenotypes was reversed by treatment with the PI3K inhibitor GDC-0941/Pictilisib. In addition, GDC-0941 restored sensitivity of E545K mutant cell lines to cisplatin as combination treatment had a larger impact on cell survival than either drug alone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2196 check_entity AN5582-4 PIK3CA E545K mutation PIK3CA NCBI:5290 gene cervix carcinoma DOID:2893 risk 60033-8 CIViC:104 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2196 check_entity AN5582-5 PIK3CA E545K mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 PubMed:19223544 In this study, a large cohort of metastatic colorectal cancer patients were treated with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). KRAS PIK3CA and PTEN were tested for mutation, and 1 patient (patient 95, see supplemental table 1) had PIK3CA E545K in the primary tumor without co-occurring mutations in the other tested genes. This response was consistent with observations made of the larger cohort, where patients with tumors harboring any PIK3CA mutation had significantly shorter progression free survival and decreased incidence of objective response than patients with wtPIK3CA tumors. However, there was one patient (Patient 55, Table S1) who had E545K as the only noted variant, but experienced partial response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2197 check_entity AN5582-5 PIK3CA E545K mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 PubMed:20619739 This was a retrospective study of 691 cetuximab treated patients with metastatic, chemotherapy refractory colorectal cancer. Of those, 16 patients harbored PIK3CA E545K (exon 10), were wt for BRAF, NRAS and PIK3CA, and had individual response data. Five patients had partial response, six had stable disease, and five progressed, resulting in a response rate of 5/16 and a clinical benefit rate of 11/16 according to author criteria. Treatments included cetuximab + irinotecan (n=13), cetuximab monotherapy (n=1), cetuximab + bevacizumab (n=1), and cetuximab + oxaliplatin + 5FU (n=1). Median PFS was 24 weeks (2-60 weeks), median OS was 43 weeks (9-107 weeks), and median number of previous chemotherapy lines was 2 (1-5). Median age was 58 years old (43-79), and there were 10 males and 6 females. Using these and data from the larger cohort, authors concluded that PIK3CA exon 10 (listed as exon 9 in source) mutations are associated with weak or no resistance to cetuximab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2197 check_entity AN5582-5 PIK3CA E545K mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 CIViC:104 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2197 check_entity AN5582-6 PIK3CA E545K mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 PubMed:18829560 PI3K mutant E545K was overexpressed in the trastuzumab sensitive HER2 BT474 breast cancer cell line, and significant resistance to trastuzumab was induced in comparison to control cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2198 check_entity AN5582-6 PIK3CA E545K mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 PubMed:26920887 As part of a pre-clinical experiment, the efficacy of ado-trastuzumab emtansine (T-DM1) was compared to that of trastuzumab against various HER2 positive cell lines. MCF7-neo/HER2 cell line harboring PIK3CA E545K was associated with similar sensitivity to T-DM1 as PIK3CA wild-type cell line SK-BR-3; reduced cell viability was observed at concentrations >0.01 ug/mL in both cell lines. Conversely, the cell line harboring PIK3CA E545K was resistant to trastuzumab in vitro at all concentrations tested (0-10 ug/mL). Further, treatment with T-DM1 on nude mice xenografted with PIK3CA E545K-harboring cells resulted in inhibition of tumor growth. A single dose of T-DM1 >3mg/kg was sufficient to induce tumor suppression lasting >20 days after administration. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2198 check_entity AN5582-6 PIK3CA E545K mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 PubMed:20453058 This preclinical study tested the efficacy on several breast cancer cell lines of GDC-0941 (pictilisib), a selective inhibitor of all four isoforms of class I PI3-kinases at a range of IC50 values. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. MDA-MB-361 is a HER2 amplified breast cancer cell line harboring PIK3CA E545K, and it had an IC50 of 0.14uM. To asses the effect of pictilisib on cell cycle progression and apoptosis, fluorescence based cell cycle and flow cytometry were used to measure the proportion of cells in various phases and the relative presence of Annexin V, a marker of apoptosis. Untreated, 68% of cells were in G1 or sub-G1. Following treatment with 1.0uM pictilisib, the proportion of cells in G1 or sub-G1 rose to 78%, and the amount of Annexin V detected rose 3 fold. A substantial reduction in phosphorylated AKT (S473) was also noted. Authors concluded that pictilisib had a modest effect on cell cycle progression and encouraged apoptosis in this cell line, and that this cell line is sensitive to pictilisib. Authors further noted that HER2 amplified cell lines were generally more sensitive, regardless of mutation, to pictilisib than basal-like breast cancer cell lines (p=0.002). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2198 check_entity AN5582-6 PIK3CA E545K mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 PubMed:19010894 In a preclinical study, efficacy of lapatinib and trastuzumab was evaluated in vitro against HER2 amplified breast cancer cell line BT474 (heterozygous for PIK3CA K111N) retrovirally transduced with PIK3CA E45K. The study found that E545K abrogated the growth inhibitory effects of lapatinib and trastuzumab, either in isolation or in combination, though increased cell death was observed with combination therapy relative to monotherapy. The authors concluded that the PIK3CA E545K induces resistance to lapatinib and trastuzumab in HER2-positive breast cancer cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2198 check_entity AN5582-6 PIK3CA E545K mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 CIViC:104 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2198 check_entity AN5582-7 PIK3CA E545K mutation PIK3CA NCBI:5290 gene lung adenocarcinoma DOID:3910 risk 60033-8 PubMed:16906227 HCC827 cell lines harboring activated PI3K (HCC827 p110α E545K cells) were more resistant to gefitinib in vitro (IC50, 1 μM) compared with those harboring GFP alone (IC50, 0.01 μM). The presence of p110α E545K also protected HCC827 cells from gefitinib-mediated apoptosis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2199 check_entity AN5582-7 PIK3CA E545K mutation PIK3CA NCBI:5290 gene lung adenocarcinoma DOID:3910 risk 60033-8 PubMed:27304188 48 tumor samples from 41 patients with EGFR mutant lung adenocarcinoma that were resistant to tyrosine kinase inhibition underwent next generation sequencing (AmpliSeq Cancer Hotspot Panel (v2) failed in 5 samples leading to a remaining 43 specimens from 39 patients). The prevalence of various mutations post-treatment was analyzed. 2 out of the 39 patients had the E545K PIK3CA mutation in the absence of EGFR T790M, indicating that E545K may be an alternative mutation contributing to resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2199 check_entity AN5582-7 PIK3CA E545K mutation PIK3CA NCBI:5290 gene lung adenocarcinoma DOID:3910 risk 60033-8 CIViC:104 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2199 check_entity AN5582-8 PIK3CA E545K mutation PIK3CA NCBI:5290 gene lung non-small cell carcinoma DOID:3908 risk 60033-8 PubMed:19513541 H460, a gefitinib-resistant NSCLC cell line harboring PIK3CA E545K (a PIK3CA activating mutation), was used to test the anti-tumor effects of PI103. Without treatment, H460 cells expressed high levels of phosphorylated AKT. Following treatment, p-AKT decreased which correlated with cell senescence. PI103 treatment resulted in greater cell senescence in the PIK3CA E545K cell line than in A549, a wildtype PIK3CA gefinitib-resistant NSCLC cell line. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2200 check_entity AN5582-8 PIK3CA E545K mutation PIK3CA NCBI:5290 gene lung non-small cell carcinoma DOID:3908 risk 60033-8 CIViC:104 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2200 check_entity AN5582-9 PIK3CA E545K mutation PIK3CA NCBI:5290 gene melanoma DOID:1909 risk 60033-8 PubMed:24265155 An in vitro study of M229 (a human melanoma cell line) endogenously expressing wildtype PIK3CA and BRAF V600E (a known BRAF inhibitor sensitizing mutation) used PIK3CA E545K as a positive control for testing resistance to BRAF inhibition by vemurafenib. M229 cells virally transduced with PIK3CA E545K were significantly more resistant to vemurafenib-mediated growth suppression than cells transduced with empty vectors (50% vs 20% survival at the highest concentration, p <.0001). Furthermore, E545K appears to confer more resistance to vemurafenib than PIK3CA D350G and similar levels of resistance as E545G. Resistance was determined by assessing cell survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2201 check_entity AN5582-9 PIK3CA E545K mutation PIK3CA NCBI:5290 gene melanoma DOID:1909 risk 60033-8 CIViC:104 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2201 check_entity AN5582-10 PIK3CA E545K mutation PIK3CA NCBI:5290 gene rectum cancer DOID:1993 prognostic 60033-8 PubMed:19903786 This study examined outcomes of 240 rectum cancer patients treated with total mesorectal excision therapy. Tumor samples were obtained at the time of surgery and genotyped for PIK3CA exon 10 and 21 mutations (listed as exon 9 and 20 in the publication, as it was common at the time of its publication to exclude non-coding exon 1). Of the 19 patients whose tumors harbored PIK3CA mutations, nine harbored PIK3CA E545K. PIK3CA E545K was associated with poor outcome compared to other PIK3CA mutations for local and distant recurrences (HR: 11.6, P < 0.001; HR 3.7, P = 0.006). Additionally, 89% of patients whose tumors harbored PIK3CA E545K experienced a relapse. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2202 check_entity AN5582-10 PIK3CA E545K mutation PIK3CA NCBI:5290 gene rectum cancer DOID:1993 prognostic 60033-8 CIViC:104 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545K sequence variation in gene PIK3CA/NCBI:5290 2202 check_entity AN5583-1 PIK3CA E545Q mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 PubMed:20619739 Two patients participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored PIK3CA E545Q (exon 10), were wildtype for NRAS, BRAF and PIK3CA, and had individual response data. Both were treated with cetuximab and irinotecan and experienced partial responses. One patient was a 44 year old female, on 5th line therapy, with a PFS of 67 weeks and an OS of 209 weeks. The other patient was a 46 year old male, on 2nd line therapy, with a PFS of 22 weeks and an OS of 105 weeks. Using these and data from the larger cohort, authors concluded that PIK3CA exon 10 (listed as exon 9 in source) mutations are associated with weak or no resistance to cetuximab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545Q sequence variation in gene PIK3CA/NCBI:5290 2203 check_entity AN5583-1 PIK3CA E545Q mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 CIViC:855 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E545Q sequence variation in gene PIK3CA/NCBI:5290 2203 check_entity AN5584-1 PIK3CA E81K mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 PubMed:20619739 Two patients participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored PIK3CA E81K, were wildtype for NRAS, BRAF and PIK3CA, and had individual response data. Both were treated with cetuximab + oxaliplatin + 5FU as 2nd line therapy and experienced stable disease, resulting in a response rate of 0/2 and a clinical benefit rate of 2/2 according to author criteria. One patient was a 57 year old female with a PFS of 24 weeks and an OS of 100 weeks. The other patient was a 60 year old male with a PFS of 23 weeks. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E81K sequence variation in gene PIK3CA/NCBI:5290 2204 check_entity AN5584-1 PIK3CA E81K mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 CIViC:1408 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E81K sequence variation in gene PIK3CA/NCBI:5290 2204 check_entity AN5585-1 PIK3CA EXON 20 MUTATION PIK3CA NCBI:5290 gene breast cancer DOID:1612 risk 60033-8 PubMed:18371219 This study of 140 patients with stage II-III breast cancer assessed the response of patients with PIK3CA mutations to 6 months of preoperative chemotherapy. Exons 1, 9, and 20 of PIK3CA were screened for mutations. 23/140 patients had PIK3CA mutations: E545K (8); E542K (3); Q546R (1); H1047R (9); H1057T (1); G1049R (1). These patients were split into 4 different chemotherapy treatment groups: FAC regimen, FEC regimen, paclitaxel followed by FEC regimen (TFEC), and paclitaxel followed by FAC regimen (TFAC). The study did not find evidence that PIK3CA mutations are associated with resistance to preoperative chemotherapy in breast cancer, regardless of whether paclitaxel was also administered. The lack of association was true of estrogen receptor (ER)-positive and ER-negative tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:20:mutation sequence variation in gene PIK3CA/NCBI:5290 2205 check_entity AN5585-1 PIK3CA EXON 20 MUTATION PIK3CA NCBI:5290 gene breast cancer DOID:1612 risk 60033-8 CIViC:4636 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:20:mutation sequence variation in gene PIK3CA/NCBI:5290 2205 check_entity AN5586-1 PIK3CA EXON 9 MUTATION PIK3CA NCBI:5290 gene breast cancer DOID:1612 risk 60033-8 PubMed:18371219 This study of 140 patients with stage II-III breast cancer assessed the response of patients with PIK3CA mutations to 6 months of preoperative chemotherapy. Exons 1, 9, and 20 of PIK3CA were screened for mutations. 23/140 patients had PIK3CA mutations: E545K (8); E542K (3); Q546R (1); H1047R (9); H1057T (1); G1049R (1). These patients were split into 4 different chemotherapy treatment groups: FAC regimen, FEC regimen, paclitaxel followed by FEC regimen (TFEC), and paclitaxel followed by FAC regimen (TFAC). The study did not find evidence that PIK3CA mutations are associated with resistance to preoperative chemotherapy in breast cancer, regardless of whether paclitaxel was also administered. The lack of association was true of estrogen receptor (ER)-positive and ER-negative tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:9:mutation sequence variation in gene PIK3CA/NCBI:5290 2206 check_entity AN5586-1 PIK3CA EXON 9 MUTATION PIK3CA NCBI:5290 gene breast cancer DOID:1612 risk 60033-8 CIViC:4636 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:9:mutation sequence variation in gene PIK3CA/NCBI:5290 2206 check_entity AN5587-1 PIK3CA Exon 10 Mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 prognostic 60033-8 PubMed:17947469 An Italian study of 163 malignant breast tumors assessed the association between PIK3CA mutations and clinical outcome. Of the 163 tumors sequenced, 118 had wild-type (wt) PIK3CA, 24 had exon 9 (helical domain) missense mutations, and 21 had exon 20 (kinase domain) missense mutations. The study found that patients with exon 9 mutations showed significantly worse 5-year overall survival (OS) and 5-year disease free survival (DFS) compared to patients with wt PIK3CA (P=.018 and P = .04, respectively). Furthermore, patients with exon 9 mut showed especially worse OS and DFS than patients with exon 20 mutations (P=.0018 and P=.0017, respectively). The 21 cases with exon 20 mutations had excellent prognosis with no recurrences or deaths, whereas there were 10 recurrences and 9 deaths among the 24 cases of exon 9 mutations, in observed period. Note these exons are now referred to as exons 10 and 21 rather than as exons 9 and 20, as it was common at the time of publication to exclude non-coding exon 1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:10:mutation sequence variation in gene PIK3CA/NCBI:5290 2207 check_entity AN5587-1 PIK3CA Exon 10 Mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 prognostic 60033-8 CIViC:106 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:10:mutation sequence variation in gene PIK3CA/NCBI:5290 2207 check_entity AN5587-2 PIK3CA Exon 10 Mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 PubMed:20619739 In chemotherapy-refractory patients with metastatic colorectal cancer and KRAS wt tumors, Exon 10 PIK3CA mutations (listed as Exon 9 in the source) had no significant impact on response rate (6/21 [28.6%] vs 115/317 [36.3%]; OR: 0.70; p = 0.47), disease control rate, median progression free survival or median overall survival (46 vs 51 weeks, HR: 1.30, p=0.28) following cetuximab + chemotherapy than wildtype PIK3CA. In multivariate analysis of KRAS wildtype patients, PIK3CA was not significantly associated with patient outcome. Authors conclude that PIK3CA exon 10 mutation status does not appear relevant to treatment response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:10:mutation sequence variation in gene PIK3CA/NCBI:5290 2208 check_entity AN5587-2 PIK3CA Exon 10 Mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 PubMed:22357840 This study analyzed tumor and patient characteristics from 1,170 colorectal cancer patients derived from the prospective cohort studies: Nurses' Health Study and Health Professionals Follow Up Study. PIK3CA mutations were found in 16% (189/1170) of patients via pyrosequencing of FFPE samples. Of patients with PIK3CA mutated tumors, 58% (109/189) had mutations in exon 10 (listed as exon 9 in the publication, as it was common at the time of its publication to exclude non-coding exon 1). The presence of an exon 10 mutation was not significantly associated with differences in colorectal cancer-specific or overall survival when compared to patients with wt PIK3CA (multivariate, stage-stratified HR = 1.15 vs 1). Authors note that they had limited data on cancer treatment data, but assume that treatment regimens did not differ substantially based on PIK3CA mutation status given that patients were diagnosed prior to clinical availability of PIK3CA genotype data. They further note that treatment decisions were typically based on cancer stage, for which their analyses adjusted.;|This was a prospective study involving 1,170 colorectal cancer patients confirmed by histology. PIK3CA mutations were found in 16% (189/1170) of cased via pyrosequencing of FFPE samples, of these 58% (109/189) had mutations in exon 10, 39% (73/189) had mutations in exon 21, and 3.7% (7/189) had mutations in both exons. Study found that exon 10 + exon 21 mutants were associated with shorter cancer specific survival and overall survival when compared to WT PIK3CA (P = 0.031, P = 0.0008). These mutants were also associated with higher colorectal cancer-specific mortality and overall mortality (multivariate hazard ratio (HR) = 3.51, multivariate HR 2.68). In contrast, mutations on either exon 10 or exon 21 alone were not statistically significant in terms of overall survival. Note that exons 10 and 21 are listed as exons 9 and 20 in the source, as it was common at the time of its publication to exclude non-coding exon 1. Authors note that they had limited data on cancer treatment data, but assume that treatment regimens did not differ substantially based on PIK3CA mutation status given that patients were diagnosed prior to clinical availability of PIK3CA genotype data. They further note that treatment decisions were typically based on cancer stage, for which their analyses adjusted. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:10:mutation sequence variation in gene PIK3CA/NCBI:5290 2208 check_entity AN5587-2 PIK3CA Exon 10 Mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 CIViC:106 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:10:mutation sequence variation in gene PIK3CA/NCBI:5290 2208 check_entity AN5587-2 PIK3CA Exon 10 Mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 CIViC:1867 condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:10:mutation sequence variation in gene PIK3CA/NCBI:5290 2208 check_entity AN5587-2 PIK3CA Exon 10 mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 PubMed:22357840 This study analyzed tumor and patient characteristics from 1,170 colorectal cancer patients derived from the prospective cohort studies: Nurses' Health Study and Health Professionals Follow Up Study. PIK3CA mutations were found in 16% (189/1170) of patients via pyrosequencing of FFPE samples. Of patients with PIK3CA mutated tumors, 58% (109/189) had mutations in exon 10 (listed as exon 9 in the publication, as it was common at the time of its publication to exclude non-coding exon 1). The presence of an exon 10 mutation was not significantly associated with differences in colorectal cancer-specific or overall survival when compared to patients with wt PIK3CA (multivariate, stage-stratified HR = 1.15 vs 1). Authors note that they had limited data on cancer treatment data, but assume that treatment regimens did not differ substantially based on PIK3CA mutation status given that patients were diagnosed prior to clinical availability of PIK3CA genotype data. They further note that treatment decisions were typically based on cancer stage, for which their analyses adjusted.;|This was a prospective study involving 1,170 colorectal cancer patients confirmed by histology. PIK3CA mutations were found in 16% (189/1170) of cased via pyrosequencing of FFPE samples, of these 58% (109/189) had mutations in exon 10, 39% (73/189) had mutations in exon 21, and 3.7% (7/189) had mutations in both exons. Study found that exon 10 + exon 21 mutants were associated with shorter cancer specific survival and overall survival when compared to WT PIK3CA (P = 0.031, P = 0.0008). These mutants were also associated with higher colorectal cancer-specific mortality and overall mortality (multivariate hazard ratio (HR) = 3.51, multivariate HR 2.68). In contrast, mutations on either exon 10 or exon 21 alone were not statistically significant in terms of overall survival. Note that exons 10 and 21 are listed as exons 9 and 20 in the source, as it was common at the time of its publication to exclude non-coding exon 1. Authors note that they had limited data on cancer treatment data, but assume that treatment regimens did not differ substantially based on PIK3CA mutation status given that patients were diagnosed prior to clinical availability of PIK3CA genotype data. They further note that treatment decisions were typically based on cancer stage, for which their analyses adjusted. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:10:mutation sequence variation in gene PIK3CA/NCBI:5290 2208 check_entity AN5587-2 PIK3CA Exon 10 mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 CIViC:1867 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:10:mutation sequence variation in gene PIK3CA/NCBI:5290 2208 check_entity AN5587-2 PIK3CA Exon 10 mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 PubMed:20619739 In chemotherapy-refractory patients with metastatic colorectal cancer and KRAS wt tumors, Exon 10 PIK3CA mutations (listed as Exon 9 in the source) had no significant impact on response rate (6/21 [28.6%] vs 115/317 [36.3%]; OR: 0.70; p = 0.47), disease control rate, median progression free survival or median overall survival (46 vs 51 weeks, HR: 1.30, p=0.28) following cetuximab + chemotherapy than wildtype PIK3CA. In multivariate analysis of KRAS wildtype patients, PIK3CA was not significantly associated with patient outcome. Authors conclude that PIK3CA exon 10 mutation status does not appear relevant to treatment response. condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:10:mutation sequence variation in gene PIK3CA/NCBI:5290 2208 check_entity AN5587-2 PIK3CA Exon 10 mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 CIViC:106 condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:10:mutation sequence variation in gene PIK3CA/NCBI:5290 2208 check_entity AN5587-3 PIK3CA Exon 10 mutation PIK3CA NCBI:5290 gene rectum cancer DOID:1993 prognostic 60033-8 PubMed:19903786 This study examined outcomes of 240 rectum cancer patients treated with total mesorectal excision therapy. Tumor samples were obtained at the time of surgery and genotyped for PIK3CA mutations in exons 10 and 21 (listed as exons 9 and 20 in the source, as it was common to exclude non-coding exon 1). PIK3CA mutations were identified in 19 cases (12 in exon 10 and 7 in exon 21). PIK3CA mutations were associated with a 3-fold increase in risk of recurrence of rectal tumors (5-year risk: 27.8% vs 9.4%, p = 0.008). Furthermore, patients with PIK3CA mutations experienced a shorter time to recurrence compared to those with WT PIK3CA (median: 7.9 vs 19.6 months, p = 0.07). Patients with concomitant PIK3CA and KRAS mutations had a similar local reoccurrence rate to patients with PIK3CA mutations only. In multivariate analysis, PIK3A mutation was an independent predictor for the development of local recurrences (HR: 3.4, P =0.017). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:10:mutation sequence variation in gene PIK3CA/NCBI:5290 2209 check_entity AN5587-3 PIK3CA Exon 10 mutation PIK3CA NCBI:5290 gene rectum cancer DOID:1993 prognostic 60033-8 CIViC:3179 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:10:mutation sequence variation in gene PIK3CA/NCBI:5290 2209 check_entity AN5588-1 PIK3CA Exon 21 Mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 prognostic 60033-8 PubMed:17947469 An Italian study of 163 malignant breast tumors assessed the association between PIK3CA mutations and clinical outcome. Of the 163 tumors sequenced, 118 had wild-type (wt) PIK3CA, 24 had exon 9 (helical domain) missense mutations, and 21 had exon 20 (kinase domain) missense mutations. The study found that patients with exon 20 mutations showed significantly better 5-year overall survival (OS) and 5-year disease free survival (DFS) compared to patients with wt PIK3CA (P=.011 and P = .01, respectively). Furthermore, patients with exon 20 mut showed especially better OS and DFS than patients with exon 9 mutations (P=.0018 and P=.0017, respectively). The 21 cases with exon 20 mutations had excellent prognosis with no recurrences or deaths, whereas there were 10 recurrences and 9 deaths among the 24 cases of exon 9 mutations, in observed period. Note these exons are now referred to as exons 10 and 21 rather than as exons 9 and 20, as it was common at the time of publication to exclude non-coding exon 1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:21:mutation sequence variation in gene PIK3CA/NCBI:5290 2210 check_entity AN5588-1 PIK3CA Exon 21 Mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 prognostic 60033-8 CIViC:105 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:21:mutation sequence variation in gene PIK3CA/NCBI:5290 2210 check_entity BB1473-1 PIK3CA Exon 21 Mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 PubMed:20619739 Chemotherapy-refractory patients with metastatic colorectal cancer harboring wildtype KRAS and Exon 21 (listed as exon 20 in the source) PIK3CA mutations had lower response rates (0/9 vs 121/329; OR: 0.00; p=0.029) and disease control rates as well as shorter progression free and overall survival (median 34 vs 51 weeks; HR: 3.29, p=0.0057) following cetuximab plus chemotherapy than those with wildtype PIK3CA. In multivariate analysis of the KRAS wildtype population, significant associations between PIK3CA exon 21 mutations and poor response to cetuximab were retained. The authors concluded that PIK3CA exon 21 mutation status is more predictive of poor response to cetuximab than PIK3CA mutation status as a whole. They also recommended screening for mutations in the following gene order: KRAS, BRAF, NRAS, PIK3CA exon 21. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:21:mutation sequence variation in gene PIK3CA/NCBI:5290 2211 check_entity BB1473-1 PIK3CA Exon 21 Mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 PubMed:22357840 This study analyzed tumor and patient characteristics from 1,170 colorectal cancer patients derived from the prospective cohort studies: Nurses' Health Study and Health Professionals Follow Up Study. PIK3CA mutations were found in 16% (189/1170) of patients via pyrosequencing of FFPE samples. Of patients with PIK3CA mutations, 39% (73/189) had mutations in exon 21 (listed as exon 20 in the publication, as it was common at the time of its publication to exclude non-coding exon 1). The presence of an exon 21 mutation was not significantly associated with colorectal cancer-specific or overall survival when compared to patients with wt PIK3CA (multivariate, stage-stratified HR = 1.11 vs 1). Authors note that they had limited data on cancer treatment data, but assume that treatment regimens did not differ substantially based on PIK3CA mutation status given that patients were diagnosed prior to clinical availability of PIK3CA genotype data. They further note that treatment decisions were typically based on cancer stage, for which their analyses adjusted.;|This was a prospective study involving 1,170 colorectal cancer patients confirmed by histology. PIK3CA mutations were found in 16% (189/1170) of cased via pyrosequencing of FFPE samples, of these 58% (109/189) had mutations in exon 10, 39% (73/189) had mutations in exon 21, and 3.7% (7/189) had mutations in both exons. Study found that exon 10 + exon 21 mutants were associated with shorter cancer specific survival and overall survival when compared to WT PIK3CA (P = 0.031, P = 0.0008). These mutants were also associated with higher colorectal cancer-specific mortality and overall mortality (multivariate hazard ratio (HR) = 3.51, multivariate HR 2.68). In contrast, mutations on either exon 10 or exon 21 alone were not statistically significant in terms of overall survival. Note that exons 10 and 21 are listed as exons 9 and 20 in the source, as it was common at the time of its publication to exclude non-coding exon 1. Authors note that they had limited data on cancer treatment data, but assume that treatment regimens did not differ substantially based on PIK3CA mutation status given that patients were diagnosed prior to clinical availability of PIK3CA genotype data. They further note that treatment decisions were typically based on cancer stage, for which their analyses adjusted. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:21:mutation sequence variation in gene PIK3CA/NCBI:5290 2211 check_entity BB1473-1 PIK3CA Exon 21 Mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 CIViC:105 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:21:mutation sequence variation in gene PIK3CA/NCBI:5290 2211 check_entity BB1473-1 PIK3CA Exon 21 Mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 CIViC:1867 condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:21:mutation sequence variation in gene PIK3CA/NCBI:5290 2211 check_entity BB1473-1 PIK3CA Exon 21 mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 PubMed:22357840 This study analyzed tumor and patient characteristics from 1,170 colorectal cancer patients derived from the prospective cohort studies: Nurses' Health Study and Health Professionals Follow Up Study. PIK3CA mutations were found in 16% (189/1170) of patients via pyrosequencing of FFPE samples. Of patients with PIK3CA mutations, 39% (73/189) had mutations in exon 21 (listed as exon 20 in the publication, as it was common at the time of its publication to exclude non-coding exon 1). The presence of an exon 21 mutation was not significantly associated with colorectal cancer-specific or overall survival when compared to patients with wt PIK3CA (multivariate, stage-stratified HR = 1.11 vs 1). Authors note that they had limited data on cancer treatment data, but assume that treatment regimens did not differ substantially based on PIK3CA mutation status given that patients were diagnosed prior to clinical availability of PIK3CA genotype data. They further note that treatment decisions were typically based on cancer stage, for which their analyses adjusted.;|This was a prospective study involving 1,170 colorectal cancer patients confirmed by histology. PIK3CA mutations were found in 16% (189/1170) of cased via pyrosequencing of FFPE samples, of these 58% (109/189) had mutations in exon 10, 39% (73/189) had mutations in exon 21, and 3.7% (7/189) had mutations in both exons. Study found that exon 10 + exon 21 mutants were associated with shorter cancer specific survival and overall survival when compared to WT PIK3CA (P = 0.031, P = 0.0008). These mutants were also associated with higher colorectal cancer-specific mortality and overall mortality (multivariate hazard ratio (HR) = 3.51, multivariate HR 2.68). In contrast, mutations on either exon 10 or exon 21 alone were not statistically significant in terms of overall survival. Note that exons 10 and 21 are listed as exons 9 and 20 in the source, as it was common at the time of its publication to exclude non-coding exon 1. Authors note that they had limited data on cancer treatment data, but assume that treatment regimens did not differ substantially based on PIK3CA mutation status given that patients were diagnosed prior to clinical availability of PIK3CA genotype data. They further note that treatment decisions were typically based on cancer stage, for which their analyses adjusted. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:21:mutation sequence variation in gene PIK3CA/NCBI:5290 2211 check_entity BB1473-1 PIK3CA Exon 21 mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 CIViC:1867 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:21:mutation sequence variation in gene PIK3CA/NCBI:5290 2211 check_entity BB1473-1 PIK3CA Exon 21 mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 PubMed:20619739 Chemotherapy-refractory patients with metastatic colorectal cancer harboring wildtype KRAS and Exon 21 (listed as exon 20 in the source) PIK3CA mutations had lower response rates (0/9 vs 121/329; OR: 0.00; p=0.029) and disease control rates as well as shorter progression free and overall survival (median 34 vs 51 weeks; HR: 3.29, p=0.0057) following cetuximab plus chemotherapy than those with wildtype PIK3CA. In multivariate analysis of the KRAS wildtype population, significant associations between PIK3CA exon 21 mutations and poor response to cetuximab were retained. The authors concluded that PIK3CA exon 21 mutation status is more predictive of poor response to cetuximab than PIK3CA mutation status as a whole. They also recommended screening for mutations in the following gene order: KRAS, BRAF, NRAS, PIK3CA exon 21. condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:21:mutation sequence variation in gene PIK3CA/NCBI:5290 2211 check_entity BB1473-1 PIK3CA Exon 21 mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 CIViC:105 condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:21:mutation sequence variation in gene PIK3CA/NCBI:5290 2211 check_entity AN5588-3 PIK3CA Exon 21 mutation PIK3CA NCBI:5290 gene rectum cancer DOID:1993 prognostic 60033-8 PubMed:19903786 This study examined outcomes of 240 rectum cancer patients treated with total mesorectal excision therapy. Tumor samples were obtained at the time of surgery and genotyped for PIK3CA mutations in exons 10 and 21 (listed as exons 9 and 20 in the source, as it was common to exclude non-coding exon 1). PIK3CA mutations were identified in 19 cases (12 in exon 10 and 7 in exon 21). PIK3CA mutations were associated with a 3-fold increase in risk of recurrence of rectal tumors (5-year risk: 27.8% vs 9.4%, p = 0.008). Furthermore, patients with PIK3CA mutations experienced a shorter time to recurrence compared to those with WT PIK3CA (median: 7.9 vs 19.6 months, p = 0.07). Patients with concomitant PIK3CA and KRAS mutations had a similar local reoccurrence rate to patients with PIK3CA mutations only. In multivariate analysis, PIK3A mutation was an independent predictor for the development of local recurrences (HR: 3.4, P =0.017). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:21:mutation sequence variation in gene PIK3CA/NCBI:5290 2212 check_entity AN5588-3 PIK3CA Exon 21 mutation PIK3CA NCBI:5290 gene rectum cancer DOID:1993 prognostic 60033-8 CIViC:3179 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:21:mutation sequence variation in gene PIK3CA/NCBI:5290 2212 check_entity AN5589-1 PIK3CA F930S mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 PubMed:28424201 A cohort of 32 colorectal cancer patients with acquired resistance to cetuximab (PFS > 12 weeks) was analyzed for resistance mutations using targeted deep sequencing of ctDNA. One patient had the PIK3CA F930S mutation. Cell viability studies of DiFi cells transfected with this PIK3CA variant confirmed resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F930S sequence variation in gene PIK3CA/NCBI:5290 2213 check_entity AN5589-1 PIK3CA F930S mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 CIViC:3535 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F930S sequence variation in gene PIK3CA/NCBI:5290 2213 check_entity AN5590-1 PIK3CA G1049R mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 PubMed:20619739 One patient participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had a tumor which harbored PIK3CA G1049R (exon 20), was wildtype for KRAS, BRAF and NRAS, and had individual response data. This patient was was a 69 year old male treated with cetuximab + FOLFIRI as 3rd line therapy who experienced progressive disease and had PFS of 13 weeks and OS of 36 weeks. Using this information and data from the larger cohort, authors concluded that PIK3CA exon 21 (listed as exon 20 in source) mutations predict poor response to cetuximab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G1049R sequence variation in gene PIK3CA/NCBI:5290 2214 check_entity AN5590-1 PIK3CA G1049R mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 CIViC:914 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G1049R sequence variation in gene PIK3CA/NCBI:5290 2214 check_entity AN5591-1 PIK3CA H1047L mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 risk 60033-8 PubMed:20453058 This preclinical study tested the efficacy on several breast cancer cell lines of GDC-0941 (pictilisib), a selective inhibitor of all four isoforms of class I PI3-kinases at a range of IC50 values. Sensitivity and resistance was categorized as less than and more than an IC50 of 1 umol/L, respectively, with a maximum tested concentration of 20 umol/L. EFM-19 is a luminal type breast cancer cell line harboring PIK3CA H1047L, and it had an IC50 of 0.09uM, suggesting sensitivity. Authors note that luminal-like cell lines were generally more sensitive, regardless of mutation, to pictilisib than basal-like (p=.02) assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047L sequence variation in gene PIK3CA/NCBI:5290 2215 check_entity AN5591-1 PIK3CA H1047L mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 risk 60033-8 CIViC:1125 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047L sequence variation in gene PIK3CA/NCBI:5290 2215 check_entity AN5591-2 PIK3CA H1047L mutation PIK3CA NCBI:5290 gene breast tubular carcinoma DOID:6587 prognostic 60033-8 PubMed:28269754 In a retrospective analysis of 32 Western Chinese female patients with invasive ductal breast cancer, PIK3CA H1047L (n=1) or H1047R (n=8) was associated with worse survival and increased incidence of lymph node invasion. The incidence of lymph node invasion was 15/23 (65%) for the PIK3CA wildtype population and 7/9 (78%) for the subset of patients whose tumors harbored PIK3CA H1047L or H1047R. Authors note that age, tumor grade, tumor size, number of lymphatic nodes and IHC results did not show significant difference between PIK3CA-mutated and non-mutated samples. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047L sequence variation in gene PIK3CA/NCBI:5290 2216 check_entity AN5591-2 PIK3CA H1047L mutation PIK3CA NCBI:5290 gene breast tubular carcinoma DOID:6587 prognostic 60033-8 CIViC:3634 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047L sequence variation in gene PIK3CA/NCBI:5290 2216 check_entity AN5591-3 PIK3CA H1047L mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 PubMed:20619739 Two patients participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored PIK3CA H1047L (exon 21), were wildtype for NRAS, BRAF and PIK3CA, and had individual response data. Both were males treated with cetuximab + irinotecan as 3rd line therapy and experienced progressive disease. One patient was 73 years old with a PFS of 11 weeks and an OS of 31 weeks. The other patient was 61 years old with a PFS and OS of 4 weeks. Authors concluded from this information and data from larger cohort that PIK3CA exon 21 (listed as exon 20 in source) mutations predict poor response to cetuximab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047L sequence variation in gene PIK3CA/NCBI:5290 2217 check_entity AN5591-3 PIK3CA H1047L mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 CIViC:1125 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047L sequence variation in gene PIK3CA/NCBI:5290 2217 check_entity AN5592-1 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 prognostic;risk 60033-8 PubMed:21558396 Breast cancer cell lines with H1047R mutation showed increased sensitivity to CH5132799 than cells with wild-type PIK3CA gene. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2218 check_entity AN5592-1 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 prognostic;risk 60033-8 PubMed:19671852 Prognostic significance of PIK3CA mutations was evaluated in a retrospective study of 590 patients with surgically resected invasive breast cancer. Patients whose tumors harbored PIK3CA H1047R (n=88, 14.9%) experienced significantly higher 10-year overall survival rate (76% vs 62%) and lower 10-year probability of breast cancer specific death (11% vs 23%) compared to those with wildtype PIK3CA. They also experienced a 2.8 and 2 fold reduction in probability of death due to breast cancer at 5 and 10 years. Authors found that PIK3CA H1047R was specifically associated with lymph node-negative status: 64% of H1047R patients were lymph-node negative compared to 48% of patients with PIK3CA WT and helical domain mutated tumors (P=0.007). PIK3CA H1047R was positively associated with lymph node negative status, lower nodal stage, lower overall stage, and smaller tumor size compared to WT PIK3CA assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2218 check_entity AN5592-1 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 prognostic;risk 60033-8 PubMed:17202311 In Japanese invasive breast cancer patients, PIK3CA mutation was associated with improved relapse-free survival (p < .05). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2218 check_entity AN5592-1 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 prognostic;risk 60033-8 PubMed:20453058 This preclinical study tested the efficacy of GDC-0941, a selective inhibitor of class I PI3K, on several cell lines of breast cancer. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. Three cell lines harbored PIK3CA H1047R. T-47D is a luminal type breast cancer cell line, and it had an IC50 of 0.22uM. Treatment with GDC-0941 resulted in a substantial reduction of phosphorylated AKT. BT-20 is a basal breast cancer cell line which had an ICD50 of 0.62uM. MFM-223 is basal cell line that had an ICD50 of 2.10uM, and experienced some reduction in pAKT. Authors note that luminal-like cell lines were generally more sensitive to GDC-0941 than basal-like (p=0.02). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2218 check_entity AN5592-1 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 prognostic;risk 60033-8 CIViC:107 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2218 check_entity AN5592-2 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene breast tubular carcinoma DOID:6587 prognostic 60033-8 PubMed:28269754 In a retrospective analysis of 32 Western Chinese female patients with invasive ductal breast cancer, PIK3CA H1047L (n=1) or H1047R (n=8) was associated with worse survival and increased incidence of lymph node invasion. The incidence of lymph node invasion was 15/23 (65%) for the PIK3CA wildtype population and 7/9 (78%) for the subset of patients whose tumors harbored PIK3CA H1047L or H1047R. Authors note that age, tumor grade, tumor size, number of lymphatic nodes and IHC results did not show significant difference between PIK3CA-mutated and non-mutated samples. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2219 check_entity AN5592-2 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene breast tubular carcinoma DOID:6587 prognostic 60033-8 CIViC:3634 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2219 check_entity AN5592-3 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 PubMed:19223544 In this study, a large cohort of metastatic colorectal cancer patients were treated with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). KRAS PIK3CA and PTEN were tested for mutation; PIK3CA H1047R was the only variant noted in the primary tumor (located in rectum) of one patient who experienced partial response (patient 38; Supplemental Table 1), following treatment. In the larger cohort, patients with tumors harboring any PIK3CA mutation had significantly shorter progression free survival and decreased incidence of objective response than patients with wtPIK3CA tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2220 check_entity AN5592-3 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 PubMed:22180495 In an in vitro study, a RKO cell line expressing BRAF V600E (a known vemurafenib sensitizing mutation) and PIK3CA H1047R co-mutation demonstrated reduced sensitivity to vemurafenib treatment. Resistance was determined by assessing cellular proliferation and AKT phosphorylation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2220 check_entity AN5592-3 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 PubMed:20619739 Five patients participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored PIK3CA H1047R (exon 21), were wildtype for KRAS, BRAF and NRAS, and had individual response data. All patients were treated with cetuximab and irinotecan, four as 3rd line therapy, one as 4th line. Patient characteristics are as follows: a 65 year old female who experienced stable disease (PFS: 33 weeks, OS: 37 weeks); a 56 year old female who experienced stable disease (PFS: 28 weeks, OS: 43 weeks); a 69 year old female who experienced progressive disease (PFS: 10 weeks, OS: 28 weeks); a 63 year old male who experienced progressive disease (PFS:11 weeks, OS: 18 weeks); a 60 year old female who experienced progressive disease (PFS: 12 weeks, OS: 34 weeks). Based off this information and clinical data compiled from the larger cohort, authors concluded that PIK3CA exon 21 (listed as exon 20 in source) mutations predict poor response to cetuximab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2220 check_entity AN5592-3 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 CIViC:107 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2220 check_entity AN5592-4 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene head and neck cancer DOID:11934 risk 60033-8 PubMed:25855885 Lentiviral transduction of PIK3CA H1047R mutation into head and neck cancer cell line SCC25 led to increased sensitivity to PI3K/mTOR inhibition with BEZ235 compared to unmanipulated cells (IC50 values 6 nM and 31 nM). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2221 check_entity AN5592-4 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene head and neck cancer DOID:11934 risk 60033-8 PubMed:23619167 'Two head and neck cancer cell lines with PIK3CA H1047R mutation were more sensitive to PI3K/mTOR inhibition with BEZ-235 (NVP-BEZ235, Dactolisib) than two wild type cell lines in vitro. One cell line with H1047R mutation was also found to be sensitive to BEZ-235 in vivo. PIK3CA (H1047R) mutation positive cell lines used were ''CAL-33'' and ''Detroit 562''. Wild type cell lines used here were ''SCC-9'' and ''PE/CA-PJ34(clone C12)''.' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2221 check_entity AN5592-4 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene head and neck cancer DOID:11934 risk 60033-8 PubMed:25550549 In a panel of head and neck cancer cell lines, 2 lines containing the PIK3CA mutation H1047R (Detroit562 and SNU-1076) were more sensitive to growth inhibition (IC50 1.10 and 6.82) by the PI3Kalpha specific inhibitor BYL719 (Alepelisib) than 3 of 4 lines with wild type PI3K (SNU-1066 IC50 1.13 μM; SNU-1041, 20.65 μM; FaDu, 19.67 μM; SCC25, 49.30 μM). In the H1047R mutant cell lines and the wildtype cell line tested, phospho-Akt and phospho-S6 levels were diminished with increasing BYL719 levels. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2221 check_entity AN5592-4 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene head and neck cancer DOID:11934 risk 60033-8 CIViC:107 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2221 check_entity AN5592-5 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene head and neck squamous cell carcinoma DOID:5520 risk 60033-8 PubMed:26589432 The Cal-33 HNSCC cell line with H1047R mutation was found to have a low antiproliferative IC50 value for the alpha, gamma and delta isoform-specific PI3K inhibitor taselisib. Increasing taselisib concentration induced reduction of phospho-Akt levels in Call-33 cells, while upregulating the cleaved PARP apoptotic marker. Among a panel of 26 HNSCC cell lines, activating PI3K mutations were associated with taselisib sensitivity in comparison to wild-type PI3K or PTEN mutant cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2222 check_entity AN5592-5 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene head and neck squamous cell carcinoma DOID:5520 risk 60033-8 CIViC:107 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2222 check_entity AN5592-6 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 PubMed:22294718 Tumor xenografts in mice were established with the KPL4 HER2 positive breast cancer cell line with PIK3CA H1047R mutation. KPL4 has suboptimal responses to trastuzumab and lapatinib. Xengraft treatment with trastuzumab and AZD5363 monotherapy induced moderate growth inhibition which was significant for AZD5363, but co-treatment with trastuzumab and AZD5363 induced significant tumor regression and enhanced growth delay upon removal of treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2223 check_entity AN5592-6 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 PubMed:27445490 Case report of a 44-year-old patient with recurrent HER2-positive breast cancer. The primary tumor was HR positive; however, the metastatic tumor was HR negative. The patient was resistant to classical chemotherapeutic agents and anti-HER2 treatment. Thus, the combination of everolimus and fulvestrant was administered. The patient experienced stable disease and PFS of 10 months. Genetic testing of pleural effusion after disease progression revealed a PIK3CA H1047R gene mutation but was positive for PTEN expression (IHC). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2223 check_entity AN5592-6 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 PubMed:20453058 This preclinical study tested the efficacy on several breast cancer cell lines of GDC-0941 (pictilisib), a selective inhibitor of all four isoforms of class I PI3-kinases at a range of IC50 values. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. KPL4 is a HER2 amplified breast cancer cell line harboring PIK3CA H1047R, and it had an IC50 of 0.28uM. To evaluate in vivo efficacy, cells were injected in the mammary fat pad of SCID mice, and allowed to grow. Subsequently, pictilisib was administered orally daily for 14 days. Mice treated with 100mg/kg experienced a 76% tumor reduction, and those treated with 150mg/kg experienced a 90% tumor reduction, with respect to untreated control. Phosphorylated AKT (S473) was substantially reduced with pictilisib administration. Three other HER2 amplified breast cancer cell lines harbored PIK3CA H1047R: UACC-893, HCC1954, MDA-MB-453, which had IC50s of 0.41uM, 0.49uM, and 0.64uM, suggesting that PIK3CA H1047R induces sensitivity to pictilisib in HER2 amplified breast cancer. Authors note that pictilisib was well tolerated in vivo and further note that HER2 amplified cell lines were generally more sensitive, regardless of mutation, to pictilisib than basal-like cell lines (p=0.002). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2223 check_entity AN5592-6 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 PubMed:26920887 As part of a pre-clinical experiment, the efficacy of ado-trastuzumab emtansine (T-DM1) was compared to that of trastuzumab against various HER2 positive cell lines. HCC1954 and KPL-4 cell lines expressing PIK3CA H1047R were associated with similar sensitivity to T-DM1 as PIK3CA wild-type cell line SK-BR-3; reduced cell viability was observed at concentrations > 0.01 ug/mL in all three cell lines. Conversely, the cell lines harboring PIK3CA H1047R were resistant to trastuzumab in vitro at all concentrations tested (0-10 ug/mL). Further, treatment with T-DM1 on SCID mice xenografted with KPL-4 (PIK3CA H1047R cells) resulted in inhibition of tumor growth. A single dose of T-DM1 >5mg/kg was sufficient to induce tumor regression >20 days after administration. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2223 check_entity AN5592-6 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 PubMed:19010894 In a preclinical study, efficacy of lapatinib and trastuzumab was evaluated in vitro against HER2 amplified breast cancer cell line BT474 (heterozygous for PIK3CA K111N) retrovirally transduced with PIK3CA H1047R. The study found that H1047R abrogated the growth inhibitory effects of lapatinib and trastuzumab, either in isolation or in combination, though somewhat increased cell death was observed with combination therapy relative to monotherapy. The authors concluded that the PIK3CA H1047R induces resistance to lapatinib and trastuzumab in HER2-positive breast cancer cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2223 check_entity AN5592-6 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 CIViC:107 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2223 check_entity AN5592-7 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene lung adenocarcinoma DOID:3910 risk 60033-8 PubMed:19029981 Doxycycline dependent expression of the PIK3CA H1047R mutation in mouse type II alveolar epithelial cells drove lung cancer in a reversible fashion, indicating the driver properties of this p110alpha catalytic domain mutation. Administration of pan-p110 isoform and mTOR inhibitor BEZ235 to H1047R mice with established tumors resulted in reduced tumor phospho-Akt and phosoho-S6 levels, and significant regression of tumor volume. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2224 check_entity AN5592-7 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene lung adenocarcinoma DOID:3910 risk 60033-8 CIViC:107 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2224 check_entity AN5592-8 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene thyroid cancer DOID:1781 risk 60033-8 PubMed:19706758 Preclinical study in thyroid cancer cell lines. 6 cell lines with alterations of the PI3K/Akt pathway were more sensitive to Akt inhibitor perifosine or MTOR inhibitor temsirolimus than 5 cell lines without genetic alterations in the PI3K/Akt pathway. Among the alterations, One cell line harbored a PIK3CA H1047R mutation. Transfection of another cell line with this mutation led to lower IC50 values to perifosine and temsirolimus than in a cell line transfected with a control vector. Perifosine treatment also increased apoptosis of a thyroid tumor xenograft with PIK3CA H1047R mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2225 check_entity AN5592-8 PIK3CA H1047R mutation PIK3CA NCBI:5290 gene thyroid cancer DOID:1781 risk 60033-8 CIViC:107 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047R sequence variation in gene PIK3CA/NCBI:5290 2225 check_entity AN5593-1 PIK3CA H1047X mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 risk 60033-8 PubMed:31091374 In a phase 3 trial, patients with hormone receptor positive, HER2 receptor negative breast were allocated to alpelisib plus fulvestrant or placebo plus fulvestrant. Patients were enrolled into two cohorts on the basis of tumor-tissue PIK3CA mutation status.PIK3CA mutation was determined according to the presence or absence of any hot spot mutation in the C2, helical, and kinase domains of PI3K (corresponding to exon 7, 9, and 20, respectively). In the cohort of patients with PIK3CA-mutated cancer, PFS was 11 months in the alpelisib-fulvestrant group, as compared with 5.7 months in the placebo-fulvestrant group (HR 0.65, p<0.001). In the cohort without PIK3CA-mutated cancer, the HR was 0.85. Analyses of PFS according to mutation types showed consistent benefit of treatment with alpelisib–fulvestrant in across prespecified subgroups, including E542K, E545X, and H1047X. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047X sequence variation in gene PIK3CA/NCBI:5290 2226 check_entity AN5593-1 PIK3CA H1047X mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 risk 60033-8 CIViC:2579 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H1047X sequence variation in gene PIK3CA/NCBI:5290 2226 check_entity AN5594-1 PIK3CA I391M mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 PubMed:26920887 As part of a pre-clinical experiment, the efficacy of ado-trastuzumab emtansine (T-DM1) was evaluated against various HER2 positive cell lines. ZR-75-30 cell line expressing PIK3CA I391M was associated with similar sensitivity to T-DM1 as PIK3CA wild-type cell line SK-BR-3; reduced cell viability was observed at concentrations > 0.01 ug/mL in both cell lines. When treated with trastuzumab, the cell line harboring PIK3CA I391M experienced similar reduction in cell viability. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I391M sequence variation in gene PIK3CA/NCBI:5290 2227 check_entity AN5594-1 PIK3CA I391M mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 CIViC:1209 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I391M sequence variation in gene PIK3CA/NCBI:5290 2227 check_entity AN5595-1 PIK3CA K111N mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 PubMed:20453058 This preclinical study tested the efficacy on several breast cancer cell lines of GDC-0941 (pictilisib), a selective inhibitor of all four isoforms of class I PI3-kinases at a range of IC50 values. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. BT-474 is a HER2 amplified breast cancer cell line harboring PIK3CA K111N, and it had an IC50 of 0.23uM. To evaluate in vivo efficacy, cells were injected in the mammary fat pad of SCID mice and allowed to grow. Mice subsequently treated with 100mg/kg pictilisib experienced a 69% tumor reduction, and those treated with 150mg/kg experienced an 82% tumor reduction, with respect to untreated control. Authors note that pictilisib was well tolerated and observed no toxicities or significant weight loss. Authors further note that HER2 amplified cell lines were generally more sensitive, regardless of mutation, to pictilisib than basal-like cell lines (p=0.002). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K111N sequence variation in gene PIK3CA/NCBI:5290 2228 check_entity AN5595-1 PIK3CA K111N mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 PubMed:26920887 As part of a pre-clinical experiment, the efficacy of ado-trastuzumab emtansine (T-DM1) was evaluated against various HER2 positive cell lines. BT-474 cell line expressing PIK3CA K111N was associated with similar sensitivity to T-DM1 as PIK3CA wild-type cell line SK-BR-3; reduced cell viability was observed at concentrations > 0.01 ug/mL in both cell lines. Conversely, when treated with trastuzumab, the cell line harboring PIK3CA K111N experienced a smaller reduction in cell viability. Further, treatment with T-DM1 on SCID mice xenografted with PIK3CA K111N cells resulted in inhibition of tumor growth. A single dose of T-DM1 >5mg/kg was sufficient to induce tumor regression >20 days after administration. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K111N sequence variation in gene PIK3CA/NCBI:5290 2228 check_entity AN5595-1 PIK3CA K111N mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 PubMed:19010894 The BT-474 HER2 positive human breast cancer cell line, which is heterozygous for the PIK3CA K111N mutation, demonstrated strongly reduced colony formation when treated with lapatinib, trastuzumab or dactolisib alone or in combination, suggesting that K111N does not induce resistance to these drugs. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K111N sequence variation in gene PIK3CA/NCBI:5290 2228 check_entity AN5595-1 PIK3CA K111N mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 CIViC:1208 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K111N sequence variation in gene PIK3CA/NCBI:5290 2228 check_entity AN5596-1 PIK3CA K944N mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 PubMed:28424201 A cohort of 32 colorectal cancer patients with acquired resistance to cetuximab (PFS > 12 weeks) was analyzed for resistance mutations using targeted deep sequencing of ctDNA. Three patients had the PIK3CA p.K944N mutation. Cell viability studies of DiFi cells transfected with this PIK3CA variant confirmed resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K944N sequence variation in gene PIK3CA/NCBI:5290 2229 check_entity AN5596-1 PIK3CA K944N mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 CIViC:3534 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K944N sequence variation in gene PIK3CA/NCBI:5290 2229 check_entity AN5597-1 PIK3CA K966E mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 PubMed:28424201 A cohort of 32 colorectal cancer patients with acquired resistance to cetuximab (PFS > 12 weeks) was analyzed for resistance mutations using targeted deep sequencing of ctDNA. One patient had the PIK3CA p.K966E mutation. Cell viability studies of DiFi cells transfected with this PIK3CA variant confirmed resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K966E sequence variation in gene PIK3CA/NCBI:5290 2230 check_entity AN5597-1 PIK3CA K966E mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 CIViC:3537 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K966E sequence variation in gene PIK3CA/NCBI:5290 2230 check_entity AN5598-1 PIK3CA L938* mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 PubMed:28424201 A cohort of 32 colorectal cancer patients with acquired resistance to cetuximab (PFS > 12 weeks) was analyzed. 1 patient had the PIK3CA p.L938* mutation. Cell viability studies of DiFi cells transfected with this PIK3CA variant did not exhibit resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L938* sequence variation in gene PIK3CA/NCBI:5290 2231 check_entity AN5598-1 PIK3CA L938* mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 CIViC:3538 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L938* sequence variation in gene PIK3CA/NCBI:5290 2231 check_entity AN5599-1 PIK3CA Mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 prognostic;risk 60033-8 PubMed:25002028 Three PI3K mutant breast cancer cell lines were rendered resistant to PI3K inhibitors (BYL719 or GDC-0941), and a panel of 42 inhibitor compounds was tested on the cells for ability to resensitize the cells to PI3K inhibition. The CDK4/6 inhibitor ribociclib (LEE011) acted synergistically with PI3K inhibitor to reduce viability in all three resistant cell lines. In a panel of 12 PIK3CA mutant and 10 wild type cell lines, synergistic effects between P110alpha inhibitor BYL719 and ribociclib were significantly stronger (weighted synergy score calculation, ANOVA, p=0.012) in PIK3CA mutant cells, indicating variant specific sensitization. Mouse xenografts of 4 different PIK3CA mutant breast cancer cells resistant to PI3K inhibitor showed stronger regression under dual PI3K inhibitor and ribociclib treatment than with either treatment alone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2232 check_entity AN5599-1 PIK3CA Mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 prognostic;risk 60033-8 PubMed:21358673 A panel of 31 breast cancer cell lines was tested for sensitivity to mTORC1 inhibitor everolimus and mTORC1/mTORC2 inhibitor PP242. Inhibitor concentrations for 50% survival fraction (SF50) were measured and SF50 less than one micro molar was considered sensitive. PIK3CA mutant cell lines were significantly more sensitive to both everolimus and PP242 than PIK3CA wild type cell lines. Apoptotic indicators and cell cycle analysis indicated that the mTOR inhibitors induced G1 arrest instead of apoptosis in the cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2232 check_entity AN5599-1 PIK3CA Mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 prognostic;risk 60033-8 PubMed:19671852 Prognostic significance of PIK3CA mutations was evaluated in a retrospective study of 590 patients with surgically resected invasive breast cancer. Patients with tumors harboring PIK3CA mutations (n=192, 32.5%; 14.9% with H1047R; 4.2% with E542K; 4.9% with E545K; 8.5% across all other variants) experienced longer PFS, OS, and breast cancer specific survival than patients with PIK3CA wt tumors (p=0.06; p=0.03; p=0.004). PIK3CA mutations were positively associated with lymph node negativity, lower tumor stage, hormone receptor positivity, and HER2 negativity. Patients with PIK3CA mutated tumors experienced a 2 fold decrease in death due to breast cancer at 5 and 10 years. Tumors with hot spot mutations (E542K, E545K, H10447), were strongly correlated with lower grade (2), ER-positive, PR-positive, HR-positive, HER2-negative compared to PIK3CA wt tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2232 check_entity AN5599-1 PIK3CA Mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 prognostic;risk 60033-8 PubMed:21594665 In retrospective study of 175 metastatic breast cancer patients treated with trastuzumab-based therapy, the presence of a PIK3CA mutation (E542K, E545K, or H1047R) was associated with a greater risk of progression (HR = 1.86, P = 0.014, multivariate analysis ) compared to wildtype PIK3CA. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2232 check_entity AN5599-1 PIK3CA Mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 prognostic;risk 60033-8 PubMed:17575221 This was a Swedish study of 270 breast tumors removed from patients with unilateral operable breast cancer, and either lymph node metastases or a tumor diameter >30mm. PIK3CA missense mutations were found in 66/270 (24%) tumors. Of these, 36 tumors (55%) harbored mutations in exon 20— 33 H1047R, 1 Y1021C, 1 G1049R, and 1 H1047P. The other 30 were missense mutations in exon 9— 11 E542K, 18 E545K, 1 Q546P. The study found that the risk of relapse with a local recurrence was significantly lower among patients with a PIK3CA mutation in comparison with those who carried wild-type PIK3CA (p= 0.023). When adjusting for other factors, including ER status, node status, tumor size, and treatment (tamoxifen vs no tamoxifen or radiotherapy vs chemotherapy), mutations in the PIK3CA gene were associated with approximately half the risk for local recurrence in comparison with wtPIK3CA (p = .07). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2232 check_entity AN5599-1 PIK3CA Mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 prognostic;risk 60033-8 PubMed:31091374 In a phase 3 trial, patients with hormone receptor positive, HER2 receptor negative breast were allocated to alpelisib plus fulvestrant or placebo plus fulvestrant. Patients were enrolled into two cohorts on the basis of tumor-tissue PIK3CA mutation status. In the cohort of patients with PIK3CA-mutated cancer (defined by the presence of any PIK3CA mutation in mutation hot spots in the C2, helical, and kinase domains of PI3K corresponding to exons 7, 9, and 20, respectively), PFS was 11 months in the alpelisib-fulvestrant group, as compared with 5.7 months in the placebo-fulvestrant group (HR 0.65, 95% CI, 0.50 to 0.85, p<0.001). In the cohort without PIK3CA-mutated cancer, the HR was 0.85 (95% CI, 0.58 to 1.25). Overall response rate was also greater in the PIK3CA-mutant group (26.6% vs. 12.8%). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2232 check_entity AN5599-1 PIK3CA Mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 prognostic;risk 60033-8 CIViC:307 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2232 check_entity AN5599-2 PIK3CA Mutation PIK3CA NCBI:5290 gene cancer DOID:162 risk 60033-8 PubMed:25855885 Analysis of drug response data from the Sanger center cell line screen. Cell lines with either PI3K and/or PTEN mutations did not show a significant difference in response to class I PI3K inhibitor GDC-0941 (p =0.07 for combined PI3K/PTEN aberrations with a trend towards lower IC50 for mutated cell lines). IC50 values with HSP90 inhibitor 17-AAG were significantly lower in PI3K and/or PTEN mutated cell lines in the sanger cell line screening but these results could not be reproduced in the cancer cell line encyclopedia screening. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2233 check_entity AN5599-2 PIK3CA Mutation PIK3CA NCBI:5290 gene cancer DOID:162 risk 60033-8 PubMed:24608574 A set of 474 cell lines from the Cancer Cell Line Encyclopedia was tested for responsiveness to the PI3Kalpha specific inhibitor BYL719 (Alpelisib). In the PIK3CA wild type subroup of cell lines, 22% were assessed as responsive, while in the subgroup of cell lines with PIK3CA mutations, 64% were labeled as responders. 7 patient derived xenografts with PIK3CA mutations (H1047R, E545K, M1043I, C420R, Q546K) were transplanted into mice and treated with BYL719. 6/7 mice responded with strong tumor growth inhibition or regression, while one (H1047R) responded with weak growth inhibition. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2233 check_entity AN5599-2 PIK3CA Mutation PIK3CA NCBI:5290 gene cancer DOID:162 risk 60033-8 PubMed:22294718 Sensitivity to pan-Akt inhibitor AZD5363 was assessed in a panel of 182 cell lines (160 with PTEN evaluated) derived from solid and hematological tumors. PTEN loss of function due to loss or mutation (N=32) was found to be significantly correlated with AZD5363 sensitivity (p=0.0099), and correlation improved in the subpopulation free of RAS mutation. Mouse xenografts with 786-0 (PTEN-null renal cancer) cells were established. 75 mg/kg twice daily AZD5363 caused tumor growth inhibition while 150 mg/kg twice daily induced moderate tumor regression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2233 check_entity AN5599-2 PIK3CA Mutation PIK3CA NCBI:5290 gene cancer DOID:162 risk 60033-8 PubMed:28489509 In a study of 37 patients with AKT1 (E13K) mutations, 5 patients harbored a concurrent PI3K/mTOR pathway alteration. The PFS of patients with a concurrent PI3K/mTOR pathway alteration was significantly longer than those without when treated with AZD-5363 (median PFS, not reached v 4.3 months, respectively; HR, 0.21; P = 0.045). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2233 check_entity AN5599-2 PIK3CA Mutation PIK3CA NCBI:5290 gene cancer DOID:162 risk 60033-8 PubMed:35133871 In this NCI-MATCH trial subprotocol Z1F, of the 35 patients enrolled harbouring PIK3CA mutations in their tumors, 25 were included in the primary efficacy analysis and treated with copanlisib. Patients with KRAS mutations were excluded. The ORR was 16% (90% CI; 6-33; p-value = 0.0341), and the clinical benefit rate (complete response, SD or PR for ≥ 6 months) was 36% (90% CI; 20-54). The 6-month PFS rate and PFS were 38% (90% CI; 22-53) and 3.4 months (90% CI; 1.8-6.6) respectively. The OS was 5.9 months (90% CI; 4.9-13.7). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2233 check_entity AN5599-2 PIK3CA Mutation PIK3CA NCBI:5290 gene cancer DOID:162 risk 60033-8 PubMed:35138919 In this phase II NCI-MATCH trial subprotocol I, 61 patients harbouring activating PIK3CA mutations were treated with taselisib. The cohort didn't include any patients with breast or squamous cell lung carcinoma, or patients harboring KRAS or PTEN mutations. No complete responses or PRs were observed in the cohort, the best response being SD in 52% of the patients. The six-month PFS rate was 19.9% (90% CI; 12-29.3), and the PFS was 3.1 months (90% CI; 1.8-3.7). The six-month OS rate was 60.7% (90% CI; 49.6-70), and the OS was 7.2 months (90% CI; 5.9-10.0). Overall, the study reported very limited activity of taselisib in patients with PIK3CA mutations and concluded that the presence of PIK3CA mutation alone is not a sufficient predictor of the drug's activity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2233 check_entity AN5599-2 PIK3CA Mutation PIK3CA NCBI:5290 gene cancer DOID:162 risk 60033-8 CIViC:307 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2233 check_entity AN5599-3 PIK3CA Mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 PubMed:25242168 20 patient-derived colorectal cancer xenografts were treated with cabozantinib, a c-MET and VEGFR2 inhibitor. 16 xenografts showed sensitivity (as defined by TGII: tumor growth of treated compared to control ≤ 20%). Among the genes tested for mutations (KRAS, TP53, PIK3CA, MET, VEGFR2, RET and AXL), PIK3CA mutations (4 PDTX) showed a significant enrichment in sensitive xenografts. PIK3CA mutations were observed in 4/5 of the most responsive tumors. Treating xenografts derived from isogenic PIK3CA wildtype or mutant cell lines corroborated this finding with PIK3CA mutant xenografts showing greater sensitivity to cabozantinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2234 check_entity AN5599-3 PIK3CA Mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 PubMed:23435830 A meta-analysis of 8 metastatic colorectal cancer studies (839 patients) was performed. PIK3CA mutations were significantly associated with shorter PFS and OS following therapy with anti-EGFR monoclonal antibodies (PFS: 8 studies, 839 patients; HR = 1.53; 95 % confidence interval (CI) 1.28-1.84; P < 0.001; OS: 5 studies; 587 patients; HR = 1.28; 95 % CI 1.05-1.56; P = 0.015). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2234 check_entity AN5599-3 PIK3CA Mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 PubMed:22586653 A cohort of patient-derived xenografts (PDX) from 85 patients with metastatic colorectal cancer was created. PDX were treated with cetuximab and mechanisms of resistance investigated. None of the xenografts harboring KRAS (N=18), NRAS (N=7) or BRAF (N=3) mutations showed a response to cetuximab and only 1 out of 4 xenografts with a PIK3CA mutation responded to cetuximab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2234 check_entity AN5599-3 PIK3CA Mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 PubMed:17590872 This retrospective study examines outcomes of 158 primary sporadic colorectal cancer patients who had undergone surgical resection and were treated with 5-fluorouracil based chemotherapy. PIK3CA mutations were associated with reduced relapse-free survival in stage II/III patients (HR:2.587, 95% CI:1.108-6.039, P=0.0280, univariate analysis; HR:2.478, 95% CI:1.028-5.973, P=0.0433, multivariate analysis) and reduced disease-specific survival in patients of any stage (n=18 vs. n=140, P=0.0357) compared to wildtype PIK3CA. Authors noted that the tumors of 6 patients harbored both PIK3CA and KRAS mutations, but stated that the presence of PIK3CA mutations did not correlate with the presence of KRAS mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2234 check_entity AN5599-3 PIK3CA Mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 PubMed:20619739 This was a retrospective study of 605 patients with metastatic, chemotherapy refractory colorectal cancer treated with cetuximab + chemotherapy. Patients with KRAS wildtype, PIK3CA assessable tumors, and individual response data (n=339) were genotyped for PIK3CA mutations. Patients harboring PIK3CA mutant tumors (n=34) had a significantly lower response rate than did patients with wildtype PIK3CA (6/34 [17.7%] vs 115/305 [37.7%]; p =.015). Patients with mutant PIK3CA also experienced lower disease control rate in response to cetuximab treatment. However, there was no significant difference between patients with mutant or wildtype PIK3CA in progression free or overall survival (median PFS: 18 vs 24 weeks; median OS: 39 vs 51 weeks). Authors suggest that PIK3CA exon 21 mutations are more relevant to cetuximab response than PIK3CA mutations as a whole, as PIK3CA exon 10 mutations do not appear to effect cetuximab response (exons are listed as exon 20 and exon 9 in the source). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2234 check_entity AN5599-3 PIK3CA Mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 PubMed:19603024 This was a retrospective clinical study of 168 metastatic colorectal cancer patients who received first line chemotherapy (made up of 5-fluorouracil (5-FU) only, 5-FU + oxaliplatin, 5-FU + irinotecan, or 5-FU + oxaliplatin + irinotecan) alone or with monoclonal antibodies (bevacizumab or cetuximab). It assessed the relationship between PIK3CA mutation status in primary tumors and post treatment PFS. Of 168 patients, 142 had wildtype PIK3CA and 26 had mutations in PIK3CA on either exon 9 or 20 (exon 9 mutations: E542K, E545K, E545G, E545D, Q546K, D549N. Exon 20 mutations: R1023Q, H1047R, H1047L, G1049A). The study found that patients harboring a PIK3CA mutation did not have a significantly worse outcome than patients expressing wildtype PIK3CA, regardless of first line chemotherapy regimen or use of monoclonal antibody treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2234 check_entity AN5599-3 PIK3CA Mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 PubMed:19223544 Mutational analysis of 110 metastatic colorectal cancer patients was used to examine objective tumor response, progression free survival (PFS), and overall survival (OS) following treatment with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). In univariate analysis, PIK3CA mutations (H1047R or E545K) were significantly associated with lack of response to panitumumab or cetuximab (objective response rate: 0/15 vs 22/95 for patients harboring PIK3CA mutated or wildtype tumors, respectively; P = 0.038). Multivariate logistic regression of KRAS mutations, PIK3CA mutations and PTEN protein expression also confirmed an independent effect of PIK3CA mutation on objective response (P = 0.0337; OR = 0.1153; CI for OR: 0.000–0.865). Patients with tumors harboring either PIK3CA H1047R or E545K mutations (15/109) had decreased PFS, compared to those with wild-type tumors (P = 0.0035), though they had a nonsignificant difference in OS. Authors note a trend in decreasing OS in patients with PIK3CA mutated tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2234 check_entity AN5599-3 PIK3CA Mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 PubMed:23094721 This was a retrospective study of 964 colorectal cancer patients who participated in the Nurses' Health Study and the Health Professionals Follow-up Study. Of 964 patients, 803 patients had wildtype PIK3CA (aspirin use: 337/803, no aspirin use: 466/803) and 161 had mutated PIK3CA (aspirin use: 66/161, no aspirin use: 95/161). This study found that—among patients with mutated PIK3CA cancer— regular use of aspirin following diagnosis was correlated with superior colorectal cancer specific survival (multivariate hazard ratio, 0.18; 95% CI, 0.06-0.61; P<0.001) and overall survival (multivariate hazard ratio, 0.54; 95% CI, 0.31-0.94; P = 0.01). Conversely, among patients with wild-type PIK3CA, regular use of aspirin after diagnosis was not significantly associated with colorectal cancer–specific survival or overall survival. Among patients with mutated-PIK3CA tumors, 23 of 90 patients who did not use aspirin after diagnosis (26%) died within 5 years after diagnosis, whereas only 2 of 62 regular users of aspirin after diagnosis (3%) died within 5 years after diagnosis (P<0.001). In contrast, among patients with wild-type PIK3CA tumors, the 5-year cumulative colorectal cancer–specific mortality was the same (15%) for users and nonusers of aspirin after diagnosis (P = 0.92). The authors conclude that PIK3CA mutation may predict response to aspirin therapy in patients with newly diagnosed colorectal cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2234 check_entity AN5599-3 PIK3CA Mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 prognostic;risk 60033-8 CIViC:307 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2234 check_entity AN5599-4 PIK3CA Mutation PIK3CA NCBI:5290 gene endometrial cancer DOID:1380 risk 60033-8 PubMed:24166148 94 endometrial cancer samples of women who had been treated with single agent mTOR inhibitors temsirolimus or ridaforolimus were retrospectively analyzed. No predictive biomarkers were identified, including PIK3CA mutations (N=21/73), KRAS mutations (10/73) or PTEN loss. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2235 check_entity AN5599-4 PIK3CA Mutation PIK3CA NCBI:5290 gene endometrial cancer DOID:1380 risk 60033-8 PubMed:23674493 A panel of 24 endometrioid endometrial cancer (EEC) cell lines was characterized for a set of mutations and sensitivity to pan PI3K class I inhibitor GDC-0941 (pictilisib) was assessed. EEC cell lines with PIK3CA mutations were significantly more sensitive to GDC-0941 (Fisher’s exact test, two-tailed, P=0.038). Some of the PIK3CA mutant cells contained PTEN and KRAS mutations, but in these cells, these mutations did not effect sensitivity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2235 check_entity AN5599-4 PIK3CA Mutation PIK3CA NCBI:5290 gene endometrial cancer DOID:1380 risk 60033-8 CIViC:307 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2235 check_entity AN5599-5 PIK3CA Mutation PIK3CA NCBI:5290 gene estrogen-receptor positive breast cancer DOID:0060075 risk 60033-8 PubMed:17575221 This was a Swedish study of 270 breast tumors removed from patients with unilateral operable breast cancer, and either lymph node metastases or a tumor diameter >30mm. PIK3CA missense mutations were found in 65/270 (24%) tumors. Of these, 36 (55%) were in exon 20— 33 H1047R, 1 Y10121C, 1 G1049R, and 1 H1047P. The other 30 were missense mutations in exon 9— 11 E542K, 18 E545K, 1 Q546P. Within the group of 188 patients with ER+ tumors, PIK3CA mutation status did not predict response to tamoxifen. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2236 check_entity AN5599-5 PIK3CA Mutation PIK3CA NCBI:5290 gene estrogen-receptor positive breast cancer DOID:0060075 risk 60033-8 CIViC:307 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2236 check_entity AN5599-6 PIK3CA Mutation PIK3CA NCBI:5290 gene head and neck cancer DOID:11934 risk 60033-8 PubMed:23619167 Preclinical analysis of the predicitive value of PIK3CA mutations for mTOR/PI3K Inhibition with BEZ-235. Two cell lines with PIK3CA Mutation (H1047R) were more sensitive to BEZ-235 than two cell lines with wild-type PIK3CA (in-vitro, results from one cell line also confirmed in-vivo). Two patient-derived xenografts with PIK3CA mutations (E110K, E542K) showed sensitivity to BEZ-235. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2237 check_entity AN5599-6 PIK3CA Mutation PIK3CA NCBI:5290 gene head and neck cancer DOID:11934 risk 60033-8 PubMed:25855885 6 head and neck cancer cell lines were tested for Response to 17-AAG, GDC-0941. Two of the cell lines did not carry PIK3CA mutations. No clear difference was shown between PIK3CA-mutant and wild-type cell lines and there was a trend towards increased resistance. SCC25 cell line was lentivirally transduced with PIK3CA E545K or H1047R mutation. Engineered cells, compared to the parental cell line, showed decreased sensitivity to 17-AAG, GDC-0941 or trametinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2237 check_entity AN5599-6 PIK3CA Mutation PIK3CA NCBI:5290 gene head and neck cancer DOID:11934 risk 60033-8 CIViC:307 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2237 check_entity AN5599-7 PIK3CA Mutation PIK3CA NCBI:5290 gene head and neck squamous cell carcinoma DOID:5520 risk 60033-8 PubMed:26589432 A panel of 26 HNSCC cell lines was tested for efficacy of the p110 alpha, delta and gamma isoform inhibitor taselisib (GDC-0032). Cell lines with PIK3CA mutation or amplification were the most sensitive. Four HNSCC cell lines with activating PIK3CA alterations showed synergistic cell death response to the combination of drug with radiation treatment. This synergism was not apparent in 4 tested HNSCC cell lines with wild-type PIK3CA or PTEN mutation. Nude mouse xenografts were established with Cal-33 PIK3CA H1047R cells. Radiation and taselisib treatments alone showed some growth inhibition in comparison to control, but only the combined treatment led durable tumor regressions. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2238 check_entity AN5599-7 PIK3CA Mutation PIK3CA NCBI:5290 gene head and neck squamous cell carcinoma DOID:5520 risk 60033-8 PubMed:30683736 In this retrospective study, the impact of nonsteroidal anti-inflammatory drugs (NSAID) on survival in PIK3CA-altered HNSCC patients (N=266) was assessed. 37 of 266 (14%) patients harbored a mutation, 29 of 266 (11%) had only amplification, and 9 patients had both. Among patients with a PIK3CA mutation or amplification, regular NSAID use was significantly associated with disease-specific (HR 0.23, p=0.0032) and overall survival (HR 0.31, p=0.0043). These findings were recreated in a panel of six patient-derived xenograft models, where treatment with NSAIDs (sulindac, Celecoxib or Aspirin) significantly reduced growth rates in PIK3CA mutant, but not wild-type models. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2238 check_entity AN5599-7 PIK3CA Mutation PIK3CA NCBI:5290 gene head and neck squamous cell carcinoma DOID:5520 risk 60033-8 CIViC:307 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2238 check_entity AN5599-8 PIK3CA Mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 PubMed:27091708 Archival tumor samples from 549 patients from the BOLERO-1 and -3 trials were analyzed for alterations in the PI3K pathway using next-generation sequencing, immunohistochemistry (IHC) and Sanger sequencing. In the BOLERO trials, patients with HER2-overexpressing advanced breast cancer were treated with trastuzumab, chemotherapy and randomized to receive either everolimus or placebo. In the pooled analysis of both trials, patients with PI3K mutations had longer progression-free survival with everolimus compared to placebo (HR 0.67 95%CI 0.45 to 1.00, P=0.05) whereas patients with PI3K wild type status did not benefit significantly (HR 1.1, 95%CI 0.83 to 1.46, P=0.5). The same was found when PI3K mutations, PTEN loss and AKT E17K mutations were combinedly analyzed as hyperactive PI3K pathway. Patients with PI3K hyperactive pathway had a hazard ratio of 0.67 (95%CI 0.48 to 0.93, P=0.02) compared to HR 1.19 (95%CI 0.87 to 1.62, P=0.28) in patients with PI3K normal pathway. These trends were independently confirmed in both trials but only pooled results showed consistent statistical significance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2239 check_entity AN5599-8 PIK3CA Mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 PubMed:17936563 The HER2 overexpressing breast cancer cell line BT-474 transduced with mutant PIK3CA H1047R demonstrated essentially normal proliferation under trastuzumab, while control cells showed negligible proliferation with trastuzumab. Sequencing of 55 HER2 breast cancer samples revealed 25% PIK3CA mutation rate and Kaplan Meier curves showed decreased time to progression for mutant PIK3CA at borderline statistical significance (p=0.052). This was potentially explained by presence of PTEN loss in wild-type PIK3CA sample and combining PTEN loss with PIK3CA mutation resulted in significant differences in time to progression (p=0.007). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2239 check_entity AN5599-8 PIK3CA Mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 PubMed:22294718 HER2 overexpressing breast cancer cell lines with PIK3CA mutation BT474c (K111N) and HCC-1954 (H1047R) were used to establish mouse tumor xenografts. In BT474c xenografts, three dosing schedules of AZD5363 caused significant tumor inhibition (200 mg/kg twice daily > 200 mg/kg once daily > 100 mg/kg once daily). In HCC-1954 xenografts two doses of AZD5363 induced significant tumor inhibition (150 mg/kg twice daily > 75 mg/kg twice daily) while 30 mg/kg twice weekly trastuzumab was inactive. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2239 check_entity AN5599-8 PIK3CA Mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 PubMed:21594665 In a retrospective study of 105 HER2-positive metastic breast cancer patients treated with trastuzumab-based therapy, the presence of a PIK3CA mutation (E542K, E545K, or H1047R) was associated with a greater risk of progression (HR = 2.50, P = 0.003, multivariate analysis) compared to wildtype PIK3CA. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2239 check_entity AN5599-8 PIK3CA Mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 PubMed:26920887 In a phase 3 clinical trial (NCT00829166), metastatic HER-2 amplified breast cancer patients whose tumors harbored PIK3CA mutations treated with ado-trastuzumab emtansine (T-DM1; n=40) were associated with similar median progression free survival (PFS), overall response rate (ORR), and overall survival (OS) compared to patients whose tumors harbored wild-type PIK3CA (n=93; PFS: 10.9 vs. 9.8 months, ORR: 50% vs 47.4%, OS not reached for either group). Of PIK3CA mutant HER2 patients, those treated with T-DM1 experienced a greater decrease in disease progression than those treated with standard of care capecitabine + lapatinib. In vitro, HER2 amplified cell lines with various PIK3CA mutations were associated with similar sensitivity to T-DM1 as PIK3CA wild-type cell line SK-BR-3. In mouse xenograft models of various PIK3CA mutations (H1047R, E545K, or K111N), tumor regression or complete tumor suppression >20 days was seen following a single dose >10mg/kg for all models. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2239 check_entity AN5599-8 PIK3CA Mutation PIK3CA NCBI:5290 gene Her2-receptor positive breast cancer DOID:0060079 risk 60033-8 CIViC:307 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2239 check_entity AN5599-9 PIK3CA Mutation PIK3CA NCBI:5290 gene lung non-small cell carcinoma DOID:3908 risk 60033-8 PubMed:21258250 In a retrospective study, 166 non-small cell lung cancer (NSCLC) patients that tended to have selected characteristics known to be predictive for TKI sensitivity (i.e. women, never smokers, and patients with ADC) were treated with either gefitinib or erlotinib. PIK3CA mutations (n=6) were associated with no difference in objective response to drug treatment (16.6% vs. 35.2%, p=0.61), shorter overall survival (9.9 vs. 30.2 months, p<0.001), and shorter median time to progression (2.3 vs. 6.0 months, p=0.01) when compared to wild-type PIK3CA. Through multivariate analyses, it was shown that PIK3CA mutations are significant predictors of worse overall survival (HR: 5.81, 95% CI: 2.43-13.91, p=0.0001) and shorter time to progression (HR: 2.71 95% CI: 1.23-4.79, p=0.03). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2240 check_entity AN5599-9 PIK3CA Mutation PIK3CA NCBI:5290 gene lung non-small cell carcinoma DOID:3908 risk 60033-8 CIViC:307 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2240 check_entity AN5599-10 PIK3CA Mutation PIK3CA NCBI:5290 gene stomach cancer DOID:10534 risk 60033-8 PubMed:24088382 In a panel of 22 gastric cancer cell lines, 4 of 6 cell lines having the highest sensitivity to AZD5363 contained a PIK3CA mutation (E542K, E453K, E545K). A patient derived gastric cancer xenograft mouse model was established with PIK3CA H1047R mutant cells, and treatment with AZD5363 induced significant tumor growth inhibition in comparison to vehicle control. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2241 check_entity AN5599-10 PIK3CA Mutation PIK3CA NCBI:5290 gene stomach cancer DOID:10534 risk 60033-8 CIViC:307 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3CA/NCBI:5290 2241 check_entity AN5600-1 PIK3CA N345K mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 PubMed:20619739 Three patients participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had tumors which harbored PIK3CA N345K, were wildtype for KRAS, BRAF and NRAS, and had individual response data. Patient characteristics are as follows: a 48 year old female treated with cetuximab + irinotecan as 3rd line therapy who experienced stable disease (PFS: 72 weeks, OS: 105 weeks); a 46 year old male treated with cetuximab monotherapy as 5th line therapy who experienced stable disease (PFS: 24 weeks, OS: 57 weeks); a 61 year old female treated with cetuximab + irinotecan as 3rd line therapy who experienced progressive disease (PFS: 12 weeks, OS: 45 weeks). The response rate was 0/3 and the clinical benefit rate was 2/3 according to author criteria. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N345K sequence variation in gene PIK3CA/NCBI:5290 2242 check_entity AN5600-1 PIK3CA N345K mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 CIViC:904 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N345K sequence variation in gene PIK3CA/NCBI:5290 2242 check_entity AN5601-1 PIK3CA P471L mutation PIK3CA NCBI:5290 gene Merkel cell carcinoma DOID:3965 risk 60033-8 PubMed:26466009 A case report of an 86-year old patient with metastasized Merkel cell carcinoma who achieved a complete clinical response under therapy with the PI3K-inhibitor Idelalisib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P471L sequence variation in gene PIK3CA/NCBI:5290 2243 check_entity AN5601-1 PIK3CA P471L mutation PIK3CA NCBI:5290 gene Merkel cell carcinoma DOID:3965 risk 60033-8 CIViC:290 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P471L sequence variation in gene PIK3CA/NCBI:5290 2243 check_entity AN5602-1 PIK3CA Q546K mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 PubMed:20619739 One patient participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had a tumor which harbored PIK3CA Q546K (exon 10), was wildtype for KRAS, BRAF and NRAS, and had individual response data. This patient was was a 75 year old female treated with cetuximab and irinotecan as 2nd line therapy (discontinued for toxic/biochemical reasons) who experienced a partial response (PFS: 43 weeks, OS: 57 weeks). Using clinical data compiled from the larger cohort, authors concluded that PIK3CA exon 10 (listed as exon 9 in the source) mutations predict weak or no resistance to cetuximab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q546K sequence variation in gene PIK3CA/NCBI:5290 2244 check_entity AN5602-1 PIK3CA Q546K mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 CIViC:859 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q546K sequence variation in gene PIK3CA/NCBI:5290 2244 check_entity AN5603-1 PIK3CA R88Q mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 PubMed:20619739 One patient participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had a tumor which harbored PIK3CA R88Q, was wildtype for KRAS, BRAF and NRAS, and had individual response data. This patient was was a 56 year old female treated with cetuximab and irinotecan as 2nd line therapy who experienced a partial response (PFS: 32 weeks, OS: 32 weeks). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R88Q sequence variation in gene PIK3CA/NCBI:5290 2245 check_entity AN5603-1 PIK3CA R88Q mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 CIViC:903 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R88Q sequence variation in gene PIK3CA/NCBI:5290 2245 check_entity AN5604-1 PIK3CA R93W mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 PubMed:20619739 One patient participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had a tumor which harbored PIK3CA R93W, was wildtype for KRAS, BRAF and NRAS, and had individual response data. This patient was was a 56 year old male treated with cetuximab + oxaliplatin + 5FU as 2nd line therapy who experienced progressive disease (PFS: 8 weeks). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R93W sequence variation in gene PIK3CA/NCBI:5290 2246 check_entity AN5604-1 PIK3CA R93W mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 CIViC:1152 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R93W sequence variation in gene PIK3CA/NCBI:5290 2246 check_entity AN5605-1 PIK3CA Rare Mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 prognostic 60033-8 PubMed:19671852 Prognostic significance of PIK3CA mutations was evaluated in a retrospective study of 590 patients with surgically resected invasive breast cancer. Tumors harboring rare PIK3CA mutations (N345K: 2.4%, C420R: 1.2%, E545A: 1.2%, E545Q: 0.3%, E545G: 0.3%, Q546R: 0.7%, Q546P: 0.2%, H1047L: 2.2%) were significantly associated with lower grade, HER2 negativity, and lymph-node negative status compared with WT. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rare:mutation sequence variation in gene PIK3CA/NCBI:5290 2247 check_entity AN5605-1 PIK3CA Rare Mutation PIK3CA NCBI:5290 gene breast cancer DOID:1612 prognostic 60033-8 CIViC:3091 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rare:mutation sequence variation in gene PIK3CA/NCBI:5290 2247 check_entity AN5606-1 PIK3CA S158L mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 PubMed:20619739 One patient participating in a large retrospective study of cetuximab in metastatic, treatment refractory colorectal cancer had a tumor which harbored PIK3CA S158L, was wildtype for KRAS, BRAF and NRAS, and had individual response data. This patient was was a 53 year old male treated with cetuximab + irinotecan as 3rd line therapy who experienced progressive disease (PFS: 1 week; OS: 3 weeks). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S158L sequence variation in gene PIK3CA/NCBI:5290 2248 check_entity AN5606-1 PIK3CA S158L mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 CIViC:1407 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S158L sequence variation in gene PIK3CA/NCBI:5290 2248 check_entity AN5607-1 PIK3CA V955G mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 PubMed:28424201 A cohort of 32 colorectal cancer patients with acquired resistance to cetuximab (PFS > 12 weeks) was analyzed for resistance mutations using targeted deep sequencing of ctDNA. One patient had the PIK3CA p.V955G mutation. Cell viability studies of DiFi cells transfected with this PIK3CA variant confirmed resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V955G sequence variation in gene PIK3CA/NCBI:5290 2249 check_entity AN5607-1 PIK3CA V955G mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 CIViC:3536 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V955G sequence variation in gene PIK3CA/NCBI:5290 2249 check_entity AN5608-1 PIK3CA V955I mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 PubMed:28424201 Among 32 colorectal cancer patients with acquired resistance (PFS > 12 weeks) to cetuximab, one was determined to have V955I mutation. V995I allelic fractions low at start of treatment but increased in frequency during treatment. PolyPhen-2 and SIFT functional predict folding changes to activation-loop domain. DiFi cells transfected with PIK3CA V955I plasmid assayed with western blot for pAKT (phosphorylated AKT) and pERK showed increased phosphorylation, which was not affected by the addition of cetuximab. PIK3CA V955I transfected cells also promoted cell viability in the presence of cetuximab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V955I sequence variation in gene PIK3CA/NCBI:5290 2250 check_entity AN5608-1 PIK3CA V955I mutation PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 CIViC:2870 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V955I sequence variation in gene PIK3CA/NCBI:5290 2250 check_entity AN5609-1 PIK3CA Wildtype PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 PubMed:23094721 This was a retrospective study of 964 colorectal cancer patients who participated in the Nurses' Health Study and the Health Professionals Follow-up Study. Of 964 patients, 803 patients had wildtype PIK3CA (aspirin use: 337/803, no aspirin use: 466/803) and 161 had mutated PIK3CA (aspirin use: 66/161, no aspirin use: 95/161). Among patients with wild-type PIK3CA, regular use of aspirin after diagnosis was not significantly associated with increased survival. The 5-year cumulative colorectal cancer specific mortality was the same (15%) for users and nonusers of aspirin after diagnosis (P = 0.92). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PIK3CA Wildtype [biomarker_term_in_review] 2251 not_mapped AN5609-1 PIK3CA Wildtype PIK3CA NCBI:5290 gene colorectal cancer DOID:9256 risk 60033-8 CIViC:2463 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PIK3CA Wildtype [biomarker_term_in_review] 2251 not_mapped AN5610-1 PIK3R1 Mutation PIK3R1 NCBI:5295 gene breast cancer DOID:1612 risk PubMed:21358673 Sensitivity to mTORC1/2 inhibitor PP242 was assessed in a panel of breast cancer cell lines with various mutation backgrounds. PTEN and PIK3CA mutations were heavily represented in the panel. However, a PTEN and PIK3CA wild type cell line 'HS578T' was found to harbor a mutation in the PI3K regulatory protein PIK3R1. Like PIK3CA mutant cell lines, the PIK3R1 mutant HS578T line was also determined to be sensitive to PP242. Approximately 70% of PIK3CA wild type lines were not sensitive to PP242. This suggests that mutations in the PI3K holoenzyme may be targetable by mTORC1/2 inhibition. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3R1/NCBI:5295 2252 check_entity AN5610-1 PIK3R1 Mutation PIK3R1 NCBI:5295 gene breast cancer DOID:1612 risk CIViC:629 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PIK3R1/NCBI:5295 2252 check_entity AN5611-1 PIK3R2 N561D mutation PIK3R2 NCBI:5296 gene melanoma DOID:1909 risk PubMed:24265155 An in vitro study of WM2664 (a human melanoma cell line) endogenously expressing wildtype PIK3R2 and BRAF V600D (a known BRAF inhibitor sensitizing mutation) found that cells virally induced to stably over-express PIK3R2 N561D were significantly more resistant to vemurafenib (a BRAF inhibitor) than cells transduced with an empty vector (40% vs 0% survival at the highest concentration, p < .0001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N561D sequence variation in gene PIK3R2/NCBI:5296 2253 check_entity AN5611-1 PIK3R2 N561D mutation PIK3R2 NCBI:5296 gene melanoma DOID:1909 risk CIViC:1560 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N561D sequence variation in gene PIK3R2/NCBI:5296 2253 check_entity AN5612-1 PIK3R2 Overexpression PIK3R2 NCBI:5296 gene melanoma DOID:1909 risk PubMed:24265155 An in vitro study of WM2664 (a human melanoma cell line) endogenously expressing wildtype PIK3R2 and BRAF V600D (a known BRAF inhibitor sensitizing mutation) found that cells induced to stably over-express PIK3R2 (via viral transduction with additional copies of wildtype PIK3R2) were not significantly more resistant to vemurafenib (a BRAFi) than cells transduced with empty vectors, which served as the negative controls. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene PIK3R2/NCBI:5296 2254 AN5612-1 PIK3R2 Overexpression PIK3R2 NCBI:5296 gene melanoma DOID:1909 risk CIViC:2236 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene PIK3R2/NCBI:5296 2254 AN5613-1 PIM1 L2V mutation PIM1 NCBI:5292 gene diffuse large B-cell lymphoma activated B-cell type DOID:0080996 risk PubMed:27904766 Foundation panel results of baseline tumour samples from 48 patients with diffuse large B cell lymphoma identified PIM1 mutations in 6 patient samples, 5 of which were the DLBCL-ABC subtype. Four out of the 5 DLBCL-ABC patients with PIM1 mutations had stable disease or progressive disease when treated with ibrutinib, suggesting innate resistance to ibrutinib therapy. Three PIM1 mutations L2V, P81S, and S97N were investigated in cell lines studies. Cells transduced with L2V, P81S, and S97N were resistant to ibrutinib compared to cells transduced with wild type PIM1. Combined treatment of PIM1 mutant lines with ibrutinib and a pan-PIM inhibitor, AZD-1208, partially rescued sensitivity to ibrutinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L2V sequence variation in gene PIM1/NCBI:5292 2255 check_entity AN5613-1 PIM1 L2V mutation PIM1 NCBI:5292 gene diffuse large B-cell lymphoma activated B-cell type DOID:0080996 risk CIViC:3511 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L2V sequence variation in gene PIM1/NCBI:5292 2255 check_entity AN5614-1 PIM1 NUCLEAR EXPRESSION PIM1 NCBI:5292 gene lung non-small cell carcinoma DOID:3908 prognostic PubMed:26918046 The expression of PIM1, p-STAT3, and c-MYC was tested (IHC) in 194 NSCLC archival tumor samples. High nuclear expression of PIM1 was detected in 43.3% of cases and was significantly correlated with advanced clinical stage (p<0.001) and poor pathologic differentiation (P = 0.004) and was an independent unfavorable prognostic factors for overall and disease-free survival (OS, P=0.009; DFS, P=0.034). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene PIM1/NCBI:5292 2256 AN5614-1 PIM1 NUCLEAR EXPRESSION PIM1 NCBI:5292 gene lung non-small cell carcinoma DOID:3908 prognostic CIViC:490 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene PIM1/NCBI:5292 2256 AN5615-1 PIM1 P81S mutation PIM1 NCBI:5292 gene diffuse large B-cell lymphoma activated B-cell type DOID:0080996 risk PubMed:27904766 Foundation panel results of baseline tumour samples from 48 patients with diffuse large B cell lymphoma identified PIM1 mutations in 6 patient samples, 5 of which were the DLBCL-ABC subtype. Four out of the 5 DLBCL-ABC patients with PIM1 mutations had stable disease or progressive disease when treated with ibrutinib, suggesting innate resistance to ibrutinib therapy. Three PIM1 mutations L2V, P81S, and S97N were investigated in cell lines studies. Cells transduced with L2V, P81S, and S97N were resistant to ibrutinib compared to cells transduced with wild type PIM1. Combined treatment of PIM1 mutant lines with ibrutinib and a pan-PIM inhibitor, AZD-1208, partially rescued sensitivity to ibrutinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P81S sequence variation in gene PIM1/NCBI:5292 2257 check_entity AN5615-1 PIM1 P81S mutation PIM1 NCBI:5292 gene diffuse large B-cell lymphoma activated B-cell type DOID:0080996 risk CIViC:3512 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P81S sequence variation in gene PIM1/NCBI:5292 2257 check_entity AN5616-1 PIM1 S97N mutation PIM1 NCBI:5292 gene diffuse large B-cell lymphoma activated B-cell type DOID:0080996 risk PubMed:27904766 Foundation panel results of baseline tumour samples from 48 patients with diffuse large B cell lymphoma identified PIM1 mutations in 6 patient samples, 5 of which were the DLBCL-ABC subtype. Four out of the 5 DLBCL-ABC patients with PIM1 mutations had stable disease or progressive disease when treated with ibrutinib, suggesting innate resistance to ibrutinib therapy. Three PIM1 mutations L2V, P81S, and S97N were investigated in cell lines (TMD8) studies. Cells transduced with L2V, P81S, and S97N were resistant to ibrutinib compared to cells transduced with wild type PIM1. Combined treatment of PIM1 mutant lines with ibrutinib and a pan-PIM inhibitor, AZD-1208, partially rescued sensitivity to ibrutinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S97N sequence variation in gene PIM1/NCBI:5292 2258 check_entity AN5616-1 PIM1 S97N mutation PIM1 NCBI:5292 gene diffuse large B-cell lymphoma activated B-cell type DOID:0080996 risk CIViC:3513 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S97N sequence variation in gene PIM1/NCBI:5292 2258 check_entity AN5617-1 PLCG2 MUTATION PLCG2 NCBI:5336 gene chronic lymphocytic leukemia DOID:1040 prognostic 99128-1 PubMed:24869598 Whole exome sequencing was performed on baseline and relapse samples from six patients with CLL. One relapse sample had mutations in BTK and PLCG2, and a second relapse sample only had a mutation in PLCG2. Both samples with PLCG2 mutations had a mutation at R665W. Mutations in PLCG2 at L845F and S707Y were observed in the relapse samples with an additional BTK C481S mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PLCG2/NCBI:5336 2259 check_entity AN5617-1 PLCG2 MUTATION PLCG2 NCBI:5336 gene chronic lymphocytic leukemia DOID:1040 prognostic 99128-1 CIViC:2046 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PLCG2/NCBI:5336 2259 check_entity AN5618-1 PML B2 DOMAIN MUTATION PML NCBI:5371 gene acute promyelocytic leukemia DOID:0060318 risk PubMed:23670176 Mutations in the B2 domain of PML in the PML-RARa fusion have been shown to be associated with resistance to standard ATRA treatment in patients with acute promyelocytic leukemia. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::b2:domain:mutation sequence variation in gene PML/NCBI:5371 2260 check_entity AN5618-1 PML B2 DOMAIN MUTATION PML NCBI:5371 gene acute promyelocytic leukemia DOID:0060318 risk CIViC:457 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::b2:domain:mutation sequence variation in gene PML/NCBI:5371 2260 check_entity AN5619-1 PML PML::RARA A216V PML NCBI:5371 gene acute promyelocytic leukemia DOID:0060318 risk PubMed:21613260 The mutation A216V in the B2 domain of PML in the PML-RARa fusion was seen in a patient with ATRA-resistant acute promyelocytic leukemia. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A216V sequence variation in gene PML/NCBI:5371 2261 check_entity AN5619-1 PML PML::RARA A216V PML NCBI:5371 gene acute promyelocytic leukemia DOID:0060318 risk PubMed:26537301 Five point mutations were identified in the PML B2 domain of PML-RARA transcripts in 9 patients diagnosed with APL and resistant to arsenic. DNA from these 9 patients was cloned into flag-tagged pCag expression vectors. Immunoblotting analyses demonstrated that after the addition of arsenic, the A216V, S214L, and A216T mutants experienced no change in expression or degradation when compared to wild type cells, indicating that these mutants were not inhibited by arsenic and demonstrate resistance. Immunofluorescent measurements indicated arsenic treatment did not alter the nuclear localization pattern of mutants A216V, S214L, or A216T, but had an effect on the localization of other mutants as well as wild type cells. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A216V sequence variation in gene PML/NCBI:5371 2261 check_entity AN5619-1 PML PML::RARA A216V PML NCBI:5371 gene acute promyelocytic leukemia DOID:0060318 risk CIViC:458 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A216V sequence variation in gene PML/NCBI:5371 2261 check_entity AN5620-1 PML PML::RARA L218P PML NCBI:5371 gene acute promyelocytic leukemia DOID:0060318 risk PubMed:21613260 The PML L218P mutation in the PML-RARa fusion was observed in a patient with previously ATRA-treated, relapsed acute promyelocytic leukemia refractory to arsenic trioxide. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L218P sequence variation in gene PML/NCBI:5371 2262 check_entity AN5620-1 PML PML::RARA L218P PML NCBI:5371 gene acute promyelocytic leukemia DOID:0060318 risk CIViC:459 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L218P sequence variation in gene PML/NCBI:5371 2262 check_entity AN5621-1 PML PML::RARA mutation PML NCBI:5371 gene acute promyelocytic leukemia DOID:0060318 diagnostic;risk PubMed:8674046 Fusion protein degradation is accelerated upon ATRA treatment of acute promyelocytic cells at pharmalogical concentrations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PML::RARA sequence variation in gene PML/NCBI:5371 2263 check_entity AN5621-1 PML PML::RARA mutation PML NCBI:5371 gene acute promyelocytic leukemia DOID:0060318 diagnostic;risk PubMed:7628753 The presence of the PML-RARa fusion protein is a diagnostic marker of Acute Promyelocytic Leukemia, or M3 AML. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PML::RARA sequence variation in gene PML/NCBI:5371 2263 check_entity AN5621-1 PML PML::RARA mutation PML NCBI:5371 gene acute promyelocytic leukemia DOID:0060318 diagnostic;risk PubMed:11704842 ATRA/Arsenic combined with standard chemotherapy has been shown to induce a complete remission rate of greater than 75% of patients with acute promyelocytic leukemia harboring the PML-RARa fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PML::RARA sequence variation in gene PML/NCBI:5371 2263 check_entity AN5621-1 PML PML::RARA mutation PML NCBI:5371 gene acute promyelocytic leukemia DOID:0060318 diagnostic;risk PubMed:21505136 A 39-year old woman who presented with acute myeloid leukemia revealed a complicated genetic profile using conventional metaphase cytogenetics and FISH analysis. Whole genome sequencing elucidated a PML-RARA fusion, which can be successfully treated with ATRA. Uncovering this mutation prevented an unnecessary allogeneic transplant and the patient remained in remission 15 months post-treatment (date of publication). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PML::RARA sequence variation in gene PML/NCBI:5371 2263 check_entity AN5621-1 PML PML::RARA mutation PML NCBI:5371 gene acute promyelocytic leukemia DOID:0060318 diagnostic;risk CIViC:108 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::PML::RARA sequence variation in gene PML/NCBI:5371 2263 check_entity AN5622-1 PMS2 K706FS*19 mutation PMS2 NCBI:5395 gene glioblastoma DOID:3068 risk 79419-8 PubMed:27001570 Two siblings (6 and 3.5 years) from nonconsanguineous parents were diagnosed with glioblastoma multiforme. Both tumors harbored TP53 mutations and lack of MGMT promoter hypermethylation as poor prognostic markers. Germline homozygous c.2117delA, p. Lys706SerfsX19 mutation in PMS2, loss of PMS2 staining in the tumor and normal tissue confirmed a diagnosis of biallelic mismatch repair deficiency (bMMRD). Both tumors harbored driver mutations in POLE and were found to harbor 24,680 and 21,919 mutations per exome. Neoantigen load was assessed in 37 bMMRD patients and all malignant tumors had high numbers of predicted neoantigens (7-16x as high as in melanoma, lung or other immunoresponsive cancers). Treatment with nivolumab was begun and both patients had radiologic response. After 9 and 5 months of therapy, respectively, the patient and her brother resumed normal schooling and daily activities. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::k706fs*19:mutation sequence variation in gene PMS2/NCBI:5395 2264 check_entity AN5622-1 PMS2 K706FS*19 mutation PMS2 NCBI:5395 gene glioblastoma DOID:3068 risk 79419-8 CIViC:504 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::k706fs*19:mutation sequence variation in gene PMS2/NCBI:5395 2264 check_entity AN5623-1 PMS2 R315* mutation PMS2 NCBI:5395 gene endometrial cancer DOID:1380 risk 79419-8 PubMed:25111426 This variant (R315*), identified in a case of microsatellite-unstable endometrial cancer, was confirmed to be somatic in a 69 year-old female patient with suspected Lynch Syndrome (LS). The patient was therefore negative for LS, which is by definition a germline condition. This patient also harbored MLH1 M490T, MSH2 E483G, and MSH6 V352I mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R315* sequence variation in gene PMS2/NCBI:5395 2265 check_entity AN5623-1 PMS2 R315* mutation PMS2 NCBI:5395 gene endometrial cancer DOID:1380 risk 79419-8 CIViC:749 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R315* sequence variation in gene PMS2/NCBI:5395 2265 check_entity AN5624-1 POLD1 C284Y mutation POLD1 NCBI:5424 gene lung adenocarcinoma DOID:3910 risk PubMed:25765070 In a retrospective study of 34 non-small cell lung cancer patients, a lung adenocarcinoma patient with POLD1 deleterious (as determined by Polyphen or SIFT) C284Y mutation and a high nonsynonymous mutation burden, treated with pembrolizumab monotherapy, was associated with a durable clinical benefit; POLD1 deleterious mutation was not identified in any patients who did not experience a durable clinical benefit. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C284Y sequence variation in gene POLD1/NCBI:5424 2266 check_entity AN5624-1 POLD1 C284Y mutation POLD1 NCBI:5424 gene lung adenocarcinoma DOID:3910 risk CIViC:1555 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C284Y sequence variation in gene POLD1/NCBI:5424 2266 check_entity AN5625-1 POLD1 E374K mutation POLD1 NCBI:5424 gene lung non-small cell carcinoma DOID:3908 risk PubMed:25765070 In a retrospective study of 34 non-small cell lung cancer patients, a patient, who never smoked, with POLD1 deleterious E374K mutation (as determined by Polyphen or SIFT) and a high nonsynonymous mutation burden, treated with pembrolizumab monotherapy, was associated with a durable clinical benefit; POLD1 deleterious mutation was not identified in patients who did not experience a durable clinical benefit. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E374K sequence variation in gene POLD1/NCBI:5424 2267 check_entity AN5625-1 POLD1 E374K mutation POLD1 NCBI:5424 gene lung non-small cell carcinoma DOID:3908 risk CIViC:1556 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E374K sequence variation in gene POLD1/NCBI:5424 2267 check_entity AN5626-1 POLE Mutation POLE NCBI:5426 gene endometrial cancer DOID:1380 risk PubMed:27159395 Case report of a patient with endometrial cancer and exceptional response to pembrolizumab (maintained at 14 months). POLE mutations V411L (exonuclease domain) and R114* were identified in the primary tumor as well as a resected lymph node metastasis. The tumor harbored a high mutational load as assessed by panel sequencing. Analysis of TCGA RNA-seq data revealed an association between POLE mutations and high immune marker expression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene POLE/NCBI:5426 2268 check_entity AN5626-1 POLE Mutation POLE NCBI:5426 gene endometrial cancer DOID:1380 risk CIViC:775 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene POLE/NCBI:5426 2268 check_entity AN5626-2 POLE Mutation POLE NCBI:5426 gene glioblastoma DOID:3068 risk PubMed:27683556 Case report of a patient with glioblastoma multiforme and POLE germline mutation. The patient was treated with pembrolizumab and lymphocyte infiltration was noted after resection of a spinal metastasis. An objective radiographic response was noted in the intracranial lesion. A high neoantigen load was identified. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene POLE/NCBI:5426 2269 check_entity AN5626-2 POLE Mutation POLE NCBI:5426 gene glioblastoma DOID:3068 risk CIViC:775 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene POLE/NCBI:5426 2269 check_entity AN5627-1 POLE P286R mutation POLE NCBI:5426 gene colorectal cancer DOID:9256 prognostic PubMed:28404093 POLE proofreading domain mutations identify a subset of immunogenic colorectal cancers with excellent prognosis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P286R sequence variation in gene POLE/NCBI:5426 2270 check_entity AN5627-1 POLE P286R mutation POLE NCBI:5426 gene colorectal cancer DOID:9256 prognostic CIViC:1706 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P286R sequence variation in gene POLE/NCBI:5426 2270 check_entity AN5628-1 POLE S459F mutation POLE NCBI:5426 gene colorectal cancer DOID:9256 prognostic PubMed:28404093 POLE proofreading domain mutations identify a subset of immunogenic colorectal cancers with excellent prognosis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S459F sequence variation in gene POLE/NCBI:5426 2271 check_entity AN5628-1 POLE S459F mutation POLE NCBI:5426 gene colorectal cancer DOID:9256 prognostic CIViC:1708 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S459F sequence variation in gene POLE/NCBI:5426 2271 check_entity AN5629-1 POLE V411L mutation POLE NCBI:5426 gene colorectal cancer DOID:9256 prognostic PubMed:28404093 POLE proofreading domain mutations identify a subset of immunogenic colorectal cancers with excellent prognosis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V411L sequence variation in gene POLE/NCBI:5426 2272 check_entity AN5629-1 POLE V411L mutation POLE NCBI:5426 gene colorectal cancer DOID:9256 prognostic CIViC:1707 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V411L sequence variation in gene POLE/NCBI:5426 2272 check_entity AN5630-1 POT1 MUTATION POT1 NCBI:25913 gene chronic lymphocytic leukemia DOID:1040 prognostic PubMed:27226433 In previously untreated patients with chronic lymphocytic leukemia, POT1 mutations (N=13) were associated with shorter overall survival than wildtype POT1 (N=148) in univariate and multivariate analysis (HR, 4.0; 95% CI, 1.6-10.1; P = .003) independent of IGHV mutation status, Binet stage, and serum beta-2-microglobulin. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene POT1/NCBI:25913 2273 check_entity AN5630-1 POT1 MUTATION POT1 NCBI:25913 gene chronic lymphocytic leukemia DOID:1040 prognostic CIViC:619 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene POT1/NCBI:25913 2273 check_entity AN5631-1 POU5F1 EXPRESSION POU5F1 NCBI:5460 gene colon cancer DOID:219 risk PubMed:26398480 OCT4B1 (POU5F1 splice variant) expression reduced sensitivity to oxaliplatin (via P-gp and ABCG2 differential expression) in vitro. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene POU5F1/NCBI:5460 2274 AN5631-1 POU5F1 EXPRESSION POU5F1 NCBI:5460 gene colon cancer DOID:219 risk CIViC:408 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene POU5F1/NCBI:5460 2274 AN5632-1 PPP1R15A RS557806 mutation PPP1R15A NCBI:23645 gene colorectal cancer DOID:9256 risk PubMed:27177629 Exome and RNA sequencing was performed in tumor and matched normal tissue of 19 patients with metastatic colorectal cancer treated with chemotherapy and bevacizumab. The variant PPP1R15A (rs557806) showed the most significant association (P = 0.000401) with FOLFIRI-bevacizumab-driven tumor inhibition rate in exome sequencing data and the highest correlation (r = 0.74) with the drug responses in RNA sequencing data. Patients who were homozygous for the reference alleles (GG) of PPP1R15A rs557806 exhibited greater disease control rates and a tendency toward greater overall response rate than those with homozygous or heterozygous substitution alleles (GC and CC; P = 0.027 and 0.073) when treated with bevacizumab-containing regimens. PPP1R15A rs557806 nonsignificantly correlated with DCR in multivariate analysis (P = 0.054). In HCT116 xenograft tumors, tumor growth IR with FRB was 25 % in mock cells, 24 % in clones with reference alleles (G alleles) of PPP1R15A rs557806, and 17 % in clones with substitution alleles (C alleles) of PPP1R15A rs557806 (P = 0.004, day 13). FDG-PET imaging on day 7 showed FDG uptake (mean SUV max) of 0.219 and 0.500 in HCT116 xenografts expressing the reference allele (G) and substitution allele (C) of PPP1R15A rs557806, respectively (P = 0.032). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS557806 sequence variation in gene PPP1R15A/NCBI:23645 2275 check_entity AN5632-1 PPP1R15A RS557806 mutation PPP1R15A NCBI:23645 gene colorectal cancer DOID:9256 risk CIViC:544 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS557806 sequence variation in gene PPP1R15A/NCBI:23645 2275 check_entity AN5633-1 PPP2R2A Mutation PPP2R2A NCBI:5520 gene castration-resistant prostate carcinoma DOID:0080909 risk PubMed:32343890 This randomized, open-label, phase 3 trial evaluated the PARP inhibitor olaparib in 387 men with metastatic castration-resistant prostate cancer (mCRPC) who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). The study found that in men with mCRPC who had somatic or germline deleterious alterations (irrespective of zygosity) in any of the following HRR genes (BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L), olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone (PFS HR 0.49 [0.38, 0.63]). For 15 patients with PPP2R2A mutations specifically, PFS HR 6.61 [1.41-46.41]. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PPP2R2A/NCBI:5520 2276 check_entity AN5633-1 PPP2R2A Mutation PPP2R2A NCBI:5520 gene castration-resistant prostate carcinoma DOID:0080909 risk CIViC:4387 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PPP2R2A/NCBI:5520 2276 check_entity AN5634-1 PRDM1 MUTATION PRDM1 NCBI:639 gene diffuse large B-cell lymphoma DOID:0050745 prognostic PubMed:27568520 Biopsies from 520 DLBCL patients treated with R-CHOP were evaluated for PRDM1 mutations or protein (BLIMP-1) expression. Patients with a homozygous deletion of PRDM1 (7%, N=19) had a significantly shorter overall survival and poorer progression free survival compared to heterozygous or wildtype PRDM1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PRDM1/NCBI:639 2277 check_entity AN5634-1 PRDM1 MUTATION PRDM1 NCBI:639 gene diffuse large B-cell lymphoma DOID:0050745 prognostic CIViC:640 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PRDM1/NCBI:639 2277 check_entity AN5635-1 PREX2 R172I mutation PREX2 NCBI:80243 gene melanoma DOID:1909 risk PubMed:24265155 In a retrospective study of 44 relapsed melanoma patients harboring BRAF V600E/K (known BRAF inhibitor sensitizing mutations), PREX2 R172I was associated with a case of acquired resistance to BRAF inhibitor (vemurafenib) monotherapy in one patient. This patient was an 83 year old male with stage IV M1c melanoma who took vemurafenib (960mg twice daily). The best overall response was a 5% increase in sum of target lesions, and progression free survival lasted 132 days. Prior to vemurafenib monotherapy, this patient harbored BRAF V600K and no other somatic genetic alterations noted in the baseline tumor. Following relapse, the patient gained PREX2 R172I in one of two disease progressive tumors. Whole exome sequencing and Sanger re-sequencing were used for all tumors. The authors indicated that the biology behind this potential resistance mutation was unknown. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R172I sequence variation in gene PREX2/NCBI:80243 2278 check_entity AN5635-1 PREX2 R172I mutation PREX2 NCBI:80243 gene melanoma DOID:1909 risk CIViC:2237 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R172I sequence variation in gene PREX2/NCBI:80243 2278 check_entity AN5636-1 PRKAA2 T172 PHOSPHORYLATION PRKAA2 NCBI:5563 gene cancer DOID:162 risk PubMed:23506848 Low levels of baseline p-AMPK (PRKAA2, measured at Thr172) were predictive of efficacy of ACLY inhibition by siRNA in cell lines of various cancer histologies. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PRKAA2 T172 PHOSPHORYLATION [biomarker_term_in_review] 2279 not_mapped AN5636-1 PRKAA2 T172 PHOSPHORYLATION PRKAA2 NCBI:5563 gene cancer DOID:162 risk CIViC:381 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PRKAA2 T172 PHOSPHORYLATION [biomarker_term_in_review] 2279 not_mapped AN5637-1 PRKACA DNAJB1::PRKACA mutation PRKACA NCBI:5566 gene fibrolamellar carcinoma DOID:5015 diagnostic PubMed:24578576 A head-to-tail in-frame fusion between exon1 of DNAJB1 and exon2 of PRKACA resulting from a ~400kb deletion was observed in 100% (15/15) fibrolamellar hepatocellular carcinomas examined. The fusion was confirmed at both RNA and DNA level in all primary and metastatic tumor samples but not in adjacent normal tissue. Immunoprecipitation and Western blot analyses confirmed that the chimeric protein is expressed in tumor tissue, and a cell culture assay indicated that it retains kinase activity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::DNAJB1::PRKACA sequence variation in gene PRKACA/NCBI:5566 2280 check_entity AN5637-1 PRKACA DNAJB1::PRKACA mutation PRKACA NCBI:5566 gene fibrolamellar carcinoma DOID:5015 diagnostic PubMed:25698061 RT-PCR and FISH assays were developed for the detection of rearrangements of the PRKACA locus. A total of 106 primary liver tumors were studied by RT-PCR (26 fibrolamellar carcinomas, 25 conventional hepatocellular carcinomas, 25 cholangiocarcinomas, 25 hepatic adenomas, and 5 hepatoblastomas). FISH was tested in 19 fibrolamellar carcinomas and in 6 scirrhous hepatocellular carcinomas. Evidence of the DNAJB1-PRKACA fusion was found in all fibrolamellar cases but not in other tumor types for both methods indicating that detection of DNAJB1-PRKACA is a very sensitive and specific finding in support of the diagnosis of fibrolamellar carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::DNAJB1::PRKACA sequence variation in gene PRKACA/NCBI:5566 2280 check_entity AN5637-1 PRKACA DNAJB1::PRKACA mutation PRKACA NCBI:5566 gene fibrolamellar carcinoma DOID:5015 diagnostic PubMed:25557953 The DNAJB1-PRKACA fusion was detected in 79% (58/73) of fibrolamellar hepatocellular carcinomas assayed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::DNAJB1::PRKACA sequence variation in gene PRKACA/NCBI:5566 2280 check_entity AN5637-1 PRKACA DNAJB1::PRKACA mutation PRKACA NCBI:5566 gene fibrolamellar carcinoma DOID:5015 diagnostic CIViC:31 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::DNAJB1::PRKACA sequence variation in gene PRKACA/NCBI:5566 2280 check_entity AN5637-2 PRKACA DNAJB1::PRKACA mutation PRKACA NCBI:5566 gene mixed fibrolamellar hepatocellular carcinoma DOID:0080182 diagnostic PubMed:27029710 A DNAJB1:PRKACA fusion transcript was detected at very high expression levels by RNA-Seq in a case of mixed fibrolamellar hepatocellular carcinoma. Subsequent analysis revealed the presence of this fusion in all primary and metastatic samples, including those with mixed or conventional HCC pathology. A second case of mFL-HCC confirmed that the fusion was detectable in conventional components. An expanded screen of 112 additional HCC samples and 44 adjacent non-tumor liver samples was positive for a third case of HCC with both conventional and fibrolamellar features but negative for all conventional HCC and adjacent non-tumor liver samples. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::DNAJB1::PRKACA sequence variation in gene PRKACA/NCBI:5566 2281 check_entity AN5637-2 PRKACA DNAJB1::PRKACA mutation PRKACA NCBI:5566 gene mixed fibrolamellar hepatocellular carcinoma DOID:0080182 diagnostic CIViC:31 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::DNAJB1::PRKACA sequence variation in gene PRKACA/NCBI:5566 2281 check_entity AN5638-1 PRKCB D427N mutation PRKCB NCBI:5579 gene adult T-cell leukemia/lymphoma DOID:0050523 diagnostic PubMed:26437031 PRKCB was mutated in 33% of ATLL cases. 93% of these mutations were within the catalytic domain at Asp427. This gene has not been reported to be significantly mutated in any other cancers. Indeed this is the first known example in any cancer that appears to involve activation by the PKC gene family. Nearly all occurrences of this mutation in COSMIC correspond to ATLL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D427N sequence variation in gene PRKCB/NCBI:5579 2282 check_entity AN5638-1 PRKCB D427N mutation PRKCB NCBI:5579 gene adult T-cell leukemia/lymphoma DOID:0050523 diagnostic CIViC:2341 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D427N sequence variation in gene PRKCB/NCBI:5579 2282 check_entity AN5639-1 PROM1 EXPRESSION PROM1 NCBI:8842 gene hepatocellular carcinoma DOID:684 risk PubMed:22596232 CD133 (PROM1) expression in 39 samples of hepatocellular carcinomas was correlated with JNK activity. Both were more highly expressed in patients not responding to sorafenib. CD133+ cells (sorted) were xenografted into mice, producing larger, more JNK inhibitor responsive tumors than CD133- xenografts. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene PROM1/NCBI:8842 2283 AN5639-1 PROM1 EXPRESSION PROM1 NCBI:8842 gene hepatocellular carcinoma DOID:684 risk CIViC:389 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene PROM1/NCBI:8842 2283 AN5640-1 PRPS1 A190T mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 prognostic;risk PubMed:25962120 PRPS1 exons were sequenced in the diagnosis and relapse samples of 358 B-Cell Childhood Acute Lymphoblastic Leukemia relapse patients (138 Chinese and 220 German). PRPS1 A190T was detected only at relapse in 10 (8 Chinese; 2 German) cases, which all relapsed early while on therapy (Chinese 8/8, 100% vs. WT PRPS1 77/120 (64%); German 2/2 (100%) vs. WT PRPS1 79/214 (37%)). Based on protocols cited and the time to relapse, all 10 relapses harboring PRPS1 A190T were exposed to maintenance therapy that consisted of daily doses of thiopurine (mercaptopurine or thioguanine) treatment. A190T could drive clonal outgrowth through the promotion of thiopurine resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A190T sequence variation in gene PRPS1/NCBI:5631 2284 check_entity AN5640-1 PRPS1 A190T mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 prognostic;risk CIViC:2798 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A190T sequence variation in gene PRPS1/NCBI:5631 2284 check_entity AN5641-1 PRPS1 A87T mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk PubMed:25962120 Lentiviral-mediated overexpression of PRPS1 A87T in Reh cells resulted in similar cytotoxic response (IC50 and apoptosis %) compared to controls (empty vector and wildtype PRPS1 overexpression) after treatment with mercaptopurine (6-MP) or thioguanine (6-TG). After 6-MP exposure, mass spectrometry revealed A87T cells possessed similar concentrations of intracellular 6-MP metabolites (TIMP, TGMP, etc.) versus controls. Intracellular concentrations of hypoxanthine and IMP were similar in A87T cells and controls. After 6-MP exposure, no difference in DNA damage response and apoptosis protein markers were observed between A87T cells and controls. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A87T sequence variation in gene PRPS1/NCBI:5631 2285 check_entity AN5641-1 PRPS1 A87T mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk CIViC:2808 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A87T sequence variation in gene PRPS1/NCBI:5631 2285 check_entity AN5642-1 PRPS1 C77S mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk PubMed:25962120 Lentiviral-mediated overexpression of PRPS1 C77S in Reh cells resulted in similar cytotoxic response to controls (empty vector and overexpression of known reduced-function PRPS1 mutants) after exposure to mercaptopurine or thioguanine. Based on the crystal structure of PRPS1, C77S is not in or near the allosteric site or dimer interface, which likely impedes the ability of the variant to impact thiopurine processing. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C77S sequence variation in gene PRPS1/NCBI:5631 2286 check_entity AN5642-1 PRPS1 C77S mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk CIViC:2805 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C77S sequence variation in gene PRPS1/NCBI:5631 2286 check_entity AN5643-1 PRPS1 D139G mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk PubMed:25962120 Lentiviral-mediated overexpression of PRPS1 D139G in Reh cells resulted in similar cytotoxic response to controls (empty vector and overexpression of known reduced-function PRPS1 mutants) after exposure to mercaptopurine or thioguanine. Based on the crystal structure of PRPS1, D139G is not in or near the allosteric site or dimer interface, which likely impedes the ability of the variant to impact thiopurine processing. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D139G sequence variation in gene PRPS1/NCBI:5631 2287 check_entity AN5643-1 PRPS1 D139G mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk CIViC:2804 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D139G sequence variation in gene PRPS1/NCBI:5631 2287 check_entity AN5644-1 PRPS1 D183E mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk PubMed:25962120 Lentiviral-mediated overexpression of PRPS1 D183E in Reh cells resulted in significant resistance against mercaptopurine (6-MP) and thioguanine (6-TG) as indicated by IC50 increases and reduced apoptosis compared to multiple controls (empty vector and overexpression of wildtype or known reduced-function PRPS1 mutants). 6-MP cytotoxicity results were confirmed using Jurkat cells. After 6-MP exposure, mass spectrometry revealed D183E cells possessed reduced concentrations of intracellular 6-MP metabolites (TIMP, TGMP, etc.) versus controls. D183E cells produce increased intracellular concentrations of hypoxanthine and IMP. Also, after 6-MP exposure, D183E cells display reduced levels of DNA damage response and apoptosis protein markers. The enhanced production of hypoxanthine likely leads to reduced conversion of thiopurines to their active form due to competitive inhibition. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D183E sequence variation in gene PRPS1/NCBI:5631 2288 check_entity AN5644-1 PRPS1 D183E mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk CIViC:2789 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D183E sequence variation in gene PRPS1/NCBI:5631 2288 check_entity AN5645-1 PRPS1 I72V mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk PubMed:25962120 Lentiviral-mediated overexpression of PRPS1 I72V in Reh cells resulted in similar cytotoxic response to controls (empty vector and overexpression of known reduced-function PRPS1 mutants) after exposure to mercaptopurine or thioguanine. Based on the crystal structure of PRPS1, I72V is not in or near the allosteric site or dimer interface, which likely impedes the ability of the variant to impact thiopurine processing. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I72V sequence variation in gene PRPS1/NCBI:5631 2289 check_entity AN5645-1 PRPS1 I72V mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk CIViC:2806 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I72V sequence variation in gene PRPS1/NCBI:5631 2289 check_entity AN5646-1 PRPS1 K176N mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk PubMed:25962120 Lentiviral-mediated overexpression of PRPS1 K176N in Reh cells resulted in significant resistance against mercaptopurine (6-MP) and thioguanine (6-TG) as indicated by IC50 increases and reduced apoptosis compared to multiple controls (empty vector and overexpression of wildtype or known reduced-function PRPS1 mutants). 6-MP cytotoxicity results were confirmed using Jurkat cells. After 6-MP exposure, mass spectrometry revealed K176N cells possessed reduced concentrations of intracellular 6-MP metabolites (TIMP, TGMP, etc.) versus controls. K176N cells produce increased intracellular concentrations of hypoxanthine and IMP. Also, after 6-MP exposure, K176N cells display reduced levels of DNA damage response and apoptosis protein markers. The enhanced production of hypoxanthine likely leads to reduced conversion of thiopurines to their active form due to competitive inhibition. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K176N sequence variation in gene PRPS1/NCBI:5631 2290 check_entity AN5646-1 PRPS1 K176N mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk CIViC:2790 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K176N sequence variation in gene PRPS1/NCBI:5631 2290 check_entity AN5647-1 PRPS1 L191F mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk PubMed:25962120 Lentiviral-mediated overexpression of PRPS1 L191F in Reh cells resulted in significant resistance against mercaptopurine (6-MP) and thioguanine (6-TG) as indicated by IC50 increases and reduced apoptosis compared to multiple controls (empty vector and overexpression of wildtype or known reduced-function PRPS1 mutants). 6-MP cytotoxicity results were confirmed using Jurkat cells. After 6-MP exposure, mass spectrometry revealed L191F cells possessed reduced concentrations of intracellular 6-MP metabolites (TIMP, TGMP, etc.) versus controls. L191F cells produce increased intracellular concentrations of hypoxanthine and IMP. Also, after 6-MP exposure, L191F cells display reduced levels of DNA damage response and apoptosis protein markers. The enhanced production of hypoxanthine likely leads to reduced conversion of thiopurines to their active form due to competitive inhibition. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L191F sequence variation in gene PRPS1/NCBI:5631 2291 check_entity AN5647-1 PRPS1 L191F mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk CIViC:2788 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L191F sequence variation in gene PRPS1/NCBI:5631 2291 check_entity AN5648-1 PRPS1 M115T mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk PubMed:25962120 Lentiviral-mediated overexpression of PRPS1 M115T in Reh cells resulted in similar cytotoxic response (IC50 and apoptosis %) compared to controls (empty vector and wildtype PRPS1 overexpression) after treatment with mercaptopurine (6-MP) or thioguanine (6-TG). After 6-MP exposure, mass spectrometry revealed M115T cells possessed similar concentrations of intracellular 6-MP metabolites (TIMP, TGMP, etc.) versus controls. Intracellular concentrations of hypoxanthine and IMP were similar in M115T cells and controls. After 6-MP exposure, no difference in DNA damage response and apoptosis protein markers were observed between M115T cells and controls. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M115T sequence variation in gene PRPS1/NCBI:5631 2292 check_entity AN5648-1 PRPS1 M115T mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk CIViC:2809 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M115T sequence variation in gene PRPS1/NCBI:5631 2292 check_entity AN5649-1 PRPS1 N144S mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk PubMed:25962120 Lentiviral-mediated overexpression of PRPS1 N144S in Reh cells resulted in significant resistance against mercaptopurine (6-MP) and thioguanine (6-TG) as indicated by IC50 increases and reduced apoptosis compared to multiple controls (empty vector and overexpression of wildtype or known reduced-function PRPS1 mutants). 6-MP cytotoxicity results were confirmed using Jurkat cells. After 6-MP exposure, mass spectrometry revealed N144S cells possessed reduced concentrations of intracellular 6-MP metabolites (TIMP, TGMP, etc.) versus controls. N144S cells produce increased intracellular concentrations of hypoxanthine and IMP. Also, after 6-MP exposure, N144S cells display reduced levels of DNA damage response and apoptosis protein markers. The enhanced production of hypoxanthine likely leads to reduced conversion of thiopurines to their active form due to competitive inhibition. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N144S sequence variation in gene PRPS1/NCBI:5631 2293 check_entity AN5649-1 PRPS1 N144S mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk CIViC:2792 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N144S sequence variation in gene PRPS1/NCBI:5631 2293 check_entity AN5650-1 PRPS1 PRPS1 MUTATION PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 prognostic PubMed:25962120 Sequencing revealed relapse specific PRPS1 mutations in 24/358 (6.7%) relapsed childhood B-ALL cases derived from multiple cohorts. In the Chinese cohort, 18/138 (13%) cases harbored relapse specific PRPS1 mutations. In the German cohort, 6/220 (6.7%) cases harbored relapse specific PRPS1 mutations. All patients with PRPS1 mutations relapsed early (< 36 months after initial diagnosis) (Chinese: 18/18 PRPS1 vs. 77/120 (64.2%) wildtype, p=.002; German: 6/6 PRPS1 vs. 79/214 (36.9%) wildtype, p<.001). All patients with PRPS1 mutations also relapsed while on therapy (Chinese: 18/18 PRPS1 vs. 77/120 (64.2%) wildtype, p<.001; German: 6/6 PRPS1 vs. 51/214 (23.8%) ( p<.001). Of the 24 cases, there were 17 unique PRPS1 mutations. Further experimental data demonstrated 12/17 mutations conferred resistance to thiopurines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PRPS1/NCBI:5631 2294 check_entity AN5650-1 PRPS1 PRPS1 MUTATION PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 prognostic CIViC:2785 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PRPS1/NCBI:5631 2294 check_entity AN5651-1 PRPS1 S103I mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk PubMed:25962120 Lentiviral-mediated overexpression of PRPS1 S103I in Reh cells resulted in significant resistance against mercaptopurine (6-MP) and thioguanine (6-TG) as indicated by IC50 increases and reduced apoptosis compared to multiple controls (empty vector and overexpression of wildtype or known reduced-function PRPS1 mutants). After 6-MP exposure, mass spectrometry revealed S103I cells possessed reduced concentrations of intracellular 6-MP metabolites (TIMP, TGMP, etc.) versus controls. S103I cells produce increased intracellular concentrations of hypoxanthine and IMP. The enhanced production of hypoxanthine likely leads to reduced conversion of thiopurines to their active form due to competitive inhibition. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S103I sequence variation in gene PRPS1/NCBI:5631 2295 check_entity AN5651-1 PRPS1 S103I mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk CIViC:2794 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S103I sequence variation in gene PRPS1/NCBI:5631 2295 check_entity AN5652-1 PRPS1 S103N mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk PubMed:25962120 Lentiviral-mediated overexpression of PRPS1 S103N in Reh cells resulted in significant resistance against mercaptopurine (6-MP) and thioguanine (6-TG) as indicated by IC50 increases and reduced apoptosis compared to multiple controls (empty vector and overexpression of wildtype or known reduced-function PRPS1 mutants). 6-MP cytotoxicity results were confirmed using Jurkat cells. After 6-MP exposure, mass spectrometry revealed S103N cells possessed reduced concentrations of intracellular 6-MP metabolites (TIMP, TGMP, etc.) versus controls. S103N cells produce increased intracellular concentrations of hypoxanthine and IMP. Also, after 6-MP exposure, S103N cells display reduced levels of DNA damage response and apoptosis protein markers. The enhanced production of hypoxanthine likely leads to reduced conversion of thiopurines to their active form due to competitive inhibition. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S103N sequence variation in gene PRPS1/NCBI:5631 2296 check_entity AN5652-1 PRPS1 S103N mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk CIViC:2795 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S103N sequence variation in gene PRPS1/NCBI:5631 2296 check_entity AN5653-1 PRPS1 S103T mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk PubMed:25962120 Lentiviral-mediated overexpression of PRPS1 S103T in Reh cells resulted in significant resistance against mercaptopurine (6-MP) and thioguanine (6-TG) as indicated by IC50 increases and reduced apoptosis compared to multiple controls (empty vector and overexpression of wildtype or known reduced-function PRPS1 mutants). 6-MP cytotoxicity results were confirmed using Jurkat cells. After 6-MP exposure, mass spectrometry revealed S103T cells possessed reduced concentrations of intracellular 6-MP metabolites (TIMP, TGMP, etc.) versus controls. S103T cells produce increased intracellular concentrations of hypoxanthine and IMP. Also, after 6-MP exposure, S103T cells display reduced levels of DNA damage response and apoptosis protein markers. S103T results in the activation of the de novo purine synthesis pathway by reducing feedback inhibition, allowing the cell to continue to create nucleotides even when concentrations are elevated. This overactivation creates increased hypoxanthine levels, which likely competitively inhibit thiopurine conversion. The enhanced production of hypoxanthine likely leads to reduced conversion of thiopurines to their active form due to competitive inhibition. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S103T sequence variation in gene PRPS1/NCBI:5631 2297 check_entity AN5653-1 PRPS1 S103T mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk CIViC:2796 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S103T sequence variation in gene PRPS1/NCBI:5631 2297 check_entity AN5654-1 PRPS1 T303S mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk PubMed:25962120 Lentiviral-mediated overexpression of PRPS1 T303S in Reh cells resulted in significant resistance against mercaptopurine (6-MP) and thioguanine (6-TG) as indicated by IC50 increases and reduced apoptosis compared to multiple controls (empty vector and overexpression of wildtype or known reduced-function PRPS1 mutants). 6-MP cytotoxicity results were confirmed using Jurkat cells. After 6-MP exposure, mass spectrometry revealed T303S cells possessed reduced concentrations of intracellular 6-MP metabolites (TIMP, TGMP, etc.) versus controls. T303S cells produce increased intracellular concentrations of hypoxanthine and IMP. Also, after 6-MP exposure, T303S cells display reduced levels of DNA damage response and apoptosis protein markers. The enhanced production of hypoxanthine likely leads to reduced conversion of thiopurines to their active form due to competitive inhibition. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T303S sequence variation in gene PRPS1/NCBI:5631 2298 check_entity AN5654-1 PRPS1 T303S mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk CIViC:2787 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T303S sequence variation in gene PRPS1/NCBI:5631 2298 check_entity AN5655-1 PRPS1 V53A mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk PubMed:25962120 Lentiviral-mediated overexpression of PRPS1 V53A in Reh cells resulted in similar cytotoxic response to controls (empty vector and overexpression of known reduced-function PRPS1 mutants) after exposure to mercaptopurine or thioguanine. Based on the crystal structure of PRPS1, V53A is not in or near the allosteric site or dimer interface, which likely impedes the ability of the variant to impact thiopurine processing. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V53A sequence variation in gene PRPS1/NCBI:5631 2299 check_entity AN5655-1 PRPS1 V53A mutation PRPS1 NCBI:5631 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 risk CIViC:2807 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V53A sequence variation in gene PRPS1/NCBI:5631 2299 check_entity AN5656-1 PSMB8 NUCLEAR EXPRESSION PSMB8 NCBI:5696 gene gastric adenocarcinoma DOID:3717 prognostic PubMed:26894977 Microarray expression data from 48 patients with gastric adenocarcinoma were analyzed for genes differentially expressed with regard to overall survival. Expression of 294 and 116 genes was enriched in good and poor prognosis subtypes, respectively. Of these genes, upregulation of proteasome subunit beta type 8 PSMB8 and PDZ binding kinase PBK was confirmed by real-time reverse transcription-PCR Analysis. IHC in 385 gastric cancer patients showed that increased nuclear expression of PSMB8 and PBK was correlated with depth of invasion, lymph node metastasis, and lower survival rates (survival durations of the (-), (+), and (++) groups, classified according to nuclear PSMB8 expression, were 77.2, 70.6, and 62.2 months, respectively; P = 0.004). Cytoplasmic staining of PSMB8 and PBK were not statistically significant. In multivariate Analysis, nuclear expression of PSMB8 and PBK were not significant predictors of overall survival (P = 0.085, P = 0.083, respectively). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene PSMB8/NCBI:5696 2300 AN5656-1 PSMB8 NUCLEAR EXPRESSION PSMB8 NCBI:5696 gene gastric adenocarcinoma DOID:3717 prognostic CIViC:434 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene PSMB8/NCBI:5696 2300 AN5657-1 PTCH1 LOH mutation PTCH1 NCBI:5727 gene medulloblastoma DOID:0050902 risk PubMed:26169613 Loss-of-heterozygosity in SHH-driven medulloblastoma was associated with increased PFS under therapy with vismodegib (AKA HhAntag691, GDC0449, GDC-0449). 43 patients total were enrolled for this study. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::loh:mutation sequence variation in gene PTCH1/NCBI:5727 2301 check_entity AN5657-1 PTCH1 LOH mutation PTCH1 NCBI:5727 gene medulloblastoma DOID:0050902 risk CIViC:298 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::loh:mutation sequence variation in gene PTCH1/NCBI:5727 2301 check_entity AN5658-1 PTCH1 Mutation PTCH1 NCBI:5727 gene cancer DOID:162 risk PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Twenty-one patients had mutations in the Hedgehog pathway (PTCH-1, n = 18; SMO, n = 3). Three patients with PTCH1 mutations had PRs to vismodegib (17%; unknown primary cancer, n = 1; squamous skin cancer, n = 1; salivary gland cancer, n = 1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PTCH1/NCBI:5727 2302 check_entity AN5658-1 PTCH1 Mutation PTCH1 NCBI:5727 gene cancer DOID:162 risk CIViC:297 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PTCH1/NCBI:5727 2302 check_entity AN5658-2 PTCH1 Mutation PTCH1 NCBI:5727 gene medulloblastoma DOID:0050902 risk PubMed:24651015 133 sonic-hedghog driven medulloblastomas were sequenced for alterations (WGS or WES). 60 cases exhibited PTCH1 mutations, most of which were likely loss-of-function (spread across the gene and of types including: stop gain, splice site, frameshift, etc.). Functional models also showed PTCH1 mutant xenografts to be sensitive to SHH inhibition with sonidegib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PTCH1/NCBI:5727 2303 check_entity AN5658-2 PTCH1 Mutation PTCH1 NCBI:5727 gene medulloblastoma DOID:0050902 risk CIViC:297 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PTCH1/NCBI:5727 2303 check_entity AN5659-1 PTEN Deletion PTEN NCBI:5728 gene prostate adenocarcinoma DOID:2526 prognostic 47969-1 PubMed:17700571 In a study of 107 prostate adenocarcinomas, those with either hemi- or homozygous deletions of PTEN (as determined by interphase FISH) have shorter biochemical recurence-free survival than those without deletions. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene PTEN/NCBI:5728 2304 check_entity AN5659-1 PTEN Deletion PTEN NCBI:5728 gene prostate adenocarcinoma DOID:2526 prognostic 47969-1 CIViC:213 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene PTEN/NCBI:5728 2304 check_entity AN5659-2 PTEN Deletion PTEN NCBI:5728 gene prostate cancer DOID:10283 prognostic;risk 47969-1 PubMed:23582881 In a phase II trial on castration-resistant prostate cancer patients, FISH detection of PTEN deletion was associated with increased progression free survival (p=0.07) and with improved PSA response (p=0.02) in response to everolimus, an mTOR pathway inhibitor. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene PTEN/NCBI:5728 2305 check_entity AN5659-2 PTEN Deletion PTEN NCBI:5728 gene prostate cancer DOID:10283 prognostic;risk 47969-1 PubMed:27470558 A meta-analysis of 26 published studies including 8097 prostate cancer patients showed that, compared to patients with normal PTEN, patients with PTEN deletion exhibited a greater aggressive Gleason score (OR: 1.284, 95% CI = 1.145–1.439), pathological stage (OR: 1.628, 95% CI = 1.270–2.087), and risk for recurrence of prostate cancer (HR: 1.738, 95% CI = 1.264–2.390). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene PTEN/NCBI:5728 2305 check_entity AN5659-2 PTEN Deletion PTEN NCBI:5728 gene prostate cancer DOID:10283 prognostic;risk 47969-1 CIViC:213 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene PTEN/NCBI:5728 2305 check_entity AN5660-1 PTEN Expression PTEN NCBI:5728 gene breast cancer DOID:1612 risk 47969-1 PubMed:16404430 Trastuzumab was more effective in cell lines (SKBR3 vs. drug-resistant SKBR3/R) and 17 patient samples that exhibit elevated PTEN expression (by IHC). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene PTEN/NCBI:5728 2306 AN5660-1 PTEN Expression PTEN NCBI:5728 gene breast cancer DOID:1612 risk 47969-1 CIViC:309 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene PTEN/NCBI:5728 2306 AN5660-2 PTEN Expression PTEN NCBI:5728 gene glioblastoma DOID:3068 risk 47969-1 PubMed:16282176 49 patients (26 pretreatment tissues available for analysis) with recurrent glioblastomas who were treated with EGFR TKIs were analyzed in this study. Results were confirmed in an independent cohort of 33 patients. EGFRvIII and PTEN coexpression were associated with responsiveness to EGFR TKI. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene PTEN/NCBI:5728 2307 AN5660-2 PTEN Expression PTEN NCBI:5728 gene glioblastoma DOID:3068 risk 47969-1 PubMed:25939761 In this preclinical study, the EGFR inhibitor dacomitinib had an effect on cell viability, self-renewal and proliferation in EGFR amplified GBM cells in-vitro and in-vivo (with or without the EGFRvIII mutation). It was less effective in one cell-line with PTEN deletion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene PTEN/NCBI:5728 2307 AN5660-2 PTEN Expression PTEN NCBI:5728 gene glioblastoma DOID:3068 risk 47969-1 CIViC:309 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene PTEN/NCBI:5728 2307 AN5660-3 PTEN Expression PTEN NCBI:5728 gene Her2-receptor positive breast cancer DOID:0060079 risk 47969-1 PubMed:27445490 Case report of a 44-year-old patient with recurrent HER2-positive breast cancer. The primary tumor was HR positive; however, the metastatic tumor was HR negative. The patient was resistant to classical chemotherapeutic agents and anti-HER2 treatment. Thus, the combination of everolimus and fulvestrant was administered. The patient experienced stable disease and PFS of 10 months. Genetic testing of pleural effusion after disease progression revealed a PIK3CA H1047R gene mutation but was positive for PTEN expression (IHC). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene PTEN/NCBI:5728 2308 AN5660-3 PTEN Expression PTEN NCBI:5728 gene Her2-receptor positive breast cancer DOID:0060079 risk 47969-1 CIViC:309 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene PTEN/NCBI:5728 2308 AN5661-1 PTEN Loss PTEN NCBI:5728 gene bladder carcinoma DOID:4007 risk 47969-1 PubMed:23989949 PTEN loss is associated with reduced response to mTOR inhibitors in patients with bladder cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2309 not_mapped AN5661-1 PTEN Loss PTEN NCBI:5728 gene bladder carcinoma DOID:4007 risk 47969-1 CIViC:214 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2309 not_mapped AN5661-2 PTEN Loss PTEN NCBI:5728 gene breast cancer DOID:1612 risk 47969-1 PubMed:24387334 PTEN loss is associated with loss of sensitivity to the HER2-antibody trastuzumab in breast cancer in smaller trials, a phase III trial (NCCTG N9831) did not show an effect of PTEN on disease-free survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2310 not_mapped AN5661-2 PTEN Loss PTEN NCBI:5728 gene breast cancer DOID:1612 risk 47969-1 PubMed:25398829 Breast and prostate cancer cell lines responsive to AZD8186 were enriched for PTEN deficiency. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2310 not_mapped AN5661-2 PTEN Loss PTEN NCBI:5728 gene breast cancer DOID:1612 risk 47969-1 PubMed:25409150 A case report described a responder to PI3K inhibitor BYL719 for a tumor with PIK3CA E542K mutation. After partial response for 9.5 months, resistance developed. Sequencing in this and other patients as well as preclinical models showed loss of PTEN as the probable mechanism of resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2310 not_mapped AN5661-2 PTEN Loss PTEN NCBI:5728 gene breast cancer DOID:1612 risk 47969-1 PubMed:21358673 In a panel of 31 breast cancer cell lines, 11 had loss of PTEN function. Cells were tested for sensitivity to mTORC1 inhibitor everolimus and mTORC1/2 inhibitor PP242, and no significant correlation was found between PTEN status and sensitivity to mTORC inhibition. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2310 not_mapped AN5661-2 PTEN Loss PTEN NCBI:5728 gene breast cancer DOID:1612 risk 47969-1 PubMed:21594665 In a retrospective study of 182 metastatic breast cancer patients of mixed HER2 status treated with trastuzumab-based therapy, PTEN loss (as measured by IHC) was associated with a higher risk of death measured from initiation of trastuzumab (HR = 1.64, P = 0.029) and diagnosis of first metastasis (HR = 1.85, P = 0.003). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2310 not_mapped AN5661-2 PTEN Loss PTEN NCBI:5728 gene breast cancer DOID:1612 risk 47969-1 PubMed:20453058 This preclinical study tested the efficacy of GDC-0941, a selective inhibitor of class I PI3K, on several cell lines of breast cancer. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. The authors tested several basal and luminal cell lines harboring PTEN loss for sensitivity to GDC-0941. ZR-75-1, a luminal-type cell line, had an IC50 of 0.15uM and reduction in phosphorylated AKT was noted following administration of GDC-0941. EVSTA-T, a luminal-type cell line, had an IC50 of 0.36uM; treatment resulted in an relative increase of Sub-G and G phase cells from 49% to 78% of total cells evaluated; there was a 12fold increase in annexin V (an apoptotic marker), and a substantial reduction in phosphorylated AKT following GDC-0941 administration. Seven basal-like cell lines harbored PTEN loss and had IC50s ranging fom 0.30uM to 20.00uM (4/7 had IC50s greater than 1 uM). There was a varied reduction in phosphorylated AKT among basal-like cell lines. Authors note that PTEN status may have low predictive power for response, and suggested that other factors such as basal/luminal characteristics may be more informative for GDC-0941 response. Authors further note that luminal type cell lines are generally more sensitive to GDC-0941 than basal type cell lines (p=0.02). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2310 not_mapped AN5661-2 PTEN Loss PTEN NCBI:5728 gene breast cancer DOID:1612 risk 47969-1 CIViC:214 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2310 not_mapped AN5661-3 PTEN Loss PTEN NCBI:5728 gene cancer DOID:162 risk 47969-1 PubMed:25672916 All three patients with PTEN loss had benefit from adding Buparlisib to carboplatin+paclitaxel therapy in a phase I study in advanced solid cancers. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2311 not_mapped AN5661-3 PTEN Loss PTEN NCBI:5728 gene cancer DOID:162 risk 47969-1 PubMed:22294718 In a panel of 182 cell lines (162 with PIK3CA mutation status known) from solid and hematological tumors, significant correlation was found between AZD5363 (pan-Akt inhibitor) sensitivity and PIK3CA mutation status (N=33, p=0.0059). In the subpopulation free of RAS mutation (N=19) the correlation was increased. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2311 not_mapped AN5661-3 PTEN Loss PTEN NCBI:5728 gene cancer DOID:162 risk 47969-1 PubMed:28330462 In a single-arm, open label phase 2 trial in PIK3CA amplified/mutated and/or PTEN loss encompassing 10 patients, no objective responses were observed but a stable disease response in 4 patients, resulting in a median PFS of 1.4 months. Everolimus failed to meet its enpoint. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2311 not_mapped AN5661-3 PTEN Loss PTEN NCBI:5728 gene cancer DOID:162 risk 47969-1 CIViC:214 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2311 not_mapped AN5661-3 PTEN Loss PTEN NCBI:5728 gene cancer DOID:162 risk 47969-1 PubMed:28281183 In one arm of this phase 1b study, 7 patients with PTEN deficient tumors were treated with continuous buparlisib (100 mg/daily) orally plus standard dose carboplatin AUC 5 and paclitaxel 175 mg/m2. No objective responses were observed. 2 patients had stable disease for ≥ 6 cycles. The authors recommended against the addition of buparlisib to carboplatin and paclitaxel, citing toxicity. Authors noted that combination therapy did not produce significant clinical activity amongst a small and heterogenous group of PTEN deficient tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2311 not_mapped AN5661-4 PTEN Loss PTEN NCBI:5728 gene colorectal cancer DOID:9256 risk 47969-1 PubMed:21163703 In 27 patients with chemotherapy-naive or chemotherapy-refractory metastatic colorectal cancer who were treated with cetuximab and chemotherapy, PTEN loss was associated with non-response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2312 not_mapped AN5661-4 PTEN Loss PTEN NCBI:5728 gene colorectal cancer DOID:9256 risk 47969-1 PubMed:19223544 In this study, 81 metastatic colorectal cancer patients were treated with anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab). Multivariate analysis demonstrated a significant association between PTEN protein expression loss and lack of response to panitumumab or cetuximab (P = 0.0012). Patients with PTEN non-expressing tumors (32/80) had shorter overall survival, compared to those with PTEN expressing tumors (P = 0.0048), though they had a nonsignificant difference in progression free survival (p = .0681). PIK3CA, PTEN, and KRAS were evaluated for mutations; PTEN loss was the only variant noted in 17 of the patients who experienced either stable disease or disease progression, while the other patients experienced PTEN loss in combination with a KRAS or PIK3CA mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2312 not_mapped AN5661-4 PTEN Loss PTEN NCBI:5728 gene colorectal cancer DOID:9256 risk 47969-1 CIViC:214 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2312 not_mapped AN5661-5 PTEN Loss PTEN NCBI:5728 gene endometrial cancer DOID:1380 risk 47969-1 PubMed:24166148 94 endometrial cancer samples of women who had been treated with single agent mTOR inhibitors temsirolimus or ridaforolimus were retrospectively analyzed. No predictive biomarkers were identified, including PIK3CA mutations, KRAS mutations or PTEN loss. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2313 not_mapped AN5661-5 PTEN Loss PTEN NCBI:5728 gene endometrial cancer DOID:1380 risk 47969-1 PubMed:23674493 A panel of 24 endometroid endometrial cancer (EEC) cell lines was characterized for mutations and 18 cell lines were found to have mutations in PTEN or absence of expression. Cell lines were assessed for sensitivity to mTORC1 allosteric inhibitor temsirolimus, and it was reported that PTEN loss had significant association with temsirolimus sensitivity. . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2313 not_mapped AN5661-5 PTEN Loss PTEN NCBI:5728 gene endometrial cancer DOID:1380 risk 47969-1 CIViC:214 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2313 not_mapped AN5661-6 PTEN Loss PTEN NCBI:5728 gene gastric adenocarcinoma DOID:3717 risk 47969-1 PubMed:25300346 In 48 patients with advanced gastric cancer, retrospectively analyzed for PTEN expression using IHC, PTEN loss was associated with a shorter duration of response (median 4.2 vs. 6.1 months, p = 0.04) to HER2-targeted therapy (trastuzumab, N=39; lapatinib, N=9). Response rates did not differ between groups. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2314 not_mapped AN5661-6 PTEN Loss PTEN NCBI:5728 gene gastric adenocarcinoma DOID:3717 risk 47969-1 CIViC:214 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2314 not_mapped AN5661-7 PTEN Loss PTEN NCBI:5728 gene Her2-receptor positive breast cancer DOID:0060079 risk 47969-1 PubMed:27091708 Archival tumor samples from 549 patients from the BOLERO-1 and -3 trials were analyzed for alterations in the PI3K pathway using next-generation sequencing, immunohistochemistry (IHC) and Sanger sequencing. In the BOLERO trials, patients with HER2-overexpressing advanced breast cancer were treated with trastuzumab, chemotherapy and randomized to receive either everolimus or placebo. In the pooled analysis of both trials, patients with PTEN loss (as defined by IHC staining intensity and proportion of positive tumor cells) had a longer progression-free survival with everolimus compared to placebo (HR 0.54 (95%CI 0.31 to 0.96, P=0.04) whereas patients with PTEN normal status had a hazard ration of 1.00 (95%CI 0.8 to 1.26, P=0.97). The same was found when PI3K mutations, PTEN loss and AKT E17K mutations were combined and analyzed as hyperactive PI3K pathway. Patients with PI3K hyperactive pathway had a hazard ratio of 0.67 (95%CI 0.48 to 0.93, P=0.02) compared to HR 1.19 (95%CI 0.87 to 1.62, P=0.28) in patients with PI3K normal pathway. These trends were independently confirmed in both trials but only pooled results showed consistent statistical significance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2315 not_mapped AN5661-7 PTEN Loss PTEN NCBI:5728 gene Her2-receptor positive breast cancer DOID:0060079 risk 47969-1 PubMed:17936563 A large-scale RNAi genetic sereen in HER2 overexpressing breast cancer cell line BT-474 was performed to discover genes whose loss induced trastuzumab resistance. The most prominently enriched gene in trastuzumab resistant populations was PTEN. Subsequent knockdown of PTEN in BT-474 cells increased cell survival when treated with trastuzumab, and growth curves showed partial restoration of proliferation in PTEN knockdown BT-474 cells treated with trastuzumab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2315 not_mapped AN5661-7 PTEN Loss PTEN NCBI:5728 gene Her2-receptor positive breast cancer DOID:0060079 risk 47969-1 PubMed:20813970 A subgroup of HER2-positive breast cancer patients that received first-line trastuzumab treatment were assessed for PTEN loss via IHC of FFPE samples. 46 samples showed PTEN loss while 41 did not, and PTEN loss alone was found to be significantly associated with resistance to trastuzumab (p=0.028) and shorter overall survival (p=0.008). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2315 not_mapped AN5661-7 PTEN Loss PTEN NCBI:5728 gene Her2-receptor positive breast cancer DOID:0060079 risk 47969-1 PubMed:15324695 Knockdown of PTEN in trastuzumab sensitive HER2 breast cancer BT474 cells induced trastuzumab resistance. PTEN null cells treated with PI3K inhibitor LY294002 also did not show substantial inhibition, but co-treatment with trastuzumab and LY294002 induced growth inhibition comparable to trastuzumab alone in normal BT474 cells. BT474 mouse xenograft tumors were injected with PTEN antisense (AS) oligonucleotides and this resulted in trastuzumab resitance. Co-treatment of PTEN AS tumor mice with LY294002 and trastuzumab inhibited tumor growth in comparison to PTEN AS tumors treated with trastuzumab or LY294002 alone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2315 not_mapped AN5661-7 PTEN Loss PTEN NCBI:5728 gene Her2-receptor positive breast cancer DOID:0060079 risk 47969-1 PubMed:21594665 In a retrospective study of 111 HER2-positive metastatic breast cancer patients treated with trastuzumab-based therapy, PTEN loss (as measured by IHC) was associated with shorter survival as measured from initiation of trastuzumab (HR = 1.92, P = 0.017) and diagnosis of first metastasis (HR = 1.69, P = 0.047). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2315 not_mapped AN5661-7 PTEN Loss PTEN NCBI:5728 gene Her2-receptor positive breast cancer DOID:0060079 risk 47969-1 PubMed:20453058 This preclinical study tested the efficacy of GDC-0941, a selective inhibitor of class I PI3K, on several cell lines of breast cancer. Sensitivity and resistance was categorized as less than and more than an IC50 of 1umol/L, respectively, with a maximum tested concentration of 20 umol/L. HCC1569 is a PTEN null, HER2 amplified breast cancer cell line. It had an IC50 of 0.46. Authors note that HER2 amplified breast cancer cell lines are generally more sensitive to GDC-0941 than basal-type cell lines (p = 0.002). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2315 not_mapped AN5661-7 PTEN Loss PTEN NCBI:5728 gene Her2-receptor positive breast cancer DOID:0060079 risk 47969-1 PubMed:19010894 In a preclinical study, efficacy of trastuzumab monotherapy was evaluated in vitro against HER2 amplified human breast cancer cell line BT474 (heterozygous for PIK3CA K111N) with shRNA-induced PTEN expression loss. Authors found that loss of PTEN expression induced resistance to trastuzumab as assessed by colony formation assay compared to PTEN expressing control cells. Among trastuzumab treated cells, concentration of phosphorylated AKT (S473 and T308) was higher in PTEN knockdown cells compared to PTEN expression cells, by western blot. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2315 not_mapped AN5661-7 PTEN Loss PTEN NCBI:5728 gene Her2-receptor positive breast cancer DOID:0060079 risk 47969-1 PubMed:26920887 In a phase 3 clinical trial (NCT00829166), metastatic HER-2 amplified breast cancer patients whose tumors had decreased, slightly decreased, or absent PTEN expression (assessed by IHC) treated with ado-trastuzumab emtansine (T-DM1; n= 113) were associated with similar median progression free survival (PFS) compared to patients whose tumors expressed PTEN normally or greater (n=21; 8.4 vs. 9.9 months). In HER2 patients with decreased or absent PTEN expression, T-DM1 was a more effective treatment than standard of care capecitabine + lapatinib as measured by PFS, although no difference in OS was seen. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2315 not_mapped AN5661-7 PTEN Loss PTEN NCBI:5728 gene Her2-receptor positive breast cancer DOID:0060079 risk 47969-1 CIViC:214 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2315 not_mapped AN5661-8 PTEN Loss PTEN NCBI:5728 gene melanoma DOID:1909 risk 47969-1 PubMed:24735930 Most BRAF mutant cell lines (mostly V600E) with PTEN mutation or loss of expression were among those sensitive to inhibition with AKT inhibitor GSK2141795B. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2316 not_mapped AN5661-8 PTEN Loss PTEN NCBI:5728 gene melanoma DOID:1909 risk 47969-1 PubMed:24265155 An in vitro study of M229 (a human melanoma cell line) endogenously expressing wildtype PTEN and BRAF V600E (a known BRAF inhibitor sensitizing mutation) found that PTEN knockdown cells (achieved via lentiviral transduction of shPTEN) were more resistant to vemurafenib (a BRAF inhibitor) than cells expressing wildtype PTEN. Lentiviral mediated reintroduction of PTEN restored vemurafenib sensitivity in WM2664, a vemurafenib resistant, PTEN non-expressing and BRAF V600D mutated human melanoma cell line. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2316 not_mapped AN5661-8 PTEN Loss PTEN NCBI:5728 gene melanoma DOID:1909 risk 47969-1 CIViC:214 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2316 not_mapped AN5661-9 PTEN Loss PTEN NCBI:5728 gene ovarian cancer DOID:2394 risk 47969-1 PubMed:15790433 A cisplatin resistant derivative of ovarian cancer cell line OVCAR-3 was generated by long term passage with increasing cisplatin levels. Western blot showed decreased PTEN level in the resistant cell line, and siRNA against PTEN in parent OVCAR-3 cells induced cisplatin resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2317 not_mapped AN5661-9 PTEN Loss PTEN NCBI:5728 gene ovarian cancer DOID:2394 risk 47969-1 CIViC:214 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2317 not_mapped AN5661-10 PTEN Loss PTEN NCBI:5728 gene pancreatic carcinoma DOID:4905 risk 47969-1 PubMed:22025163 Among 33 patients treated with pan-AKT inhibitor MK-2206 in this phase 1 study, one patient with pancreatic adenocarcinoma and PTEN loss/KRAS G12D mutation experienced a decrease of approximately 60% in cancer antigen 19-9 levels and 23% shrinkage in tumor measurements. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2318 not_mapped AN5661-10 PTEN Loss PTEN NCBI:5728 gene pancreatic carcinoma DOID:4905 risk 47969-1 CIViC:214 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2318 not_mapped AN5661-11 PTEN Loss PTEN NCBI:5728 gene prostate cancer DOID:10283 risk 47969-1 PubMed:11504908 In prostate cancer xenographs, PTEN null tumors had a significant decrease in cell size and proliferation when treated with Temsirolimus (CCI-779). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2319 not_mapped AN5661-11 PTEN Loss PTEN NCBI:5728 gene prostate cancer DOID:10283 risk 47969-1 CIViC:214 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2319 not_mapped AN5661-12 PTEN Loss PTEN NCBI:5728 gene stomach cancer DOID:10534 risk 47969-1 PubMed:24088382 A patient derived mouse xenograft model was established with gastric cancer cells having PTEN loss. The xenograft was resistant to monotherapy with both the pan-Akt inhibitor AZD5363, and also to the commonly used gastric cancer chemotheraputic docetaxel. When used in combination, AZD5363 and docetaxel induced significant tumor growth inhibition in comparison to monotherapy and vehicle control. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2320 not_mapped AN5661-12 PTEN Loss PTEN NCBI:5728 gene stomach cancer DOID:10534 risk 47969-1 CIViC:214 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2320 not_mapped AN5661-13 PTEN Loss PTEN NCBI:5728 gene stomach carcinoma DOID:5517 risk 47969-1 PubMed:15900596 Cancer and normal tissue samples were taken from 68 gastric cancer patients undergoing surgery without prior chemotherapy. Tissue samples were divided into high grade and low grade for phospho Akt (p-Akt) expression, and tested for PTEN LOH by sequencing. Patients with PTEN LOH were significantly more likely to have elevated p-Akt (p=0.0081), and high p-Akt samples were significantly less sensitive to chemotherapy agents 5-flourouracil, adriamycin, mitomycin and cis-platinum in MTT assay. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2321 not_mapped AN5661-13 PTEN Loss PTEN NCBI:5728 gene stomach carcinoma DOID:5517 risk 47969-1 CIViC:214 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTEN Loss [biomarker_term_in_review] 2321 not_mapped AN5662-1 PTEN Mutation PTEN NCBI:5728 gene cancer DOID:162 risk 47969-1 PubMed:23287563 IC50 for the pan-Akt inhibitor ipatasertib (GDC-0068) was determined over a panel of 100 cancer cell lines. Loss or mutation of PTEN (e.g. PTEN deletion, T319fsX1/Y155C, etc.) was significantly associated with ipatasertib sensitivity (p=0.000071). Non-transformed human mammary epithelial MCF10A cells were compared to an isogenic line with PTEN knockout. With low or high EGF culture conditions, a 4x or 3.5x decrease in IC50 for ipatasertib was seen in PTEN knockout cells, respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PTEN/NCBI:5728 2322 check_entity AN5662-1 PTEN Mutation PTEN NCBI:5728 gene cancer DOID:162 risk 47969-1 CIViC:506 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PTEN/NCBI:5728 2322 check_entity AN5662-2 PTEN Mutation PTEN NCBI:5728 gene endometrial carcinoma DOID:2871 risk 47969-1 PubMed:23238879 Tumors from 35 patients (12 with partial response or stable disease) with advanced endometrial carcinoma were assessed for PTEN mutational status, revealing 12 tumors with non-identical PTEN gene mutations. No mutations found in PTEN were effective in predicting tumor response to everolimus treatment. The clinical trial associated with this study is NCT00870337. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PTEN/NCBI:5728 2323 check_entity AN5662-2 PTEN Mutation PTEN NCBI:5728 gene endometrial carcinoma DOID:2871 risk 47969-1 CIViC:506 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PTEN/NCBI:5728 2323 check_entity AN5662-3 PTEN Mutation PTEN NCBI:5728 gene glioblastoma DOID:3068 diagnostic 47969-1 PubMed:9331072 Rasheed et al. identified that PTEN mutations occur with significantly greater frequency in adults with high-grade gliomas (42 adult glioblastoma multiforme and 13 adult anaplastic astrocytoma) compared to low-grade and child gliomas (68 others, varied). Mutation analysis performed using SSCP. No further testing was done. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PTEN/NCBI:5728 2324 check_entity AN5662-3 PTEN Mutation PTEN NCBI:5728 gene glioblastoma DOID:3068 diagnostic 47969-1 CIViC:506 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PTEN/NCBI:5728 2324 check_entity AN5662-4 PTEN Mutation PTEN NCBI:5728 gene head and neck cancer DOID:11934 risk 47969-1 PubMed:25855885 Analysis of drug response data from the Sanger center cell line screen. Cell lines with either PI3K and/or PTEN mutations did not show a significant difference in response to the class I PI3K inhibitor GDC-0941(p =0.07 for combined PI3K/PTEN aberrations with a trend towards lower IC50 for mutated cell lines). IC50 values with HSP90 inhibitor 17-AAG were significantly lower in PI3K and/or PTEN mutated cell lines in the Sanger cell line screening but these results could not be reproduced in the Broad cancer cell line encyclopedia screening. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PTEN/NCBI:5728 2325 check_entity AN5662-4 PTEN Mutation PTEN NCBI:5728 gene head and neck cancer DOID:11934 risk 47969-1 CIViC:506 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PTEN/NCBI:5728 2325 check_entity AN5662-5 PTEN Mutation PTEN NCBI:5728 gene head and neck squamous cell carcinoma DOID:5520 risk 47969-1 PubMed:26589432 In a panel of 26 HNSCC cell lines tested for sensitivity to taselisib (an alpha, delta and gamma isoform-specific PI3K inhibitor) the UD-SCC-2 cell line with homozygous PTEN deletion had considerably higher antiproliferative IC50 than taselisib sensitized cell lines. Western blots of UD-SCC-3 cells with increasing taselisib concentration showed reduction of phospho-Akt only at micro-molar doses, in contrast to nano-molar range for sensitized cells. Slight induction of the apoptotic marker cleaved PARP was only apparent at 4 micro-molar dose. Similar results were reported with the PTEN mutant HNSCC cell line UPCI-SCC-90, and 4 of the 6 most taselisib resistant cell lines had PTEN mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PTEN/NCBI:5728 2326 check_entity AN5662-5 PTEN Mutation PTEN NCBI:5728 gene head and neck squamous cell carcinoma DOID:5520 risk 47969-1 CIViC:506 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PTEN/NCBI:5728 2326 check_entity AN5662-6 PTEN Mutation PTEN NCBI:5728 gene prostate cancer DOID:10283 risk 47969-1 PubMed:25544636 Castrated mice bearing androgen-sensitive human prostate adenocarcinomas (LNCaP tumors) were treated with PI3K inhibitors (AZD8186, BYL719) and an androgen receptor inhibitor (MDV3100). Mice treated with single therapy of either MDV3100, BYL719, or AZD8186 resulted in mild tumor growth inhibition of 90%, 36%, and 40% respectively (n=5 mice/group). However, triple therapy of MDV300, BYL719, and AZD8186 resulted in tumor regression of 113% (n=5 mice). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PTEN/NCBI:5728 2327 check_entity AN5662-6 PTEN Mutation PTEN NCBI:5728 gene prostate cancer DOID:10283 risk 47969-1 CIViC:506 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PTEN/NCBI:5728 2327 check_entity AN5663-1 PTEN R130* mutation PTEN NCBI:5728 gene thyroid cancer DOID:1781 risk 47969-1 PubMed:19706758 Preclinical study in thyroid cancer cell lines. 6 cell lines with alterations of the PI3K/Akt pathway were more sensitive to Akt inhibitor perifosine or MTOR inhibitor temsirolimus than 5 cell lines without genetic alterations in the PI3K/Akt pathway. Among the alterations, one cell line harbored a PTEN allele deletion and R130* mutation. This cell line harbored the lowest IC50 values to both perifosine and temsirolimus and also showed increased apoptosis with perifosine in a xenograft model. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R130* sequence variation in gene PTEN/NCBI:5728 2328 check_entity AN5663-1 PTEN R130* mutation PTEN NCBI:5728 gene thyroid cancer DOID:1781 risk 47969-1 CIViC:632 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R130* sequence variation in gene PTEN/NCBI:5728 2328 check_entity AN5664-1 PTEN R173C mutation PTEN NCBI:5728 gene cancer DOID:162 diagnostic 47969-1 PubMed:10866302 'Han et al functionally tested the R173C mutation in PTEN using an expression vector construct, assessing phosphatase activity of the mutant construct with two phosphoinositide substrates (''with[ PtdIns(3,4,5)P3] or without[ Ins(1,3,4,5)P4] a diacylglycerol chain''). R173C resides in the NH2-terminal phosphatase domain of PTEN. R173C was one of four mutations (out of 42 tested) that displayed no significant phosphatase activity against either substrate, indicating, by this assay, that the mutation negatively impacts the function of PTEN. However this mutation did not affect the ability of PTEN to bind lipid membranes in-vivo. This data justifies PS3 level evidence for pathogenicity according to ACMG guidelines.' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R173C sequence variation in gene PTEN/NCBI:5728 2329 check_entity AN5664-1 PTEN R173C mutation PTEN NCBI:5728 gene cancer DOID:162 diagnostic 47969-1 CIViC:812 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R173C sequence variation in gene PTEN/NCBI:5728 2329 check_entity AN5664-2 PTEN R173C mutation PTEN NCBI:5728 gene endometrial hyperplasia DOID:0080365 risk 47969-1 PubMed:9635567 Maxwell et al identified R173C in 1 subject (of 51 endometrial hyperplasias assayed for mutations in PTEN), and identified 10 mutations of 51 in PTEN overall (20%). No additional functional testing or clinical description was given. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R173C sequence variation in gene PTEN/NCBI:5728 2330 check_entity AN5664-2 PTEN R173C mutation PTEN NCBI:5728 gene endometrial hyperplasia DOID:0080365 risk 47969-1 CIViC:812 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R173C sequence variation in gene PTEN/NCBI:5728 2330 check_entity AN5664-3 PTEN R173C mutation PTEN NCBI:5728 gene PTEN hamartoma tumor syndrome DOID:0080191 diagnostic 47969-1 PubMed:22628360 Hopman et al presents a case study with an affected proband carrying PTEN R173C, and meeting the pediatric criteria for PTEN testing of Tan et al (2011). The proband died at 2 years due to a fatal chylothorax, having been seen at 1 year with progressive dyspnoea and displaying extensive lymphatic and venus malformations that displaced the right lung, as well as osteolytic lesions of the bones. Proband's mother and two siblings (one 7 years and one 7 months) also carried the PTEN R173C mutation and were thus far asymptomatic. The mother's parents did not carry the R173C mutation. PP4 ACMG evidence criteria are met as PTEN hamartoma tumor syndrome is a disease with a single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R173C sequence variation in gene PTEN/NCBI:5728 2331 check_entity AN5664-3 PTEN R173C mutation PTEN NCBI:5728 gene PTEN hamartoma tumor syndrome DOID:0080191 diagnostic 47969-1 CIViC:812 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R173C sequence variation in gene PTEN/NCBI:5728 2331 check_entity AN5665-1 PTEN R233* mutation PTEN NCBI:5728 gene breast cancer DOID:1612 risk 47969-1 PubMed:20085938 Cells with PTEN deficiency have been shown to exhibit slowed growth in reponse to PI3K-mTOR inhibitors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R233* sequence variation in gene PTEN/NCBI:5728 2332 check_entity AN5665-1 PTEN R233* mutation PTEN NCBI:5728 gene breast cancer DOID:1612 risk 47969-1 CIViC:110 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R233* sequence variation in gene PTEN/NCBI:5728 2332 check_entity AN5665-2 PTEN R233* mutation PTEN NCBI:5728 gene glioblastoma DOID:3068 prognostic 47969-1 PubMed:22479427 PTEN nonsense mutations, including R233*, have been shown to be inactivating and loss-of-function, but do not have prognostic value in glioblastoma multiforme patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R233* sequence variation in gene PTEN/NCBI:5728 2333 check_entity AN5665-2 PTEN R233* mutation PTEN NCBI:5728 gene glioblastoma DOID:3068 prognostic 47969-1 CIViC:110 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R233* sequence variation in gene PTEN/NCBI:5728 2333 check_entity AN5666-1 PTEN V317FS mutation PTEN NCBI:5728 gene skin melanoma DOID:8923 risk 47969-1 PubMed:24504448 A 26-year old patient presented with vemurafenib resistant BRAF V600E-mutated cutaneous melanoma. Five metastases were evaluated using whole genome sequencing and a 4-bp deletion in PTEN (frameshift mutation at V317) was identified as unanimously present in all five tumors and a pre-treatment biopsy. The other copy of PTEN was lost with a chromosome-wide loss of chr 10. Subsequently, a patient-derived tumor cell line (designated 22 092) was suspended in a solution of PD184352/MK2206 combination therapy and cell growth inhibition confirmed tumor sensitivity to MEK/AKT inhibitors compared to the BRAF V600E-containing A375P cell line. ERK inhibitor resistance was demonstrated as a result of a GNAQ Q209P mutation also identified in the patient. This cell line showed overexpression of AKT and no expression of PTEN. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::v317fs:mutation sequence variation in gene PTEN/NCBI:5728 2334 check_entity AN5666-1 PTEN V317FS mutation PTEN NCBI:5728 gene skin melanoma DOID:8923 risk 47969-1 CIViC:601 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::v317fs:mutation sequence variation in gene PTEN/NCBI:5728 2334 check_entity AN5667-1 PTP4A3 OVEREXPRESSION PTP4A3 NCBI:11156 gene colorectal cancer DOID:9256 risk PubMed:23867504 In-vitro studies linked PRL-3 (PP4A3) expression to hyperactivation and dependence on EGFR signaling (through downregulation of PTP1B, an inhibitory phosphatase of EGFR). Retrospective analysis of 68 patients showed improved clinical response to the EGFR inhibitor cetuximab in tumors expressing PRL-3. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene PTP4A3/NCBI:11156 2335 AN5667-1 PTP4A3 OVEREXPRESSION PTP4A3 NCBI:11156 gene colorectal cancer DOID:9256 risk CIViC:374 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene PTP4A3/NCBI:11156 2335 AN5668-1 PTPN11 Overexpression PTPN11 NCBI:5781 gene laryngeal carcinoma DOID:2600 prognostic 34679-1 PubMed:24297342 Study explored the expression of the PTPN11 protein (SHP2) and found that expression was increased in a cohort of 112 laryngeal cancer samples. Expression was also associated with poor survival (p=.02) and in vitro models showed SHP2 expression promoted tumor growth. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene PTPN11/NCBI:5781 2336 AN5668-1 PTPN11 Overexpression PTPN11 NCBI:5781 gene laryngeal carcinoma DOID:2600 prognostic 34679-1 CIViC:535 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene PTPN11/NCBI:5781 2336 AN5669-1 PTPRB Loss-of-function PTPRB NCBI:5787 gene angiosarcoma DOID:0001816 diagnostic;risk PubMed:24633157 The endothelial phosphatase PTPRB, a negative regulator of vascular growth factor tyrosine kinases, harbored truncating mutations in 10 of 39 angiosarcomas (26%) which correlated with MYC amplifications. In HUVEC cell line model, silencing of PTPRB induced features of angiogenesis which were abolished in the presence of sunitinib or vatalinib, inhibitors of VEGFR. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTPRB Loss-of-function [biomarker_term_in_review] 2337 not_mapped AN5669-1 PTPRB Loss-of-function PTPRB NCBI:5787 gene angiosarcoma DOID:0001816 diagnostic;risk CIViC:797 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTPRB Loss-of-function [biomarker_term_in_review] 2337 not_mapped AN5670-1 PTPRD Mutation PTPRD NCBI:5789 gene head and neck carcinoma DOID:1542 risk PubMed:26267899 In this preclinical study, loss-of-function of PTPRD was mainly caused by mutation in head and neck cancer, as identified in TCGA data. PTPRD mutated cell-lines were more sensitive to STAT3 inhibition (JSI-124) than wild-type cells. The authors generated several representative HNSCC-derived PTPRD mutants by site-directed mutagenesis (S384R, K1502M, T1100M and L1147F). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PTPRD/NCBI:5789 2338 check_entity AN5670-1 PTPRD Mutation PTPRD NCBI:5789 gene head and neck carcinoma DOID:1542 risk CIViC:323 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene PTPRD/NCBI:5789 2338 check_entity AN5671-1 PTPRD V253I mutation PTPRD NCBI:5789 gene Ewing sarcoma of bone DOID:3368 risk PubMed:23800680 Report of complete response to IGF1-R antibody, with or without mTOR inhibitor tensirolimus in 2/3 Ewing Sarcoma patients with germline PTPRD mutations (V253I and W775*, R995C). The third patient had stable disease (T781A mutant). Four wildtype patients had stable or progressive disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V253I sequence variation in gene PTPRD/NCBI:5789 2339 check_entity AN5671-1 PTPRD V253I mutation PTPRD NCBI:5789 gene Ewing sarcoma of bone DOID:3368 risk CIViC:770 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V253I sequence variation in gene PTPRD/NCBI:5789 2339 check_entity AN5672-1 PTPRT Promoter Hypermethylation PTPRT NCBI:11122 gene head and neck squamous cell carcinoma DOID:5520 risk PubMed:25982282 PTPRT promoter hypermethylation was associated with increased sensitivity to STAT3 inhibition in this preclinical study in HNSCC. The authors found that PTPRT promoter methylation and sensitivity to Stattic (a STAT3 SH2 domain inhibitor) or JSI-124 (a JAK/STAT3 pathway inhibitor) are significantly correlated (P<0.05). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTPRT Promoter Hypermethylation [biomarker_term_in_review] 2340 not_mapped AN5672-1 PTPRT Promoter Hypermethylation PTPRT NCBI:11122 gene head and neck squamous cell carcinoma DOID:5520 risk CIViC:329 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition PTPRT Promoter Hypermethylation [biomarker_term_in_review] 2340 not_mapped AN5673-1 PTTG1 OVEREXPRESSION PTTG1 NCBI:9232 gene meningioma DOID:3565 prognostic PubMed:26894859 144 cases (discovery set: N=62 discovery; independent validation set: N = 82) of meningiomas were analyzed for transcriptional features defining aggressive clinical course (recurrent, malignantly progressing, or WHO grade III). Meningiomas were categorized into non-recurrent (NR), recurrent (R), and tumors undergoing malignant progression (M). Unsupervised transcriptomic analysis in 62 meningiomas revealed a large set of differentially expressed genes in aggressive subgroups (R+M tumors and WHO grade III, n=332; p<0.01, FC>1.25). Multivariate analysis identified PTTG1 and LEPR mRNA expression independent of gender, WHO grade and extent of resection. The patient group with the longest progression free survival was characterized by co-occurrence of low PTTG1 and high LEPR mRNA expression. IHC in 36 tumors validated these results at the protein level. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene PTTG1/NCBI:9232 2341 AN5673-1 PTTG1 OVEREXPRESSION PTTG1 NCBI:9232 gene meningioma DOID:3565 prognostic CIViC:436 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene PTTG1/NCBI:9232 2341 AN5674-1 RAC1 P29S mutation RAC1 NCBI:5879 gene melanoma DOID:1909 risk PubMed:25056119 Melanoma cell lines harboring the RAC1 P29S hotspot mutation were shown to be resistant to BRAF inhibition with vemurafenib or dabrafenib and knock-in or knock-out of this mutation decreased and increased sensitivity to these drugs. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P29S sequence variation in gene RAC1/NCBI:5879 2342 check_entity AN5674-1 RAC1 P29S mutation RAC1 NCBI:5879 gene melanoma DOID:1909 risk CIViC:363 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P29S sequence variation in gene RAC1/NCBI:5879 2342 check_entity AN5675-1 RAD23B EXPRESSION RAD23B NCBI:5887 gene sarcoma DOID:1115 risk PubMed:27499916 Western blot analyses were performed for HR23b (RAD23B) expression sarcoma cell lines after treatment with vorinostat, belinostat, mocetinostat and entinostat. All HDACi were able to regulate proliferation and apoptosis in vitro. Sensitivity to vorinostat correlated significantly with HR23b protein expression. IHC in 523 patient samples revealed high HR23b expression in 12.5% of sarcomas (among them malignant peripheral nerve sheath tumours, pleomorphic liposarcomas, leiomyosarcomas, dedifferentiated liposarcomas, synovial sarcomas and angiosarcomas) and 23.2% of GIST. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene RAD23B/NCBI:5887 2343 AN5675-1 RAD23B EXPRESSION RAD23B NCBI:5887 gene sarcoma DOID:1115 risk CIViC:621 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene RAD23B/NCBI:5887 2343 AN5676-1 RAD50 L1237F mutation RAD50 NCBI:10111 gene ureter small cell carcinoma DOID:6886 risk PubMed:24934408 A 51-year-old woman with an invasive small-cell cancer of the ureter showed a durable complete response at 3-years when treated with AZD7762 (an ATP-competitive checkpoint kinase inhibitor) and irinotecan (a topoisomerase I inhibitor). Whole genome sequencing of the tumor revealed a somatic RAD50 (L1237F) mutation, which was identified as a potential sensitizing lesion contributing to the profound response. Six rad50-mutant yeast strains and genetically engineered mouse embryonic fibroblasts were established and demonstrated severe sensitivity to camptothecin (Chk1 inhibitor). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L1237F sequence variation in gene RAD50/NCBI:10111 2344 check_entity AN5676-1 RAD50 L1237F mutation RAD50 NCBI:10111 gene ureter small cell carcinoma DOID:6886 risk CIViC:2044 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L1237F sequence variation in gene RAD50/NCBI:10111 2344 check_entity AN5677-1 RAD51B Mutation RAD51B NCBI:5890 gene castration-resistant prostate carcinoma DOID:0080909 risk PubMed:32343890 This randomized, open-label, phase 3 trial evaluated the PARP inhibitor olaparib in 387 men with metastatic castration-resistant prostate cancer (mCRPC) who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). The study found that in men with mCRPC who had somatic or germline deleterious alterations (irrespective of zygosity) in any of the following HRR genes (BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L), olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone (PFS HR 0.49 [0.38, 0.63]). A total of 7 patients had RAD51B mutations, 5 in olaparib arm and 2 in control arm. Based on the results of this study, on May 19, 2020, the Food and Drug Administration approved olaparib (LYNPARZA) for adult patients with deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC, who have progressed following prior treatment with enzalutamide or abiraterone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene RAD51B/NCBI:5890 2345 check_entity AN5677-1 RAD51B Mutation RAD51B NCBI:5890 gene castration-resistant prostate carcinoma DOID:0080909 risk CIViC:4393 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene RAD51B/NCBI:5890 2345 check_entity AN5678-1 RAD51D Mutation RAD51D NCBI:5892 gene castration-resistant prostate carcinoma DOID:0080909 risk PubMed:32343890 This randomized, open-label, phase 3 trial evaluated the PARP inhibitor olaparib in 387 men with metastatic castration-resistant prostate cancer (mCRPC) who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). The study found that in men with mCRPC who had somatic or germline deleterious alterations (irrespective of zygosity) in any of the following HRR genes (BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L), olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone (PFS HR 0.49 [0.38, 0.63]). A total of 2 patients had RAD51D mutations, both in the olaparib arm. Based on the results of this study, on May 19, 2020, the Food and Drug Administration approved olaparib (LYNPARZA) for adult patients with deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC, who have progressed following prior treatment with enzalutamide or abiraterone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene RAD51D/NCBI:5892 2346 check_entity AN5678-1 RAD51D Mutation RAD51D NCBI:5892 gene castration-resistant prostate carcinoma DOID:0080909 risk CIViC:4395 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene RAD51D/NCBI:5892 2346 check_entity AN5679-1 RAD51D R186* mutation RAD51D NCBI:5892 gene breast cancer DOID:1612 diagnostic PubMed:25445424 A healthy, 36-year-old woman presented with a palpable right breast mass upon biopsy determined to be high-grade, triple negative invasive ductal carcinoma. Her family history was notable for multiple relatives on her maternal side with breast cancer, including a distant male relative with breast cancer. Multigene panel testing with an 18-gene panel revealed a germline truncating pathogenic mutation in RAD51D (p.R186X; c. 556C>T). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R186* sequence variation in gene RAD51D/NCBI:5892 2347 check_entity AN5679-1 RAD51D R186* mutation RAD51D NCBI:5892 gene breast cancer DOID:1612 diagnostic CIViC:467 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R186* sequence variation in gene RAD51D/NCBI:5892 2347 check_entity AN5680-1 RAD54L Mutation ATRX NCBI:546 gene castration-resistant prostate carcinoma DOID:0080909 risk PubMed:32343890 This randomized, open-label, phase 3 trial evaluated the PARP inhibitor olaparib in 387 men with metastatic castration-resistant prostate cancer (mCRPC) who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). The study found that in men with mCRPC who had somatic or germline deleterious alterations (irrespective of zygosity) in any of the following HRR genes (BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L), olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone (PFS HR 0.49 [0.38, 0.63]). For 6 patients with RAD54L mutations specifically, PFS HR 0.33 [0.05-2.54]. Based on the results of this study, on May 19, 2020, the Food and Drug Administration approved olaparib (LYNPARZA) for adult patients with deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC, who have progressed following prior treatment with enzalutamide or abiraterone. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rad54l:mutation sequence variation in gene ATRX/NCBI:546 2348 check_entity AN5680-1 RAD54L Mutation ATRX NCBI:546 gene castration-resistant prostate carcinoma DOID:0080909 risk CIViC:4388 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rad54l:mutation sequence variation in gene ATRX/NCBI:546 2348 check_entity AN5681-1 RAF1 Amplification RAF1 NCBI:5894 gene skin melanoma DOID:8923 risk 82537-2 PubMed:26307133 Retrospective analysis of somatic mutations and copy number changes in 119 patients treated with carboplatin, paclitaxel, ± sorafenib (CPS) in the E2603 trial. CPS therapy was associated with improved progression-free survival (PFS) compared with CP in patients with tumors that were positive for RAF1 gene copy gains (HR = 0.372; P = 0.025). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene RAF1/NCBI:5894 2349 AN5681-1 RAF1 Amplification RAF1 NCBI:5894 gene skin melanoma DOID:8923 risk 82537-2 CIViC:587 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene RAF1/NCBI:5894 2349 AN5682-1 RAF1 QKI::RAF1 mutation RAF1 NCBI:5894 gene spindle cell sarcoma DOID:4235 risk 82537-2 PubMed:35050712 Case report of a 27-year old female patient with spindle cell sarcoma. Initial treatment consisted of eight cycles of alternating vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide plus definitive radiation for suspected Ewing's sarcoma. An Archer panel revealed a QKI-RAF1 gene fusion, no EWSR1 and SS18 gene rearrangement were identified and a diagnosis of spindle cell tumor (S100 and CD34 coexpression with recurrent gene fusion) was made. Three months after end of treatment a relapse was diagnosed which progressed under temozolomide-irinotecan. Third-line therapy with trametinib was started which led to a complete metabolic response. The patient died 10months later from septic shock. No tumor progression was noted. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::QKI::RAF1 sequence variation in gene RAF1/NCBI:5894 2350 check_entity AN5682-1 RAF1 QKI::RAF1 mutation RAF1 NCBI:5894 gene spindle cell sarcoma DOID:4235 risk 82537-2 CIViC:3868 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::QKI::RAF1 sequence variation in gene RAF1/NCBI:5894 2350 check_entity AN5683-1 RASA1 Loss-of-function RASA1 NCBI:5921 gene lung non-small cell carcinoma DOID:3908 risk PubMed:29127119 Approximately 2% of NSCLCs had RASA1 truncating mutations, and this alteration was statistically, but not completely, mutually exclusive with known activating EGFR (p=0.02) and KRAS (p=0.02) mutations. Unexpectedly, RASA1 truncating mutations had a strong tendency to co-occur with NF1 truncating mutations (p<0.001). While growth of cell lines with inactivation of only one of these two RasGAPs showed moderate and variable sensitivity to inhibitors of MEK or PI3K, cells with concurrent RASA1/NF1 mutations were profoundly more sensitive (IC50: 0.040μM trametinib). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition RASA1 Loss-of-function [biomarker_term_in_review] 2351 not_mapped AN5683-1 RASA1 Loss-of-function RASA1 NCBI:5921 gene lung non-small cell carcinoma DOID:3908 risk CIViC:2111 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition RASA1 Loss-of-function [biomarker_term_in_review] 2351 not_mapped AN5684-1 RB1 EXPRESSION RB1 NCBI:5925 gene lung non-small cell carcinoma DOID:3908 prognostic 21731-5 PubMed:22619677 Positive RB1 expression (2+ by IHC) was associated with adverse outcomes in a cohort of 73 cases with stage I and II NSCLC (P<0.001) in this retrospective study. This finding was independent from other genomic and clinical factors explored by the authors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene RB1/NCBI:5925 2352 AN5684-1 RB1 EXPRESSION RB1 NCBI:5925 gene lung non-small cell carcinoma DOID:3908 prognostic 21731-5 CIViC:533 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene RB1/NCBI:5925 2352 AN5685-1 RB1 Loss-of-function RB1 NCBI:5925 gene breast cancer DOID:1612 risk 21731-5 PubMed:20473330 In 3 ER positive and 2 ER negative breast cancer cell lines with intact Rb, significant growth inhibition, as measured by BrdU incorporation, was seen with incubation in CDK4/6 inhibitor palbociclib (PD-0332991). In contrast, two ER negative cell lines lacking detectable Rb were fully resistant to palbociclib. Knockdown of Rb in 3 of the tested Rb positive cell lines led to moderate palbociclib resistance in short term incubation experiments. In longer term (15 day) palbociclib incubations of ER negative MDA-MB-231 cells and ER positive MCF-7 cells, significant resistance to palbociclib was seen in Rb knockdown conditions while wild-type Rb cells maintained sensitivity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition RB1 Loss-of-function [biomarker_term_in_review] 2353 not_mapped AN5685-1 RB1 Loss-of-function RB1 NCBI:5925 gene breast cancer DOID:1612 risk 21731-5 CIViC:602 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition RB1 Loss-of-function [biomarker_term_in_review] 2353 not_mapped AN5685-2 RB1 Loss-of-function RB1 NCBI:5925 gene glioblastoma DOID:3068 risk 21731-5 PubMed:20354191 A panel of 21 glioblastoma cell lines harboring various mutations was treated with palbociclib. 16 of the cell lines with intact Rb showed decreased proliferation (bromodeoxyuridine incorporation, BrdU flow cytometry) and growth arrest characteristic of senescence, while the 5 cell lines that did not show a palbociclib response had homozygous deletion of Rb. Rb positive and palbociclib responsive GBM cell line U87MG was treated with shRNA against Rb. shRb treated cells showed restoration of cell proliferation (BrdU incorporation) under palbociclib treatment, indicating resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition RB1 Loss-of-function [biomarker_term_in_review] 2354 not_mapped AN5685-2 RB1 Loss-of-function RB1 NCBI:5925 gene glioblastoma DOID:3068 risk 21731-5 CIViC:602 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition RB1 Loss-of-function [biomarker_term_in_review] 2354 not_mapped AN5686-1 RB1 M695FS*26 mutation RB1 NCBI:5925 gene estrogen-receptor positive breast cancer DOID:0060075 risk 21731-5 PubMed:27020857 Preclinical study in breast cancer cell lines treated with CDK4/6 inhibitor palbociclib. Palbociclib-resistant xenografts from one cell line (PDX244) were developed in-vivo. In resistant xenografts, western blot analysis showed a decrease of pRb protein levels in 4 of 7 CDK4/6-acquired resistant tumors and a sustained expression of the E2F target cyclin E2, in contrast to CDK4/6 inhibitor-sensitive PDX244. Genomic characterization of PDX244LR1 showed the acquisition of an RB1 frameshift mutation (RB1 p.M695fs*26). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::m695fs*26:mutation sequence variation in gene RB1/NCBI:5925 2355 check_entity AN5686-1 RB1 M695FS*26 mutation RB1 NCBI:5925 gene estrogen-receptor positive breast cancer DOID:0060075 risk 21731-5 CIViC:634 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::m695fs*26:mutation sequence variation in gene RB1/NCBI:5925 2355 check_entity AN5687-1 RB1 Mutation RB1 NCBI:5925 gene lung small cell carcinoma DOID:5409 risk 21731-5 PubMed:26802149 Study evaluated a total of 50 small cell lung cancer patients with extensive stage disease. Multivariate analysis identified RB1 as a factor in predicting response to first-line chemotherapy (odds ratio 5.58 compared to WT, p=.038). Kaplan-Meier survival analysis revealed patients with RB1 mutations exhibited better overall survival (p = .04, 11.7 versus 9.1 months, CI = 1.1-28.2). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene RB1/NCBI:5925 2356 check_entity AN5687-1 RB1 Mutation RB1 NCBI:5925 gene lung small cell carcinoma DOID:5409 risk 21731-5 CIViC:777 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene RB1/NCBI:5925 2356 check_entity AN5688-1 RB1 Overexpression RB1 NCBI:5925 gene pancreatic adenocarcinoma DOID:4074 risk 21731-5 PubMed:11792751 In Capan-1 cell lines engineered to reduce pRB expression (by transfection with p16), resensitization to chemotherapy-induced apoptosis was observed. The effect was asserted to be specific to pRB depletion because, in two separate cell lines, also transfected with p16, that retained high pRB expression, chemotherapy resistance was still observed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene RB1/NCBI:5925 2357 AN5688-1 RB1 Overexpression RB1 NCBI:5925 gene pancreatic adenocarcinoma DOID:4074 risk 21731-5 CIViC:543 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene RB1/NCBI:5925 2357 AN5689-1 RB1 PHOSPHORYLATION RB1 NCBI:5925 gene breast cancer DOID:1612 risk 21731-5 PubMed:25002028 The p110alpha-specific PI3K inhibitor BYL719 (Alpelisib) was used on a panel of five PI3K inhibitor sensitive and five resistant breast cancer cell lines. Sensitive cells (IC50<400nM) showed reduced phospho-Rb (p-Rb) western blot levels in response to BYL719 treatment, while resistant cell lines (IC50>800nM) showed significantly less reduction in p-Rb after BYL719. Paired biopsies before and after treatment were taken from a set of eight patients classified as either responder or non-responder to BYL719. Responder samples showed significantly reduced p-Rb staining after treatment in comparison to non-responder biopsies. In biopsies taken from a group of three responders who progressed, p-Rb levels were increased after progression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition RB1 PHOSPHORYLATION [biomarker_term_in_review] 2358 not_mapped AN5689-1 RB1 PHOSPHORYLATION RB1 NCBI:5925 gene breast cancer DOID:1612 risk 21731-5 CIViC:628 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition RB1 PHOSPHORYLATION [biomarker_term_in_review] 2358 not_mapped AN5690-1 RB1 Wildtype RB1 NCBI:5925 gene lung non-small cell carcinoma DOID:3908 risk 21731-5 PubMed:35050752 A phase II clinical study was conducted with 29 patients with Non-Small-Cell Lung Cancer harboring CDKN2A alterations and wild-type Rb. The study reported one patient with a partial response, and six patients with SD for a duration of at least 16 weeks. The disease control rate was 31% (90% CI, 19-40). The PFS and OS observed were 8.1 weeks (95% CI, 7.1 - 16.0) and 21.6 weeks (95% CI. 14.1-41.1) respectively. At least one grade 3 or 4 adverse event or serious adverse event was reported in 11 patients, likely associated with palbociclib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition RB1 Wildtype [biomarker_term_in_review] 2359 not_mapped AN5690-1 RB1 Wildtype RB1 NCBI:5925 gene lung non-small cell carcinoma DOID:3908 risk 21731-5 CIViC:4750 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition RB1 Wildtype [biomarker_term_in_review] 2359 not_mapped AN5691-1 REL AMPLIFICATION REL NCBI:5966 gene diffuse large B-cell lymphoma DOID:0050745 diagnostic 100029-8 PubMed:12075054 Amplification of REL is shown to be associated with germinal-center B-cell–like diffuse large-B-cell lymphomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene REL/NCBI:5966 2360 AN5691-1 REL AMPLIFICATION REL NCBI:5966 gene diffuse large B-cell lymphoma DOID:0050745 diagnostic 100029-8 CIViC:154 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene REL/NCBI:5966 2360 AN5692-1 RET C609Y mutation RET NCBI:5979 gene thyroid gland medullary carcinoma DOID:3973 diagnostic 21733-1 PubMed:19472011 Study of a family with three generations of history indicating co-segregation of RET C609Y and multiple endocrine neoplasia type 2A, many of whom exhibited medullary thyroid cancers specifically. 22 individuals in this family were carriers of C609Y. Of these, 9 exhibited medullary thyroid cancers. While the variant is strongly suspected of being pathogenic for these tumors, this variant appears to result in later onset of cancer than some other variants and the authors recommend delaying prophylactic thyroidectomy until 10-15 years of age. In addition to this large family, the authors also provide an extensive review of prior reports of C609 variants, identifying a total of 111 patients from 19 publications, representing 21 affected kindreds and 15 sporadic cases. 89 of these cases had C609Y specifically. The authors also summarize prior functional work that suggests that C609Y has transforming activity that is significant but not as strong as some other variants. Based on all of this analysis, the authors conclude that C609Y causes medullary thyroid cancers but a milder form than some other variants. Based on this paper, the following ACMG evidence codes seem potentially valid: 'PS1', 'PS3', 'PM5', 'PP1', 'PP4', and 'PP5'. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C609Y sequence variation in gene RET/NCBI:5979 2361 check_entity AN5692-1 RET C609Y mutation RET NCBI:5979 gene thyroid gland medullary carcinoma DOID:3973 diagnostic 21733-1 CIViC:1234 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C609Y sequence variation in gene RET/NCBI:5979 2361 check_entity AN5693-1 RET C634W mutation RET NCBI:5979 gene thyroid gland medullary carcinoma DOID:3973 risk 21733-1 PubMed:21422803 Medullary thyroid cancer cells with RET C634W mutation are insensitive to motesanib, compared to wild-type RET. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C634W sequence variation in gene RET/NCBI:5979 2362 check_entity AN5693-1 RET C634W mutation RET NCBI:5979 gene thyroid gland medullary carcinoma DOID:3973 risk 21733-1 CIViC:112 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C634W sequence variation in gene RET/NCBI:5979 2362 check_entity AN5694-1 RET CCDC6::RET mutation RET NCBI:5979 gene colorectal cancer DOID:9256 risk 21733-1 PubMed:29538669 A patient with right-sided, MSI-High and CCDC6-RET positive metastatic colorectal cancer showed complete response to the selective RET inhibitor RXDX-105. The patient remained progression-free after 19 months on treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CCDC6::RET sequence variation in gene RET/NCBI:5979 2363 check_entity AN5694-1 RET CCDC6::RET mutation RET NCBI:5979 gene colorectal cancer DOID:9256 risk 21733-1 CIViC:622 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CCDC6::RET sequence variation in gene RET/NCBI:5979 2363 check_entity AN5694-2 RET CCDC6::RET mutation RET NCBI:5979 gene lung non-small cell carcinoma DOID:3908 risk 21733-1 PubMed:26787234 Case report of a 60-year old woman with lung adenocarcinoma. After negative testing for EGFR mutations and ALK translocations and failure of platinum-based chemotherapy she was enrolled on a nintedanib-docetaxel trial. Docetaxel was discontinued after 22 cycles because of edema and fatigue. A total of 48 treatment cycles (26 cycles of nintedanib alone) was administered over 33 months before documentation of disease progression in March 2013. Genomic testing revealed a CCDC6-RET fusion but no other actionable mutations (confirmed by FISH). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CCDC6::RET sequence variation in gene RET/NCBI:5979 2364 check_entity AN5694-2 RET CCDC6::RET mutation RET NCBI:5979 gene lung non-small cell carcinoma DOID:3908 risk 21733-1 CIViC:622 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::CCDC6::RET sequence variation in gene RET/NCBI:5979 2364 check_entity AN5695-1 RET Fusion RET NCBI:5979 gene lung adenocarcinoma DOID:3910 risk 21733-1 PubMed:27825636 RET rearrangements are found in 1-2% of non-small-cell lung cancers. Cabozantinib is a multikinase inhibitor with activity against RET that produced a 10% overall response in unselected patients with lung cancers. This was an open-label, two-stage, single-centre, phase 2, single-arm trial in the USA in metastatic/unresectable lung cancer harbouring RET rearrangement. 26 Patients with lung adenocarcinomas were given 60 mg of cabozantinib orally per day. The primary objective was overall response. Confirmed PR was seen in 7/25 (ORR 28% [95% CI 12–49%]) response-evaluable patients, meeting the primary endpoint. KIF5B-RET was the predominant fusion in 16 (62%) patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene RET/NCBI:5979 2365 check_entity AN5695-1 RET Fusion RET NCBI:5979 gene lung adenocarcinoma DOID:3910 risk 21733-1 CIViC:1595 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene RET/NCBI:5979 2365 check_entity AN5695-2 RET Fusion RET NCBI:5979 gene lung non-small cell carcinoma DOID:3908 risk 21733-1 PubMed:27803005 RET rearrangements involving RET are found in about 1% of NSCLC and define a unique molecular subset. This study was a multi-center, open-label, phase II clinical trial to examine the safety and efficacy of Vandetanib (300 mg/d) in RET positive NSCLC patients (confirmed by FISH), Primary endpoint was the objective response rate. 18 patients were enrolled, the majority were a heavily pretreated population. Among the 17 evaluable patients, three had a partial response (ORR = 18%) and eight had a stable disease (DCR = 65%). Among these patients, the PR or SD was durable for more than 6 months in 8 patients. Vandetanib also showed a PFS of 4.5 months, and an OS of 11.6 months during a median follow-up duration of 14 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene RET/NCBI:5979 2366 check_entity AN5695-2 RET Fusion RET NCBI:5979 gene lung non-small cell carcinoma DOID:3908 risk 21733-1 PubMed:27825616 We aimed to assess the efficacy and safety of vandetanib in patients with advanced RET-rearranged NSCLC. In this open-label, multicentre, phase 2 trial (LURET), patients with advanced RET-rearranged NSCLC continuously received 300 mg of oral vandetanib daily. 1536 patients with EGFR mutation-negative NSCLC were screened, 34 were RET-positive (2%). 19 were enrolled and 17 patients were eligible for primary analysis. 9 patients (53%) achieved an objective response. At data cutoff, median PFS was 4.7 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene RET/NCBI:5979 2366 check_entity AN5695-2 RET Fusion RET NCBI:5979 gene lung non-small cell carcinoma DOID:3908 risk 21733-1 PubMed:27544060 Alectinib is an anaplastic lymphoma kinase tyrosine kinase inhibitor (TKI) that also has anti-RET activity in vitro. 4 patients with metastatic RET-rearranged NSCLC were identified. 3 of 4 had received prior RET TKIs, including cabozantinib and experimental RET inhibitors. We observed two (50%) objective radiographic responses after treatment with alectinib (one confirmed and one unconfirmed), with durations of therapy of 6 months and more than 5 months (treatment ongoing). Notably, one of these two patients had his dose of alectinib escalated to 900 mg twice daily and had clinical improvement in central nervous system metastases. In addition, one patient (25%) experienced a best response of stable disease lasting approximately 6 weeks. A fourth patient who was RET TKI-naive had primary progression while receiving alectinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene RET/NCBI:5979 2366 check_entity AN5695-2 RET Fusion RET NCBI:5979 gene lung non-small cell carcinoma DOID:3908 risk 21733-1 PubMed:161573 In this phase 1 trial, 57 patients with RET fusion- or mutation positive cancers were treated in 7 dose levels. Among patients with RET-Fusion positive NSCLC, objective response rates were 65% (n = 17/26). Responses occurred independent of fusion partner (9/13 KIF5B vs 7/9 non-KIF5B) and included 3 pts w/ baseline brain metastases. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene RET/NCBI:5979 2366 check_entity AN5695-2 RET Fusion RET NCBI:5979 gene lung non-small cell carcinoma DOID:3908 risk 21733-1 PubMed:32846060 Patients with RET-fusion positive non-small cell lung cancer were enrolled in this phase 1-2 trial of RET inhibitor selpercatinib. Among 105 consecutively enrolled patients who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene RET/NCBI:5979 2366 check_entity AN5695-2 RET Fusion RET NCBI:5979 gene lung non-small cell carcinoma DOID:3908 risk 21733-1 PubMed:34118197 In an open-label, phase 1/2 trial on 87 patients with NSCLC including RET-fusion were given 400 mg once-daily oral pralsetinib, with the outcome measured as overall response rate. Overall responses were seen in 53 patients (95% CI: 50 – 71),nicluding five patients with a complete response. Further, 80% of the patients had responses lasting at least 6 months. Lastly, the median progression-free survival was 17.1 months (95% CI: 8.3 – 22.1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene RET/NCBI:5979 2366 check_entity AN5695-2 RET Fusion RET NCBI:5979 gene lung non-small cell carcinoma DOID:3908 risk 21733-1 CIViC:1595 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene RET/NCBI:5979 2366 check_entity AN5695-3 RET Fusion RET NCBI:5979 gene thyroid cancer DOID:1781 risk 21733-1 PubMed:32846061 In this phase 1/2 trial (NCT03157128), patients with RET altered thyroid cancers were enrolled to receive the highly selective RET inhibitor selpercatinib. Among 19 patients with previously treated RET fusion positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). Responses included 8 of 11 (73%) papillary thyroid cancers, 2 of 3 poorly differentiated thyroid cancers, 1 of 2 anaplastic thyroid cancers, and 1 of 1 Hurthle-cell thyroid cancer. The most common fusions were CCDC6::RET and NCOA4::RET seen in 47% and 32% of fusion cases respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene RET/NCBI:5979 2367 check_entity AN5695-3 RET Fusion RET NCBI:5979 gene thyroid cancer DOID:1781 risk 21733-1 PubMed:34118198 In a phase 1/2, open-label trial, 122 patients with RET-mutant medullary cancer and 20 with RET-fusion positive thyroid cancer were administered 400 mg daily oral pralsetinib. The overall response rates (ORR) were 15/21 in patients with treatment-naive RET-mutant medullary thyroid cancer (95% CI: 48 - 89) and 33 of 55 who had previously received cabozantinib or vandetanib, or both (95% CI: 46 - 73), and 8/9 in patients with RET fusion-positive thyroid cancer (95% CI: 52 - 100). For the 8/9 patients with RET fusion-positive thyroid cancer, all had responses lasting 6 months or longer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene RET/NCBI:5979 2367 check_entity AN5695-3 RET Fusion RET NCBI:5979 gene thyroid cancer DOID:1781 risk 21733-1 CIViC:1595 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene RET/NCBI:5979 2367 check_entity AN5695-4 RET Fusion RET NCBI:5979 gene thyroid gland papillary carcinoma DOID:3969 risk 21733-1 PubMed:161573 In this phase 1 trial, patients with RET-fusion or mutation positive cancers were treated with the selective RET-inhibitor selpercatinib (LOXO-292). Among the 6 patients with RET-fusion positive papillary thyroid cancers, 83% (n = 5/6) response rate was observed. Selpercatinib was well tolerated with no dose limiting toxicities observed and maximum tolerated dose was not reached. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene RET/NCBI:5979 2368 check_entity AN5695-4 RET Fusion RET NCBI:5979 gene thyroid gland papillary carcinoma DOID:3969 risk 21733-1 CIViC:1595 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene RET/NCBI:5979 2368 check_entity AN5696-1 RET KIF5B::RET mutation RET NCBI:5979 gene lung adenocarcinoma DOID:3910 risk 21733-1 PubMed:23584301 A case study of a patient with EGFR, KRAS, BRAF, HER2, ALK, ROS1 and MET negative adenocarcinoma of the lung. FISH analysis revealed a KIF5B-RET fusion. The RET inhibitor Vandetanib led to remission in the patient. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KIF5B::RET sequence variation in gene RET/NCBI:5979 2369 check_entity AN5696-1 RET KIF5B::RET mutation RET NCBI:5979 gene lung adenocarcinoma DOID:3910 risk 21733-1 PubMed:25982012 Case report of a 74-year old woman with EGFR- and ALK-negative lung adenocarcinoma. FISH identified a deletion of 5'RET (FISH, indicating RET-gene rearrangement) and genomic testing confirmed a fusion of KIF5B and RET. The patient was enrolled in a clinical trial with vandetanib and everolimus (NCT01582191) with everolimus used to enhance brain accumulation of vandetanib. After two cycles of therapy a repeat MRI brain showed a decrease in the intracranial disease burden and PET/CT showed systemic response as well. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KIF5B::RET sequence variation in gene RET/NCBI:5979 2369 check_entity AN5696-1 RET KIF5B::RET mutation RET NCBI:5979 gene lung adenocarcinoma DOID:3910 risk 21733-1 CIViC:269 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::KIF5B::RET sequence variation in gene RET/NCBI:5979 2369 check_entity AN5697-1 RET M918T mutation RET NCBI:5979 gene thyroid gland medullary carcinoma DOID:3973 diagnostic;prognostic;risk 21733-1 PubMed:18073307 In patients with medullary carcinoma, the presence of RET M918T mutation is associated with increased probability of lymph node metastases. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M918T sequence variation in gene RET/NCBI:5979 2370 check_entity AN5697-1 RET M918T mutation RET NCBI:5979 gene thyroid gland medullary carcinoma DOID:3973 diagnostic;prognostic;risk 21733-1 PubMed:21422803 Medullary thyroid cancer cells with RET M918T mutation are insensitive to motesanib, compared to wild-type RET. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M918T sequence variation in gene RET/NCBI:5979 2370 check_entity AN5697-1 RET M918T mutation RET NCBI:5979 gene thyroid gland medullary carcinoma DOID:3973 diagnostic;prognostic;risk 21733-1 PubMed:23056499 The use of AZD1480 on RET-mutated/rearranged cell lines in vitro led to strong repression of tyroid cancer cell growth. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M918T sequence variation in gene RET/NCBI:5979 2370 check_entity AN5697-1 RET M918T mutation RET NCBI:5979 gene thyroid gland medullary carcinoma DOID:3973 diagnostic;prognostic;risk 21733-1 PubMed:9839497 Compared to those who harbor a wild type RET, patients with RET M918T mutation develop larger and more aggressive medullary thyroid cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M918T sequence variation in gene RET/NCBI:5979 2370 check_entity AN5697-1 RET M918T mutation RET NCBI:5979 gene thyroid gland medullary carcinoma DOID:3973 diagnostic;prognostic;risk 21733-1 PubMed:20368568 In a phase 2 clinical trial of sorafenib in patients with hereditary or sporadic advanced medullary thyroid cancer, 10 out of 12 patients genotyped in arm B (sporadic MTC) tested positive for RET mutations. In response to sorafenib, 8 patients with RET M918T mutations had stable disease, 1 RET M918T mutant had partial response, and 1 patient with a RET C634R mutation had stable disease. Prior to study entry, all patients with RET M918T mutations had progressive disease or were newly diagnosed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M918T sequence variation in gene RET/NCBI:5979 2370 check_entity AN5697-1 RET M918T mutation RET NCBI:5979 gene thyroid gland medullary carcinoma DOID:3973 diagnostic;prognostic;risk 21733-1 PubMed:27525386 In this retrospective analysis of a phase 3 trial of cabozantinib or placebo in 330 patients. Among those, 51.2% were RET mutation-positive (38.2% with RET M918T), 34.8% were RET mutation-unknown, and 13.9% were RET mutation-negative. Sixteen patients were RAS mutation-positive. Cabozantinib appeared to prolong PFS versus the placebo in the RET mutation-positive subgroup (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.14-0.38; P < .0001). Patients in a RET mutation-negative population showed relatively smaller benefits from cabozantinib (HR 0.53). The RET M918T subgroup achieved the greatest observed PFS benefit from cabozantinib versus the placebo (HR 0.15). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M918T sequence variation in gene RET/NCBI:5979 2370 check_entity AN5697-1 RET M918T mutation RET NCBI:5979 gene thyroid gland medullary carcinoma DOID:3973 diagnostic;prognostic;risk 21733-1 CIViC:113 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M918T sequence variation in gene RET/NCBI:5979 2370 check_entity AN5698-1 RET Mutation RET NCBI:5979 gene thyroid gland medullary carcinoma DOID:3973 risk 21733-1 PubMed:32846061 In this international phase 1/2 trial (NCT03157128), 55 RET-mutant medullary thyroid cancer patients who had previously received the multi-kinase inhibitors vandetanib and/or cabozantinib received the highly selective RET-inhibitor selpercatinib. Response in this previously treated population was 69% (95% CI, 55 to 81) with 5 complete responses (CR) and 33 partial responses (PR). The 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the response rate was 73% (95% CI, 62 to 82) with 10 CR and 54 PR. The 1-year progression-free survival was 92% (95% CI, 82 to 97). The most frequent RET mutations overall included RET M918T (57%)in the kinase domain, RET mutations in extracellular cysteines residues at positions 609, 611, 618, 620, 630, and 634 (19%), and the RET V804M/L (7.6%) gatekeeper mutation. Responses were seen across all qualifying RET mutations including the V804M/L gatekeeper which is an acquired resistance mechanism seen with vandetanib and cabozantinib treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene RET/NCBI:5979 2371 check_entity AN5698-1 RET Mutation RET NCBI:5979 gene thyroid gland medullary carcinoma DOID:3973 risk 21733-1 CIViC:1598 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene RET/NCBI:5979 2371 check_entity AN5699-1 RET Overexpression RET NCBI:5979 gene breast cancer DOID:1612 risk 21733-1 PubMed:26686064 Vandetanib was tested in 4 murine models of patient-derived xenografts. In xenografts with high expression of EGFR or RET, vandetanib led to tumor regression, in those without high expression, vandetanib slowed tumor growth. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene RET/NCBI:5979 2372 AN5699-1 RET Overexpression RET NCBI:5979 gene breast cancer DOID:1612 risk 21733-1 CIViC:593 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene RET/NCBI:5979 2372 AN5699-2 RET Overexpression RET NCBI:5979 gene lung adenocarcinoma DOID:3910 prognostic 21733-1 PubMed:24037524 ASCL1 and RET mRNA levels were examined by microarray analysis in lung cancer samples. High expression of RET (RET-high) correlated with shorter overall survival compared to the RET-low group in patients with ASCL1 expression in stage I (P=0.007, N=15 vs 38) and all adenocarcinoma (P=0.037, N=31 vs 58). However, expression of RET did not affect survival in the ASCL1- tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene RET/NCBI:5979 2373 AN5699-2 RET Overexpression RET NCBI:5979 gene lung adenocarcinoma DOID:3910 prognostic 21733-1 CIViC:593 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene RET/NCBI:5979 2373 AN5699-3 RET Overexpression RET NCBI:5979 gene papillary adenocarcinoma DOID:3112 risk 21733-1 PubMed:20696054 A 78-year-old man presented with oral papillary adenocarcinoma and lung metastases that were refractory to standard treatment. Tumor sequencing showed increased MAPK activity due to RET over-expression and PTEN deletion, therefore sunitinib (RET inhibitor) was initiated. After 28 days post-administration, the lung metastases decreased in size by 22% (28mm to 21mm) and no new metastatic lesions had appeared. After 4 months, the patient grew resistant to treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene RET/NCBI:5979 2374 AN5699-3 RET Overexpression RET NCBI:5979 gene papillary adenocarcinoma DOID:3112 risk 21733-1 CIViC:593 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene RET/NCBI:5979 2374 AN5700-1 RET V804M mutation RET NCBI:5979 gene thyroid gland medullary carcinoma DOID:3973 risk 21733-1 PubMed:161573 In this phase 1 trial, 57 patients were treated with the selective RET Inhibitor selpercatinib (LOXO-292). A 57-year-old male with a hereditary RET V804M gatekeeper mutation treated with 3 prior multi-kinase inhibitors had a complete response that remained in effect at 6 months. Significant decreases in calcitonin and CEA were noted. Drug dosing was initiated at 80 mg BID and escalated to 120 mg BID by the time of the CR confirmation and then further increased to 160 mg BID. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V804M sequence variation in gene RET/NCBI:5979 2375 check_entity AN5700-1 RET V804M mutation RET NCBI:5979 gene thyroid gland medullary carcinoma DOID:3973 risk 21733-1 CIViC:2441 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V804M sequence variation in gene RET/NCBI:5979 2375 check_entity AN5701-1 RHOA MUTATION RHOA NCBI:387 gene stomach carcinoma DOID:5517 prognostic PubMed:27313181 285 intestinal-type tumors and 183 diffuse-type tumors were evaluated for mutational profiles. RHOA mutations are associated with diffuse type mucinous gastric carcinoma, which indicate worse prognosis when compared to intestinal type (p<0.001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene RHOA/NCBI:387 2376 check_entity AN5701-1 RHOA MUTATION RHOA NCBI:387 gene stomach carcinoma DOID:5517 prognostic CIViC:661 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene RHOA/NCBI:387 2376 check_entity AN5702-1 RICTOR Amplification RICTOR NCBI:253260 gene lung adenocarcinoma DOID:3910 risk PubMed:26370156 Study describes an 18 year old never smoker patient presenting with lung adenocarcinoma. A genomic profiling assay (FoundationOne) revealed a 7-copy amplification of RICTOR as the only somatic alteration. RICTOR amplification was confirmed via FISH and IHC. On two separate treatments with dual mTOR1/2 inhibitors patient exhibited stable disease for more than 18 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene RICTOR/NCBI:253260 2377 AN5702-1 RICTOR Amplification RICTOR NCBI:253260 gene lung adenocarcinoma DOID:3910 risk CIViC:569 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene RICTOR/NCBI:253260 2377 AN5702-2 RICTOR Amplification RICTOR NCBI:253260 gene lung small cell carcinoma DOID:5409 risk PubMed:173496 In a phase 2 basket trial, patients with small-cell lung carcinoma (SLC) who failed platinum-based chemotherapy and harbored RICTOR amplification were treated with mTOR 1/2 inhibitor vistusertib (AZD2014). Among 4 patients enrolled in this study, no patients showed tumor response or disease control. Progression free survival was 1.25 months, and three patients experienced adverse effects grade 3 or greater. Authors conclude that further development of the tested AZD2014 regimen is not warranted. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene RICTOR/NCBI:253260 2378 AN5702-2 RICTOR Amplification RICTOR NCBI:253260 gene lung small cell carcinoma DOID:5409 risk CIViC:569 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene RICTOR/NCBI:253260 2378 AN5703-1 RIT1 Mutation RIT1 NCBI:6016 gene lung adenocarcinoma DOID:3910 risk 57990-4 PubMed:24469055 'RIT1 mutations were identified in approx. 2% of lung adenocarcinomas (5/87 in the ''oncogene negative'' samples of TCGA - no RIT1 mutations were observed in 143 samples with a known driver mutation). GDC-0941 impaired tumor growth of NCI-H2110 (RIT1 M90I mutated) xenografts in nude mice. GDC-0941 and AZD-6244 (selumetinib) impaired colony formation in-vitro. Combined PI3K/MEK inhibition was more effective than single agent treatment in-vitro.' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene RIT1/NCBI:6016 2379 check_entity AN5703-1 RIT1 Mutation RIT1 NCBI:6016 gene lung adenocarcinoma DOID:3910 risk 57990-4 CIViC:293 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene RIT1/NCBI:6016 2379 check_entity AN5704-1 RIT1 OVEREXPRESSION RIT1 NCBI:6016 gene endometrial cancer DOID:1380 prognostic 57990-4 PubMed:26617739 After preliminary studies in cell lines, GEO datasets and fresh frozen tissues, RIT1 expression was determined in 257 tumors and 31 normal tissues. Elevated expression of RIT1 was correlated with poorer overall survival, pathological type, clinical stage, grade and vascular invasion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene RIT1/NCBI:6016 2380 AN5704-1 RIT1 OVEREXPRESSION RIT1 NCBI:6016 gene endometrial cancer DOID:1380 prognostic 57990-4 CIViC:292 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene RIT1/NCBI:6016 2380 AN5705-1 ROBO4 EXPRESSION ROBO4 NCBI:54538 gene cancer DOID:162 risk PubMed:26956051 Biomarkers for Response to antiangiogenic treatment were screened for in hepatocellular cancer (n = 11), renal cell cancer (n = 7) and non-small cell lung cancer (n = 2). Increased expression of tumor endothelial markers: Robo4 and ECSCR, nonsignificantly correlated with prolonged antiangiogenic time to progression (ECSCR high = 275 days vs. ECSCR low = 92.5 days; p = 0.07 and for Robo4 high = 387 days vs. Robo4 low = 90.0 days; p = 0.08). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene ROBO4/NCBI:54538 2381 AN5705-1 ROBO4 EXPRESSION ROBO4 NCBI:54538 gene cancer DOID:162 risk CIViC:489 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene ROBO4/NCBI:54538 2381 AN5706-1 ROS1 CD74::ROS1 G2032R ROS1 NCBI:6098 gene lung adenocarcinoma DOID:3910 risk 48161-4 PubMed:23724914 Resistance to crizotinib developed in a patient with metastatic lung adenocarcinoma harboring a CD74-ROS1 rearrangement who had initially shown a dramatic response to treatment. An acquired G2032R mutation in the ROS1 kinase domain was observed in the resistant tumor, and was found to confer resistance to ROS1 kinase inhibition through steric interference with drug binding. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G2032R sequence variation in gene ROS1/NCBI:6098 2382 check_entity AN5706-1 ROS1 CD74::ROS1 G2032R ROS1 NCBI:6098 gene lung adenocarcinoma DOID:3910 risk 48161-4 CIViC:461 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G2032R sequence variation in gene ROS1/NCBI:6098 2382 check_entity AN5706-2 ROS1 CD74::ROS1 G2032R ROS1 NCBI:6098 gene lung non-small cell carcinoma DOID:3908 risk 48161-4 PubMed:25351743 Cabozantinib was assessed in the CD74-ROS1-mutant Ba/F3 cells and crizotinib-resistant patient-derived cancer cells (MGH047) harboring G2032R-mutated CD74-ROS1. It effectively inhibited the survival of CD74-ROS1 wild-type (WT) and resistant mutants harboring Ba/F3 and MGH047 cells. Furthermore, cabozantinib could overcome all the resistance by all newly identified secondary mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G2032R sequence variation in gene ROS1/NCBI:6098 2383 check_entity AN5706-2 ROS1 CD74::ROS1 G2032R ROS1 NCBI:6098 gene lung non-small cell carcinoma DOID:3908 risk 48161-4 PubMed:26372962 Preclinical study analyzing the efficacy of dual ROS1/ALK and more specific ROS1 inhibitors on cell lines (Ba/F3) expressing CD74-ROS1 with and without the G2032R mutation. Selective ROS1 inhibitors retained activity against the G2032R mutation (cabozatinib, foretinib), whereas dual ALK/ROS inhibitors (crizotinib, brigatinib, ceritinib, AZD3463) or ALK-selective inhibitors (alectinib) were ineffective. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G2032R sequence variation in gene ROS1/NCBI:6098 2383 check_entity AN5706-2 ROS1 CD74::ROS1 G2032R ROS1 NCBI:6098 gene lung non-small cell carcinoma DOID:3908 risk 48161-4 PubMed:25733882 Preclinical study of PF-06463922 in NSCLC in-vitro, in-vivo and in enzyme assays. PF-06463922 showed inhibition of kinase activity, cell viability and tumor growth in wild-type, G2032R and L2026M mutations in ROS1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G2032R sequence variation in gene ROS1/NCBI:6098 2383 check_entity AN5706-2 ROS1 CD74::ROS1 G2032R ROS1 NCBI:6098 gene lung non-small cell carcinoma DOID:3908 risk 48161-4 PubMed:25688157 ROS1 kinase domain mutations were assessed in two patients with stage IIIa/IV pulmonary adenocarcinoma and a cell line. The ROS1 G2032R mutation was identified in a crizotinib-resistant tumor from one of the patients harboring the CD74–ROS1 fusion. Expression of CD74–ROS1 G2032R in Ba/F3 cells conferred resistance to crizotinib combared to CD74–ROS1 (IC50=353.62+/-20.15 vs. 2.76+/-0.82). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G2032R sequence variation in gene ROS1/NCBI:6098 2383 check_entity AN5706-2 ROS1 CD74::ROS1 G2032R ROS1 NCBI:6098 gene lung non-small cell carcinoma DOID:3908 risk 48161-4 CIViC:461 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G2032R sequence variation in gene ROS1/NCBI:6098 2383 check_entity AN5707-1 ROS1 CD74::ROS1 G2101A ROS1 NCBI:6098 gene lung non-small cell carcinoma DOID:3908 risk 48161-4 PubMed:25688157 Ba/F3 cells expressing CD74–ROS1 G2101A showed resistance to crizotinib, compared with those expressing wild-type CD74–ROS1, and were sensitive to foretinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G2101A sequence variation in gene ROS1/NCBI:6098 2384 check_entity AN5707-1 ROS1 CD74::ROS1 G2101A ROS1 NCBI:6098 gene lung non-small cell carcinoma DOID:3908 risk 48161-4 CIViC:514 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G2101A sequence variation in gene ROS1/NCBI:6098 2384 check_entity AN5708-1 ROS1 CD74::ROS1 L2026M ROS1 NCBI:6098 gene lung non-small cell carcinoma DOID:3908 risk 48161-4 PubMed:25733882 Preclinical study of PF-06463922 in NSCLC in-vitro, in-vivo and in enzyme assays. BaF3 cells expressing CD74-ROS1 L2026M were more resistant to crizotinib treatment than wildtype CD74-ROS1 in both cell viability and ROS1 phosphorylation. Crizotinib was also less effective at inhibiting kinase activity in ROS1 with L2026M mutation than wildtype. In contrast, PF-06463922 was effectively inhibited the fusion harboring this mutation in these assays. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L2026M sequence variation in gene ROS1/NCBI:6098 2385 check_entity AN5708-1 ROS1 CD74::ROS1 L2026M ROS1 NCBI:6098 gene lung non-small cell carcinoma DOID:3908 risk 48161-4 PubMed:25688157 Ba/F3 cells expressing CD74–ROS1 L2026M mutation showed resistance to crizotinib (~10 fold higher IC50 value), compared with those expressing wild-type CD74–ROS1; however, showed similar sensitivity to foretinib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L2026M sequence variation in gene ROS1/NCBI:6098 2385 check_entity AN5708-1 ROS1 CD74::ROS1 L2026M ROS1 NCBI:6098 gene lung non-small cell carcinoma DOID:3908 risk 48161-4 CIViC:512 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L2026M sequence variation in gene ROS1/NCBI:6098 2385 check_entity AN5709-1 ROS1 CD74::ROS1 L2155S ROS1 NCBI:6098 gene lung non-small cell carcinoma DOID:3908 risk 48161-4 PubMed:25688157 The L2155S mutation in ROS1 was identified in the HCC78CR1, -2 and -3 cell lines which harbor the SLC34A2–ROS1 rearrangement and in 2 patients with NSCLC with progressive disease following crizotinib treatment and CD74–ROS1 rearrangment. Crystal structure predicted ROS1 L2155S mutation to be highly destabilizating and cause protein structural modification. HCC78CR1, 2, and 3 cells and Ba/F3 cells transfected with CD74–ROS1 L2155S, showed resistance to crizotinib compared with parental HCC78 and Ba/F3 cells. In addition, these cell lines showed resistance to foretinib, a potent ROS1 inhibitor that is effective against ROS1 G2032R-mutant cells (16), and TAE684, a potent ALK inhibitor assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L2155S sequence variation in gene ROS1/NCBI:6098 2386 check_entity AN5709-1 ROS1 CD74::ROS1 L2155S ROS1 NCBI:6098 gene lung non-small cell carcinoma DOID:3908 risk 48161-4 CIViC:513 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L2155S sequence variation in gene ROS1/NCBI:6098 2386 check_entity AN5710-1 ROS1 Fusion ROS1 NCBI:6098 gene lung non-small cell carcinoma DOID:3908 risk 48161-4 PubMed:30980071 In the ongoing phase 1 study PROFILE 1001, NSCLC patients with ROS1 rearrangement confirmed by FISH or RT-PCR received crizotinib 250mg twice daily. Among 53 patients, the ORR was 72% (95% CI, 58% to 83%), with 6 complete responses and 32 partial responses. The median duration of response was 24.7 months (95% CI, 15.2-45.3), mPFS was 19.3 months (95% CI, 15.2-39.1) and mOS was 51.4 months (95% CI, 29.3 to not reached). Most treatment related adverse events (TRAEs) were grade 1 or 2, with no grade 4 or 5 TRAEs being reported. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ROS1/NCBI:6098 2387 check_entity AN5710-1 ROS1 Fusion ROS1 NCBI:6098 gene lung non-small cell carcinoma DOID:3908 risk 48161-4 PubMed:31838015 Describes a meta-analysis of three separate phase I or II trials: ALKA-372-001, STARTRK-1, and STARTRK-2. All of these evaluate entrectinib in ROS-1 fusion-positive NSCLC (locally advanced or metastatic, no previous ROS1 tyrosine kinase inhibitors). 41/53 patients had objective response (77%; 95% CI 64—88). Median duration of response was 24·6 months (95% CI 11·4–34·8) with median follow-up of 15·5 months (IQR 13·4–20·2). Fusions included: CD74-ROS1 (21), SLC34A2-ROS1 (7), SDC4-ROS1 (6), EZR-ROS1 (5), TPM3-ROS1 (2), and unknown partner because results were only from FISH (12). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ROS1/NCBI:6098 2387 check_entity AN5710-1 ROS1 Fusion ROS1 NCBI:6098 gene lung non-small cell carcinoma DOID:3908 risk 48161-4 CIViC:2562 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene ROS1/NCBI:6098 2387 check_entity AN5706-1 ROS1 G2032R mutation ROS1 NCBI:6098 gene lung adenocarcinoma DOID:3910 risk 48161-4 PubMed:23724914 Resistance to crizotinib developed in a patient with metastatic lung adenocarcinoma harboring a CD74-ROS1 rearrangement who had initially shown a dramatic response to treatment. A biopsy of a resistant tumor showed an acquired G2032R mutation in the ROS1 kinase domain. Although this mutation does not lie at the gatekeeper residue, it confers resistance to ROS1 kinase inhibition through steric interference with drug binding. The same resistance mutation was observed at all the metastatic sites that were examined at autopsy, suggesting that this mutation was an early event in the clonal evolution of resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G2032R sequence variation in gene ROS1/NCBI:6098 2388 check_entity AN5706-1 ROS1 G2032R mutation ROS1 NCBI:6098 gene lung adenocarcinoma DOID:3910 risk 48161-4 CIViC:1245 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G2032R sequence variation in gene ROS1/NCBI:6098 2388 check_entity AN5712-1 ROS1 GOPC::ROS1 mutation ROS1 NCBI:6098 gene glioblastoma DOID:3068 risk 48161-4 PubMed:30171048 Ectopic expression of GOPC–ROS1 in Ba/F3 cells induced cytokine-independent growth whereas overexpression of ROS1 alone did not. Using a series of tyrosine kinase inhibitors, lorlatinib was the most effective inhibitor of cytokine-independent growth. The glioblastoma cell line U118MG was shown to have the GOPC–ROS1 fusion. Lorlatinib and other TKIs were unable to inhibit growth of U118MG in standard growth assays (2D). However, lorlatinib did induce cell death in both ultra-low attachment dishes and spheroid assays, and significantly increased overall survival in an orthotopic intracranial xenograft model using this cell line (N=4) compared to mice on vehicle alone (N=4, p<0.001, ANOVA). Authors postulated that cell adhesion permitted sufficient to bypass survival signaling. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::GOPC::ROS1 sequence variation in gene ROS1/NCBI:6098 2389 check_entity AN5712-1 ROS1 GOPC::ROS1 mutation ROS1 NCBI:6098 gene glioblastoma DOID:3068 risk 48161-4 CIViC:2639 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::GOPC::ROS1 sequence variation in gene ROS1/NCBI:6098 2389 check_entity AN5713-1 ROS1 Rearrangement ROS1 NCBI:6098 gene bronchiolo-alveolar adenocarcinoma DOID:4926 risk 48161-4 PubMed:22215748 Study describes a 31-year old male, never-smoker patient with advanced NSCLC with a ROS1 rearrangement. The patient was treated with crizotinib with marked response at 1 week and resolution of the tumor confirmed at 8 and 12 weeks via CT-scans. It was also demonstrated that crizotinib inhibits ROS1 phosphorylation in HEK 293 cells transfected with a CD14-ROS1 fusion gene, and crizotinib inhibited growth in the HCC78 cell line containing a ROS1 rearrangement to a similar degree as ALK-fusion positive cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene ROS1/NCBI:6098 2390 check_entity AN5713-1 ROS1 Rearrangement ROS1 NCBI:6098 gene bronchiolo-alveolar adenocarcinoma DOID:4926 risk 48161-4 CIViC:265 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene ROS1/NCBI:6098 2390 check_entity AN5713-2 ROS1 Rearrangement ROS1 NCBI:6098 gene cancer DOID:162 risk 48161-4 PubMed:28183697 Two phase I studies included 119 patients with advanced or metastatic solid tumors, which included 28 patients with ROS1 rearrangements (n=28) where the overall safety and antitumor activity of entrectinib was examined. Entrectinib was shown to be safe and well tolerated. For phase 2, 14 ROS1-rearranged solid tumors were eligible and demonstrated an overall objective response rate of 86% (95% CI: 60–96) to entrectinib. Of the 14, 13 were Non-small cell lung cancer cases, 12 of which showed response with 2 of these patients demonstrated a complete response. A single melanoma case with a ROS1 rearrangement also showed a response to treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene ROS1/NCBI:6098 2391 check_entity AN5713-2 ROS1 Rearrangement ROS1 NCBI:6098 gene cancer DOID:162 risk 48161-4 PubMed:35233056 This clinical study was conducted on patients harboring either ROS1 or ALK rearrangements, and were treated with Crizotinib. The two sub-protocols F(ALK rearrangements) and G(ROS1 rearrangements) had 4 evaluable patients each. Sub-protocols F and G had the response rates of 50% (90% CI; 9.8%-90.2%), and 25% (90% CI; 1.3-75.1) respectively. The PFS for sub-protocol F was 3.8 months and that for sub-protocol G was 4.3 months. Median overall survival for the sub-protocols F and G were 4.8 months and 6.2 months respectively. The study suggested modest antitumor activity for both the sub-protocols. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene ROS1/NCBI:6098 2391 check_entity AN5713-2 ROS1 Rearrangement ROS1 NCBI:6098 gene cancer DOID:162 risk 48161-4 CIViC:265 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene ROS1/NCBI:6098 2391 check_entity AN5713-2 ROS1 Rearrangement ROS1 NCBI:6098 gene cancer DOID:162 risk 48161-4 CIViC:4708 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene ROS1/NCBI:6098 2391 check_entity AN5713-3 ROS1 Rearrangement ROS1 NCBI:6098 gene colorectal adenocarcinoma DOID:0050861 risk 48161-4 PubMed:24296758 A tissue microarray of 268 patients with histologically confirmed colorectal adenocarcinoma was performed to search for ROS1 gene fusion events to guide potential targeted therapy in future cases. Break apart FISH assay, which does not distinguish ROS1-fusion partner, was used on the tissue microarray to determine ROS1 fusion status. 2 cases of ROS1 fusions were found. 1 case was verified by RT-PCR to be a SLC34A2-ROS1 fusion, but this case was also positive for BRAF V600E. The second case of ROS1 fusion was of undetermined fusion partner, where known ROS1 fusion parters SLC34A2, CD74 and SDC4 were tested. This case did not have KRAS or BRAF mutations, indicating that ROS1 fusion may act in a small subset of colorectal cancer as a driver targetable by crizotinib or other inhibitors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene ROS1/NCBI:6098 2392 check_entity AN5713-3 ROS1 Rearrangement ROS1 NCBI:6098 gene colorectal adenocarcinoma DOID:0050861 risk 48161-4 CIViC:265 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene ROS1/NCBI:6098 2392 check_entity AN5713-4 ROS1 Rearrangement ROS1 NCBI:6098 gene lung adenocarcinoma DOID:3910 risk 48161-4 PubMed:26917690 'Case report of a 77-year old male patient with lung adenocarcinoma (T2aN1M0, stage IIA) without EGFR, KRAS, or BRAF mutations, and no ALK gene rearrangement. CD72-ROS1 was identified in sequencing after progression on chemotherapy. Crizotinib at 250 mg orally twice daily led to resolution of metastatic disease. The patient remained disease-free for 13 months when a CT-scan showed a relapse with two nodules in the right lower lobe. Stereotactic radiation therapy, gamma knife radiosurgery, and ipilimumab did not lead to a relevant response (new pleural nodules, new intracranial metastases). The patient next received ceritinib on a “Signature Trial'' for tumors with aberrations in ALK or ROS1 that are treated with oral ceritinib (LDK378) at 750 mg daily (NCT02186821). Restaging scans after two cycles showed a partial response confirmed after four cycles (56% decrease) per RECIST1.1. MRI showed that his brain metastases decreased as well.' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene ROS1/NCBI:6098 2393 check_entity AN5713-4 ROS1 Rearrangement ROS1 NCBI:6098 gene lung adenocarcinoma DOID:3910 risk 48161-4 PubMed:25922291 In an evaluation of a patient and never smoker with crizotinib-sensitive lung adenocarcinoma, an SDC4-ROS1 rearrangement was identified using comprehensive genomic profiling. The patient attained a decrease in RESIST target lesions by 26.8% (stable disease); however, the patient relapsed 4 months later. This patient also harbored a TP53 mutation, MCL1 amplification and CDKN2A deletion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene ROS1/NCBI:6098 2393 check_entity AN5713-4 ROS1 Rearrangement ROS1 NCBI:6098 gene lung adenocarcinoma DOID:3910 risk 48161-4 CIViC:265 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene ROS1/NCBI:6098 2393 check_entity AN5713-5 ROS1 Rearrangement ROS1 NCBI:6098 gene lung non-small cell carcinoma DOID:3908 risk 48161-4 PubMed:25264305 An expansion cohort of a phase-1 Crizotinib study found a 72% objective response rate among 50 patients with ROS1 rearrangement. The study did not compare to patients without rearrangement that were treated with Crizotinib. Several different ROS1 fusion partners were identified, but no clinical differences in outcome were associated with the identity of the 5' partner. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene ROS1/NCBI:6098 2394 check_entity AN5713-5 ROS1 Rearrangement ROS1 NCBI:6098 gene lung non-small cell carcinoma DOID:3908 risk 48161-4 PubMed:25667280 In a retrospective study, 30 patients were evaluated after crizotinib treatment for stage IV NSCLC confirmed for ROS1 rearrangement. On crizotinib, 24 of the patients achieved objective responses including 5 complete responses. Median progression free survival was 9.1 months and all patients had been pretreated with 1 or more lines of chemotherapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene ROS1/NCBI:6098 2394 check_entity AN5713-5 ROS1 Rearrangement ROS1 NCBI:6098 gene lung non-small cell carcinoma DOID:3908 risk 48161-4 PubMed:29596029 A phase 2 clinical trial studied the efficacy of Crizotinib in East Asian NSCLC patients positive for ROS1 rearrangements (detected by RT-PCR AmoyDx assay) and negative for ALK1 rearrangements. Of the 127 patients enrolled, 17 achieved complete response and 74 achieved partial response. Overall response rate by independent radiology review was 71.7% (95% CI 63-79.3%) Time to response was rapid (median 1.9 months) and durable (Duration of response median 19.7 months). Median progression free survival was 15.9 months. Crizotinib was clinically beneficial regardless of demographics and prior therapy. Based on these results, Crizotinib was approved for the treatment of ROS1 positive NSCLC in 2017 in Japan, Taiwan, China, and Korea. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene ROS1/NCBI:6098 2394 check_entity AN5713-5 ROS1 Rearrangement ROS1 NCBI:6098 gene lung non-small cell carcinoma DOID:3908 risk 48161-4 CIViC:265 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene ROS1/NCBI:6098 2394 check_entity AN5714-1 ROS1 TFG::ROS1 mutation ROS1 NCBI:6098 gene inflammatory myofibroblastic tumor DOID:0050905 risk 48161-4 PubMed:24875859 Case report of a pediatric patient with treatment-refactory inflammatory myofibroblastic tumor negative for ALK expression and rearrangement. Next generation sequencing of the patient revealed a TFG-ROS1 fusion. CT scans after 3 cycles of crizotinib treatment showed a reduction of the tumor mass which continued to decrease at the time of publication after 4 months of crizonitib treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::TFG::ROS1 sequence variation in gene ROS1/NCBI:6098 2395 check_entity AN5714-1 ROS1 TFG::ROS1 mutation ROS1 NCBI:6098 gene inflammatory myofibroblastic tumor DOID:0050905 risk 48161-4 CIViC:572 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::TFG::ROS1 sequence variation in gene ROS1/NCBI:6098 2395 check_entity AN5715-1 RPS6 PHOSPHORYLATION RPS6 NCBI:6194 gene gastric adenocarcinoma DOID:3717 risk 35290-6 PubMed:22343617 54 patients with advanced gastric cancer were treated with everolimus. Two patient responsed and potential biomarkers were explored. High pre-treatment expression of phosphorylated RPS6 (pS6; at Ser240/4) was associated with higher disease control rate and progression free survival (P=0.043, P=0.001 respectively; N=28). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition RPS6 PHOSPHORYLATION [biomarker_term_in_review] 2396 not_mapped AN5715-1 RPS6 PHOSPHORYLATION RPS6 NCBI:6194 gene gastric adenocarcinoma DOID:3717 risk 35290-6 CIViC:391 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition RPS6 PHOSPHORYLATION [biomarker_term_in_review] 2396 not_mapped AN5716-1 RRM1 Overexpression RRM1 NCBI:6240 gene pancreatic cancer DOID:1793 risk PubMed:17224927 The mRNA expression level of RRM1 was analyzed by RT-PCR in 3 human pancreatic cancer cell lines cultured in incrementally increased concentrations of gemcitabine. Expression levels of RRM1 progressively increased during the development of gemcitabine resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene RRM1/NCBI:6240 2397 AN5716-1 RRM1 Overexpression RRM1 NCBI:6240 gene pancreatic cancer DOID:1793 risk CIViC:773 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene RRM1/NCBI:6240 2397 AN5717-1 RRM1 Underexpression RRM1 NCBI:6240 gene lung non-small cell carcinoma DOID:3908 risk PubMed:24595080 In the personalized therapy group of this study, patients received chemotherapy based on RRM-1 IHC expression levels, whereas the standard therapy group received non-customized chemotherapy. There were statistically significant improvements between the personalized therapy group versus the standard therapy group in disease control rate (82.9% vs 55.3%, P=0.004), and progression-free survival (median: 5.5 months vs 3.0 months, P=0.005). Besides, the overall survival had a tendency to become more prolonged (median: 16.0 months vs 12.4 months, P=0.286). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene RRM1/NCBI:6240 2398 AN5717-1 RRM1 Underexpression RRM1 NCBI:6240 gene lung non-small cell carcinoma DOID:3908 risk PubMed:24647522 In this study, 229 tumors were analyzed for RRM1 expression. This resulted in 146 that were negative for RRM1 expression and 83 that were positive. These tumors were studied for a relationship between RRM1 expression and chemotherapy regimens, gemcitabine, docetaxel and carboplatin, and vinorelbine and carboplatin. In the patients receiving gemcitabine treatment, the progression-free survival of RRM1-negative patients was significantly higher than that of RRM1-positive patients (8.8 months vs. 7.6 months, P = 0.01). The patients that were positive for RRM1 expression, had a better response to docetaxel or vinorelbine treatment than gemcitabine (P=0.047 and P=0.047). However, there were no differences of response to docetaxel and vinorelbine in regards to RRM1 expression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene RRM1/NCBI:6240 2398 AN5717-1 RRM1 Underexpression RRM1 NCBI:6240 gene lung non-small cell carcinoma DOID:3908 risk PubMed:23038758 The study began with a total of 443 patients that were randomly assigned to either regimen A (Paclitaxel and cisplatin with gemcitabine) or regimen B ( cisplatin and vinorelbine). Of those patients, 261 had tissue available for RRM1 evaluation. In regimen B, survival increased significantly in patients with low RRM1 expression as compared to those with a high expression (P=0.046). However, in regimen A, the increase in survival for patients with low RRM1 expression as opposed to those with a high RRM1 expression was not as significant (P=0.366). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene RRM1/NCBI:6240 2398 AN5717-1 RRM1 Underexpression RRM1 NCBI:6240 gene lung non-small cell carcinoma DOID:3908 risk PubMed:19884554 As part of a randomized phase III trial (USO-03012) in advanced NSCLC of gemcitabine vs. combination gemcitabine and carboplatin, protein expression levels for RRM1 (n=69) and ERCC1 (n=65) were evaluated using fluorescence-based IHC. RRM1 levels were significantly inversely correlated with response (r = −0.41; P = .001, n=58), as were ERCC1 levels (r = −0.39; P = .003, n=55). RRM1 and ERCC1 levels were correlated with each other (r = 0.36; P = .003, n=65). There was no significant interaction with treatment arm (P = .64 for RRM1; P = .79 for ERCC1). The authors conclude that RRM1 and ERCC1 expression levels are predictive of response to gemcitabine, and gemcitabine and carboplatin. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene RRM1/NCBI:6240 2398 AN5717-1 RRM1 Underexpression RRM1 NCBI:6240 gene lung non-small cell carcinoma DOID:3908 risk CIViC:1231 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene RRM1/NCBI:6240 2398 AN5717-2 RRM1 Underexpression RRM1 NCBI:6240 gene pancreatic cancer DOID:1793 risk PubMed:19543324 There were 68 patients enrolled in this study, 28 of which were treated with gemcitabine. Of those 28, 14 patients had a low RRM1 expression and 14 had a high RRM1 expression. Only the patients with low RRM1 expression received a significant benefit from gemcitabine (p=0.0010) whereas the benefit for those with a high RRM1 expression was not significantly better (p=0.3309). The study also tested the role of ERCC1 expression and its correlation to RRM1 expression. It was found that patients with a combined high RRM1 and ERCC1 expression had good prognosis with the highest survival rate (P=0.0127). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene RRM1/NCBI:6240 2399 AN5717-2 RRM1 Underexpression RRM1 NCBI:6240 gene pancreatic cancer DOID:1793 risk PubMed:17131328 In this study, human pancreatic carcinoma cell line MiaPaCa2, which is a gemcitabine-sensitive cell line, was used for the establishment of chemoresistant cells MiaPaCa2-RG. Analysis for identifying genetic alterations relating to gemcitabine resistance revealed that RRM1 was the most upregulated gene with a 4.5 fold expression. RRM1-specific RNAi transfection significantly reduced the gemcitabine chemoresistance of MiaPaCa2-RG to the same level as that of gemcitabine sensitive MiaPaCa2. Moreover, gemcitabine response of MiaPaCa2 also became more sensitive. Next, patients with pancreatic cancer were recruited and 18 tissue samples were taken. The patients with a low RRM1 expression had a significantly better outcome after gemcitabine treatment than those patients with high RRM1 expression (P=0.016). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene RRM1/NCBI:6240 2399 AN5717-2 RRM1 Underexpression RRM1 NCBI:6240 gene pancreatic cancer DOID:1793 risk CIViC:1231 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene RRM1/NCBI:6240 2399 AN5718-1 RRM2 OVEREXPRESSION RRM2 NCBI:6241 gene pancreatic cancer DOID:1793 risk 94080-9 PubMed:17224927 The mRNA expression level of RRM2 was analyzed by RT-PCR in 3 human pancreatic cancer cell lines cultured in incrementally increased concentrations of gemcitabine. Expression levels of RRM2 progressively increased during the development of gemcitabine resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene RRM2/NCBI:6241 2400 AN5718-1 RRM2 OVEREXPRESSION RRM2 NCBI:6241 gene pancreatic cancer DOID:1793 risk 94080-9 CIViC:774 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene RRM2/NCBI:6241 2400 AN5719-1 RSF1 Amplification RSF1 NCBI:51773 gene breast cancer DOID:1612 risk 40463-2 PubMed:24367492 In retrospective study, 413 patients were assessed for RSF1 amplification. 28 patients with RSF1 amplification did not show a benefit from adjuvant tamoxifen compared to placebo (12 treated vs 16 placebo). 381 patients without amplification did show a benefit compared to placebo (187 treated vs 194 placebo). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene RSF1/NCBI:51773 2401 AN5719-1 RSF1 Amplification RSF1 NCBI:51773 gene breast cancer DOID:1612 risk 40463-2 CIViC:354 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene RSF1/NCBI:51773 2401 AN5720-1 RUNX1 A107P mutation RUNX1 NCBI:861 gene acute myeloid leukemia DOID:9119 diagnostic PubMed:12060124 A pedigree of 3 generations and 8 individuals with familial platelet disease with propensity to acute myeloid leukemia (FPD/AML) was assessed for mutation in RUNX1 exons 3, 4, 5 and 6. Mutation was found in DNA binding RUNT domain at amino acid 107 from alanine to proline. This mutation was found in 5/8 individuals with FPD/AML but not in 3/8 unaffected individuals as well as 10 unrelated control samples. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A107P sequence variation in gene RUNX1/NCBI:861 2402 check_entity AN5720-1 RUNX1 A107P mutation RUNX1 NCBI:861 gene acute myeloid leukemia DOID:9119 diagnostic CIViC:785 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A107P sequence variation in gene RUNX1/NCBI:861 2402 check_entity AN5721-1 RUNX1 D198Y mutation RUNX1 NCBI:861 gene acute myeloid leukemia DOID:9119 diagnostic PubMed:11675361 In a pedigree with familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML) spanning three generations, five members of generation II were sequenced at exons 3, 4 and 5 of the RUNX1 (or CBFA2) gene and the D198Y mutation (in the DNA binding RUNT domain) was found in 3/5 of the individuals with FPD/AML but not in 2/5 without FPD/AML. The mutation was not found in 108 control subjects. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D198Y sequence variation in gene RUNX1/NCBI:861 2403 check_entity AN5721-1 RUNX1 D198Y mutation RUNX1 NCBI:861 gene acute myeloid leukemia DOID:9119 diagnostic CIViC:784 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D198Y sequence variation in gene RUNX1/NCBI:861 2403 check_entity AN5722-1 RUNX1 K83E mutation RUNX1 NCBI:861 gene acute myeloid leukemia DOID:9119 diagnostic PubMed:11830488 A pedigree of 48 individuals with multiple instances of bleeding and platelet disorders and 8 cases of leukemia showed an A>G substitution in RUNX1 exon 3 which segregated with Familial Platelet Disorder and Acute Myeloid Leukemia. The mutation was not present in 188 unrelated control chromosomes. Functional assay suggested the mutant RUNX1 transcription factor had impaired DNA binding. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K83E sequence variation in gene RUNX1/NCBI:861 2404 check_entity AN5722-1 RUNX1 K83E mutation RUNX1 NCBI:861 gene acute myeloid leukemia DOID:9119 diagnostic CIViC:780 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K83E sequence variation in gene RUNX1/NCBI:861 2404 check_entity AN5723-1 RUNX1 Mutation RUNX1 NCBI:861 gene acute lymphoblastic leukemia DOID:9952 prognostic PubMed:23341344 In univariate analysis, mutations in RUNX1 were significantly associated with shorter overall survival compared to wildtype RUNX1 in adult (18-87 years old) T-cell acute lymphoblastic leukemia (N=9 mutated, 62 wild type patients; P=0.014) and the early subtype (N=7 mutated, 23 wild type patients; P=0.027). RUNX1 mutations were associated with other poor-risk parameters, early subtype and older age. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene RUNX1/NCBI:861 2405 check_entity AN5723-1 RUNX1 Mutation RUNX1 NCBI:861 gene acute lymphoblastic leukemia DOID:9952 prognostic CIViC:155 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene RUNX1/NCBI:861 2405 check_entity AN5723-2 RUNX1 Mutation RUNX1 NCBI:861 gene acute myeloid leukemia DOID:9119 prognostic;risk PubMed:21343560 In non-APL patients with AML (age 18-60), those who had mutations in RUNX1 had significantly shorter relapse-free survival following conventional post-remission treatment (repetitive cycles of high-dose cytarabine) than those treated with an allogeneic hematopoietic stem-cell transplantation (N=32) at first remission (4-year RFS; 0% vs 52%; P<0.0001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene RUNX1/NCBI:861 2406 check_entity AN5723-2 RUNX1 Mutation RUNX1 NCBI:861 gene acute myeloid leukemia DOID:9119 prognostic;risk PubMed:22753902 In a study of patients with cytogenically normal acute myeloid leukemia, RUNX1 mutations were more frequent in patients 60 years old or older. Patients with RUNX1 mutations had shorter disease-free (younger, P = 0.058; older, P < 0.001), event-free (both, P < 0.001), and overall survival (younger, P = 0.003; older, P < 0.001) as well as lower complete remission rates (younger, P = 0.005; older, P = 0.006). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene RUNX1/NCBI:861 2406 check_entity AN5723-2 RUNX1 Mutation RUNX1 NCBI:861 gene acute myeloid leukemia DOID:9119 prognostic;risk PubMed:27137476 In patients with acute myeloid leukemia, those with RUNX1 mutations (n=245) had significantly worse outcomes when compared to those with RUNX1 wild-type alleles (n=2,194). The complete remission rate for patients with RUNX1 mutations was significantly lower (48.4% vs. 68.1%; p <0.0001), the refractory disease rate was significantly higher (40.6% 23.4%; p=0.03), the 5-year event free survival rate was significantly lower (9%, 24%; p<0.0001), the 5-year relapse free survival rate was significantly lower (22%, 36%; p=0.0007), and the 5-year overall survival rate was significantly lower (22%, 37%; p=0.0001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene RUNX1/NCBI:861 2406 check_entity AN5723-2 RUNX1 Mutation RUNX1 NCBI:861 gene acute myeloid leukemia DOID:9119 prognostic;risk CIViC:155 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene RUNX1/NCBI:861 2406 check_entity AN5724-1 RUNX1 R135FSX177 mutation RUNX1 NCBI:861 gene acute myeloid leukemia DOID:9119 diagnostic PubMed:11830488 A pedigree (Pedigree number 2) with familial platelet disorder and acute myeloid leukemia (FPD/AML) was studied and a one-base deletion was found in RUNX1 splice donor site. This resulted in use of a cryptic donor splice site and a novel transcript with frameshift, 41 novel amino acids and termination at codon 177. This mutation segregated with FDP/AML and was not found in 184 unrelated control chromosomes. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::r135fsx177:mutation sequence variation in gene RUNX1/NCBI:861 2407 check_entity AN5724-1 RUNX1 R135FSX177 mutation RUNX1 NCBI:861 gene acute myeloid leukemia DOID:9119 diagnostic CIViC:782 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::r135fsx177:mutation sequence variation in gene RUNX1/NCBI:861 2407 check_entity AN5725-1 RUNX1 T148HFSX9 mutation RUNX1 NCBI:861 gene acute myeloid leukemia DOID:9119 diagnostic PubMed:18478040 A 2 year old male presented with easy bruising and bleeding. At 6 years old he was diagnosed with AML. The patients mother showed mile thrombocytopenia. Sequencing of RUNX1 exons 3-6 revealed an 8 bp deletion which was hypothesized to result in a null allele. The mutation was found in the mother and son. The patient's maternal grandparents were haematologicaly normal. Relevant ACMG codes from this paper are 'PVS1' (frameshift/null variant) and 'PP1' (limited segregation data). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::t148hfsx9:mutation sequence variation in gene RUNX1/NCBI:861 2408 check_entity AN5725-1 RUNX1 T148HFSX9 mutation RUNX1 NCBI:861 gene acute myeloid leukemia DOID:9119 diagnostic CIViC:788 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::t148hfsx9:mutation sequence variation in gene RUNX1/NCBI:861 2408 check_entity AN5726-1 RUNX1 Y260* mutation RUNX1 NCBI:861 gene acute myeloid leukemia DOID:9119 diagnostic PubMed:11830488 A pedigree (Pedigree number 3) with 24 members with multiple instances of bleeding disorder and three cases of familial leukemia showed a C>A substitution in exon 7B of the transcription factor RUNX1. This mutation resulted in a nonsense mutation, and the mutation segregated with familial platelet disorder and acute myeloid leukemia in the pedigree. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y260* sequence variation in gene RUNX1/NCBI:861 2409 check_entity AN5726-1 RUNX1 Y260* mutation RUNX1 NCBI:861 gene acute myeloid leukemia DOID:9119 diagnostic CIViC:781 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y260* sequence variation in gene RUNX1/NCBI:861 2409 check_entity AN5727-1 SDHB p.193_196dupSTSC (c.577_588dupAGCACCAGCTGC) SDHB NCBI:6390 gene paraganglioma DOID:0050773 diagnostic 34510-8 PubMed:20193854 An in-frame duplication of 12 nucleotides resulting in the insertion of 4 amino acids within exon 6 of the SDHB gene was found in a single female case (a 13-year-old) with confirmed paraganglioma. The patient also exhibited refractory hypertension, sweating and headaches, and elevated norepinephrine concentrations in plasma and urine. The same mutation was in four other family members with no evidence of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.577_588dupAGCACCAGCTGC) sequence variation in gene SDHB/NCBI:6390 2410 check_entity AN5727-1 SDHB p.193_196dupSTSC (c.577_588dupAGCACCAGCTGC) SDHB NCBI:6390 gene paraganglioma DOID:0050773 diagnostic 34510-8 CIViC:2284 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.577_588dupAGCACCAGCTGC) sequence variation in gene SDHB/NCBI:6390 2410 check_entity AN5728-1 SETBP1 Exon 4 Mutation SETBP1 NCBI:26040 gene atypical chronic myeloid leukemia, BCR-ABL1 negative DOID:0060597 prognostic 100024-9 PubMed:23222956 Atypical Chronic Myeloid Leukemia has the same symptoms as CML, but it lacks the BCR-ABL1 fusion. Targeted sequencing of 70 aCML patients identified SETBP1 mutations between codons 858 and 871 in 24.3% of the patients. Patients with this mutation had a 22 month median survival compared to 77 months in aCML patients without the mutation (P=.01). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:4:mutation sequence variation in gene SETBP1/NCBI:26040 2411 check_entity AN5728-1 SETBP1 Exon 4 Mutation SETBP1 NCBI:26040 gene atypical chronic myeloid leukemia, BCR-ABL1 negative DOID:0060597 prognostic 100024-9 CIViC:346 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:4:mutation sequence variation in gene SETBP1/NCBI:26040 2411 check_entity AN5729-1 SETBP1 G870S mutation SETBP1 NCBI:26040 gene chronic myeloid leukemia DOID:8552 prognostic 100024-9 PubMed:23222956 Atypical Chronic Myeloid Leukemia has the same symptoms as CML, but it lacks the BCR-ABL1 fusion. The researchers transfected 293T cells with SETBP1 G870S, a variant found to be associated with poor prognosis in aCML, and found those cells had higher proliferation and higher expression of SET and SETBP1 proteins. This may be linked to the mutation abrogating a ubiquitination site. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G870S sequence variation in gene SETBP1/NCBI:26040 2412 check_entity AN5729-1 SETBP1 G870S mutation SETBP1 NCBI:26040 gene chronic myeloid leukemia DOID:8552 prognostic 100024-9 CIViC:347 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G870S sequence variation in gene SETBP1/NCBI:26040 2412 check_entity AN5730-1 SF3B1 K666N mutation SF3B1 NCBI:23451 gene breast cancer DOID:1612 risk 99129-9 PubMed:25424858 Mutations in SF3B1 were identified in 21/936 ER positive vs. 1/289 ER negative breast cancers. Mutation was recurrent (K700E in 74% or K666Q or K666E in another 9% of tumors). Treatment of two SF3B1 mutant cell lines (pancreatic and endometrial with K700 and K666 mutation, respectively) and six wild-type controls showed that mutant cell lines were significantly more sensitive to spliceostatin A (SF3b complex inhibitor). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K666N sequence variation in gene SF3B1/NCBI:23451 2413 check_entity AN5730-1 SF3B1 K666N mutation SF3B1 NCBI:23451 gene breast cancer DOID:1612 risk 99129-9 CIViC:114 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K666N sequence variation in gene SF3B1/NCBI:23451 2413 check_entity AN5731-1 SF3B1 K700E mutation SF3B1 NCBI:23451 gene breast cancer DOID:1612 risk 99129-9 PubMed:25424858 Mutations in SF3B1 were identified in 21/936 ER positive vs. 1/289 ER negative breast cancers. Mutation was recurrent (K700E in 74% or K666Q or K666E in another 9% of tumors). Treatment of two SF3B1 mutant cell lines (pancreatic and endometrial with K700 and K666 mutation, respectively) and six wild-type controls showed that mutant cell lines were significantly more sensitive to spliceostatin A (SF3b complex inhibitor). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K700E sequence variation in gene SF3B1/NCBI:23451 2414 check_entity AN5731-1 SF3B1 K700E mutation SF3B1 NCBI:23451 gene breast cancer DOID:1612 risk 99129-9 CIViC:561 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K700E sequence variation in gene SF3B1/NCBI:23451 2414 check_entity AN5731-2 SF3B1 K700E mutation SF3B1 NCBI:23451 gene leukemia DOID:1240 risk 99129-9 PubMed:35027467 The cancer-associated SF3B1-K700E mutation compromises homologous recombination repair and increases the sensitivity to ionising radiation and DNA damaging agents, such as etoposide or small molecule inhibitors including olaparib in isogenic K562 cell line. The SF3B1-WT and SF3B1-K700E cell lines were also engrafted subcutaneously into immunocompromised mice, and the mice were treated with etoposide, olaparib or a vehicle control and monitored tumour growth for 28 days. Treatment with either etoposide or olaparib significantly reduced the volume of the SF3B1-K700E mutant tumours, but had little effect on the volume of SF3B1-WT tumours. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K700E sequence variation in gene SF3B1/NCBI:23451 2415 check_entity AN5731-2 SF3B1 K700E mutation SF3B1 NCBI:23451 gene leukemia DOID:1240 risk 99129-9 CIViC:561 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K700E sequence variation in gene SF3B1/NCBI:23451 2415 check_entity AN5732-1 SF3B1 Mutation SF3B1 NCBI:23451 gene chronic lymphocytic leukemia DOID:1040 prognostic 99129-9 PubMed:23568491 In patients with chronic lymphocytic leukemia, those with mutations in SF3B1 had shorter time to treatment, progression-free survival, and overall survival. A majority of the mutations are in the C-terminal domain with the most frequent location being K700E (50% of reported cases). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene SF3B1/NCBI:23451 2416 check_entity AN5732-1 SF3B1 Mutation SF3B1 NCBI:23451 gene chronic lymphocytic leukemia DOID:1040 prognostic 99129-9 PubMed:23086750 In the randomized phase 3 UK LRF CCL4 trial comparing first-line treatment with chlorambucil, fludarabine, or fludarabine plus cyclophosphamide, SF3B1 mutations (73/437 patients) were associated with poorer overall survival (median 54.3 vs 79 months, P <0.001), independent of treatment. Additionally, controlling for cases with TP53 deletions/mutations, SF3B1 mutations were associated with reduced progression free survival for patients in the fludarabine plus cyclophosphamide treatment arm when compared to wildtype SF3B1 (29.4 vs 46 months, P=0.002). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene SF3B1/NCBI:23451 2416 check_entity AN5732-1 SF3B1 Mutation SF3B1 NCBI:23451 gene chronic lymphocytic leukemia DOID:1040 prognostic 99129-9 PubMed:24943832 In a multivariate analysis of 774 CLL patients, SF3B1 mutations were significantly correlated with shorter time to first treatment (HR=1.644; 95% CI=1.134-2.383). This finding was independent of IGHV mutation status. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene SF3B1/NCBI:23451 2416 check_entity AN5732-1 SF3B1 Mutation SF3B1 NCBI:23451 gene chronic lymphocytic leukemia DOID:1040 prognostic 99129-9 PubMed:26837699 In a study of 406 previously untreated CLL cases, a multivariate analysis indicated SF3B1 mutations (N=51) were significantly associated with reduced time to first treatment (HR: 1.73; 95%CI: 1.05-2.86; P = 0.031). While clonal mutations (VAF >= 12%) were associated with reduced time to first treatment by univariate analysis (N=28, P<0.0001), subclonal mutations were not (N=21, P=0.22). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene SF3B1/NCBI:23451 2416 check_entity AN5732-1 SF3B1 Mutation SF3B1 NCBI:23451 gene chronic lymphocytic leukemia DOID:1040 prognostic 99129-9 CIViC:215 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene SF3B1/NCBI:23451 2416 check_entity AN5732-2 SF3B1 Mutation SF3B1 NCBI:23451 gene myelodysplastic syndrome DOID:0050908 prognostic 99129-9 PubMed:21995386 Patients with SF3B1 mutations had a statistically significant longer overall survival as well as event free-survival. Both before and after adjustment for age, karyotype and sex. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene SF3B1/NCBI:23451 2417 check_entity AN5732-2 SF3B1 Mutation SF3B1 NCBI:23451 gene myelodysplastic syndrome DOID:0050908 prognostic 99129-9 CIViC:215 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene SF3B1/NCBI:23451 2417 check_entity AN5733-1 SGK1 Overexpression SGK1 NCBI:6446 gene breast cancer DOID:1612 risk PubMed:27451907 SGK1 mRNA expression was elevated in five breast cancer cell lines which were resistant to PI3Kalpha inhibitor alpelisib (NVP-BYL719) in comparison to five sensitive cell lines. Western blots showed clear elevation of protein levels in 3/5 resistant cell lines. Ectopic SGK1 expression in sensitive MDA-MB-361 cells resulted in alpelisib resistance and preservation of phopho-S6K and phospho-4EBP with alpelisib treatment. Knockdown of SGK1 in resistant HCC1954 cells increased alpelisib sensitivity and reduced p-S6K and p-4EBP levels with alpelisib treatment. Promoter methylation at SGK1 was increased in sensitive cells compared to alpelisib resistant cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene SGK1/NCBI:6446 2418 AN5733-1 SGK1 Overexpression SGK1 NCBI:6446 gene breast cancer DOID:1612 risk CIViC:674 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene SGK1/NCBI:6446 2418 AN5734-1 SH2B3 RS3184504 mutation SH2B3 NCBI:10019 gene colorectal cancer DOID:9256 diagnostic PubMed:26621817 A genome wide association study (GWAS) meta-analysis of 13,265 cancer cases (colorectal cancer and endometrial cancer) and 40,245 controls found this variant to be associated with colorectal cancer (OR = 1.10, P = 7.23 × 10−9). The authors speculated that since this polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, it might influence cancer risk through its role in the immune response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS3184504 sequence variation in gene SH2B3/NCBI:10019 2419 check_entity AN5734-1 SH2B3 RS3184504 mutation SH2B3 NCBI:10019 gene colorectal cancer DOID:9256 diagnostic CIViC:680 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS3184504 sequence variation in gene SH2B3/NCBI:10019 2419 check_entity AN5735-1 SIRT1 Overexpression SIRT1 NCBI:23411 gene pancreatic cancer DOID:1793 risk PubMed:24088390 In-vitro study with MiaPaCa-2 and PANC-1 pancreatic cancer cell lines. Inhibition of Sirt1 by increasing concentrations of nicotinamide led to a decrease in viability. Gefitinib treatment with concentrations of 50 μM showed similar effects as observed for the application of 25 mM nicotinamide. Combinatory treatment with gefitinib and nicotinamide showed a synergistic effect on cell viability. In cell lines overexpressing Sirt1, higher concentrations of nicotinamide were required to abrogate increased cell viability mediated by Sirt1 overexpression compared to controls. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene SIRT1/NCBI:23411 2420 AN5735-1 SIRT1 Overexpression SIRT1 NCBI:23411 gene pancreatic cancer DOID:1793 risk CIViC:525 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene SIRT1/NCBI:23411 2420 AN5735-2 SIRT1 Overexpression SIRT1 NCBI:23411 gene pancreatic ductal carcinoma DOID:3587 prognostic PubMed:24088390 Nuclear Sirt1 expression was identified by IHC in 36 (27.9%) of 129 pancreatic ductal adenocarcinoma cases. SIRT1 expression was associated with poor survival in univariate (p = 0.002) and multivariate (HR 1.65, p = 0.045) analyses. Overexpression of Sirt1 in pancreas cancer cell lines MiaPaCa-2 and PANC-1 led to increased cell viability. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene SIRT1/NCBI:23411 2421 AN5735-2 SIRT1 Overexpression SIRT1 NCBI:23411 gene pancreatic ductal carcinoma DOID:3587 prognostic CIViC:525 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene SIRT1/NCBI:23411 2421 AN5736-1 SLC29A1 Overexpression SLC29A1 NCBI:2030 gene pancreatic adenocarcinoma DOID:4074 risk PubMed:22705007 Surgically resected PDACs were used to create tissue microarrays, which were scored for antibody staining of hENT1 (SLC29A1). For patients treated with gemcitabine (n=243), high levels of hENT1 were associated with longer survival time in Kaplan-Meier survival analysis (HR 0.43, 95% CI 0.29-0.63, P < .0001) and by multivariate proportional hazards model (HR 0.34, 95% CI 0.22-0.53, P < .0001). For patients treated with surgery alone (n=142), there was no association with survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene SLC29A1/NCBI:2030 2422 AN5736-1 SLC29A1 Overexpression SLC29A1 NCBI:2030 gene pancreatic adenocarcinoma DOID:4074 risk CIViC:3596 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene SLC29A1/NCBI:2030 2422 AN5737-1 SLCO1B1 N130D mutation SLCO1B1 NCBI:10599 gene cancer DOID:162 risk 93412-5 PubMed:23652803 499 children from ALL trials treated with methotrexate were genotyped for 8 SNPs in 5 genes. The SLCO1B1 RS2306283 variant was significantly associated with MTX AUC0-48h and as such associated with increased toxicity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N130D sequence variation in gene SLCO1B1/NCBI:10599 2423 check_entity AN5737-1 SLCO1B1 N130D mutation SLCO1B1 NCBI:10599 gene cancer DOID:162 risk 93412-5 CIViC:759 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N130D sequence variation in gene SLCO1B1/NCBI:10599 2423 check_entity AN5738-1 SLCO1B1 RS4149056 mutation SLCO1B1 NCBI:10599 gene cancer DOID:162 risk 93412-5 PubMed:23652803 499 children from ALL trials treated with methotrexate were genotyped for 8 SNPs in 5 genes. The SLCO1B1 rs4149056 variant was significantly associated with MTX AUC0-48h and as such associated with increased toxicity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS4149056 sequence variation in gene SLCO1B1/NCBI:10599 2424 check_entity AN5738-1 SLCO1B1 RS4149056 mutation SLCO1B1 NCBI:10599 gene cancer DOID:162 risk 93412-5 CIViC:758 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS4149056 sequence variation in gene SLCO1B1/NCBI:10599 2424 check_entity AN5739-1 SLFN11 EXPRESSION SLFN11 NCBI:91607 gene colorectal cancer DOID:9256 risk PubMed:25089570 In this study, SLFN11 expression was associated with sensitivity to SN-38 (an active metabolite of topoisomerase inhibitor irinotecan). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene SLFN11/NCBI:91607 2425 AN5739-1 SLFN11 EXPRESSION SLFN11 NCBI:91607 gene colorectal cancer DOID:9256 risk CIViC:362 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene SLFN11/NCBI:91607 2425 AN5740-1 SMAD4 Deletion SMAD4 NCBI:4089 gene colorectal cancer DOID:9256 risk 100027-2 PubMed:12237773 A retrospective study with 202 colorectal cancer patients found that SMAD4 deletion was associated with worse outcomes during 5-fluorouracil treatment. The hazard ratio for disease-free survival was 2.89 times greater for patients with SMAD4 deletion as compared to those with normal SMAD4 diploidy (P = .045). For overall survival, the hazard ratio was 3.23 times greater for SMAD4 deletion (P = .056). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene SMAD4/NCBI:4089 2426 check_entity AN5740-1 SMAD4 Deletion SMAD4 NCBI:4089 gene colorectal cancer DOID:9256 risk 100027-2 CIViC:642 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene SMAD4/NCBI:4089 2426 check_entity AN5741-1 SMAD4 Expression SMAD4 NCBI:4089 gene pancreatic ductal adenocarcinoma DOID:3498 prognostic 100027-2 PubMed:11751510 In 249 patients that have undergone a pancreaticoduodenectomy (Whipple) for the resection of pancreatic ductal adenocarcinoma, expression of SMAD4 is associated with favorable prognosis. SMAD4 was assessed by IHC in 56 of 249 (22%). Relative hazard of mortality for cancers lacking SMAD4 after adjusting for other prognostic factors was 1.36 (95% confidence interval, 1.01-1.83; P = 0.04). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene SMAD4/NCBI:4089 2427 AN5741-1 SMAD4 Expression SMAD4 NCBI:4089 gene pancreatic ductal adenocarcinoma DOID:3498 prognostic 100027-2 CIViC:529 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene SMAD4/NCBI:4089 2427 AN5742-1 SMAD4 LOSS SMAD4 NCBI:4089 gene pancreatic cancer DOID:1793 prognostic 100027-2 PubMed:19273710 'Study employed a rapid autopsy technique on a cohort of 76 patients with pancreatic cancer and explored the status of several genes. 63% (41/65) of carcinomas analyzed showed inactivation of SMAD4 (DPC4) via immunolabeling. Among the patterns of failure ''metastatic and locally destructive'', It was discovered that DPC4 loss was significantly associated with metastatic disease (p=.007).' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition SMAD4 LOSS [biomarker_term_in_review] 2428 not_mapped AN5742-1 SMAD4 LOSS SMAD4 NCBI:4089 gene pancreatic cancer DOID:1793 prognostic 100027-2 CIViC:560 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition SMAD4 LOSS [biomarker_term_in_review] 2428 not_mapped AN5743-1 SMAD4 Mutation SMAD4 NCBI:4089 gene colorectal cancer DOID:9256 risk 100027-2 PubMed:26508446 In a retrospective analysis of 65 patients with metastatic colorectal cancer, SMAD4 mutations were more common among patients with no benefit from EGFR-inhibition (cetuximab or panitumumab) (4 patients) than with patients with response to EGFR directed treatment (1 patient). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene SMAD4/NCBI:4089 2429 check_entity AN5743-1 SMAD4 Mutation SMAD4 NCBI:4089 gene colorectal cancer DOID:9256 risk 100027-2 CIViC:216 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene SMAD4/NCBI:4089 2429 check_entity AN5743-2 SMAD4 Mutation SMAD4 NCBI:4089 gene pancreatic adenocarcinoma DOID:4074 prognostic 100027-2 PubMed:19584151 In a study of 89 patients with adenocarcinoma of the pancreas who underwent a pancreaticoduodenectomy, those with mutations in SMAD4 had shorter overall survival than wild-type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene SMAD4/NCBI:4089 2430 check_entity AN5743-2 SMAD4 Mutation SMAD4 NCBI:4089 gene pancreatic adenocarcinoma DOID:4074 prognostic 100027-2 CIViC:216 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene SMAD4/NCBI:4089 2430 check_entity AN5744-1 SMAD4 R361C mutation SMAD4 NCBI:4089 gene juvenile polyposis syndrome DOID:0050787 diagnostic 100027-2 PubMed:9811934 The goal of this study was to find out if there was a link between the mutation of SMAD4 and Juvenile polyposis syndrome (JPS). Eight families of JPS were analyzed and there was no evidence of linkage to SMAD4. The eight families and an additional 13 JPS cases were then tested for germline mutations. A single familial JPS patient had the missense mutation R361C in the MH2 domain of SMAD4, with potentially profound effects on protein function. No samples from family members of the patient were available for sequencing. Also, this mutation was not found in 50 control individuals or the other JPS patients in the study. ACMG evidence codes: 'PM1' based on R361 being a hotspot. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R361C sequence variation in gene SMAD4/NCBI:4089 2431 check_entity AN5744-1 SMAD4 R361C mutation SMAD4 NCBI:4089 gene juvenile polyposis syndrome DOID:0050787 diagnostic 100027-2 CIViC:2720 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R361C sequence variation in gene SMAD4/NCBI:4089 2431 check_entity AN5745-1 SMAD4 Underexpression SMAD4 NCBI:4089 gene head and neck squamous cell carcinoma DOID:5520 risk 100027-2 PubMed:26046389 In this study, SMAD4 underexpression was associated with an epithelial-to-mesenchymal transition and resistance to EGFR-directed treatment with Cetuximab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene SMAD4/NCBI:4089 2432 AN5745-1 SMAD4 Underexpression SMAD4 NCBI:4089 gene head and neck squamous cell carcinoma DOID:5520 risk 100027-2 CIViC:278 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene SMAD4/NCBI:4089 2432 AN5746-1 SMARCA4 INACTIVATING MUTATION SMARCA4 NCBI:6597 gene lung adenocarcinoma DOID:3910 prognostic PubMed:24658004 In patients with lung adenocarcinoma, those with loss-of-function mutations in SMARCA4 had worse overall survival than those with only missense or no mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::inactivating:mutation sequence variation in gene SMARCA4/NCBI:6597 2433 check_entity AN5746-1 SMARCA4 INACTIVATING MUTATION SMARCA4 NCBI:6597 gene lung adenocarcinoma DOID:3910 prognostic CIViC:218 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::inactivating:mutation sequence variation in gene SMARCA4/NCBI:6597 2433 check_entity AN5747-1 SMARCA4 Loss SMARCA4 NCBI:6597 gene lung non-small cell carcinoma DOID:3908 risk PubMed:30718506 Preclinical evidence showing that SMARCA4 inactivation results in downregulation of Cyclin D1 in NSCLC cells and confers sensitivity of such to CDK4/6 inhibitors. SMARCA4 loss is synthetic letha with CDK4/6 inhibition. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition SMARCA4 Loss [biomarker_term_in_review] 2434 not_mapped AN5747-1 SMARCA4 Loss SMARCA4 NCBI:6597 gene lung non-small cell carcinoma DOID:3908 risk CIViC:2513 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition SMARCA4 Loss [biomarker_term_in_review] 2434 not_mapped AN5748-1 SMARCA4 MUTATION SMARCA4 NCBI:6597 gene small-cell carcinoma of the ovary of hypercalcemic type DOID:7651 diagnostic PubMed:24658004 Nonsense mutations in SMARCA4 were associated with small cell carcinoma of the ovary, hypercalcemic type in 10/10 tumor samples, and were rarely found in other solid tumor types catalogued by TCGA. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene SMARCA4/NCBI:6597 2435 check_entity AN5748-1 SMARCA4 MUTATION SMARCA4 NCBI:6597 gene small-cell carcinoma of the ovary of hypercalcemic type DOID:7651 diagnostic CIViC:217 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene SMARCA4/NCBI:6597 2435 check_entity AN5749-1 SMARCA4 Underexpression SMARCA4 NCBI:6597 gene lung non-small cell carcinoma DOID:3908 prognostic;risk PubMed:26671993 SMARCA4 expression was determined with gene expression microarray in 133 patients. Improved five-year disease-specific survival (DSS) was noted only in patients with low SMARCA4 expression when treated with adjuvant cisplatin/vinorelbine (n=36) (HR=0.1, 95% CI: 0.0-0.5, P=0.002 [low]; HR 1.0, 95% CI: 0.5-2.3, P=0.92 [high]) compared to patients in the observation arm (N=30). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene SMARCA4/NCBI:6597 2436 AN5749-1 SMARCA4 Underexpression SMARCA4 NCBI:6597 gene lung non-small cell carcinoma DOID:3908 prognostic;risk CIViC:345 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene SMARCA4/NCBI:6597 2436 AN5750-1 SMARCB1 Deletion SMARCB1 NCBI:6598 gene rhabdoid cancer DOID:3672 risk PubMed:23620515 EPZ-6438 (Tazemetostat) induces apoptosis and differentiation specifically in SMARCB1-deleted malignant rhabdoid tumors (MRT) cells. This study compared in vitro EPZ-6438 treatment of four SMARCB1-deleted MRT cell lines to three control (wild-type) cell lines. These data demonstrate the dependency of SMARCB1 mutant MRTs on EZH2 enzymatic activity and suggest treatment of these genetically defined cancers with EZH2 inhibitors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene SMARCB1/NCBI:6598 2437 check_entity AN5750-1 SMARCB1 Deletion SMARCB1 NCBI:6598 gene rhabdoid cancer DOID:3672 risk CIViC:677 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene SMARCB1/NCBI:6598 2437 check_entity AN5751-1 SMARCB1 Loss SMARCB1 NCBI:6598 gene atypical teratoid rhabdoid tumor DOID:2129 diagnostic PubMed:15105654 53 pediatric tumors consisting of 20 AT/RT, 10 PNET, and 23 other central nervous system tumors were classified using microscopic diagnosis, and then tested for expression of the SMARCB1 gene product INI1. In the 20 cases of AT/RT, expression of INI1 was not detected in tumor cells using the BAF47/SNF5 monoclonal INI1 antibody. Expression of INI1 was detected in 31 out of the 33 remaining tumors, with one Oligodendroglioma showing no expression, and one pituitary adenoma showing weak expression. The authors conclude that immunohistochemical staining with an INI1 antibody may be useful in confirming histologic diagnosis of AT/RT. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition SMARCB1 Loss [biomarker_term_in_review] 2438 not_mapped AN5751-1 SMARCB1 Loss SMARCB1 NCBI:6598 gene atypical teratoid rhabdoid tumor DOID:2129 diagnostic CIViC:3071 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition SMARCB1 Loss [biomarker_term_in_review] 2438 not_mapped AN5751-2 SMARCB1 Loss SMARCB1 NCBI:6598 gene renal carcinoma DOID:4451 diagnostic PubMed:30980040 In a retrospective analysis of 20 patients with renal medullary carcinoma, all patients had loss of SMARCB1 staining by IHC. FISH revealed 11 (55%) had a SMARCB1 translocation with loss of the second allele, 6 (30%) had biallelic SMARCB1 loss, and 3 (15%) did not have structural or copy number alteration detected. Of these 3, one had a somatic SMARCB1 mutation (H68Qfs*). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition SMARCB1 Loss [biomarker_term_in_review] 2439 not_mapped AN5751-2 SMARCB1 Loss SMARCB1 NCBI:6598 gene renal carcinoma DOID:4451 diagnostic PubMed:22686875 In a comparison of 6 renal medullary carcinomas (RMC) and 22 collecting duct carcinomas (CDC), all 6 RMC were negative for SMARCB1 by IHC whereas only 1 of 22 CDC lost SMARCB1 expressing, supporting SMARCB1 loss as a specific feature of RMC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition SMARCB1 Loss [biomarker_term_in_review] 2439 not_mapped AN5751-2 SMARCB1 Loss SMARCB1 NCBI:6598 gene renal carcinoma DOID:4451 diagnostic PubMed:28558987 In a retrospective analysis of 23 renal medullary carcinoma patients with tumor sample available for IHC staining, all exhibited a loss of SMARCB1 expression. Of 10 tumors analyzed by FISH, SMARCB1 gene translocations with concurrent loss of heterozygosity were detected in 8 and biallelic SMARCB1 loss was detected in 2. Of 6 patients analyzed by NGS, none had SMARCB1 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition SMARCB1 Loss [biomarker_term_in_review] 2439 not_mapped AN5751-2 SMARCB1 Loss SMARCB1 NCBI:6598 gene renal carcinoma DOID:4451 diagnostic CIViC:3071 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition SMARCB1 Loss [biomarker_term_in_review] 2439 not_mapped AN5752-1 SMARCB1 Underexpression SMARCB1 NCBI:6598 gene synovial sarcoma DOID:5485 risk PubMed:27391784 Treatment with tazemetostat , a small-molecule inhibitor of EZH2, results in concentration-dependent cell growth inhibition and cell death specifically in SS18-SSX-positive, SMARCB1-deficient synovial sarcomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene SMARCB1/NCBI:6598 2440 AN5752-1 SMARCB1 Underexpression SMARCB1 NCBI:6598 gene synovial sarcoma DOID:5485 risk CIViC:676 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene SMARCB1/NCBI:6598 2440 AN5753-1 SMO D473H mutation SMO NCBI:6608 gene basal cell carcinoma DOID:2513 risk PubMed:25759020 D473 mutations were identified in 5/30 resistant basal cell carcinomas. Crystal structure indicated this mutation interacts with a water molecule in the ligand binding pocket, putatively altering its interaction with the SMO inhibitor vismodegib. SMO-/- mouse embryonic fibroblasts expressing the SMO D473G mutant maintained hedgehog signaling in the presence of the drug and had IC50 values >40 fold higher than cells expressing wildtype SMO. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D473H sequence variation in gene SMO/NCBI:6608 2441 check_entity AN5753-1 SMO D473H mutation SMO NCBI:6608 gene basal cell carcinoma DOID:2513 risk CIViC:295 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D473H sequence variation in gene SMO/NCBI:6608 2441 check_entity AN5753-2 SMO D473H mutation SMO NCBI:6608 gene medulloblastoma DOID:0050902 risk PubMed:19726788 In this case report, the D473H mutation was reported as an acquired mechanism of resistance to the hedgehog pathway inhibitor GDC-0449 (vismodegib). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D473H sequence variation in gene SMO/NCBI:6608 2442 check_entity AN5753-2 SMO D473H mutation SMO NCBI:6608 gene medulloblastoma DOID:0050902 risk PubMed:22550175 Saridegib treatment induced tumor reduction and significantly prolonged survival in a Shh-driven mouse medulloblastoma model, and was found to be active in cells with the D473H point mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D473H sequence variation in gene SMO/NCBI:6608 2442 check_entity AN5753-2 SMO D473H mutation SMO NCBI:6608 gene medulloblastoma DOID:0050902 risk CIViC:295 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D473H sequence variation in gene SMO/NCBI:6608 2442 check_entity AN5754-1 SMO L412F mutation SMO NCBI:6608 gene basal cell carcinoma DOID:2513 risk PubMed:25759020 In an in vitro study, mouse embryonic fibroblasts (MEFs), null for the Smo mouse gene expressing SMO L412F mutation, demonstrated resistance to vismodegib treatment (IC50: >320 nmol/L vs. 8.23 nmol/L) compared to MEFs expressing wild-type SMO. Resistance was determined by assessing GLI1 mRNA expression levels. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L412F sequence variation in gene SMO/NCBI:6608 2443 check_entity AN5754-1 SMO L412F mutation SMO NCBI:6608 gene basal cell carcinoma DOID:2513 risk PubMed:26822128 An Arab basal cell carcinoma patient harboring SMO L412F mutation was associated with response to vismodegib monotherapy. Prior to the identification of the mutation, the patient was treated with acitretin, but did not achieve any response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L412F sequence variation in gene SMO/NCBI:6608 2443 check_entity AN5754-1 SMO L412F mutation SMO NCBI:6608 gene basal cell carcinoma DOID:2513 risk CIViC:1478 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L412F sequence variation in gene SMO/NCBI:6608 2443 check_entity AN5755-1 SMO Mutation SMO NCBI:6608 gene basal cell carcinoma DOID:2513 risk PubMed:25759020 In basal cell carcinoma, H231R, D473G, W281C and Q477E mutations conferred resistance to SMO-inhibitor vismodegib. SMO mutations were identified in 22 of 44 resistant basal cell carcinomas in 15 patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene SMO/NCBI:6608 2444 check_entity AN5755-1 SMO Mutation SMO NCBI:6608 gene basal cell carcinoma DOID:2513 risk PubMed:26546616 Study explored the response to the SMO inhibitor sonidegib (LDE225) in a cohort of 9 patients with advanced basal cell carcinoma that exhibited treatment resistance with vismodegib (GDC0449). Sequencing revealed that 5 of these patients harbored SMO mutations known to confer resistance to the Smoothened inhibitors (D473G, D473H, Q477E, S533N, W535L) an additional patient harbored a SMO mutation of unknown consequence (R168H). Of these patients, 4 with a SMO mutation displayed progressive disease and 1 stable disease for 58 weeks according to RECIST v1.1 criteria. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene SMO/NCBI:6608 2444 check_entity AN5755-1 SMO Mutation SMO NCBI:6608 gene basal cell carcinoma DOID:2513 risk CIViC:296 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene SMO/NCBI:6608 2444 check_entity AN5755-2 SMO Mutation SMO NCBI:6608 gene cancer DOID:162 risk PubMed:29320312 The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Twenty-one patients had mutations in the Hedgehog pathway (PTCH-1, n = 18; SMO, n = 3). None of the patients with SMO mutations responded to SHH-inhibition with vismodegib. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene SMO/NCBI:6608 2445 check_entity AN5755-2 SMO Mutation SMO NCBI:6608 gene cancer DOID:162 risk CIViC:296 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene SMO/NCBI:6608 2445 check_entity AN5756-1 SOX10 Loss SOX10 NCBI:6663 gene melanoma DOID:1909 risk PubMed:24670642 FACS-assisted shRNA genetic screen identified SOX10 as a determinant of vemurafenib resistance. Suppression of SOX10 in melanoma cells confers resistance to BRAF and MEK inhibitors through activation of TGF-β signalling and upregulation of EGFR and PDGFRB. EGFR expression or exposure to TGF-β becomes beneficial for proliferation of melanoma cells in the presence of BRAF or MEK inhibitors. Melanoma cells with low SOX10 and consequently high EGFR expression are enriched in the presence of vemurafenib. This study finds evidence for SOX10 loss (N=2) and/or activation of TGF-β signalling (N=2) in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition SOX10 Loss [biomarker_term_in_review] 2446 not_mapped AN5756-1 SOX10 Loss SOX10 NCBI:6663 gene melanoma DOID:1909 risk CIViC:668 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition SOX10 Loss [biomarker_term_in_review] 2446 not_mapped AN5757-1 SPHK1 OVEREXPRESSION SPHK1 NCBI:8877 gene cervical cancer DOID:4362 prognostic PubMed:26311741 SPHK1 protein expression was assessed in 287 cervical cancer and 5 normal cervical tissue samples using IHC. Univariate analysis for OS showed SPHK1 expression (p = 0.033; Figure 1C), tumor size (p = 0.033), and lymph node metastasis (p = 0.008) as associated with OS. SPHK1 expression did not directly predict OS. High SPHK1 expression was also associated with larger tumor size (p < 0.001), deeper invasion depth (p < 0.001), presence of lymph node metastasis (p = 0.029), higher FIGO stage (p = 0.029), presence of lymphovascular invasion (p = 0.045), and higher preoperative squamous cell carcinoma (SCC) antigen level (p = 0.009). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene SPHK1/NCBI:8877 2447 AN5757-1 SPHK1 OVEREXPRESSION SPHK1 NCBI:8877 gene cervical cancer DOID:4362 prognostic CIViC:341 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene SPHK1/NCBI:8877 2447 AN5758-1 SRSF2 MUTATION SRSF2 NCBI:6427 gene acute myeloid leukemia DOID:9119 prognostic 100025-6 PubMed:27276561 Patients with Acute Myeloid Leukemia showed an synergistic mortality rate with ASXL1 and SRSF2 co-mutations such that individual mutations of either ASXL1 or SRSF2 resulted in ~20% probability of survival after 10 years, whereas co-mutations resulted in a 100% mortality rate after 4 years. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene SRSF2/NCBI:6427 2448 check_entity AN5758-1 SRSF2 MUTATION SRSF2 NCBI:6427 gene acute myeloid leukemia DOID:9119 prognostic 100025-6 CIViC:591 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene SRSF2/NCBI:6427 2448 check_entity AN5759-1 SRSF2 P95H mutation SRSF2 NCBI:6427 gene myeloid neoplasm DOID:0070004 risk 100025-6 DOI:10.1182/blood-2021-148205 Several splicing factors known to drive myeloid neoplasms (including SRSF2) require phosphorylation by CLK family kinases for nuclear translocation. The authors describe development of an inhibiter of a CLK family kinase called CTX-712 and evaluate its efficacy in cell line and murine models. CTX-712 efficacy was confirmed in MDS/AML-derived xenografts (PDX). One PDX model with an SRSF2 P95H variant showed a significant response to CTX-712 in a dose-dependent manner. 4 out of 5 mice receiving a high dose protocol achieved complete remission. CLK inhibition also induced aberrant splicing events including skipped exons and this effect was more prevalent in the SRSF2-mutated model. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P95H sequence variation in gene SRSF2/NCBI:6427 2449 check_entity AN5759-1 SRSF2 P95H mutation SRSF2 NCBI:6427 gene myeloid neoplasm DOID:0070004 risk 100025-6 CIViC:4180 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P95H sequence variation in gene SRSF2/NCBI:6427 2449 check_entity AN5760-1 SRSF2 P95L mutation SRSF2 NCBI:6427 gene myeloid neoplasm DOID:0070004 risk 100025-6 DOI:10.1182/blood-2021-148205 Several splicing factors known to drive myeloid neoplasms (including SRSF2) require phosphorylation by CLK family kinases for nuclear translocation. The authors describe development of an inhibiter of a CLK family kinase called CTX-712 and evaluate its efficacy in cell line and murine models. CTX-712 efficacy was confirmed in MDS/AML-derived xenografts (PDX). One PDX model with an SRSF2 P95L variant exhibited significant reduction in tumor volume 2 weeks after CTX-712 high dose treatment compared to vehicle (P=0.0162, N=6). CTX-712 treatment also improved survival in the SRSF2 P95L-mutated model (P=0.0030, N=6 mice). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P95L sequence variation in gene SRSF2/NCBI:6427 2450 check_entity AN5760-1 SRSF2 P95L mutation SRSF2 NCBI:6427 gene myeloid neoplasm DOID:0070004 risk 100025-6 CIViC:4179 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P95L sequence variation in gene SRSF2/NCBI:6427 2450 check_entity AN5761-1 SSTR5 expression SSTR5 NCBI:6755 gene neuroendocrine tumor DOID:169 risk PubMed:25376618 Phase II study of pasireotide in metastatic neuroendocrine tumours enrolled 29 patients. Overall median PFS was 11 months (95% CI, 7.6–16 months). High SSTR5 expression (seen in 17/22 samples measured) was associated with prolonged PFS (P=0.0068). Median PFS for low-SSTR5 tumours was 2.8 months (95% CI, 2.3–12.1 months) vs high tumours 19.9 months (95% CI, 7.7–29.1 months). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene SSTR5/NCBI:6755 2451 AN5761-1 SSTR5 expression SSTR5 NCBI:6755 gene neuroendocrine tumor DOID:169 risk CIViC:3620 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene SSTR5/NCBI:6755 2451 AN5762-1 SSX1 SS18::SSX1 mutation SSX1 NCBI:6756 gene malignant peripheral nerve sheath tumor DOID:5940 diagnostic PubMed:11144931 In this study, 141 spindle cell sarcomas were evaluated for the presence of t(X;18) by RT-PCR. 75% of the malignant peripheral nerve sheath tumors (MPNSTs) were positive for this event. The study did not indicate the specific fusion detected but from related studies we know that the majority of these fusions are SYT-SSX1 (aka SS18-SSX1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SS18::SSX1 sequence variation in gene SSX1/NCBI:6756 2452 check_entity AN5762-1 SSX1 SS18::SSX1 mutation SSX1 NCBI:6756 gene malignant peripheral nerve sheath tumor DOID:5940 diagnostic CIViC:444 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SS18::SSX1 sequence variation in gene SSX1/NCBI:6756 2452 check_entity AN5762-2 SSX1 SS18::SSX1 mutation SSX1 NCBI:6756 gene synovial sarcoma DOID:5485 diagnostic;prognostic PubMed:11607825 A t(X;18) translocation resulting in the fusion SYT-SSX (SS18-SSX1 or SS18-SSX2) is detected cytogenetically in over 90% of synovial sarcomas, regardless of histologic subtype. The prevalence of this fusion in synovial sarcoma approaches 100% when there is adequate tumor RNA for RT-PCR. Its specificity for synovial sarcoma, has been confirmed by molecular screening of other morphologically similar sarcomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SS18::SSX1 sequence variation in gene SSX1/NCBI:6756 2453 check_entity AN5762-2 SSX1 SS18::SSX1 mutation SSX1 NCBI:6756 gene synovial sarcoma DOID:5485 diagnostic;prognostic PubMed:9428816 A characteristic SYT-SSX fusion gene resulting from the chromosomal translocation t(X;18)(p11;q11) is detectable in almost all synovial sarcomas. SYT (aka SS18) pairs with various 3' partners know as SSX (especially SSX1, and SSX2). In this study, 45 synovial sarcomas were assayed for SYT-SSX by RT-PCR using tumor cDNA as template. 29 (64%) had a SYT–SSX1 (SS18-SSX1) fusion transcript. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SS18::SSX1 sequence variation in gene SSX1/NCBI:6756 2453 check_entity AN5762-2 SSX1 SS18::SSX1 mutation SSX1 NCBI:6756 gene synovial sarcoma DOID:5485 diagnostic;prognostic PubMed:11122430 In this review, the author summarize the role of this fusion in diagnosis of synovial sarcomas. Cytogenetic studies have repeatedly demonstrated the t(X;18)(p11;q11) translocation in approximately 90% of both monophasic and biphasic synovial sarcomas. The fusion has clear diagnostic value, though the authors caution that it is not perfectly specific to synovial sarcomas, and suggest that demonstration of t(X;18) in a spindle cell neoplasm should be integrated with the morphology, immunoprofile, and clinical setting of the tumour. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SS18::SSX1 sequence variation in gene SSX1/NCBI:6756 2453 check_entity AN5762-2 SSX1 SS18::SSX1 mutation SSX1 NCBI:6756 gene synovial sarcoma DOID:5485 diagnostic;prognostic PubMed:11144931 In this study, 141 spindle cell sarcomas were evaluated for the presence of t(X;18) by RT-PCR. 85% of the synovial sarcomas were positive for this event. The study did not indicate the specific fusion detected but from related studies we know that the majority of these fusions are SYT-SSX1 (aka SS18-SSX1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SS18::SSX1 sequence variation in gene SSX1/NCBI:6756 2453 check_entity AN5762-2 SSX1 SS18::SSX1 mutation SSX1 NCBI:6756 gene synovial sarcoma DOID:5485 diagnostic;prognostic PubMed:11782370 This study collected data on SYT-SSX fusion type, pathology, and clinical course in a retrospective multi-institutional study of 243 patients (age range, 6-82) with synovial sarcoma. SYT-SSX1 and SYT-SSX2 fusions were detected in 147 tumors (61%) and 91 tumors (37%), respectively. Histologically, 61 (25%) were classified as biphasic type and 180 (74%) as monophasic type based on the presence or absence of areas of glandular epithelial differentiation, respectively. Median and 5-year overall survivals for the SYT-SSX1 and SYT-SSX2 groups were 6.1 years and 53%, and 13.7 years and 73%, respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SS18::SSX1 sequence variation in gene SSX1/NCBI:6756 2453 check_entity AN5762-2 SSX1 SS18::SSX1 mutation SSX1 NCBI:6756 gene synovial sarcoma DOID:5485 diagnostic;prognostic CIViC:444 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SS18::SSX1 sequence variation in gene SSX1/NCBI:6756 2453 check_entity AN5763-1 SSX2 SS18::SSX2 mutation SSX2 NCBI:6757 gene synovial sarcoma DOID:5485 diagnostic;prognostic PubMed:11607825 A t(X;18) is detected cytogenetically in over 90% of synovial sarcomas, regardless of histologic subtype. This translocation results primarily in two fusions. SYT-SSX1 (aka SS18-SSX1) and SYT-SSX2 (aka SS18-SSX2). The ratio of SYT-SSX1 to SYT-SSX2 cases is close to 2:1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SS18::SSX2 sequence variation in gene SSX2/NCBI:6757 2454 check_entity AN5763-1 SSX2 SS18::SSX2 mutation SSX2 NCBI:6757 gene synovial sarcoma DOID:5485 diagnostic;prognostic PubMed:9428816 A characteristic SYT-SSX fusion gene resulting from the chromosomal translocation t(X;18)(p11;q11) is detectable in almost all synovial sarcomas. SYT (aka SS18) pairs with various 3' partners know as SSX (especially SSX1, and SSX2). In this study, 45 synovial sarcomas were assayed for SYT-SSX by RT-PCR using tumor cDNA as template. 16 (36%) contained a SYT–SSX2 (SS18-SSX2) fusion transcript. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SS18::SSX2 sequence variation in gene SSX2/NCBI:6757 2454 check_entity AN5763-1 SSX2 SS18::SSX2 mutation SSX2 NCBI:6757 gene synovial sarcoma DOID:5485 diagnostic;prognostic PubMed:11782370 This study collected data on SYT-SSX fusion type, pathology, and clinical course in a retrospective multi-institutional study of 243 patients (age range, 6-82) with synovial sarcoma. SYT-SSX1 and SYT-SSX2 fusions were detected in 147 tumors (61%) and 91 tumors (37%), respectively. Histologically, 61 (25%) were classified as biphasic type and 180 (74%) as monophasic type based on the presence or absence of areas of glandular epithelial differentiation, respectively. Median and 5-year overall survivals for the SYT-SSX1 and SYT-SSX2 groups were 6.1 years and 53%, and 13.7 years and 73%, respectively. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SS18::SSX2 sequence variation in gene SSX2/NCBI:6757 2454 check_entity AN5763-1 SSX2 SS18::SSX2 mutation SSX2 NCBI:6757 gene synovial sarcoma DOID:5485 diagnostic;prognostic CIViC:445 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SS18::SSX2 sequence variation in gene SSX2/NCBI:6757 2454 check_entity AN5764-1 SSX4 SS18::SSX4 mutation SSX4 NCBI:6759 gene synovial sarcoma DOID:5485 diagnostic PubMed:10359553 Three synovial sarcomas were assayed for SYT-SSX fusion messenger RNA by nested RT-PCR. In a single case an SYT-SSX4 (SS18-SSX4) fusion was detected. The majority of synovial sarcomas are characterized by SS18-SSX1 or SS18-SSX2, but other rare events such as this SS18-SSX4 may explain some or all of the synovial sarcomas that are negative for the most common fusions. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SS18::SSX4 sequence variation in gene SSX4/NCBI:548313 2455 check_entity AN5764-1 SSX4 SS18::SSX4 mutation SSX4 NCBI:6759 gene synovial sarcoma DOID:5485 diagnostic CIViC:446 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::SS18::SSX4 sequence variation in gene SSX4/NCBI:548313 2455 check_entity AN5765-1 STAG2 MUTATION STAG2 NCBI:10735 gene acute myeloid leukemia DOID:9119 prognostic PubMed:24335498 In a retrospective cohort study of 389 uniformly treated acute myeloid leukemia (AML) patients, 23 patients harbored mutations in genes of the cohesin complex including 5 who harbored mutations in STAG2. Mutation in the cohesin complex was not associated with worse overall survival (OS) or relapse free survival (RFS) compared to wildtype patients. The presence of STAG2 mutations had no influence on OS or RFS compared to wildtype (OS HR: 1.53, p = 0.4; RFS HR: 1.26, P = 0.7), though the authors note that the analysis was limited by the small number of patients. Authors speculate that co-occurring mutations in NPM1 may mask prognostic effects of STAG2 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene STAG2/NCBI:10735 2456 check_entity AN5765-1 STAG2 MUTATION STAG2 NCBI:10735 gene acute myeloid leukemia DOID:9119 prognostic CIViC:665 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene STAG2/NCBI:10735 2456 check_entity AN5765-2 STAG2 MUTATION STAG2 NCBI:10735 gene Ewing sarcoma of bone DOID:3368 prognostic PubMed:25186949 In a study of 96 Ewing sarcoma tumors, 15% showed heterogenous loss of STAG2 expression in IHC analysis. Of those with STAG2 expression loss, 88% presented with metastatic disease compared to only 27% of patients who expressed STAG2 on IHC (P=0.002). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene STAG2/NCBI:10735 2457 check_entity AN5765-2 STAG2 MUTATION STAG2 NCBI:10735 gene Ewing sarcoma of bone DOID:3368 prognostic CIViC:665 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene STAG2/NCBI:10735 2457 check_entity AN5766-1 STAG2 Underexpression STAG2 NCBI:10735 gene bladder carcinoma DOID:4007 prognostic PubMed:26838030 Tumor samples from 125 patients with bladder cancer were assessed by IHC for STAG2 expression. STAG2-negativity was associated with lower histological grade (p = 0.009). Complete loss of STAG2 expression was associated with a lower risk of recurrence (P = 0.023) and diminished risk of death (P = 0.034) in log-rank analysis and was a beneficial factor in uni- and multivariate analysis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene STAG2/NCBI:10735 2458 AN5766-1 STAG2 Underexpression STAG2 NCBI:10735 gene bladder carcinoma DOID:4007 prognostic CIViC:418 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene STAG2/NCBI:10735 2458 AN5766-2 STAG2 Underexpression STAG2 NCBI:10735 gene melanoma DOID:1909 risk PubMed:27500726 A375 melanoma cells containing an inducible shRNA for STAG2 were grown as xenograft tumors in nude mice. The mice in which STAG2 was silenced had tumors that were less sensitive to vemurafenib-induced tumor shrinkage than the tumors of the control mice (P < .01). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene STAG2/NCBI:10735 2459 AN5766-2 STAG2 Underexpression STAG2 NCBI:10735 gene melanoma DOID:1909 risk CIViC:418 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene STAG2/NCBI:10735 2459 AN5767-1 STAG3 Underexpression STAG3 NCBI:10734 gene melanoma DOID:1909 risk PubMed:27500726 A375 melanoma cells containing an inducible shRNA for STAG3 were grown as xenograft tumors in nude mice. The mice in which STAG3 was silenced had tumors that were less sensitive to vemurafenib-induced tumor shrinkage than the tumors of the control mice (P < .01). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene STAG3/NCBI:10734 2460 AN5767-1 STAG3 Underexpression STAG3 NCBI:10734 gene melanoma DOID:1909 risk CIViC:650 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene STAG3/NCBI:10734 2460 AN5768-1 STAT3 SH2 DOMAIN MUTATION STAT3 NCBI:6774 gene T-cell large granular lymphocyte leukemia DOID:0050751 diagnostic PubMed:22591296 Mutations in the Src homology 2 (SH2) domain (exon 21) of STAT3 were found in 31 of 77 patients (40%) with large granular lymphocytic leukemia. Recurrent mutational hot spots included Y640F, D661V, D661Y, and N647I. Patients with these mutations presented more often with neutropenia and rheumatoid arthritis than did patients without. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::sh2:domain:mutation sequence variation in gene STAT3/NCBI:6774 2461 check_entity AN5768-1 STAT3 SH2 DOMAIN MUTATION STAT3 NCBI:6774 gene T-cell large granular lymphocyte leukemia DOID:0050751 diagnostic CIViC:407 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::sh2:domain:mutation sequence variation in gene STAT3/NCBI:6774 2461 check_entity AN5769-1 STK11 D194E mutation STK11 NCBI:6794 gene pancreatic cancer DOID:1793 risk 53795-1 PubMed:21189378 Case study of a 46-year old male patient with Peutz-Jeghers Syndrome and pancreatic cancer. A germline STK11 D194E mutation was identified with LOH in the tumor sample. phospho-S6 ribosomal protein staining was observed in the tumor indicating mTOR pathway activation. Everolimus treatement led to partial response (but no change in phospho-S6 ribosomal protein staining) for 9 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D194E sequence variation in gene STK11/NCBI:6794 2462 check_entity AN5769-1 STK11 D194E mutation STK11 NCBI:6794 gene pancreatic cancer DOID:1793 risk 53795-1 CIViC:630 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D194E sequence variation in gene STK11/NCBI:6794 2462 check_entity AN5770-1 STK11 EXON 1-2 MUTATION STK11 NCBI:6794 gene lung non-small cell carcinoma DOID:3908 prognostic 53795-1 PubMed:26625312 In a retrospective analysis of 567 non-squamous, non-small cell lung cancer patients, Exon 1-2 mutations in STK11 were significantly associated with shorter OS (24 vs. 69 months) also after multivariate analysis. Results were validated in public datasets. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:1-2:mutation sequence variation in gene STK11/NCBI:6794 2463 check_entity AN5770-1 STK11 EXON 1-2 MUTATION STK11 NCBI:6794 gene lung non-small cell carcinoma DOID:3908 prognostic 53795-1 CIViC:299 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:1-2:mutation sequence variation in gene STK11/NCBI:6794 2463 check_entity AN5771-1 STK11 Loss STK11 NCBI:6794 gene lung non-small cell carcinoma DOID:3908 risk 53795-1 PubMed:22425996 A clinical trial comparing selumetinib and docetaxel vs. docetaxel and placebo in KRAS mutant NSCLC was recapitulated in mice. Tumors were induced in lung epithelium by nasal instillation of CRE-bearing adenovirus in conditionally targeted mice. Kras(G12D) and Lkb1 (STK11) knockout mutant mice showed only mild response to combined treatment and very low response rates to docetaxel monotherapy compared to mice with Kras(G12D) alone or Kras(G12D) and Trp53 knockout. In a small number of human NSCLC patients with these genotypes FDG-PET signal intensity changes and pERK IHC staining correlated with mouse data. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition STK11 Loss [biomarker_term_in_review] 2464 not_mapped AN5771-1 STK11 Loss STK11 NCBI:6794 gene lung non-small cell carcinoma DOID:3908 risk 53795-1 PubMed:26027660 Preclinical study in 5 NSCLC cell lines. Two LKB1 (STK11) mutant cell lines had higher basal levels of mTOR activity (pS6K and p4EBP1 levels) but were not more sensitive to mTOR inhibitors (everolimus or rapamycin) than two wild type cell lines. Knockdown of LKB1 in one additional cell line did not lead to an increase in sensitivity to mTOR inhibitors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition STK11 Loss [biomarker_term_in_review] 2464 not_mapped AN5771-1 STK11 Loss STK11 NCBI:6794 gene lung non-small cell carcinoma DOID:3908 risk 53795-1 CIViC:481 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition STK11 Loss [biomarker_term_in_review] 2464 not_mapped AN5771-2 STK11 Loss STK11 NCBI:6794 gene Peutz-Jeghers syndrome DOID:3852 diagnostic;risk 53795-1 PubMed:18281551 Preclinical study in a mouse model of Peutz-Jeghers syndrome. Heterozygous Lkb1 (STK11) knockout mice were generated and treated with rapamycin after the onset of polyposis at 9 months of age. Rapamycin treatment significantly suppressed polyposis (p=0.017) and pS6 staining (IHC, p=0.011). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition STK11 Loss [biomarker_term_in_review] 2465 not_mapped AN5771-2 STK11 Loss STK11 NCBI:6794 gene Peutz-Jeghers syndrome DOID:3852 diagnostic;risk 53795-1 PubMed:19541609 Treatment of mice with a heterozygous loss of Lkb1 (STK11) with rapamycin led to reduction in polyp size (p < 0.0001) and number of polyps (p=0.00022). pS6 staining was also reduced after rapamycin treatment. Rapamycin treatment abolished FDG-PET signal on imaging. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition STK11 Loss [biomarker_term_in_review] 2465 not_mapped AN5771-2 STK11 Loss STK11 NCBI:6794 gene Peutz-Jeghers syndrome DOID:3852 diagnostic;risk 53795-1 PubMed:12865922 In a series of 33 patients with Peutz-Jeghers Syndrome, 17 mutations in STK11/LKB1 were observed in exons 1-8 (none in exon 9). 11 of these mutations were predicted to be truncating. These mutations occurred in 10/13 patients with familial PJS and 7/20 patients with sporadic PJS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition STK11 Loss [biomarker_term_in_review] 2465 not_mapped AN5771-2 STK11 Loss STK11 NCBI:6794 gene Peutz-Jeghers syndrome DOID:3852 diagnostic;risk 53795-1 CIViC:481 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition STK11 Loss [biomarker_term_in_review] 2465 not_mapped AN5772-1 STK11 Mutation STK11 NCBI:6794 gene lung adenocarcinoma DOID:3910 risk 53795-1 PubMed:29773717 In a retrospective analysis in two separate datasets (Stand Up To Cancer 2 Cohort and Checkmate-057), patients with concomitant KRAS and STK11 mutations had significantly worse response rates, PFS and OS compares to KRAS only and KRAS-TP53 Mutant Patients. This work identifies STK11/LKB1 alterations as the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in KRAS-mutant lung adenocarcinoma. Genomic profiling may enhance the predictive utility of PD-L1 expression and tumor mutation burden and facilitate establishment of personalized combination immunotherapy approaches for genomically defined LUAC subsets. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene STK11/NCBI:6794 2466 check_entity AN5772-1 STK11 Mutation STK11 NCBI:6794 gene lung adenocarcinoma DOID:3910 risk 53795-1 CIViC:696 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene STK11/NCBI:6794 2466 check_entity AN5772-2 STK11 Mutation STK11 NCBI:6794 gene Peutz-Jeghers syndrome DOID:3852 diagnostic 53795-1 PubMed:26979979 Retrospective analysis of the Danish tumor bank. 43 patients with Peutz-Jeghers Syndrome were identified (clinical criteria + STK11 mutations). STK11 mutations were detected in 86% of those tested (18 of 21 probands) and included eight nonsense mutations, five frameshift mutations, two splice site mutations, two large genomic rearrangements, and one missense mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene STK11/NCBI:6794 2467 check_entity AN5772-2 STK11 Mutation STK11 NCBI:6794 gene Peutz-Jeghers syndrome DOID:3852 diagnostic 53795-1 CIViC:696 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene STK11/NCBI:6794 2467 check_entity AN5773-1 STK11 Underexpression STK11 NCBI:6794 gene prostate cancer DOID:10283 risk 53795-1 PubMed:26391455 STK11-deficient cells were sensitive to treatment with MAPK11 inhibitor SB202190. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene STK11/NCBI:6794 2468 AN5773-1 STK11 Underexpression STK11 NCBI:6794 gene prostate cancer DOID:10283 risk 53795-1 CIViC:300 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene STK11/NCBI:6794 2468 AN5774-1 STMN1 EXPRESSION STMN1 NCBI:3925 gene endometrial carcinoma DOID:2871 risk PubMed:24587245 33 patients were retrospectively analyzed for Stathmin expression by IHC. High protein expression was correlated with poor response to paclitaxel but not other chemotherapy. The authors supported this conclusion with pre-clinical studies that showed that knock-down of stathmin improved sensitivity to paclitaxel in endometrial carcinoma cell lines with both naturally higher and lower sensitivity to paclitaxel. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene STMN1/NCBI:3925 2469 AN5774-1 STMN1 EXPRESSION STMN1 NCBI:3925 gene endometrial carcinoma DOID:2871 risk CIViC:353 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene STMN1/NCBI:3925 2469 AN5775-1 SYK OVEREXPRESSION SYK NCBI:6850 gene ovarian cancer DOID:2394 risk PubMed:26096845 Overexpression and high p-SYK/SYK ratio were associated with resistance to paclitaxel. Inhibition of SYK with R406 resensitized cell lines to paclitaxel. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene SYK/NCBI:6850 2470 AN5775-1 SYK OVEREXPRESSION SYK NCBI:6850 gene ovarian cancer DOID:2394 risk CIViC:301 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene SYK/NCBI:6850 2470 AN5776-1 TBK1 Overexpression TBK1 NCBI:29110 gene melanoma DOID:1909 risk PubMed:24962318 Preclinical study in melanoma cell lines. TBK1 depletion (siRNA) inhibited migration and invasion, whereas its constitutive overexpression led to an increase in invasion. In MEK-resistant NRAS mutant melanoma cell lines, TBK1 depletion or inhibition (AZ909) in combination with MEK inhibitors (selumetinib) promoted apoptosis in 3D culture. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene TBK1/NCBI:29110 2471 AN5776-1 TBK1 Overexpression TBK1 NCBI:29110 gene melanoma DOID:1909 risk CIViC:479 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene TBK1/NCBI:29110 2471 AN5777-1 TERT Amplification TERT NCBI:7015 gene acral lentiginous melanoma DOID:6367 prognostic 95778-7 PubMed:25219713 In patients with acral lentiginous melanoma, those with amplification of TERT had shorter overall survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene TERT/NCBI:7015 2472 AN5777-1 TERT Amplification TERT NCBI:7015 gene acral lentiginous melanoma DOID:6367 prognostic 95778-7 CIViC:219 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene TERT/NCBI:7015 2472 AN5778-1 TERT C228T mutation TERT NCBI:7015 gene thyroid cancer DOID:1781 diagnostic 95778-7 PubMed:25121551 In 308 thyroid fine-needle aspiration biopsies, 0 of the 179 benign tumors displayed either the C228T or the C250T TERT promoter mutation; however, 9 of the 129 differentiated thyroid cancers had either of these mutations. The biomarker displayed 100% diagnostic specificity and 7% sensitivity. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C228T sequence variation in gene TERT/NCBI:7015 2473 check_entity AN5778-1 TERT C228T mutation TERT NCBI:7015 gene thyroid cancer DOID:1781 diagnostic 95778-7 CIViC:244 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C228T sequence variation in gene TERT/NCBI:7015 2473 check_entity AN5778-2 TERT C228T mutation TERT NCBI:7015 gene thyroid gland papillary carcinoma DOID:3969 prognostic 95778-7 PubMed:25024077 In patients with papillary thyroid cancer harboring both BRAF V600E and the TERT promotor mutation C228T, recurrence-free survival is worse than in patients harboring one of these mutations or no mutations in either gene. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C228T sequence variation in gene TERT/NCBI:7015 2474 check_entity AN5778-2 TERT C228T mutation TERT NCBI:7015 gene thyroid gland papillary carcinoma DOID:3969 prognostic 95778-7 CIViC:244 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C228T sequence variation in gene TERT/NCBI:7015 2474 check_entity AN5779-1 TERT Promoter Mutation TERT NCBI:7015 gene brain glioma DOID:0060108 diagnostic 95778-7 PubMed:26765760 In this meta-analysis of 16 Trials, TERT mutations were more common in glioblastomas (69%), oligodendrogliomas (72%) in comparison to astrocytomas (24%) and oligoastrocytomas (38%). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::promoter:mutation sequence variation in gene TERT/NCBI:7015 2475 check_entity AN5779-1 TERT Promoter Mutation TERT NCBI:7015 gene brain glioma DOID:0060108 diagnostic 95778-7 CIViC:220 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::promoter:mutation sequence variation in gene TERT/NCBI:7015 2475 check_entity AN5779-2 TERT Promoter Mutation TERT NCBI:7015 gene childhood low-grade glioma DOID:0080830 prognostic 95778-7 PubMed:29948154 The aim of this Chinese study was to identify prognostic biomarkers for pediatric low-grade gliomas (PLGG). Approximately 300 patients were included. Using Sanger sequencing, mutations at TERT promoter (TERTp) regions were identified (C228T: 3/278; C250T: 4/278). The median age of patients with TERTp mutations was 15 years. There were 5 males and 2 females. Six patients had diffuse astrocytoma and one had pilocytic astrocytoma. Tumors were found in the midline of four patients, the hemisphere of two, and the cerebellum of one. Kaplan-Meier survival analysis showed that TERTp mutations were associated with shorter progression-free survival and overall survival [mt (n=6) vs wt (n=205); p<0.0001 for both OS and PFS]. However, the association of TERTp mutations with OS and PFS was no longer statistically significant after adjusting for age, grade, histology, tumor location, and extent of resection in multivariate analysis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::promoter:mutation sequence variation in gene TERT/NCBI:7015 2476 check_entity AN5779-2 TERT Promoter Mutation TERT NCBI:7015 gene childhood low-grade glioma DOID:0080830 prognostic 95778-7 CIViC:220 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::promoter:mutation sequence variation in gene TERT/NCBI:7015 2476 check_entity AN5779-3 TERT Promoter Mutation TERT NCBI:7015 gene glioblastoma DOID:3068 prognostic 95778-7 PubMed:23955565 In 187 patients with glioblastoma, those with TERT promoter mutations had worse cummulative survival than wild-type patients. The most common mutation was C228T (73% of mutants) followed by C250T (27% of mutants). However, most of the Prognostic value of TERT mutations is thought to be derived from their inverse coorelation with IDH1 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::promoter:mutation sequence variation in gene TERT/NCBI:7015 2477 check_entity AN5779-3 TERT Promoter Mutation TERT NCBI:7015 gene glioblastoma DOID:3068 prognostic 95778-7 PubMed:23530248 In 50 patients with primary glioblastomas, patients without TERT promoter mutations (N=13, median 27 mo) survived longer than those harboring mutations (N=37, 14 mo; P = 0.01 by the log rank test; HR 0.38, 95% CI [0.18, 0.81]). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::promoter:mutation sequence variation in gene TERT/NCBI:7015 2477 check_entity AN5779-3 TERT Promoter Mutation TERT NCBI:7015 gene glioblastoma DOID:3068 prognostic 95778-7 CIViC:220 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::promoter:mutation sequence variation in gene TERT/NCBI:7015 2477 check_entity AN5779-4 TERT Promoter Mutation TERT NCBI:7015 gene skin melanoma DOID:8923 prognostic 95778-7 PubMed:25217772 In patients with nonacral cutaneous melanoma, those with mutations in the TERT promoter had shorter overall survival than wild-type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::promoter:mutation sequence variation in gene TERT/NCBI:7015 2478 check_entity AN5779-4 TERT Promoter Mutation TERT NCBI:7015 gene skin melanoma DOID:8923 prognostic 95778-7 CIViC:220 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::promoter:mutation sequence variation in gene TERT/NCBI:7015 2478 check_entity AN5779-5 TERT Promoter Mutation TERT NCBI:7015 gene thyroid cancer DOID:1781 diagnostic;prognostic 95778-7 PubMed:23766237 TERT promoter mutations are prevalent in aggressive sub-types of thyroid cancers. This work showed that TERT promoter mutations were significantly more prevalent in the tall cell papillary thyroid carcinoma (PTC) samples than in the conventional PTC and follicular variant PTC samples. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::promoter:mutation sequence variation in gene TERT/NCBI:7015 2479 check_entity AN5779-5 TERT Promoter Mutation TERT NCBI:7015 gene thyroid cancer DOID:1781 diagnostic;prognostic 95778-7 CIViC:220 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::promoter:mutation sequence variation in gene TERT/NCBI:7015 2479 check_entity AN5780-1 TERT RS2736100 mutation TERT NCBI:7015 gene brain glioma DOID:0060108 diagnostic 95778-7 PubMed:26765760 Meta-analysis of 10 studies (9,411 patients, 13,708 controls) showed that TERT polymorphisms (rs2736100) were associated with an increased glioma risk (RR=1.28, 95% CI 1.23-1.33). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS2736100 sequence variation in gene TERT/NCBI:7015 2480 check_entity AN5780-1 TERT RS2736100 mutation TERT NCBI:7015 gene brain glioma DOID:0060108 diagnostic 95778-7 CIViC:417 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS2736100 sequence variation in gene TERT/NCBI:7015 2480 check_entity AN5781-1 TET2 Mutation TET2 NCBI:54790 gene acute myeloid leukemia DOID:9119 prognostic PubMed:22430270 In a cohort of 783 young adult patients with acute myeloid leukemia, those with TET2 mutations did not have significantly different rates of complete recovery, refractory disease, or hypoplastic death. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TET2/NCBI:54790 2481 check_entity AN5781-1 TET2 Mutation TET2 NCBI:54790 gene acute myeloid leukemia DOID:9119 prognostic PubMed:21343549 In patients with cytogenetically normal acute myeloid leukemia, those in the intermediate-I risk group with TET2 mutations did not have significantly different rates of event-free survival, complete remission, disease-free survival, or overall survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TET2/NCBI:54790 2481 check_entity AN5781-1 TET2 Mutation TET2 NCBI:54790 gene acute myeloid leukemia DOID:9119 prognostic PubMed:21828143 In patients classified as intermediate-risk via cytogenetics, TET2 mutations have been shown to be correlated with poor prognosis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TET2/NCBI:54790 2481 check_entity AN5781-1 TET2 Mutation TET2 NCBI:54790 gene acute myeloid leukemia DOID:9119 prognostic CIViC:157 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TET2/NCBI:54790 2481 check_entity AN5781-2 TET2 Mutation TET2 NCBI:54790 gene myelodysplastic syndrome DOID:0050908 prognostic PubMed:19666869 In patients with myelodysplastic syndromes, those with TET2 mutations have been shown to have better overall survival than patients without TET2 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TET2/NCBI:54790 2482 check_entity AN5781-2 TET2 Mutation TET2 NCBI:54790 gene myelodysplastic syndrome DOID:0050908 prognostic CIViC:157 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TET2/NCBI:54790 2482 check_entity AN5782-1 TFE3 ASPSCR1::TFE3 mutation TFE3 NCBI:7030 gene alveolar soft part sarcoma DOID:4239 diagnostic;risk PubMed:25453902 Goodwin, et al. (2014) presented in vivo study on mice carrying the ASPSCR1-TFE3 fusion gene. The results showed that Rosa26-LSL-AT3/CreER mice expressed tumors histological equal to the human’s alveolar soft part sarcoma (ASPS; Fig.3) and recapitulate human’s transcriptome profile (Fig.4). The study also showed that tumors were formed in location high in lactate (Fig.6B), had a high degree of lactate importers (Fig.6A), expressed up-regulation of mitochondrial genes (Fig.7A-B), and responded to the addition of lactate with a proliferation of tumor as well as with angiogenesis (Fig.8D-F). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ASPSCR1::TFE3 sequence variation in gene TFE3/NCBI:7030 2483 check_entity AN5782-1 TFE3 ASPSCR1::TFE3 mutation TFE3 NCBI:7030 gene alveolar soft part sarcoma DOID:4239 diagnostic;risk PubMed:11244503 Alveolar soft part sarcoma (ASPS) is characterized by the presence of an unbalanced translocation der(17)t(X;17)(p11;q25). In this 2001 paper, FISH with YAC and cosmid probes was used to localize the breakpoint to a 160 kb region with additional analyses (including Southern blotting, RACE PCR, and RT-PCR) identifying a fusion between ASPSCR1 (referred to as ASPL in this paper) and the TFE3 transcription factor. RT-PCR performed on 12 ASPS patient samples showed the presence of a fusion transcript containing 5' sequences of the novel gene ASPSCR1 fused with a 3' sequences of TFE3 in all cases. Of note, the reciprocal fusion was not detected in 11 of 12 cases consistent with cytogenetic analysis. The ASPSCR1::TFE3 fusion was absent in control cell lines (K562 leukemia cell line). Like other TFE3 gene fusions reported in cancer, this transcript retains the bHLH-LZ DNA motif, encoded by exons 5 to 7 of TFE3. The ASPSCR1::TFE3 is of potential clinical utility in ASPS diagnosis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ASPSCR1::TFE3 sequence variation in gene TFE3/NCBI:7030 2483 check_entity AN5782-1 TFE3 ASPSCR1::TFE3 mutation TFE3 NCBI:7030 gene alveolar soft part sarcoma DOID:4239 diagnostic;risk PubMed:21835426 In this 2012 paper, the authors assessed potential characteristic markers in 24 alveolar soft part sarcoma (ASPS cases), age range from 13 to 61 years, and 23 non-ASPS tumors. Nuclear immunoreactivity for the TFE3 protein was observed in 22 of 24 ASPS specimens. The ASPSCR1::TFE3 fusion transcript was detected by RT-PCR in all 24 cases and was not detected in any of the 23 non-ASPS tumors. The ASPSCR1::TFE3 involves either exon 3 or 4 of TFE3 fused to ASPSCR1, which replaces the N-terminus of TFE3 but retains the DNA-binding region, activation domain, and nuclear localization signal. The fusion transcripts were composed of 7 type 1 (ASPCR1 fusion to TFE3 exon 4) and 17 type 2 (ASPCR1 fusion to TFE3 exon 3) transcripts. The authors conclude that ASPSCR1::TFE3 fusion detection is an effective diagnostic technique for ASPS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ASPSCR1::TFE3 sequence variation in gene TFE3/NCBI:7030 2483 check_entity AN5782-1 TFE3 ASPSCR1::TFE3 mutation TFE3 NCBI:7030 gene alveolar soft part sarcoma DOID:4239 diagnostic;risk PubMed:28766250 This study by Ju, et al. (2018) consisted of nine cases of alveolar soft part sarcoma (ASPS). The age of patients ranged from 7 to 36 years. Total mRNA was extracted from seven of the nine ASPS paraffin specimens successfully. RT-PCR detected the fusion ASPSCR1::TFE3 type 1 (ASPSCR1 to TFE3 exon 4) in 3 cases and ASPSCR1::TFE3 type 2 (ASPSCR1 to TFE3 exon 3) in the other 4 cases. Of note, ASPSCR1::TFE3 is referred to by the alternative name ASPL-TFE3 in this paper. The authors conclude that detection of this fusion may aid in diagnosis in atypical cases. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ASPSCR1::TFE3 sequence variation in gene TFE3/NCBI:7030 2483 check_entity AN5782-1 TFE3 ASPSCR1::TFE3 mutation TFE3 NCBI:7030 gene alveolar soft part sarcoma DOID:4239 diagnostic;risk CIViC:3490 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ASPSCR1::TFE3 sequence variation in gene TFE3/NCBI:7030 2483 check_entity AN5782-2 TFE3 ASPSCR1::TFE3 mutation TFE3 NCBI:7030 gene renal cell carcinoma with MiT translocations DOID:0081413 diagnostic PubMed:11438465 Argani, et al. (2001) included eight morphologically distinctive renal cell carcinomas with the t(X;17) translocation as seen in alveolar soft part sarcoma (ASPS), with the distinction that the t(X;17) translocation is cytogenetically balanced in these renal tumors. The patients ranged from 17 months to 17 years of age. RT-PCR performed on the extracted RNA identified the ASPSCR1::TFE3 fusion product in all eight cases. Seven of the cases contained the type 1 product, a fusion of ASPSCR1 to TFE3 exon 4, whereas one cases showed a type 2 product, a fusion of ASPSCR1 to TFE3 exon 3. These cases were initially diagnosed as renal cell carcinoma (RCC) but upon further analysis were recognized to contain similarities to ASPS, likely due to the ASPSCR1::TFE3 fusion suggesting they are a distinctive subset of RCC. Of note, ASPSCR1::TFE3 is referred to by the alternative name ASPL-TFE3 in this paper. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ASPSCR1::TFE3 sequence variation in gene TFE3/NCBI:7030 2484 check_entity AN5782-2 TFE3 ASPSCR1::TFE3 mutation TFE3 NCBI:7030 gene renal cell carcinoma with MiT translocations DOID:0081413 diagnostic CIViC:3490 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ASPSCR1::TFE3 sequence variation in gene TFE3/NCBI:7030 2484 check_entity AN5783-1 TFE3 Fusion TFE3 NCBI:7030 gene renal cell carcinoma with MiT translocations DOID:0081413 diagnostic PubMed:26169997 'This study screened 983 Renal Cell Carcinoma (RCC) cases and identified 65 tumors with morphologic features suspicious of RCC with Xp11.2 translocation/TFE3 gene fusion (Xp11.2 RCC). TFE3 immunohistochemical staining and fluorescence in situ hybridization (FISH) testing confirmed 22 of these (34%) were Xp11.2 RCC. TFE3 rearrangements define RCCs with Xp11.2 translocation/TFE3 gene fusion, which, in the 2016 World Health Organization (WHO) classification, further belongs to the category of ''MiT family translocation renal cell carcinoma.'' The MiT family (microphthalmia-associated transcription factor family) translocation RCC comprises of the Xp11 translocation RCC harboring TFE3 gene fusions and the t(6;11) renal cell carcinoma harboring TFEB gene fusion. This study showed that the Xp11.2 translocation/TFE3 gene fusion RCC can be difficult to diagnose by pathology, and that evaluation by FISH is a useful diagnostic tool for this tumor type.' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene TFE3/NCBI:7030 2485 check_entity AN5783-1 TFE3 Fusion TFE3 NCBI:7030 gene renal cell carcinoma with MiT translocations DOID:0081413 diagnostic PubMed:26975036 Argani. et al,. (2016) included a total of 60 cases with known TFE3 gene rearrangements in this study of Xp11 translocation positive neoplasms (47 RCC, 8 PEComa, and 5 melanotic renal cancers). The age range for the RCC cases was 5 to 73 years. Fusion partners of TFE3 were identified using FISH (with confirmation by RNA sequencing in 5 cases) for 41/47 RCC cases, and included 7 SFPQ::TFE3 (PSF), 16 PRCC::TFE3, 12 ASPSCR1::TFE3 (ASPL), 5 NONO::TFE3, and 1 DVL2::TFE3. For the remaining 6 cases, the fusion partner of TFE3 was unable to be determined. The authors conclude that despite an identical gene fusion, the RCCs are distinct from the corresponding mesenchymal neoplasms and that the data can expand further the clinicopathologic features of cancers with specific TFE3 gene fusions. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene TFE3/NCBI:7030 2485 check_entity AN5783-1 TFE3 Fusion TFE3 NCBI:7030 gene renal cell carcinoma with MiT translocations DOID:0081413 diagnostic PubMed:19228722 A study of 443 renal cell carcinoma identified 7 cases with an Xp11 translocation. The median age of the 7 patients was 41 years (range, 15 to 59 years). Of the 244 cases with a successful karyotype, 4 were identified to have an Xp11 translocation. The fusion types of two cases were determined to be PSF::TFE3 and PRCC::TFE3. The other two cases were assumed to have the ASPSCR1::TFE3 gene fusion. The ASPSCR1::TFE3 fusion in one cases was confirmed by RT-PCR. Likewise, the PRCC::TFE3 fusion was detected by RT-PCR and confirmed by direct sequencing. Of the 199 samples, for which the karyotype was not determined 3 cases were assumed Xp11 translocation by positive immunostaining for TFE3. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene TFE3/NCBI:7030 2485 check_entity AN5783-1 TFE3 Fusion TFE3 NCBI:7030 gene renal cell carcinoma with MiT translocations DOID:0081413 diagnostic PubMed:34986355 Bakouny, et al. (2022) performed a comprehensive study of the molecular and clinical features of 90 translocation renal cell carcinomas (tRCCs), defined as subtype of kidney cancer driven by MiT/TFE gene fusions. Across the combined tRCC cohort, the majority of cases (88.6%) harbored TFE3 fusions with 12 different fusion partners identified. ASPSCR1 (13), SFPQ (13), PRCC (13), NONO (5), MED15 (4), RBM10 (4) were recurrent partners while U2AF2, MATR3, LUC7L3, KHSRP, FUBP1, and DVL2 were each seen in 1 case. All fusions analyzed preserve the helix-loop-helix/leucine zipper domain of the TFE3 transcription factor, which is critical for dimerization and DNA binding. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene TFE3/NCBI:7030 2485 check_entity AN5783-1 TFE3 Fusion TFE3 NCBI:7030 gene renal cell carcinoma with MiT translocations DOID:0081413 diagnostic CIViC:3598 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene TFE3/NCBI:7030 2485 check_entity AN5784-1 TFEB Fusion TFEB NCBI:7942 gene renal cell carcinoma with MiT translocations DOID:0081413 diagnostic PubMed:34986355 Bakouny, et al. (2022) performed a comprehensive study of the molecular and clinical features of translocation renal cell carcinomas (tRCCs), defined as subtype of kidney cancer driven by MiT/TFE gene fusions. Across the combined tRCC cohort, the majority of cases (78 cases; 88.6%) harbored TFE3 fusions, while the remainder harbored TFEB (8 cases; 9.1%) or MITF (2 cases; 2.3%) fusions. Four different TFEB fusion partners were observed including CADM2, CLTC, COL21A1 and MALAT1. TFEB and MITF fusion partners tended to preserve less of the N-terminal fusion partner in the fusion product compared to TFE3. The authors conclude that most tRCCs harbor few somatic alterations apart from MiT/TFE fusions. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene TFEB/NCBI:7942 2486 check_entity AN5784-1 TFEB Fusion TFEB NCBI:7942 gene renal cell carcinoma with MiT translocations DOID:0081413 diagnostic PubMed:22895266 Renal cell carcinomas (RCCs) with t(6;11)(p21;q12) are extremely rare and are characterized by a specific chromosome translocation involving the transcription factor EB (TFEB). Identification of either overexpression of the TFEB protein or translocation is a useful method for the diagnosis of TFEB RCCs. However, the results of immunostainings can be inconsistent. This 2012 study included 7 genetically confirmed cases of this rare tumor. The patients’ ages ranged from 21 to 37 years. All of these tumors showed moderate to strong immunoreactivity for TFEB. DNA PCR performed on genomic DNA extracted from FFPE tissue samples of the tumor identified the Alpha::TFEB fusion gene in 2 cases. The TFEB partner gene MALAT1 (Alpha) is an intronless, untranslated (non-protein coding) gene of unknown function. The Alpha::TFEB fusion genes were not identified in the other 5 cases. Using a FISH split probe assay all 7 TFEB RCCs showed a high percentage of cells with separation signals, and using a fusion probe assay all 7 TFEB RCCs demonstrated fusion signals. They concluded that the diagnosis of such tumors should be based not only on morphology itself but also on immunophenotype and molecular genetic findings. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene TFEB/NCBI:7942 2486 check_entity AN5784-1 TFEB Fusion TFEB NCBI:7942 gene renal cell carcinoma with MiT translocations DOID:0081413 diagnostic PubMed:15644781 A subset of renal neoplasms of children and young adults contains t(6;11)(p21;q12), fusion of the MALAT1 (Alpha) gene with the transcription factor gene TFEB. Argani, et al. (2005) included 7 renal neoplasms with cytogenetic and/or molecular evidence of the t(6;11)(p21;q12). The patients ranged from 9 to 33 years in age. All of the 7 renal neoplasms demonstrated either moderate or strong nuclear immunoreactivity for TFEB protein, and 1089 other neoplasms were tested but none showed significant labeling for TFEB. In 3 cases frozen tissue was available for RNA extraction, and RT-PCR detected the MALAT1(Alpha0::TFEB fusion. The potentially wide size range of MALAT1(Alpha)::TFEB fusion transcripts complicates the detection of this fusion by RT-PCR for robust detection in clinical RNA samples. The lack of splice signals in Alpha resulted in DNA PCR products of the same size as the RT-PCR products when the reverse primer binds to TFEB exon 3. The authors conclude that immunoreactivity for TFEB protein is a highly sensitive and specific diagnostic marker for these renal neoplasms and suggest that long-range DNA PCR may a useful alternative to RT-PCR due to the special molecular features of the Alpha::TFEB gene fusion. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene TFEB/NCBI:7942 2486 check_entity AN5784-1 TFEB Fusion TFEB NCBI:7942 gene renal cell carcinoma with MiT translocations DOID:0081413 diagnostic CIViC:4747 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::fusion sequence variation in gene TFEB/NCBI:7942 2486 check_entity AN5785-1 TFF3 EXPRESSION TFF3 NCBI:7033 gene breast cancer DOID:1612 risk PubMed:25900183 TFF3 expression was assessed by IHC in 75 patients, 187 patients were identified for the validation cohort. TFF3 expression was associated with response to endocrine therapy (tamoxifen, aminoglutethimide or oophorectomy) and outperformed ER, PR and TFF1 as biomarkers. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene TFF3/NCBI:7033 2487 AN5785-1 TFF3 EXPRESSION TFF3 NCBI:7033 gene breast cancer DOID:1612 risk CIViC:335 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene TFF3/NCBI:7033 2487 AN5786-1 TGFA EXPRESSION TGFA NCBI:7039 gene head and neck squamous cell carcinoma DOID:5520 prognostic PubMed:9625170 Primary tumors of 91 patients with head and neck squamous cell carcinoma were analyzed for expression of EGFR and TGF-alpha using IHC. Expression of EGFR or TGF-alpha were associated with reduced disease-free and cause-specific survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene TGFA/NCBI:7039 2488 AN5786-1 TGFA EXPRESSION TGFA NCBI:7039 gene head and neck squamous cell carcinoma DOID:5520 prognostic CIViC:312 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene TGFA/NCBI:7039 2488 AN5787-1 THBS2 UNDEREXPRESSION THBS2 NCBI:7058 gene colorectal cancer DOID:9256 prognostic PubMed:26807188 172 patients treated with neoadjuvant concurrent chemoradiotherapy (CCRT) were retrospectively analyzed for expression of thrombospondin 2 (THBS2) using IHC (discovery set with 46 rectal cancer patients, GSE35452). Low expression was associated with advanced pretreatment tumor, nodal status, post-treatment tumor, vascular invasion and inferior regression grade. In multivariate analysis, low expression served as negative prognostic factor for disease-free survival (Hazard ratio=3.057, P=0.002). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene THBS2/NCBI:7058 2489 AN5787-1 THBS2 UNDEREXPRESSION THBS2 NCBI:7058 gene colorectal cancer DOID:9256 prognostic CIViC:413 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene THBS2/NCBI:7058 2489 AN5788-1 TIMP1 Overexpression TIMP1 NCBI:7076 gene breast cancer DOID:1612 risk PubMed:23881388 TIMP1 overexpression was associated with resistance to fulvestrant in breast cancer cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene TIMP1/NCBI:7076 2490 AN5788-1 TIMP1 Overexpression TIMP1 NCBI:7076 gene breast cancer DOID:1612 risk PubMed:22544540 High expression of TIMP-1 was assessed by IHC in 99 primary breast cancers that had not spread beyond the breast after 6 postoperative courses of paclitaxel-based chemotherapy. High TIMP1 levels were associated with worse 5-year disease free survival (71.1%) than low levels (88.5 %; P = 0.020). High TIMP-1 levels were also associated with worse 5-year overall survival (78.9 %) than low levels (96.7 %; P = 0.004). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene TIMP1/NCBI:7076 2490 AN5788-1 TIMP1 Overexpression TIMP1 NCBI:7076 gene breast cancer DOID:1612 risk CIViC:373 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene TIMP1/NCBI:7076 2490 AN5789-1 TLK2 Amplification TLK2 NCBI:11011 gene breast cancer DOID:1612 risk PubMed:27694828 TLK2 inhibition selectively inhibits the growth of TLK2-high breast cancer cells, downregulates ERα, BCL2 and SKP2, impairs G1/S cell cycle progression, induces apoptosis and significantly improves progression-free survival in vivo. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene TLK2/NCBI:11011 2491 AN5789-1 TLK2 Amplification TLK2 NCBI:11011 gene breast cancer DOID:1612 risk CIViC:2116 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene TLK2/NCBI:11011 2491 AN5790-1 TOP1 Amplification TOP1 NCBI:7150 gene colorectal cancer DOID:9256 risk PubMed:24256029 FFPE tumor samples from 78 patients with colorectal cancer, who had received irinotecan monotherapy were analyzed with a FISH dual-probe. TOP1 gain was nonsignificantly associated with objective response to irinotecan Odds ratio (OR): 1.62; p = 0.07. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene TOP1/NCBI:7150 2492 AN5790-1 TOP1 Amplification TOP1 NCBI:7150 gene colorectal cancer DOID:9256 risk CIViC:367 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene TOP1/NCBI:7150 2492 AN5791-1 TOP1 EXPRESSION TOP1 NCBI:7150 gene colorectal cancer DOID:9256 risk PubMed:19775480 498 patients were retrospectively analyzed for topoisomerase 1 expression (IHC). In the subgroup of patients treated with irinotecan (38% of the 498), those patients expressing Topoisomerase I had a better overall survival according to multivariate analysis (HR = 0.47, 95% CI 0.23-0.94, p = 0.033). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene TOP1/NCBI:7150 2493 AN5791-1 TOP1 EXPRESSION TOP1 NCBI:7150 gene colorectal cancer DOID:9256 risk CIViC:380 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene TOP1/NCBI:7150 2493 AN5791-2 TOP1 EXPRESSION TOP1 NCBI:7150 gene ovarian cancer DOID:2394 risk PubMed:19648970 Shorter progression free survival was observed in patients with low expression (IHC) of topoisomerase 1 in 16 patients with relapsed or persistent ovarian or peritoneal carcinoma after treatment with topotecan, cyclophosphamide and carboplatin followed by an autologous hematopoietic stem cell transplant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene TOP1/NCBI:7150 2494 AN5791-2 TOP1 EXPRESSION TOP1 NCBI:7150 gene ovarian cancer DOID:2394 risk CIViC:380 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene TOP1/NCBI:7150 2494 AN5792-1 TOP2A EXPRESSION TOP2A NCBI:7153 gene breast cancer DOID:1612 risk PubMed:15486187 In a retrospective study, TOP2A expression was assessed by IHC for 108 breast cancer patients (from TAX 303 trial). TOP2A expression was associated with a higher probability of response in doxorubicin treated but not in docetaxel treated breast cancer patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene TOP2A/NCBI:7153 2495 AN5792-1 TOP2A EXPRESSION TOP2A NCBI:7153 gene breast cancer DOID:1612 risk CIViC:379 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene TOP2A/NCBI:7153 2495 AN5793-1 TP53 ALTERATION TP53 NCBI:7157 gene ovarian cancer DOID:2394 prognostic;risk 21739-8 PubMed:11595686 In a group of patients with invasive ovarian carcinoma who had undergone surgery, a subset of 74 patients treated with platinum based chemotherapy were assessed for p53 alteration (p53 mutation or p53 overexpression by immunostaining >10% positive). Significant decreased time to progression (p=0.037) was seen in the subset of patients with p53 alteration (n=54) in comparison to the group with normatl p53 (n=20) assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TP53 ALTERATION [biomarker_term_in_review] 2496 not_mapped AN5793-1 TP53 ALTERATION TP53 NCBI:7157 gene ovarian cancer DOID:2394 prognostic;risk 21739-8 CIViC:1281 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TP53 ALTERATION [biomarker_term_in_review] 2496 not_mapped AN5793-2 TP53 ALTERATION TP53 NCBI:7157 gene rhabdomyosarcoma DOID:3247 prognostic 21739-8 PubMed:34166060 This study evaluated 641 cases of rhabdomyosarcoma (RMS) that were enrolled in the Children’s Oncology Group (COG) trials from 1998 to 2017 and the UK malignant mesenchymal tumor and RMS2005 trails from 1995 to 2016. Molecular testing included 39 genes which had been implicated in the past with regards to RMS. The analysis was performed with a custom-capture sequencing assay. Altered TP53 was noted in 69 out of 515 FOXO1 fusion-negative RMS cases (13%), with the most frequent mutations at codons G245S (6 cases), R248Q or W (6 cases), R175H (4 cases), and P72A (4 cases). These cases displayed a worse event free survival. In FOXO1 fusion-positive RMS subtype, there was a small number of cases with altered TP53 (3 and 2 cases in the COG and UK patient cohorts, respectively), but they were universally fatal. Due to lack of a matched germline sample, it could not be determined whether the TP53 abnormalities were of somatic or germline origin. Nevertheless, both cohorts show that mutations in TP53 are associated with a poor prognosis in both fusion-negative and fusion-positive RMS, with a particularly bleak outcome in fusion-positive RMS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TP53 ALTERATION [biomarker_term_in_review] 2497 not_mapped AN5793-2 TP53 ALTERATION TP53 NCBI:7157 gene rhabdomyosarcoma DOID:3247 prognostic 21739-8 CIViC:1281 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TP53 ALTERATION [biomarker_term_in_review] 2497 not_mapped AN5794-1 TP53 C238Y mutation TP53 NCBI:7157 gene breast cancer DOID:1612 prognostic 21739-8 PubMed:11051239 Cys-238 was directly bound to zinc molecule. Patients with missense mutations affecting amino acids directly involved in DNA or zinc binding displayed a very aggressive clinical phenotype. When patients were split into three groups based on TP53 mutation effect, those with mutations in the very aggressive group had worse rates of freedom from distant metastasis (P<0.0001), disease-specific survival (P<0.0001), and overall survival (P<0.0001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C238Y sequence variation in gene TP53/NCBI:7157 2498 check_entity AN5794-1 TP53 C238Y mutation TP53 NCBI:7157 gene breast cancer DOID:1612 prognostic 21739-8 CIViC:2517 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C238Y sequence variation in gene TP53/NCBI:7157 2498 check_entity AN5795-1 TP53 CONSERVED DOMAIN MUT TP53 NCBI:7157 gene ovarian cancer DOID:2394 prognostic 21739-8 PubMed:11595686 Patients with conserved domain p53 mutation (n=61) were compared with those with wild type or non-conserved domain p53 mutation (n=117) in a cohort of 178 invasive ovarian carcinoma patients who had undergone surgery. Overall survival was decreased in the cohort with conserved domian mutation (p=0.005). Conserved domain mutation was an independent factor in univariate (but not multivariate) analysis of overall survival with relative risk 1.70 (1.17-2.47, p<0.007). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TP53 CONSERVED DOMAIN MUT [biomarker_term_in_review] 2499 not_mapped AN5795-1 TP53 CONSERVED DOMAIN MUT TP53 NCBI:7157 gene ovarian cancer DOID:2394 prognostic 21739-8 CIViC:1274 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TP53 CONSERVED DOMAIN MUT [biomarker_term_in_review] 2499 not_mapped AN5796-1 TP53 DNA Binding Domain Mutation TP53 NCBI:7157 gene breast cancer DOID:1612 risk 21739-8 PubMed:10786679 In a study 202 breast cancer patients undergoing first line tamoxifen treatment, 65 patients had mutations in TP53. Among the p53 wild type population a 66% response rate was reported, where response was considered as complete response, partial response or stable disease. In a patient subgroup with mutations in p53 amino acids that directly interact with DNA, 2 of 11 (18%) of patients responded to tamoxifen. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::dna:binding:domain:mutation sequence variation in gene TP53/NCBI:7157 2500 check_entity AN5796-1 TP53 DNA Binding Domain Mutation TP53 NCBI:7157 gene breast cancer DOID:1612 risk 21739-8 CIViC:238 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::dna:binding:domain:mutation sequence variation in gene TP53/NCBI:7157 2500 check_entity AN5796-2 TP53 DNA Binding Domain Mutation TP53 NCBI:7157 gene oral squamous cell carcinoma DOID:0050866 prognostic 21739-8 PubMed:12509970 Oral squamous cell carcinoma patients with TP53 mutations in the DNA binding domain (L2, L3 and the LSH motif) have significantly reduced cumulative survival when compared to patients with TP53 mutations outside of this DNA binding domain. These mutations were also significantly associated with locoregional failure, cervical lymph node metastasis and distant metastasis, likely contributing to this finding. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::dna:binding:domain:mutation sequence variation in gene TP53/NCBI:7157 2501 check_entity AN5796-2 TP53 DNA Binding Domain Mutation TP53 NCBI:7157 gene oral squamous cell carcinoma DOID:0050866 prognostic 21739-8 CIViC:238 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::dna:binding:domain:mutation sequence variation in gene TP53/NCBI:7157 2501 check_entity AN5797-1 TP53 Deleterious Mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 PubMed:25730903 MDM2 Inhibitor screen in a panel of 260 cancer cell lines with well characterized TP53 status shows that only cancer cell lines with unaltered TP53 may be sensitive to MDM2 Inhibitor AMGMDS3, while those with p53 mutations demonstrated resistance. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deleterious:mutation sequence variation in gene TP53/NCBI:7157 2502 check_entity AN5797-1 TP53 Deleterious Mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 PubMed:17671205 MDM2 Inhibitor Nutlin-3a induced senescence in presence of functional TP53 in murine primary fibroblasts, oncogenically transformed fibroblasts, and fibrosarcoma cell lines. TP53 mutant cells lacking functional TP53 were completely insensitive to the drug. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deleterious:mutation sequence variation in gene TP53/NCBI:7157 2502 check_entity AN5797-1 TP53 Deleterious Mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 CIViC:221 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deleterious:mutation sequence variation in gene TP53/NCBI:7157 2502 check_entity AN5797-2 TP53 Deleterious Mutation TP53 NCBI:7157 gene head and neck squamous cell carcinoma DOID:5520 prognostic 21739-8 PubMed:22090360 In a study of 74 patients with head and neck squamous cell carcinoma, those with disruptive mutations in TP53 had shorter overall survival and a higher rate of locoregional recurrence than those without mutations or with nondisruptive mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deleterious:mutation sequence variation in gene TP53/NCBI:7157 2503 check_entity AN5797-2 TP53 Deleterious Mutation TP53 NCBI:7157 gene head and neck squamous cell carcinoma DOID:5520 prognostic 21739-8 CIViC:221 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deleterious:mutation sequence variation in gene TP53/NCBI:7157 2503 check_entity AN5797-3 TP53 Deleterious Mutation TP53 NCBI:7157 gene leukemia DOID:1240 risk 21739-8 PubMed:26459177 Phase I Trial of MDM2 inhibitor RG7112 in 116 patients with AML, ALL, CML, CLL, sCLL demonstrated sustained clinical improvement and induction of TP53 target genes in subset of patients with wild type TP53. No sustained clinical improvement or induction of TP53 target genes was observed in patients with mutant TP53. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deleterious:mutation sequence variation in gene TP53/NCBI:7157 2504 check_entity AN5797-3 TP53 Deleterious Mutation TP53 NCBI:7157 gene leukemia DOID:1240 risk 21739-8 CIViC:221 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deleterious:mutation sequence variation in gene TP53/NCBI:7157 2504 check_entity AN5797-4 TP53 Deleterious Mutation TP53 NCBI:7157 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21739-8 PubMed:26899019 Pooled analysis of TP53 mutations (exons 5-8) from 4 randomized trials (IALT, JBR10, CALGB-9633 and ANITA). Mutations (434; 36%) had no prognostic effect (OBS: HROS=0.99; [95%CI 0.77-1.28], p=0.95; HRDFS=0.99 [0.78-1.25], p=0.92) but were marginally predictive of benefit from ACT for OS (test for interaction: OS: p=0.06; DFS: p=0.11). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deleterious:mutation sequence variation in gene TP53/NCBI:7157 2505 check_entity AN5797-4 TP53 Deleterious Mutation TP53 NCBI:7157 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21739-8 CIViC:221 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deleterious:mutation sequence variation in gene TP53/NCBI:7157 2505 check_entity AN5797-5 TP53 Deleterious Mutation TP53 NCBI:7157 gene sarcoma DOID:1115 risk 21739-8 PubMed:26646755 19 advanced sarcoma patients treated with pazopanib were retrospectively assessed for mutations associated with response using the Foundation one sarcoma/heme panel. Progression-free survival (PFS) of patients with TP53 mutations (all predicted to be loss of function) was significantly greater than TP53 wild-type tumors with the median PFS of 208 versus 136 days, respectively [P = 0.036, hazards ratio 0.38 (95% confidence interval 0.09-0.83)]. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deleterious:mutation sequence variation in gene TP53/NCBI:7157 2506 check_entity AN5797-5 TP53 Deleterious Mutation TP53 NCBI:7157 gene sarcoma DOID:1115 risk 21739-8 CIViC:221 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deleterious:mutation sequence variation in gene TP53/NCBI:7157 2506 check_entity AN5798-1 TP53 G245S mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 PubMed:25730903 Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 G245S loss of function mutation is present in 3 cell lines and all are insensitive to MDM2 Inhibitor AMGMDS3. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G245S sequence variation in gene TP53/NCBI:7157 2507 check_entity AN5798-1 TP53 G245S mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 CIViC:853 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G245S sequence variation in gene TP53/NCBI:7157 2507 check_entity AN5799-1 TP53 Loss TP53 NCBI:7157 gene lung non-small cell carcinoma DOID:3908 risk 21739-8 PubMed:22425996 A clinical trial comparing selumetinib and docetaxel vs. docetaxel and placebo in KRAS mutant NSCLC was recapitulated in mice. Tumors were induced in lung epithelium by nasal instillation of CRE-bearing adenovirus in conditionally targeted mice. Kras(G12D) and Trp53 knockout mutant mice were resistant to docetaxel monotherapy but sensitive to combined treatment. In a small number of human NSCLC patients with these genotypes FDG-PET signal intensity changes and pERK IHC staining correlated with mouse data. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TP53 Loss [biomarker_term_in_review] 2508 not_mapped AN5799-1 TP53 Loss TP53 NCBI:7157 gene lung non-small cell carcinoma DOID:3908 risk 21739-8 CIViC:4407 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TP53 Loss [biomarker_term_in_review] 2508 not_mapped AN5800-1 TP53 M237I mutation TP53 NCBI:7157 gene glioblastoma DOID:3068 risk 21739-8 PubMed:25730903 Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 M237I loss of function mutation is present in 1 cell line (T98G, glioblastoma) and it is insensitive to MDM2 Inhibitor AMGMDS3 (IC50: 49.97uM). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M237I sequence variation in gene TP53/NCBI:7157 2509 check_entity AN5800-1 TP53 M237I mutation TP53 NCBI:7157 gene glioblastoma DOID:3068 risk 21739-8 CIViC:1040 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M237I sequence variation in gene TP53/NCBI:7157 2509 check_entity AN5801-1 TP53 Mutation TP53 NCBI:7157 gene acute myeloid leukemia DOID:9119 prognostic 21739-8 PubMed:26771088 In a study of 97 patients with AML treated with HSCT, 40 had TP53 mutations comprising a total of 44 mutations. Patients with a TP53 mutation had a reduced three year probability of overall survival and event-free survival compared to patients with the wild-type TP53. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2510 check_entity AN5801-1 TP53 Mutation TP53 NCBI:7157 gene acute myeloid leukemia DOID:9119 prognostic 21739-8 CIViC:222 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2510 check_entity AN5801-2 TP53 Mutation TP53 NCBI:7157 gene adrenocortical carcinoma DOID:3948 prognostic 21739-8 PubMed:15922892 TP53 mutation was shown to be associated with shorter overall survival in patients with adrenocortical tumors (log-rank test; P=0.098). Of 20 patients studied, 5 had coding mutation in TP53. Four of the 5 patients with a TP53 mutation had metastases at diagnosis or detected soon thereafter, and 3 of 4 died of disease within 12 months of surgical resection. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2511 check_entity AN5801-2 TP53 Mutation TP53 NCBI:7157 gene adrenocortical carcinoma DOID:3948 prognostic 21739-8 CIViC:222 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2511 check_entity AN5801-3 TP53 Mutation TP53 NCBI:7157 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 prognostic 21739-8 PubMed:22699455 In children with bone marrow relapsed B-cell precursor acute lymphoblastic leukemia, in multivariate analysis those with mutations in TP53 had worse event-free survival than patients without mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2512 check_entity AN5801-3 TP53 Mutation TP53 NCBI:7157 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 prognostic 21739-8 PubMed:21747090 In relapsed B-ALL patients, TP53 mutations were associated with morphologic nonresponse to therapy (>5% blasts in the bone marrow after 9 weeks of treatment) as well as reduced event free and overall survival when compared to TP53 wildtype patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2512 check_entity AN5801-3 TP53 Mutation TP53 NCBI:7157 gene B-lymphoblastic leukemia/lymphoma DOID:0080630 prognostic 21739-8 CIViC:222 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2512 check_entity AN5801-4 TP53 Mutation TP53 NCBI:7157 gene breast cancer DOID:1612 risk 21739-8 PubMed:22698404 In this preclinical study, MMTV-Wnt1 mammary tumors with mutant TP53 showed a better clinical response to chemotherapy (doxorubicin) than TP53 wild-type tumors. This was mediated by wild-type TP53-induced cell-arrest under chemotherapy even in the context of heterozygous TP53 point mutations or absence of p21. Thus the status of both TP53 alleles should be assessed because even one copy of wild-type TP53 may contribute to poor response to chemotherapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2513 check_entity AN5801-4 TP53 Mutation TP53 NCBI:7157 gene breast cancer DOID:1612 risk 21739-8 PubMed:10786679 In a study 202 breast cancer patients undergoing tamoxifen treatment, a higher frequency of wildtype TP53 patients responded to treatment compared to those with mutations in TP53 (66% wild-type vs. 31%, odds ratio (OR):0.22, 95CI:0.12-0.42, P<0.0001, univariate analysis; OR:0.29, 95% CI:0.12-0.42, P=0.0014, multivariate analysis). The median survival after start of therapy was shorter in patients with mutations in TP53 than for patients with wild-type TP53 (20mo vs. 29mo, HR:1.99,95% CI:1.43-2.75, P<0.001). Breast cancer patients with TP53 mutations also had a decrease in progression-free survival (HR:2.61, 95% CI:1.90-3.6, P<0.001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2513 check_entity AN5801-4 TP53 Mutation TP53 NCBI:7157 gene breast cancer DOID:1612 risk 21739-8 CIViC:222 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2513 check_entity AN5801-5 TP53 Mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 PubMed:25669829 Patients with a hotspot TP53 mutation had a higher rate of SD ≥6 months/PR, longer median PFS, and median OS compared to patients without a hotspot TP53 mutation. Mutations observed in this study include loss of function (A159fs, R213*, and DNA-binding domain truncation) or gain of function (R175H, H179R, H193R, V216M, G245S, and R273C). These mutations were seen in 11 of 36 patients in enrolled in the clinical trial. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2514 check_entity AN5801-5 TP53 Mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 CIViC:222 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2514 check_entity AN5801-6 TP53 Mutation TP53 NCBI:7157 gene chronic lymphocytic leukemia DOID:1040 prognostic;risk 21739-8 PubMed:8241511 A study of 53 patients with B-CLL found a significant resistance to chemotherapy and corresponding poor clinical outcomes among the 7 treated patients with p53 mutations compared to the 29 treated patients without. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2515 check_entity AN5801-6 TP53 Mutation TP53 NCBI:7157 gene chronic lymphocytic leukemia DOID:1040 prognostic;risk 21739-8 PubMed:18689542 In a study of 126 patients with long-term follow-up, TP53 mutations were significantly associated with shorter median survival in patients (P = 0.002) from time of diagnosis. The median survival from the time of first observation of a TP53 mutation was much more pronounced (P = <0.001). These findings were statistically independent of 17p deletions. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2515 check_entity AN5801-6 TP53 Mutation TP53 NCBI:7157 gene chronic lymphocytic leukemia DOID:1040 prognostic;risk 21739-8 PubMed:20697090 The authors analyzed 328 patients with CLL, of which 28 were identified to have TP53 mutations. Patients with TP53 mutations were found to have significantly shorter progression-free (HR = 3.8; P < 0.001) and overall survival (HR = 7.2; P < 0.001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2515 check_entity AN5801-6 TP53 Mutation TP53 NCBI:7157 gene chronic lymphocytic leukemia DOID:1040 prognostic;risk 21739-8 PubMed:21483000 In the CLL4 trial assessing first line treatment with chlorambucil or fludarabine with or without cyclophosphamide, patients with TP53 mutations experienced poorer overall response rates (27% vs 83%), shorter progression free survival (5 year PFS 5% vs 17%), and overall survival (20% vs 59%) compared to patients without TP53 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2515 check_entity AN5801-6 TP53 Mutation TP53 NCBI:7157 gene chronic lymphocytic leukemia DOID:1040 prognostic;risk 21739-8 PubMed:14726385 Thirty-six patients with CLL were treated with alemtuzumab. Partial or complete response was achieved in 6 of 15 patients with p53 mutations, compared to 4 of 21 without. These findings are not statistically significant, but the authors suggest that alemtuzumab is an effective therapy for patients with p53 mutations or deletions. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2515 check_entity AN5801-6 TP53 Mutation TP53 NCBI:7157 gene chronic lymphocytic leukemia DOID:1040 prognostic;risk 21739-8 PubMed:24943832 In a multivariate analysis of 774 CLL patients, TP53 aberrations were significantly correlated with shorter time to first treatment (HR=2.081; 95% CI=1.431-3.021). This finding was independent of IGHV mutation status. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2515 check_entity AN5801-6 TP53 Mutation TP53 NCBI:7157 gene chronic lymphocytic leukemia DOID:1040 prognostic;risk 21739-8 PubMed:26837699 In a cohort of 406 patients with CLL, those patients with clonal or sub-clonal mutations in TP53 had significantly shorter overall survival (HR: 1.71; 95% CI: 1.28-2.26; P = .0001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2515 check_entity AN5801-6 TP53 Mutation TP53 NCBI:7157 gene chronic lymphocytic leukemia DOID:1040 prognostic;risk 21739-8 CIViC:222 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2515 check_entity AN5801-7 TP53 Mutation TP53 NCBI:7157 gene esophagus squamous cell carcinoma DOID:3748 prognostic 21739-8 PubMed:19941080 In a retrospective study of patients with esophageal carcinoma, those with mutations in TP53 had worse overall survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2516 check_entity AN5801-7 TP53 Mutation TP53 NCBI:7157 gene esophagus squamous cell carcinoma DOID:3748 prognostic 21739-8 CIViC:222 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2516 check_entity AN5801-8 TP53 Mutation TP53 NCBI:7157 gene gastric adenocarcinoma DOID:3717 risk 21739-8 PubMed:24740294 In this meta-analysis of 13 studies (564 patients) p53 positivity as defined by high protein expression and/or p53 mutation was associated with improved response to chemotherapy (risk ratio [RR] = 0.704; 95% confidence intervals [CI] = 0.550-0.903; P = 0.006). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2517 check_entity AN5801-8 TP53 Mutation TP53 NCBI:7157 gene gastric adenocarcinoma DOID:3717 risk 21739-8 CIViC:222 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2517 check_entity AN5801-9 TP53 Mutation TP53 NCBI:7157 gene head and neck squamous cell carcinoma DOID:5520 prognostic 21739-8 PubMed:8901856 Unlike other studies, in this study of 110 patients with head and neck squamous cell carcinoma, there was no significant difference in the overall survival of patients with and without any TP53 mutations. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2518 check_entity AN5801-9 TP53 Mutation TP53 NCBI:7157 gene head and neck squamous cell carcinoma DOID:5520 prognostic 21739-8 PubMed:11325447 Tumors from 114 patients with head and neck squamous cell carcinoma were analyzed for TP53 mutations, 21 of which were treated with surgery. Unlike those treated with radiotherapy, those treated with surgery did not show a significant difference in rates of loco-regional control between those with and without mutations in TP53. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2518 check_entity AN5801-9 TP53 Mutation TP53 NCBI:7157 gene head and neck squamous cell carcinoma DOID:5520 prognostic 21739-8 CIViC:222 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2518 check_entity AN5801-10 TP53 Mutation TP53 NCBI:7157 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21739-8 PubMed:22425996 A clinical trial comparing selumetinib and docetaxel vs. docetaxel and placebo in KRAS mutant NSCLC was recapitulated in mice. Tumors were induced in lung epithelium by nasal instillation of CRE-bearing adenovirus in conditionally targeted mice. Kras(G12D) and Trp53 knockout mutant mice were resistant to docetaxel monotherapy but sensitive to combined treatment. In a small number of human NSCLC patients with these genotypes FDG-PET signal intensity changes and pERK IHC staining correlated with mouse data. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2519 check_entity AN5801-10 TP53 Mutation TP53 NCBI:7157 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21739-8 PubMed:28453411 A pooled analysis to investigate the prognostic and predictive roles of TP53/KRAS and TP53/EGFR comutations (cm) in randomized trials of adjuvant chemotherapy compared to observational therapy encompassing a total of 3,553 patients. TP53/KRAS cm showed no prognostic effects but a borderline predictive effect (p=0,04) for negative effect of chemotherapy as compared to tp53/KRAS wt/wt. TP53/EGFR cm in was neither prognostic ( P = .83), nor significantly predictive ( P = .86). Similar results were observed for both groups for disease-free survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2519 check_entity AN5801-10 TP53 Mutation TP53 NCBI:7157 gene lung non-small cell carcinoma DOID:3908 prognostic;risk 21739-8 CIViC:222 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2519 check_entity AN5801-11 TP53 Mutation TP53 NCBI:7157 gene medulloblastoma SHH activated DOID:0080703 prognostic 21739-8 PubMed:28545823 In the childhood (≥4.3 years) SHH-MB subgroup, TP53 mutations (n=13) are associated with shorter progression-free survival (PFS) compared to the no mutation group (n=35) (HR, 3.47; 95% CI, 1.29 to 9.3; p<0.014). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2520 check_entity AN5801-11 TP53 Mutation TP53 NCBI:7157 gene medulloblastoma SHH activated DOID:0080703 prognostic 21739-8 CIViC:222 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2520 check_entity AN5801-12 TP53 Mutation TP53 NCBI:7157 gene myelodysplastic syndrome DOID:0050908 prognostic 21739-8 PubMed:24836762 In patients with myelodysplastic syndrome, in a multivariate analysis those with mutations in TP53 had shorter overall survival than wild-type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2521 check_entity AN5801-12 TP53 Mutation TP53 NCBI:7157 gene myelodysplastic syndrome DOID:0050908 prognostic 21739-8 CIViC:222 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2521 check_entity AN5801-13 TP53 Mutation TP53 NCBI:7157 gene myeloid neoplasm DOID:0070004 prognostic 21739-8 PubMed:17215851 In patients with myeloma, those with mutations in TP53 had worse overall survival than those without. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2522 check_entity AN5801-13 TP53 Mutation TP53 NCBI:7157 gene myeloid neoplasm DOID:0070004 prognostic 21739-8 CIViC:222 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2522 check_entity AN5801-14 TP53 Mutation TP53 NCBI:7157 gene stomach carcinoma DOID:5517 risk 21739-8 PubMed:14514923 In a study of 25 patients with advanced gastric cancer, mutations in TP53 were identified in 32% of primary tumors. TP53 mutations were associated with an improved response to preoperative treatment of a modified EAP protocol (combination of doxorubicin, etoposide and cisplatin). Patients with mutations in TP53 had an increased median survival compared to patients with wildtype TP53 (18.5mo vs. 10.2mo, P=0.044). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2523 check_entity AN5801-14 TP53 Mutation TP53 NCBI:7157 gene stomach carcinoma DOID:5517 risk 21739-8 CIViC:222 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene TP53/NCBI:7157 2523 check_entity AN5802-1 TP53 Overexpression TP53 NCBI:7157 gene ovarian cancer DOID:2394 prognostic;risk 21739-8 PubMed:11595686 p53 overexpression (>10% positive stained nuclei) was found in 110 cases from a 178 patient cohort with invasive ovarian carcinoma who had undergone surgery. Overexpression of p53 was correlated with poor differentiation (p<0.001) and high S-phase fraction (p<0.001). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene TP53/NCBI:7157 2524 AN5802-1 TP53 Overexpression TP53 NCBI:7157 gene ovarian cancer DOID:2394 prognostic;risk 21739-8 CIViC:1280 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene TP53/NCBI:7157 2524 AN5802-2 TP53 Overexpression TP53 NCBI:7157 gene renal Wilms' tumor DOID:5176 prognostic 21739-8 PubMed:21525573 44 archival FFPE samples from confirmed cases of Wilms tumor with mean age 3 years 2 months, and taken from the most histologically aggressive parts of each tumor, were stained with p53 monoclonal antibody and the corresponding patient clinical data was analyzed. 24 samples were p53 positive, and did not correlate with age or sex. All tumors with unfavorable histology were p53 positive, in contrast to 13 of 33 tumors with favorable histology, with weak-moderate p53 signal (p<0.001). 2 year overall survival rate was 89.2% in p53 negative, and 55.7% for p53 positive cases (P = .01), and mean survival was 46 months in p53 negative and 26 months in p53 positive cases (P = .02). Compared with p53 negative, tumors with week to moderate p53 signal had HR 3.75 (P = .05), and high signal had HR 8.61 (P = .01). No significant correlation was seen between tumor clinicopathological stage and p53 expression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene TP53/NCBI:7157 2525 AN5802-2 TP53 Overexpression TP53 NCBI:7157 gene renal Wilms' tumor DOID:5176 prognostic 21739-8 CIViC:1280 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene TP53/NCBI:7157 2525 AN5802-3 TP53 Overexpression TP53 NCBI:7157 gene stomach cancer DOID:10534 risk 21739-8 PubMed:14514923 In a Phase II trial of 25 patients with metastaic gastric cancer, patients received preoperative high dose chemotherapy (HDCT) consisting of etoposide, cisplatin and mitomycin. Patients with greater than 50% regression in response to HDCT received surgery. TP53 overexpression was assayed by immunohistochemistry. 14 patients showed p53 overexpression, and 12 of these qualified for resection. Overall survival in patients with p53 overexpression was 17.3 months in contrast to patients with negative p53 immunohistochemistry, where it was 7.2 months (p=0.0003). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene TP53/NCBI:7157 2526 AN5802-3 TP53 Overexpression TP53 NCBI:7157 gene stomach cancer DOID:10534 risk 21739-8 CIViC:1280 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene TP53/NCBI:7157 2526 AN5803-1 TP53 P47S mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 PubMed:27034505 The P47S (rs1800371) variant of TP53 is observed in 1.5% in African Americans and between 6% and 8% in certain African populations but has not been detected in Caucasian Americans. This paper reports functional studies of this variant. Mouse models with this variant show an increase in spontaneous tumor formation. 16 out of 20 (80%) of S47 homozygous mice developed cancer between 12 and 18 months of age. Cancers predominantly included hepatocellular carcinoma, B-cell lymphoma, and histiocytic sarcoma, as well as other tumor types. In S47/wild-type heterozygote mice an increased cancer incidence, with a predisposition for hepatocellular carcinoma, was also found. Mouse embryonic fibroblasts and human lymphoblastoid cell lines with S47 mutations were significantly less sensitive to cisplatinum treatment compared to TP53 wild-type cells (apoptosis and viability). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P47S sequence variation in gene TP53/NCBI:7157 2527 check_entity AN5803-1 TP53 P47S mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 CIViC:500 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P47S sequence variation in gene TP53/NCBI:7157 2527 check_entity AN5804-1 TP53 P72R mutation TP53 NCBI:7157 gene breast cancer DOID:1612 diagnostic 21739-8 PubMed:17909070 Large meta-analysis of 5,191 breast cancer patients and 3,834 controls did not find a conclusive link between codon 72 allele and breast cancer susceptibility. Odds ratios were 0.98 (95% CI, 0.91–1.05) for heterozygotes and 0.97 (95% CI, 0.86–1.11) in homozygotes (per-allele OR, 0.98; 95% CI, 0.91–1.04). Median age of onset was also not different between genotypes (GG: 49 years, GC: 50, CC: 50). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P72R sequence variation in gene TP53/NCBI:7157 2528 check_entity AN5804-1 TP53 P72R mutation TP53 NCBI:7157 gene breast cancer DOID:1612 diagnostic 21739-8 CIViC:527 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P72R sequence variation in gene TP53/NCBI:7157 2528 check_entity AN5804-2 TP53 P72R mutation TP53 NCBI:7157 gene cervical cancer DOID:4362 prognostic 21739-8 PubMed:11535556 In a relatively small meta-analysis of 119 women with cervical cancer and 127 controls, associations with homozygosity for arginine, and heterozygosity at this locus were both associated with odds ratios above one (3.5 and 2.2, respectively) after adjusting for age and HPV infection. However, both confidence intervals had minimums below one (0.9 and 0.6, respectively). So the overall conclusion remains mixed on the significance of this polymorphism in the prognosis for cervical cancer. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P72R sequence variation in gene TP53/NCBI:7157 2529 check_entity AN5804-2 TP53 P72R mutation TP53 NCBI:7157 gene cervical cancer DOID:4362 prognostic 21739-8 CIViC:527 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P72R sequence variation in gene TP53/NCBI:7157 2529 check_entity AN5804-3 TP53 P72R mutation TP53 NCBI:7157 gene lung carcinoma DOID:3905 prognostic 21739-8 PubMed:12840112 Pooled data from 13 studies of patients with lung cancer found little effect of codon 72 allele on the overall survival of patients with lung cancer. Proline homozygous patients were correlated with slightly poorer outcome, odds ratio 1.18 with a 95% confidence interval of 0.99-1.41. Heterozygotes had an OR of 1.02 (95% CI 0.86-1.20). Authors conclude that the effect of these alleles on prognosis in lung cancer is inconclusive at best. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P72R sequence variation in gene TP53/NCBI:7157 2530 check_entity AN5804-3 TP53 P72R mutation TP53 NCBI:7157 gene lung carcinoma DOID:3905 prognostic 21739-8 CIViC:527 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P72R sequence variation in gene TP53/NCBI:7157 2530 check_entity AN5805-1 TP53 R158H mutation TP53 NCBI:7157 gene vulva squamous cell carcinoma DOID:2101 risk 21739-8 PubMed:25730903 Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 R158H loss of function mutation is present in 1 cell line (SW954) and it is insensitive to MDM2 Inhibitor AMGMDS3. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R158H sequence variation in gene TP53/NCBI:7157 2531 check_entity AN5805-1 TP53 R158H mutation TP53 NCBI:7157 gene vulva squamous cell carcinoma DOID:2101 risk 21739-8 CIViC:1603 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R158H sequence variation in gene TP53/NCBI:7157 2531 check_entity AN5806-1 TP53 R158L mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 PubMed:25730903 Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 R158L loss of function mutation is present in 2 cell lines and all are insensitive to MDM2 Inhibitor AMGMDS3. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R158L sequence variation in gene TP53/NCBI:7157 2532 check_entity AN5806-1 TP53 R158L mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 CIViC:1607 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R158L sequence variation in gene TP53/NCBI:7157 2532 check_entity AN5807-1 TP53 R175H mutation TP53 NCBI:7157 gene breast cancer DOID:1612 prognostic;risk 21739-8 PubMed:22698404 Breast tumors in a mouse model with R172H mutation (homologous to human R175H) are more responsive to doxorubicin than breast tumors with wild type TP53. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R175H sequence variation in gene TP53/NCBI:7157 2533 check_entity AN5807-1 TP53 R175H mutation TP53 NCBI:7157 gene breast cancer DOID:1612 prognostic;risk 21739-8 PubMed:16489069 Breast cancer patients who harbor R175H mutation have worse overall survival than those with wild type TP53, but have better prognosis than those with R248W mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R175H sequence variation in gene TP53/NCBI:7157 2533 check_entity AN5807-1 TP53 R175H mutation TP53 NCBI:7157 gene breast cancer DOID:1612 prognostic;risk 21739-8 CIViC:116 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R175H sequence variation in gene TP53/NCBI:7157 2533 check_entity AN5807-2 TP53 R175H mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 PubMed:25730903 Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 R175H loss of function mutation is present in 4 cell lines and all are insensitive to MDM2 Inhibitor AMGMDS3. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R175H sequence variation in gene TP53/NCBI:7157 2534 check_entity AN5807-2 TP53 R175H mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 CIViC:116 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R175H sequence variation in gene TP53/NCBI:7157 2534 check_entity AN5807-3 TP53 R175H mutation TP53 NCBI:7157 gene stomach carcinoma DOID:5517 risk 21739-8 PubMed:14514923 In a study of 25 patients with advanced gastric cancer, mutations in TP53 were identified in 32% of primary tumors. TP53 mutations were associated with an improved response to preoperative treatment of a modified EAP protocol (combination of doxorubicin, etoposide and cisplatin). Patients with mutations in TP53 had an increased median survival compared to patients with wildtype TP53 (18.5mo vs. 10.2mo, P=0.044). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R175H sequence variation in gene TP53/NCBI:7157 2535 check_entity AN5807-3 TP53 R175H mutation TP53 NCBI:7157 gene stomach carcinoma DOID:5517 risk 21739-8 CIViC:116 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R175H sequence variation in gene TP53/NCBI:7157 2535 check_entity AN5808-1 TP53 R213P mutation TP53 NCBI:7157 gene stomach carcinoma DOID:5517 risk 21739-8 PubMed:14514923 In a study of 25 patients with advanced gastric cancer, mutations in TP53 were identified in 32% of primary tumors. TP53 mutations were associated with an improved response to preoperative treatment of a modified EAP protocol (combination of doxorubicin, etoposide and cisplatin). Patients with mutations in TP53 had an increased median survival compared to patients with wildtype TP53 (18.5mo vs. 10.2mo, P=0.044). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R213P sequence variation in gene TP53/NCBI:7157 2536 check_entity AN5808-1 TP53 R213P mutation TP53 NCBI:7157 gene stomach carcinoma DOID:5517 risk 21739-8 CIViC:1083 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R213P sequence variation in gene TP53/NCBI:7157 2536 check_entity AN5809-1 TP53 R248Q mutation TP53 NCBI:7157 gene breast cancer DOID:1612 prognostic 21739-8 PubMed:16489069 Breast cancer patients who harbor a R248Q mutation (N=18) have worse overall survival than those with wild type TP53 (N=1460), but have better prognosis than those with a R248W mutation (N=8). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R248Q sequence variation in gene TP53/NCBI:7157 2537 check_entity AN5809-1 TP53 R248Q mutation TP53 NCBI:7157 gene breast cancer DOID:1612 prognostic 21739-8 PubMed:9569050 In breast cancer patients harboring TP53 mutation, mutations in DNA contact regions such as R248 (N=10, 6 at R248) are prognostic for a worse relapse-free survival compared to other non-silent mutations in TP53 (N=43). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R248Q sequence variation in gene TP53/NCBI:7157 2537 check_entity AN5809-1 TP53 R248Q mutation TP53 NCBI:7157 gene breast cancer DOID:1612 prognostic 21739-8 CIViC:117 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R248Q sequence variation in gene TP53/NCBI:7157 2537 check_entity AN5809-2 TP53 R248Q mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 PubMed:25730903 Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 R248Q loss of function mutation is present in 5 cell lines and all are insensitive to MDM2 Inhibitor AMGMDS3. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R248Q sequence variation in gene TP53/NCBI:7157 2538 check_entity AN5809-2 TP53 R248Q mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 CIViC:117 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R248Q sequence variation in gene TP53/NCBI:7157 2538 check_entity AN5809-3 TP53 R248Q mutation TP53 NCBI:7157 gene lymphoma DOID:0060058 diagnostic 21739-8 PubMed:23538418 In mouse models, the R248Q variant had accelerated onset of all tumor types and accelerated death rate. Endogenous R248Q proteins are devoid of several important wildtype tp53 tumor-suppressor functions including transcription of cell cycle arrest genes, replicative senescence and irradiation-induced apoptosis. Patients with germline R248Q/+ genotype showed a drastically younger median age until first tumor onset compared with patients with a null/+ genotype (19.5 vs 30 years, P=0.023). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R248Q sequence variation in gene TP53/NCBI:7157 2539 check_entity AN5809-3 TP53 R248Q mutation TP53 NCBI:7157 gene lymphoma DOID:0060058 diagnostic 21739-8 CIViC:117 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R248Q sequence variation in gene TP53/NCBI:7157 2539 check_entity AN5810-1 TP53 R248W mutation TP53 NCBI:7157 gene breast cancer DOID:1612 prognostic 21739-8 PubMed:16489069 In breast cancer patients harboring R248W mutation, the prognosis is worse than any other hotspot TP53 mutation, as well as worse than patients with wild type TP53. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R248W sequence variation in gene TP53/NCBI:7157 2540 check_entity AN5810-1 TP53 R248W mutation TP53 NCBI:7157 gene breast cancer DOID:1612 prognostic 21739-8 CIViC:118 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R248W sequence variation in gene TP53/NCBI:7157 2540 check_entity AN5810-2 TP53 R248W mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 PubMed:25730903 Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 R248W loss of function mutation is present in 4 cell lines and all are insensitive to MDM2 Inhibitor AMGMDS3. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R248W sequence variation in gene TP53/NCBI:7157 2541 check_entity AN5810-2 TP53 R248W mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 CIViC:118 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R248W sequence variation in gene TP53/NCBI:7157 2541 check_entity AN5811-1 TP53 R249 mutation TP53 NCBI:7157 gene breast cancer DOID:1612 prognostic;risk 21739-8 PubMed:9569050 In breast cancer patients harboring TP53 mutation, mutations in conserved regions such as R249 are prognostic for a worse overall survival compared to those harboring wild-type TP53. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R249 sequence variation in gene TP53/NCBI:7157 2542 check_entity AN5811-1 TP53 R249 mutation TP53 NCBI:7157 gene breast cancer DOID:1612 prognostic;risk 21739-8 CIViC:119 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R249 sequence variation in gene TP53/NCBI:7157 2542 check_entity AN5812-1 TP53 R249S mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 PubMed:25730903 Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 R249S loss of function mutation is present in 1 cell line and it is insensitive to MDM2 Inhibitor AMGMDS3. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R249S sequence variation in gene TP53/NCBI:7157 2543 check_entity AN5812-1 TP53 R249S mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 CIViC:1604 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R249S sequence variation in gene TP53/NCBI:7157 2543 check_entity AN5813-1 TP53 R273C mutation TP53 NCBI:7157 gene breast cancer DOID:1612 prognostic 21739-8 PubMed:16489069 Breast cancer patients who harbor R273C mutation have worse overall survival than those with wild type TP53, but have better prognosis than those with R248W mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R273C sequence variation in gene TP53/NCBI:7157 2544 check_entity AN5813-1 TP53 R273C mutation TP53 NCBI:7157 gene breast cancer DOID:1612 prognostic 21739-8 PubMed:9569050 In breast cancer patients harboring TP53 mutation, mutations in DNA contact regions such as R273 are prognostic for a worse relapse-free survival compared to other non-silent mutations in TP53. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R273C sequence variation in gene TP53/NCBI:7157 2544 check_entity AN5813-1 TP53 R273C mutation TP53 NCBI:7157 gene breast cancer DOID:1612 prognostic 21739-8 CIViC:121 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R273C sequence variation in gene TP53/NCBI:7157 2544 check_entity AN5813-2 TP53 R273C mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 PubMed:25730903 Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 R273C loss of function mutation is present in 2 cell lines and all are insensitive to MDM2 Inhibitor AMGMDS3. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R273C sequence variation in gene TP53/NCBI:7157 2545 check_entity AN5813-2 TP53 R273C mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 CIViC:121 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R273C sequence variation in gene TP53/NCBI:7157 2545 check_entity AN5813-3 TP53 R273C mutation TP53 NCBI:7157 gene stomach carcinoma DOID:5517 risk 21739-8 PubMed:14514923 A female patient taking part in a 25 patient gastric cancer trial was diagnosed at age 46, and received preoperative high dose chemotherapy (HDCT). Japanese Society for Gastric Cancer Response Score was 0. Resection was performed on patients with greater than 50% size reduction of the lesion. This patient did not undergo resection, and had on overall survival of 7.4 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R273C sequence variation in gene TP53/NCBI:7157 2546 check_entity AN5813-3 TP53 R273C mutation TP53 NCBI:7157 gene stomach carcinoma DOID:5517 risk 21739-8 CIViC:121 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R273C sequence variation in gene TP53/NCBI:7157 2546 check_entity AN5814-1 TP53 R273H mutation TP53 NCBI:7157 gene breast cancer DOID:1612 prognostic 21739-8 PubMed:16489069 Breast cancer patients who harbor R273H mutation have worse overall survival than those with wild type TP53, but have better prognosis than those with R248W mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R273H sequence variation in gene TP53/NCBI:7157 2547 check_entity AN5814-1 TP53 R273H mutation TP53 NCBI:7157 gene breast cancer DOID:1612 prognostic 21739-8 PubMed:9569050 In breast cancer patients harboring TP53 mutation, mutations in DNA contact regions such as R273 are prognostic for a worse relapse-free survival compared to other non-silent mutations in TP53. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R273H sequence variation in gene TP53/NCBI:7157 2547 check_entity AN5814-1 TP53 R273H mutation TP53 NCBI:7157 gene breast cancer DOID:1612 prognostic 21739-8 CIViC:122 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R273H sequence variation in gene TP53/NCBI:7157 2547 check_entity AN5814-2 TP53 R273H mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 PubMed:25730903 Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 R273H loss of function mutation is present in 7 cell lines and all are insensitive to MDM2 Inhibitor AMGMDS3. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R273H sequence variation in gene TP53/NCBI:7157 2548 check_entity AN5814-2 TP53 R273H mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 CIViC:122 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R273H sequence variation in gene TP53/NCBI:7157 2548 check_entity AN5814-3 TP53 R273H mutation TP53 NCBI:7157 gene osteosarcoma DOID:3347 risk 21739-8 PubMed:17363498 Several preclinical studies were testing drug resistance mechanisms of TP53-R273H variant. Saos-2 cells were transfected with TP53-R273H mutation and these cells were used in the study. Using a western blot, Saos-2/TP53-R273H cells were shown to have a 0.6-fold down-regulation (compared to the Control) for Procaspase-3 protein expression. In addition, Saos-2/TP53-R273H cells were shown to be more resistant to methotrexate and doxorubicin. Reduced levels of drug-induced apoptosis were seen in Saos-2/TP53-R273H cells treated with doxorubicin (0.05 uM and 0.10 uM) and methotrexate (25 nM and 50 nM) in DNA fragmentation assays. According to the results, TP53-R273H induces drug resistance when procaspase-3 is down-regulated. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R273H sequence variation in gene TP53/NCBI:7157 2549 check_entity AN5814-3 TP53 R273H mutation TP53 NCBI:7157 gene osteosarcoma DOID:3347 risk 21739-8 CIViC:122 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R273H sequence variation in gene TP53/NCBI:7157 2549 check_entity AN5815-1 TP53 R273L mutation TP53 NCBI:7157 gene ovarian cancer DOID:2394 risk 21739-8 PubMed:11595686 Ovarian cancer patients with TP53 missense mutations were refractory to platinum-based chemotherapy (66% vs. 34% in wildtype, P=0.008) and had a shorter time to disease progression (n=54, P=0.037). A study of ovarian carcinoma patients (n=178) reported a reduced overall survival (HR:1.59, 95% CI:1.09-2.33, P=0.014) for patients with mutations in TP53. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R273L sequence variation in gene TP53/NCBI:7157 2550 check_entity AN5815-1 TP53 R273L mutation TP53 NCBI:7157 gene ovarian cancer DOID:2394 risk 21739-8 CIViC:892 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R273L sequence variation in gene TP53/NCBI:7157 2550 check_entity AN5816-1 TP53 R280K mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 PubMed:25730903 Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 R280K loss of function mutation is present in 1 cell line and it is insensitive to MDM2 Inhibitor AMGMDS3. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R280K sequence variation in gene TP53/NCBI:7157 2551 check_entity AN5816-1 TP53 R280K mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 CIViC:1605 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R280K sequence variation in gene TP53/NCBI:7157 2551 check_entity AN5817-1 TP53 R280T mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 PubMed:25730903 Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 R280T loss of function mutation is present in 1 cell line and it is insensitive to MDM2 Inhibitor AMGMDS3. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R280T sequence variation in gene TP53/NCBI:7157 2552 check_entity AN5817-1 TP53 R280T mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 CIViC:1606 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R280T sequence variation in gene TP53/NCBI:7157 2552 check_entity AN5818-1 TP53 R282L mutation TP53 NCBI:7157 gene stomach carcinoma DOID:5517 risk 21739-8 PubMed:14514923 In a study of 25 patients with advanced gastric cancer, mutations in TP53 were identified in 32% of primary tumors. TP53 mutations were associated with an improved response to preoperative treatment of a modified EAP protocol (combination of doxorubicin, etoposide and cisplatin). Patients with mutations in TP53 had an increased median survival compared to patients with wildtype TP53 (18.5mo vs. 10.2mo, P=0.044). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R282L sequence variation in gene TP53/NCBI:7157 2553 check_entity AN5818-1 TP53 R282L mutation TP53 NCBI:7157 gene stomach carcinoma DOID:5517 risk 21739-8 CIViC:1082 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R282L sequence variation in gene TP53/NCBI:7157 2553 check_entity AN5819-1 TP53 Truncating Mutation TP53 NCBI:7157 gene head and neck squamous cell carcinoma DOID:5520 prognostic 21739-8 PubMed:21467160 In patients with head and neck squamous cell carcinoma, in a multivariate analysis those with truncating mutations in TP53 had worse progression-free and overall survival than wild-type patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::truncating:mutation sequence variation in gene TP53/NCBI:7157 2554 check_entity AN5819-1 TP53 Truncating Mutation TP53 NCBI:7157 gene head and neck squamous cell carcinoma DOID:5520 prognostic 21739-8 CIViC:223 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::truncating:mutation sequence variation in gene TP53/NCBI:7157 2554 check_entity AN5820-1 TP53 V157F mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 PubMed:25730903 Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 V157F loss of function mutation is present in 1 cell line and it is insensitive to MDM2 Inhibitor AMGMDS3. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V157F sequence variation in gene TP53/NCBI:7157 2555 check_entity AN5820-1 TP53 V157F mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 CIViC:1066 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V157F sequence variation in gene TP53/NCBI:7157 2555 check_entity AN5821-1 TP53 Wildtype TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 PubMed:17671205 MDM2 Inhibitor Nutlin-3a induced senescence in presence of functional TP53 in murine primary fibroblasts, oncogenically transformed fibroblasts, and fibrosarcoma cell lines. Cells lacking functional TP53 were completely insensitive to the drug. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TP53 Wildtype [biomarker_term_in_review] 2556 not_mapped AN5821-1 TP53 Wildtype TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 PubMed:25730903 MDM2 Inhibitor screen in a panel of 260 cancer cell lines with well characterized TP53 status shows that only cancer cell lines with unaltered TP53 may be sensitive to MDM2 Inhibitor. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TP53 Wildtype [biomarker_term_in_review] 2556 not_mapped AN5821-1 TP53 Wildtype TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 CIViC:365 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TP53 Wildtype [biomarker_term_in_review] 2556 not_mapped AN5821-2 TP53 Wildtype TP53 NCBI:7157 gene colorectal cancer DOID:9256 risk 21739-8 PubMed:24957073 In this retrospective biomarker analysis of the EXPERT-C trial, patients with TP53 wild-type status had a statistically significant better progression free survival (PFS) (89.3% vs 65.0% at 5 years; hazard ratio [HR] = 0.23; 95% confidence interval [CI] = 0.07 to 0.78; two-sided P = .02 by Cox regression) and overall survival (OS) (92.7% vs 67.5% at 5 years; HR = 0.16; 95% CI = 0.04 to 0.70; two-sided P = .02 by Cox regression) when treated with Cetuximab + CAPOX (Capecitabine, Oxaliplatin) than in the control arm without Cetuximab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TP53 Wildtype [biomarker_term_in_review] 2557 not_mapped AN5821-2 TP53 Wildtype TP53 NCBI:7157 gene colorectal cancer DOID:9256 risk 21739-8 CIViC:365 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TP53 Wildtype [biomarker_term_in_review] 2557 not_mapped AN5821-3 TP53 Wildtype TP53 NCBI:7157 gene esophageal carcinoma DOID:1107 risk 21739-8 PubMed:23515910 Patients with p53 wild type (as defined by low expression and/or wild-type tp53 gene) had a higher response rate to chemotherapy-based treatment (total major response [MR]: risk ratio [RR] = 1.09, 95 % CI = 1.03-1.16, P = .003; pathological MR: RR = 1.15, 95 % CI = 1.06-1.25, P = .001; total complete response [CR]: RR = 1.08, 95 % CI = 1.00-1.17, P = .040) in this meta-analysis (28 studies, 1497 cases). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TP53 Wildtype [biomarker_term_in_review] 2558 not_mapped AN5821-3 TP53 Wildtype TP53 NCBI:7157 gene esophageal carcinoma DOID:1107 risk 21739-8 CIViC:365 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TP53 Wildtype [biomarker_term_in_review] 2558 not_mapped AN5821-4 TP53 Wildtype TP53 NCBI:7157 gene leukemia DOID:1240 risk 21739-8 PubMed:26459177 Phase I Trial of RG7112 in 116 heavily pretreated patients with AML, ALL, CML, CLL, sCLL demonstrated sustained clinical improvement and induction of TP53 target genes in subset of patients with wild type TP53. 96 patients were tested for TP53 mutation and 19 cases of mutation were detected. No sustained clinical improvement or induction of TP53 target genes was observed in patients with mutant TP53. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TP53 Wildtype [biomarker_term_in_review] 2559 not_mapped AN5821-4 TP53 Wildtype TP53 NCBI:7157 gene leukemia DOID:1240 risk 21739-8 CIViC:365 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TP53 Wildtype [biomarker_term_in_review] 2559 not_mapped AN5821-5 TP53 Wildtype TP53 NCBI:7157 gene lung non-small cell carcinoma DOID:3908 risk 21739-8 PubMed:26899019 Pooled analysis of TP53 mutations (exons 5-8) from 4 randomized trials (IALT, JBR10, CALGB-9633 and ANITA, 1209 patients, median follow-up 5.5 years) of platinum-based adjuvant chemotherapy (ACT) versus observation (OBS). Patients with wild-type TP53 had better outcomes with ACT than OBS (HROS=0.77 [0.62-0.95], p=0.02; HRDFS=0.75 [0.62-0.92], p=0.005). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TP53 Wildtype [biomarker_term_in_review] 2560 not_mapped AN5821-5 TP53 Wildtype TP53 NCBI:7157 gene lung non-small cell carcinoma DOID:3908 risk 21739-8 CIViC:365 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TP53 Wildtype [biomarker_term_in_review] 2560 not_mapped AN5822-1 TP53 Y220C mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 PubMed:25730903 Subset of 58 cancer cell lines with unaltered TP53 is sensitive to MDM2 Inhibitor AMGMDS3. None of 115 cancer cell lines with TP53 mutation and absence of WT allele are sensitive to MDM2 Inhibitor. TP53 Y220C loss of function mutation is present in 1 cell line and it is insensitive to MDM2 Inhibitor AMGMDS3. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y220C sequence variation in gene TP53/NCBI:7157 2561 check_entity AN5822-1 TP53 Y220C mutation TP53 NCBI:7157 gene cancer DOID:162 risk 21739-8 CIViC:896 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y220C sequence variation in gene TP53/NCBI:7157 2561 check_entity AN5822-2 TP53 Y220C mutation TP53 NCBI:7157 gene stomach carcinoma DOID:5517 risk 21739-8 PubMed:14514923 A male patient taking part in a 25 patient gastric cancer trial was diagnosed at age 50, harbored a TP53 mutation and received preoperative high dose chemotherapy (HDCT). Japanese Society for Gastric Cancer Response Score was 2. Resection was performed on patients with >50% size reduction of the lesion. Consistent with response to preoperative chemotherapy, this patient did undergo resection, and had an overall survival of 12.6 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y220C sequence variation in gene TP53/NCBI:7157 2562 check_entity AN5822-2 TP53 Y220C mutation TP53 NCBI:7157 gene stomach carcinoma DOID:5517 risk 21739-8 CIViC:896 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y220C sequence variation in gene TP53/NCBI:7157 2562 check_entity AN5823-1 TP53 Y234C mutation TP53 NCBI:7157 gene ovarian cancer DOID:2394 risk 21739-8 PubMed:11595686 Ovarian cancer patients with TP53 missense mutations were refractory to platinum-based chemotherapy (66% vs. 34% in wildtype, P=0.008) and had a shorter time to disease progression (n=54, P=0.037). A study of ovarian carcinoma patients (n=178) reported a reduced overall survival (HR:1.59, 95% CI:1.09-2.33, P=0.014) for patients with mutations in TP53. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y234C sequence variation in gene TP53/NCBI:7157 2563 check_entity AN5823-1 TP53 Y234C mutation TP53 NCBI:7157 gene ovarian cancer DOID:2394 risk 21739-8 CIViC:1042 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y234C sequence variation in gene TP53/NCBI:7157 2563 check_entity AN5824-1 TSC1 Frameshift Truncation TSC1 NCBI:7248 gene invasive bladder transitional cell carcinoma DOID:6477 risk 48979-9 PubMed:22923433 A patient with metastatic bladder cancer that responded well to the mTOR inhibitor everolimus was shown to harbor a TSC1 frameshift truncation mutation (c.1907_1908del, p.Glu636fs) and a nonsense NF2 mutation. 2/3 additional patients with TSC1 mutations also had mild responses to everolimus. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TSC1 Frameshift Truncation [biomarker_term_in_review] 2564 not_mapped AN5824-1 TSC1 Frameshift Truncation TSC1 NCBI:7248 gene invasive bladder transitional cell carcinoma DOID:6477 risk 48979-9 CIViC:124 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TSC1 Frameshift Truncation [biomarker_term_in_review] 2564 not_mapped AN5824-2 TSC1 Frameshift Truncation TSC1 NCBI:7248 gene lung non-small cell carcinoma DOID:3908 risk 48979-9 PubMed:19966866 Following rapamycin treatment of mice with KrasG12D-induced lung tumors, mice with Tsc1 deletion (exon17/18 deletion resulting in frameshift) in the lung exhibit increased overall survival, increased apoptosis, reduced proliferation and reduced tumor burden compared to Tsc1 wildtype mice. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TSC1 Frameshift Truncation [biomarker_term_in_review] 2565 not_mapped AN5824-2 TSC1 Frameshift Truncation TSC1 NCBI:7248 gene lung non-small cell carcinoma DOID:3908 risk 48979-9 CIViC:124 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TSC1 Frameshift Truncation [biomarker_term_in_review] 2565 not_mapped AN5825-1 TSC1 Loss-of-function TSC1 NCBI:7248 gene bladder carcinoma DOID:4007 risk 48979-9 PubMed:22923433 Tumors expressing TSC1 or TSC2 mutations show notably more sensitivity to everolimus than their wild-type counterparts. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TSC1 Loss-of-function [biomarker_term_in_review] 2566 not_mapped AN5825-1 TSC1 Loss-of-function TSC1 NCBI:7248 gene bladder carcinoma DOID:4007 risk 48979-9 CIViC:125 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TSC1 Loss-of-function [biomarker_term_in_review] 2566 not_mapped AN5826-1 TSC1 R1062W mutation TSC1 NCBI:7248 gene tuberous sclerosis DOID:13515 diagnostic 48979-9 PubMed:20165957 Deep sequencing of TSC1 and TSC2 was performed on blood from a group of 38 sporadic Tuberous Sclerosis patients who had been previously studied with no mutation identified in TSC1 or TSC2. Five patients had readily observable mutations in these genes, one of which was a previously unidentified TSC1 missense change R1062W. The authors indicate that the mutation may not be pathogenic. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R1062W sequence variation in gene TSC1/NCBI:7248 2567 check_entity AN5826-1 TSC1 R1062W mutation TSC1 NCBI:7248 gene tuberous sclerosis DOID:13515 diagnostic 48979-9 PubMed:21309039 The authors used a transfection based immunoblot assay to assess the impact of TSC1 (and TSC2) variants. Numerous variants were tested independently across 4 replicates and the mean and s.e.m. were plotted relative to wild type TSC1. The R1062W variant does not display a significant functional impact relative to the wildtype. The authors state that SIFT (an in-silico missense functional prediction program) predicts the variant is tolerated. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R1062W sequence variation in gene TSC1/NCBI:7248 2567 check_entity AN5826-1 TSC1 R1062W mutation TSC1 NCBI:7248 gene tuberous sclerosis DOID:13515 diagnostic 48979-9 CIViC:695 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R1062W sequence variation in gene TSC1/NCBI:7248 2567 check_entity AN5827-1 TSC2 Q1178* mutation TSC2 NCBI:7249 gene thyroid gland carcinoma DOID:3963 risk 48980-7 PubMed:25295501 The pretreatment tumor contained a somatic nonsense mutation (Q1178*) in the tumor-suppressor gene TSC2 that inactivates the gene, allowing for activation of the mTOR pathway and resulting in sensitivity to mTOR inhibition by everolimus. The patient received a sustained response to everolimus for 18 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q1178* sequence variation in gene TSC2/NCBI:7249 2568 check_entity AN5827-1 TSC2 Q1178* mutation TSC2 NCBI:7249 gene thyroid gland carcinoma DOID:3963 risk 48980-7 CIViC:465 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q1178* sequence variation in gene TSC2/NCBI:7249 2568 check_entity AN5828-1 TTF1 AMPLIFICATION TTF1 NCBI:7270 gene lung adenocarcinoma DOID:3910 prognostic PubMed:19040416 6 of 89 patients with lung adenocarcinoma had amplification of TTF1. There was no statistical difference in overall survival between patients with and without gene amplification. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene TTF1/NCBI:7270 2569 AN5828-1 TTF1 AMPLIFICATION TTF1 NCBI:7270 gene lung adenocarcinoma DOID:3910 prognostic CIViC:224 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene TTF1/NCBI:7270 2569 AN5829-1 TUBB3 EXPRESSION TUBB3 NCBI:10381 gene breast cancer DOID:1612 risk PubMed:23218766 High expression of betaIII-tubulin, as assessed in 85 breast cancers by IHC, was associated with better pathological response. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene TUBB3/NCBI:10381 2570 AN5829-1 TUBB3 EXPRESSION TUBB3 NCBI:10381 gene breast cancer DOID:1612 risk CIViC:385 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene TUBB3/NCBI:10381 2570 AN5829-2 TUBB3 EXPRESSION TUBB3 NCBI:10381 gene cancer DOID:162 risk PubMed:21576762 High expression of class 3 beta-tubulin led to decreased effect of paclitaxel on cell motility in HeLa, MCF-7 and CHO cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene TUBB3/NCBI:10381 2571 AN5829-2 TUBB3 EXPRESSION TUBB3 NCBI:10381 gene cancer DOID:162 risk CIViC:385 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene TUBB3/NCBI:10381 2571 AN5830-1 TYMS 5' TANDEM REPEAT TYMS NCBI:7298 gene colorectal cancer DOID:9256 risk PubMed:20628391 The TYMS 5' 3TPR germline variant was significantly correlated with lower response to irinotecan plus 5-fluorouracil treatment in colorectal cancer patients. 149 metastatic CRC patients treated with irinotecan/5FU as first-line chemotherapy were followed in this study. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TYMS 5' TANDEM REPEAT [biomarker_term_in_review] 2572 not_mapped AN5830-1 TYMS 5' TANDEM REPEAT TYMS NCBI:7298 gene colorectal cancer DOID:9256 risk CIViC:261 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition TYMS 5' TANDEM REPEAT [biomarker_term_in_review] 2572 not_mapped AN5831-1 TYMS Amplification TYMS NCBI:7298 gene lung adenocarcinoma DOID:3910 risk PubMed:23645741 TYMS copy number was lower in clinical samples responding to pemetrexed in combination with platinum (n=25). The same was found in 17 cell lines. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene TYMS/NCBI:7298 2573 AN5831-1 TYMS Amplification TYMS NCBI:7298 gene lung adenocarcinoma DOID:3910 risk CIViC:375 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:level Increased level of gene TYMS/NCBI:7298 2573 AN5832-1 TYMS Overexpression TYMS NCBI:7298 gene gastric adenocarcinoma DOID:3717 risk PubMed:22422354 In 125 gastric tumors, plasma and tissue mRNA levels of TYMS were lower in the raltitrexed sensitive group compared to the resistant group (p = 0.007 and 0.013, respectively). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene TYMS/NCBI:7298 2574 AN5832-1 TYMS Overexpression TYMS NCBI:7298 gene gastric adenocarcinoma DOID:3717 risk CIViC:343 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene TYMS/NCBI:7298 2574 AN5832-2 TYMS Overexpression TYMS NCBI:7298 gene lung non-small cell carcinoma DOID:3908 risk PubMed:26502926 mRNA expression of thymidylate synthase (TYMS) in 62 NSCLC patients correlated with response rate to pemetrexed mono- or combination therapy. Response rate with low TYMS expression was 0.29 compared with 0.03 in patients with overexpression (P = 0.025). Patients with low expression exhibited a benefit in time to progression (average TTP = 56 vs. 23 months, P = 0.001) and in overall survival (average OS = 60 vs. 25 months, P = 0.002). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene TYMS/NCBI:7298 2575 AN5832-2 TYMS Overexpression TYMS NCBI:7298 gene lung non-small cell carcinoma DOID:3908 risk PubMed:23060591 mRNA levels of TYMS, DHFR and GARFT were assessed (rt-PCR) in 50 patient samples of NSCLC. TYMS mRNA levels were lower in responders compared to non-responders to pemetrexed (1.671 ± 0.844 versus 5.978 ± 1.895, p=0.0142). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene TYMS/NCBI:7298 2575 AN5832-2 TYMS Overexpression TYMS NCBI:7298 gene lung non-small cell carcinoma DOID:3908 risk CIViC:343 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:increased;aspect_type:expression Increased expression of gene TYMS/NCBI:7298 2575 AN5833-1 TYMS RS34743033 mutation TYMS NCBI:7298 gene cancer DOID:162 risk PubMed:23652803 499 children from ALL trials treated with methotrexate were genotyped for 8 SNPs in 5 genes. The TYMS rs34743033 tandem repeat polymorphism was the only significant predictor of stomatitis in a multiple regression model considering sex, age, MRD class, WBC, MTX AUC0-48h, and genotypes as independent variables (B = −0.48; 95% CI, −0.84, −0.12; R2 = 0.018; P = .009). Stomatitis toxicity was reduced with increasing *3 (3R) alleles as the *2/*2 (2R/2R) genotype displayed the highest incidence of stomatitis, *2/*3 (2R/3R) showed intermediate toxicity, and *3/*3 (3R/3R) had the lowest incidence of stomatitis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS34743033 sequence variation in gene TYMS/NCBI:7298 2576 check_entity AN5833-1 TYMS RS34743033 mutation TYMS NCBI:7298 gene cancer DOID:162 risk CIViC:760 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS34743033 sequence variation in gene TYMS/NCBI:7298 2576 check_entity AN5834-1 TYMS Underexpression TYMS NCBI:7298 gene lung non-small cell carcinoma DOID:3908 risk PubMed:21367480 49 tumor specimens from 268 NSCLC patients treated with pemetrexed were evaluated for expression of TYMS and DHFR by IHC and compared to treatment outcomes. Patients with low TS (≤150) expression had a longer median progression-free survival (PFS) than those with high TS (>150) expression (4.8 vs. 3.4 months; p=0.01). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene TYMS/NCBI:7298 2577 AN5834-1 TYMS Underexpression TYMS NCBI:7298 gene lung non-small cell carcinoma DOID:3908 risk CIViC:378 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene TYMS/NCBI:7298 2577 AN5834-2 TYMS Underexpression TYMS NCBI:7298 gene prostate cancer DOID:10283 risk PubMed:24782778 Case report of a patient with metastatic prostate cancer and underexpression of TYMS who showed a nonspecified response to pemetrexed for at least 4 months. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene TYMS/NCBI:7298 2578 AN5834-2 TYMS Underexpression TYMS NCBI:7298 gene prostate cancer DOID:10283 risk CIViC:378 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene TYMS/NCBI:7298 2578 AN5835-1 U2AF1 MUTATION U2AF1 NCBI:7307 gene myelofibrosis DOID:4971 prognostic PubMed:27058230 In a large study of patients with primary myelofibrosis evaluating mutations associated with anemia, 457 patients were evaluated for U2AF1 mutations. U2AF1 mutations were significantly associated with anemia in univariate and multivariate analysis (72 mutated vs 385 wildtype; P<0.0001). U2AF1 mutations were significantly associated with shorter overall survival in univariate analysis (P < 0.0001) but not in multivariate analysis with adjustment for age and anemia (P=0.24). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene U2AF1/NCBI:7307 2579 check_entity AN5835-1 U2AF1 MUTATION U2AF1 NCBI:7307 gene myelofibrosis DOID:4971 prognostic CIViC:517 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene U2AF1/NCBI:7307 2579 check_entity AN5836-1 U2AF1 Q157P/R mutation U2AF1 NCBI:7307 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic PubMed:23029227 Age, sex, FAB subtype and karyotypes were not statistically significant between AML patients with U2AF Q157P/R mutations and those who harbor wild type U2AF. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::q157p/r:mutation sequence variation in gene U2AF1/NCBI:7307 2580 check_entity AN5836-1 U2AF1 Q157P/R mutation U2AF1 NCBI:7307 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic CIViC:127 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::q157p/r:mutation sequence variation in gene U2AF1/NCBI:7307 2580 check_entity AN5836-2 U2AF1 Q157P/R mutation U2AF1 NCBI:7307 gene myelodysplastic syndrome DOID:0050908 prognostic PubMed:23029227 In patients with MDS, those who harbor Q157P/R mutation of U2AF do not show statistical significance in complete remission rate compared to those who harbor wild type U2AF. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::q157p/r:mutation sequence variation in gene U2AF1/NCBI:7307 2581 check_entity AN5836-2 U2AF1 Q157P/R mutation U2AF1 NCBI:7307 gene myelodysplastic syndrome DOID:0050908 prognostic PubMed:23861105 After adjusting for age and cancer stage, presence of U2AF mutation such as Q157P/R is prognostic for poorer survival outcomes in patients with MDS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::q157p/r:mutation sequence variation in gene U2AF1/NCBI:7307 2581 check_entity AN5836-2 U2AF1 Q157P/R mutation U2AF1 NCBI:7307 gene myelodysplastic syndrome DOID:0050908 prognostic CIViC:127 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::q157p/r:mutation sequence variation in gene U2AF1/NCBI:7307 2581 check_entity AN5837-1 U2AF1 S34Y/F mutation U2AF1 NCBI:7307 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic PubMed:23029227 Age, sex, FAB subtype and karyotypes were not statistically significant between AML patients with U2AF S34Y/F mutations and those who harbor wild type U2AF. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::s34y/f:mutation sequence variation in gene U2AF1/NCBI:7307 2582 check_entity AN5837-1 U2AF1 S34Y/F mutation U2AF1 NCBI:7307 gene acute myeloid leukemia DOID:9119 diagnostic;prognostic CIViC:128 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::s34y/f:mutation sequence variation in gene U2AF1/NCBI:7307 2582 check_entity AN5837-2 U2AF1 S34Y/F mutation U2AF1 NCBI:7307 gene myelodysplastic syndrome DOID:0050908 prognostic PubMed:23861105 After adjusting for age and cancer stage, the presence of U2AF mutations such as S34Y/F are prognostic for poorer survival outcomes in patients with MDS. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::s34y/f:mutation sequence variation in gene U2AF1/NCBI:7307 2583 check_entity AN5837-2 U2AF1 S34Y/F mutation U2AF1 NCBI:7307 gene myelodysplastic syndrome DOID:0050908 prognostic CIViC:128 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::s34y/f:mutation sequence variation in gene U2AF1/NCBI:7307 2583 check_entity AN5838-1 UGT1A EXPRESSION UGT1A NCBI:7361 gene colorectal cancer DOID:9256 risk 34509-0 PubMed:25210794 Colorectal cancer cell lines were evaluated for response to the HSP90 inhibitor ganetespib. Correlating cell line-specific IC50s with the corresponding gene expression patterns revealed a possible relationship to UGT1A expression. High UGT1A expression was correlated with ganetespib resistance. Knockdown of UGT1A sensitized HT29 cells to HSP90 inhibition. HCT116 and SW480 cell lines became resistant through UGT1A overexpression. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene UGT1A/NCBI:7361 2584 AN5838-1 UGT1A EXPRESSION UGT1A NCBI:7361 gene colorectal cancer DOID:9256 risk 34509-0 CIViC:359 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene UGT1A/NCBI:7361 2584 AN5839-1 UGT1A1 UGT1A1*28 mutation UGT1A1 NCBI:54658 gene cancer DOID:162 risk 34509-0 PubMed:26313268 The FDA approved package insert for Belinostat recommends dose adjustment for UGT1A1*28 allele homozygotes. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::ugt1a1*28:mutation sequence variation in gene UGT1A1/NCBI:54658 2585 check_entity AN5839-1 UGT1A1 UGT1A1*28 mutation UGT1A1 NCBI:54658 gene cancer DOID:162 risk 34509-0 CIViC:710 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::ugt1a1*28:mutation sequence variation in gene UGT1A1/NCBI:54658 2585 check_entity AN5840-1 UGT1A1 UGT1A1*60 mutation UGT1A1 NCBI:54658 gene cancer DOID:162 risk 34509-0 PubMed:26313268 In a phase 1 trial belinostat (400-800mg/m2/24h) was administered to 25 patients in combination with cisplatin and etoposide. Endpoints were associations between genotype of UGT1A1 and pharmacokinetics, toxicities and proteine lysine acetylation. Belinostat AUC and half-life was significantly increased in UGT1A1*60 carriers, and they were at greater risk for thrombocytopenia. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::ugt1a1*60:mutation sequence variation in gene UGT1A1/NCBI:54658 2586 check_entity AN5840-1 UGT1A1 UGT1A1*60 mutation UGT1A1 NCBI:54658 gene cancer DOID:162 risk 34509-0 CIViC:713 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::ugt1a1*60:mutation sequence variation in gene UGT1A1/NCBI:54658 2586 check_entity AN5841-1 VEGFA Decreased Peri-therapeutic Expression VEGFA NCBI:7422 gene colorectal cancer DOID:9256 risk 94470-2 PubMed:25973082 Decreased peri- and post-therapeutic expression of VEGFA were significantly associated with response to FOLFIRI plus bevacizumab in 57 patients with metastatic CRC. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene VEGFA/NCBI:7422 2587 AN5841-1 VEGFA Decreased Peri-therapeutic Expression VEGFA NCBI:7422 gene colorectal cancer DOID:9256 risk 94470-2 CIViC:330 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene VEGFA/NCBI:7422 2587 AN5842-1 VHL *214C (c.641_642insC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12673678 A female of unknown age (Patient 8) from Europe presented with a unilateral adrenal pheochromocytoma. Genetic testing confirmed a germline frameshift mutation found at c.641insC in the VHL gene. Family history and patient demographic is unknown. This patient underwent surgical resection. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::*214C (c.641_642insC) sequence variation in gene VHL/NCBI:7428 2588 check_entity AN5842-1 VHL *214C (c.641_642insC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2362 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::*214C (c.641_642insC) sequence variation in gene VHL/NCBI:7428 2588 check_entity AN5843-1 VHL *214C (c.642A>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20560986 This paper identified run-on mutations in 5 members of 4 distinct families. More specifically, genetic testing demonstrated the above mutation (X214CextX15) in 1 individual in a single family. Clinical manifestations included: pheochromocytoma, CNS hemangioblastoma, retinal hemangioblastoma, clear cell renal cell carcinoma, and pancreatic neuroendocrine tumor. Relevant HPO terms: Pheochromocytoma, Hemangioblastoma, Retinal hemangioblastoma, Clear cell renal cell carcinoma, Neuroendocrine neoplasm. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::*214C (c.642A>T) sequence variation in gene VHL/NCBI:7428 2589 check_entity AN5843-1 VHL *214C (c.642A>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1864 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::*214C (c.642A>T) sequence variation in gene VHL/NCBI:7428 2589 check_entity AN5844-1 VHL *214G (c.640T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12673678 A 49 year old female (Patient 3) from Europe presented with a unilateral adrenal pheochromocytoma. Genetic testing confirmed germline missense mutation found at c.640T>G in the VHL gene (reported as T852G in the paper). Family history and patient demographic is unknown. This patient underwent surgical resection. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::*214G (c.640T>G) sequence variation in gene VHL/NCBI:7428 2590 check_entity AN5844-1 VHL *214G (c.640T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2361 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::*214G (c.640T>G) sequence variation in gene VHL/NCBI:7428 2590 check_entity AN5845-1 VHL *214L (c.641G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20560986 Families with VHL disease type 2A were were evaluated for mutations in the VHL gene. In four families, three different coding sequence substitutions causing a 15 amino-acid extension from the original stop codon of the VHL gene were described. Genomic DNA was extracted from peripheral blood lymphocytes using standard procedures. Sequence analysis consisted of polymerase chain reaction (PCR) amplification and automated fluorescence sequencing of all three VHL exons. Patient 1 (family 1), female, presented with a pheochromocytoma at age 11, a pheochromocytoma at age 20, bilateral retinal hemangioblastoma at age 20, and a pancreatic neuroendocrine tumor at age 20. She had a family history of early onset pheochromocytoma. She was found to have a substitution mutation in the VHL gene causing a loss of the stop codon, and an extension of 14 amino acids on the C-terminal end of the protein (c.641G>T (p.*241Lext*14). This mutation is noted as p.*241Lext*15 in the paper due to a difference in nomenclature.) Her mother was found to have the same mutation. Her mother had two pheochromocytomas at age 12, and was found to have bilateral retinal hemangioblastomas at age 40. Her brother was found to have a pheochromocytoma at age 13, but was not sequenced. Her maternal gradnfather was noted to have had liver cancer at 72, her great grandfather had unpecified cancer, and her great aunt had Hodgkin's lymphoma at age 38. A second patient (patient 2) from an independent family was found to have the same mutation as patient 1. Patient 2 was also female and presented with bilateral retinal hemangioblastomas. Her last recorded age was 38 years old, and no age of diagnosis was provided. ACMG evidence codes: 'PP1'- Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease, and 'PP4'- patients' phenotypes or family history are highly specific for a disease with a single genetic etiology, and 'PS3' because in-vitro studies demonstrated this variant was unable to perform normal cellular functions (downregulate JunB). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::*214L (c.641G>T) sequence variation in gene VHL/NCBI:7428 2591 check_entity AN5845-1 VHL *214L (c.641G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1862 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::*214L (c.641G>T) sequence variation in gene VHL/NCBI:7428 2591 check_entity AN5846-1 VHL *214W (c.642A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20560986 This paper identified run-on mutations in 5 members of 4 distinct families. More specifically, genetic testing demonstrated the above mutation (X214WextX15) in 1 individual in a single family. Clinical manifestations included: pheochromocytoma and pancreatic cysts. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::*214W (c.642A>G) sequence variation in gene VHL/NCBI:7428 2592 check_entity AN5846-1 VHL *214W (c.642A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1863 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::*214W (c.642A>G) sequence variation in gene VHL/NCBI:7428 2592 check_entity AN5847-1 VHL 106insR (c.316insGCC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11850829 36 VHL-related pheochromocytomas (from 21 patients) and 10 VHL-related CNS hemangioblastomas (from 6 patients) were studied using comparative genomic hybridization (CGH) to detect genetic imbalances. Patient I with VHL-Associated hemangioblastoma was found with a germline insertion mutation (c.316insGCC) in the VHL gene. ACMG evidence codes: 'PP4' because the patients' phenotypes are highly specific for a disease with single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.316insGCC) sequence variation in gene VHL/NCBI:7428 2593 check_entity AN5847-1 VHL 106insR (c.316insGCC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2799 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.316insGCC) sequence variation in gene VHL/NCBI:7428 2593 check_entity AN5848-1 VHL 3'UTR alteration (c.*70C>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:22357542 Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This mutation was found in a 30-year-old VHL patient with hemangioblastomas of the central nervous system, retinal angiomas, renal cell carcinoma, and pancreatic cysts (proband no. 16). HPO terms: hemangioblastoma, retinal hemangioblastoma, renal cell carcinoma, multiple pancreatic cysts. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.*70C>A) sequence variation in gene VHL/NCBI:7428 2594 check_entity AN5848-1 VHL 3'UTR alteration (c.*70C>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2028 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.*70C>A) sequence variation in gene VHL/NCBI:7428 2594 check_entity AN5849-1 VHL 3'UTR alteration (c.639+10C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11409863 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 80). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.639+10C>G) sequence variation in gene VHL/NCBI:7428 2595 check_entity AN5849-1 VHL 3'UTR alteration (c.639+10C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1900 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.639+10C>G) sequence variation in gene VHL/NCBI:7428 2595 check_entity AN5850-1 VHL 3p26.3-25.3 11Mb del VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26365017 A case report of a woman with de novo 3p deletion syndrome (encompassing the VHL gene) was associated with cerebellar hemangioblastoma at the age of 16 years old. This is the first report of a patient with 3p- with cerebral hemangioblastoma that may be associated with VHL disease. ACMG: PVS1, PS2, PP4 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition VHL 3p26.3-25.3 11Mb del [biomarker_term_in_review] 2596 not_mapped AN5850-1 VHL 3p26.3-25.3 11Mb del VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2240 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition VHL 3p26.3-25.3 11Mb del [biomarker_term_in_review] 2596 not_mapped AN5851-1 VHL A122I (c.364_365GC>AT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the A122I mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A122I (c.364_365GC>AT) sequence variation in gene VHL/NCBI:7428 2597 check_entity AN5851-1 VHL A122I (c.364_365GC>AT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12000816 Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This mutation was found in the VHL gene and one patient with pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A122I (c.364_365GC>AT) sequence variation in gene VHL/NCBI:7428 2597 check_entity AN5851-1 VHL A122I (c.364_365GC>AT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1904 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A122I (c.364_365GC>AT) sequence variation in gene VHL/NCBI:7428 2597 check_entity AN5852-1 VHL A149S (c.445G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9435426 Study of a large kindred with von Hippel-Lindau disease (VHLD) and pheochromocytoma (spread over four generations). 25 proven cases of VHLD and 17 cases with pheochromocytoma were identified. Mutation analysis was performed in 14 family members (7 affected, 7 unaffected). 11 cases had the same mutation resulting in a predicted amino acid substitution of A149S. The cases with mutation that appeared unaffected were all very young (before the likely age of onset). The three cases without the mutation that appeared unaffected were aged 18, 54, and 69. ACMG evidence codes: 'PP1' based on segregation results, 'PM5' because the authors describe a prior report of a similar mutation at the same site (A149T), 'PP2' because they observe a missense variant in gene where missense variants are common mechanism of disease, and 'PP4' because the patients phenotypes and family history are highly specific for a disease with single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A149S (c.445G>T) sequence variation in gene VHL/NCBI:7428 2598 check_entity AN5852-1 VHL A149S (c.445G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:23673869 49 family members from three generations of a Turkish family were examined. A clinical presentation of VHL type 2B was noted. Genetic testing was performed on 17 family members. 11 members with the mutation had manifestations, while 6 members with the mutation were asymptomatic. 1 of the asymptomatic individuals belonged to generation 2, while the remaining 5 belonged to the fourth generation, suggesting they may be too young to present manifestations. From the members that had manifestations: 9 had pheochromocytoma (5 bilateral), 1 had lumbar spine hemangioblastoma, 1 had retinal hemangioblastoma, 4 had renal cell carcinoma (2 bilateral), and 3 had pancreatic neuroendocrine tumours (1 also had a serous cystadenoma in addition to the neuroendocrine tumour). ACMG evidence codes: 'PP1' because of segregation results, 'PP2' because there is a missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease, 'PP4' because the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Relevant HPO terms: Renal cell carcinoma, Spinal hemangioblastoma, Multiple pancreatic cysts, Pheochromocytoma, Neuroendocrine neoplasm, Retinal hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A149S (c.445G>T) sequence variation in gene VHL/NCBI:7428 2598 check_entity AN5852-1 VHL A149S (c.445G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:798 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A149S (c.445G>T) sequence variation in gene VHL/NCBI:7428 2598 check_entity AN5853-1 VHL A149T (c.445G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in 2 family members with VHL (Family ID 3969 in publication). One carried pheochromocytoma, while both carried angiomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A149T (c.445G>A) sequence variation in gene VHL/NCBI:7428 2599 check_entity AN5853-1 VHL A149T (c.445G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1620 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::A149T (c.445G>A) sequence variation in gene VHL/NCBI:7428 2599 check_entity AN5854-1 VHL A149fs (c.445delG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12114495 A study of 34 Polish families revealed germline mutations in 30 families. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). This mutation was found in a VHL family of 3 individuals. All 3 had retinal hemangioblastomas, 2 had hemangioblastomas of the central nervous system, and one had renal cell carcinoma (family no. 13). ACMG codes as follows: A frameshift variant in a gene where loss-of-function is a known mechanism of disease (PVS1). HPO terms: hemangioblastoma, retinal hemangioblastoma, renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.445delG) sequence variation in gene VHL/NCBI:7428 2600 check_entity AN5854-1 VHL A149fs (c.445delG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1918 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.445delG) sequence variation in gene VHL/NCBI:7428 2600 check_entity AN5855-1 VHL A149fs (c.449del14-nt) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11409863 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 75). This study contains very strong evidence of pathogenicity in the form of a frameshift variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.449del14-nt) sequence variation in gene VHL/NCBI:7428 2601 check_entity AN5855-1 VHL A149fs (c.449del14-nt) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1899 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.449del14-nt) sequence variation in gene VHL/NCBI:7428 2601 check_entity AN5856-1 VHL A56FS (c.164_165insG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 c.164insG causes a framehift and truncation allele. One family is described with this allele segregating with disease; 10 affected individuals: 2 patients with renal cell carcinoma, 3 with pheochromocytoma, 7 with retinal angioma, 3 with central nervous system hemangioma. ACMG evidence codes supported by this paper are possibly PVS1 and PP1. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.164_165insG) sequence variation in gene VHL/NCBI:7428 2602 check_entity AN5856-1 VHL A56FS (c.164_165insG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:752 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.164_165insG) sequence variation in gene VHL/NCBI:7428 2602 check_entity AN5857-1 VHL A56_P59del (c.166_178del) VHL NCBI:7428 gene renal cell carcinoma DOID:4450 diagnostic 34502-5 PubMed:7977367 'Tissue analysis from 61 VHL patients, 30 sporadic renal cell carcinoma (RCC) tumor samples, and 6 sporadic RCC cell lines revealed 22 variants within VHL patients, 10 variants in tumor samples and variants in all cell lines. All mutations cluster to the 3’ end of the VHL gene open reading frame, implicating this region as important for the tumor-suppressor function of the VHL protein. From findings VHL gene was concluded to have ''an important and specific role in the etiology of sporadic RCCs.'' This in-frame deletion results in a premature stop codon at amino acid 62 and was found in one of the tumor samples (tumor no. 22). No phenotype described.' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.166_178del) sequence variation in gene VHL/NCBI:7428 2603 check_entity AN5857-1 VHL A56_P59del (c.166_178del) VHL NCBI:7428 gene renal cell carcinoma DOID:4450 diagnostic 34502-5 CIViC:2141 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.166_178del) sequence variation in gene VHL/NCBI:7428 2603 check_entity AN5858-1 VHL A56fs (c.164_165insA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 A variants resulting in A56G frameshift (with stop introduced at position 131) was observed in a single patient of a VHL family. (family #146 in the publication). Neither the VHL phenotype details or segregation data were provided by this publication. Since this is a frameshift occurring early in the protein sequence we can assign an ACMG evidence code of 'PVS1'. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.164_165insA) sequence variation in gene VHL/NCBI:7428 2604 check_entity AN5858-1 VHL A56fs (c.164_165insA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:771 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.164_165insA) sequence variation in gene VHL/NCBI:7428 2604 check_entity AN5859-1 VHL A56fs (c.166_167insA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the mutation segregated with the disease. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma (VHL type 1) and 2 of 12 families with pheochromocytoma (VHL type 2). This mutation causes a frameshift and premature stop codon at amino acid 131 and was found in a VHL type 1 patient (kindred no. 110). This variant is likely to cause a dramatic alteration in protein function in a gene where loss-of-function mutations are a known mechanism (ACMG code: PVS1). Relevant HPO terms: Pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.166_167insA) sequence variation in gene VHL/NCBI:7428 2605 check_entity AN5859-1 VHL A56fs (c.166_167insA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1661 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.166_167insA) sequence variation in gene VHL/NCBI:7428 2605 check_entity AN5860-1 VHL A56fs (c.166dup) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in a VHL patient with retinal angiomas at 24Y old and cerebellar hemangioblastoma at 15Y old. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). HPO terms: retinal hemangioblastoma, hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.166dup) sequence variation in gene VHL/NCBI:7428 2606 check_entity AN5860-1 VHL A56fs (c.166dup) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2020 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.166dup) sequence variation in gene VHL/NCBI:7428 2606 check_entity AN5861-1 VHL C162F (c.485G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in 4 family members with VHL type 1 phenotype (Family ID 3820 in publication). All 4 family members carried cerebellar hemangioblastomas, 2 of 4 carried retinal hemangioblastomas and one carried renal cell carcinoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma, Renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C162F (c.485G>T) sequence variation in gene VHL/NCBI:7428 2607 check_entity AN5861-1 VHL C162F (c.485G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in a VHL type 1 family (lineage 69). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C162F (c.485G>T) sequence variation in gene VHL/NCBI:7428 2607 check_entity AN5861-1 VHL C162F (c.485G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21463266 In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This missense mutation was found in a 34 yr old VHL patient with multiple pancreatic cysts, pheochromocytoma, multiple renal cysts, and central nervous system and retinal hemangioblastomas (index case 74). There is supporting evidence for pathogenicity because the patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). Relevant HPO terms: Hemangioblastoma, retinal hemangioblastoma, multiple renal cysts, multiple pancreatic cysts, pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C162F (c.485G>T) sequence variation in gene VHL/NCBI:7428 2607 check_entity AN5861-1 VHL C162F (c.485G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26763786 A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. This mutation was present in 1 individual of the 122 total number of variants captured in this population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C162F (c.485G>T) sequence variation in gene VHL/NCBI:7428 2607 check_entity AN5861-1 VHL C162F (c.485G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1649 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C162F (c.485G>T) sequence variation in gene VHL/NCBI:7428 2607 check_entity AN5862-1 VHL C162R (c.484T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. Missense mutation detected in a VHL type 1 patient (Family ID 3509 in publication) with angiomas, cerebellar hemangioblastomas, and renal cell carcinoma. Only supporting evidence for pathogenicity because patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C162R (c.484T>C) sequence variation in gene VHL/NCBI:7428 2608 check_entity AN5862-1 VHL C162R (c.484T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:19270817 Germline VHL mutations were found in all Korean patients who fulfilled clinical criteria for VHL disease. No mutation of VHL was detected in other patients who did not meet clinical criteria. In all cases, samples from both parents were not available and evidence of de novo mutations could not further be evaluated. This missense mutation (p.C162R) was found in a 30 year old Korean female with hemangioblastomas of the central nervous system, retinal hemangioblastomas, and renal cell carcinoma (patient no. 7). This patient's phenotype is highly specific for a disease with a single etiology (ACMG code: PP4). Relevant HPO terms: hemangioblastoma, Retinal hemangioblastoma, Renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C162R (c.484T>C) sequence variation in gene VHL/NCBI:7428 2608 check_entity AN5862-1 VHL C162R (c.484T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8641976 Blood samples from 5 Japanese families revealed 4 germline mutations. This missense mutation was found in a family of 7 individuals. Two VHL patients were identified, 1 with brain stem hemangioblastomas and retinal angiomas, the other with renal cell carcinoma (family D). Single-strand conformational polymorphism (SSCP) analysis showed bands for the 2 affected individuals that were absent from 5 normal individuals. Direct sequencing was performed on SSCP positive patients. Supporting evidence for pathogenicity due to cosegregation with disease in multiple affected family members (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C162R (c.484T>C) sequence variation in gene VHL/NCBI:7428 2608 check_entity AN5862-1 VHL C162R (c.484T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8634692 Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb) renal cell carcinoma (RCC), and pheochromocytoma was available. Case 4 had a C162R (c.484T>C) mutation. 2 members were affected: both had RCC, 1 had retinal angioma, and 1 had CNS Hb (ACMG PP4). We were not able to determine which member had more than one phenotype. Other demographics of the members were not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C162R (c.484T>C) sequence variation in gene VHL/NCBI:7428 2608 check_entity AN5862-1 VHL C162R (c.484T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1648 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C162R (c.484T>C) sequence variation in gene VHL/NCBI:7428 2608 check_entity AN5863-1 VHL C162W (c.486C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was detected in VHL type 1 patient (Family ID 3618 in publication) with cerebellar hemangioblastomas. Only supporting evidence for pathogenicity because patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). Relevant HPO terms: Cerebellar hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C162W (c.486C>G) sequence variation in gene VHL/NCBI:7428 2609 check_entity AN5863-1 VHL C162W (c.486C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 2B patient (patient no. V345). No additional family was screened for this mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C162W (c.486C>G) sequence variation in gene VHL/NCBI:7428 2609 check_entity AN5863-1 VHL C162W (c.486C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found in a German, VHL type 1 patient with retinal angiomas, hemangioblastomas of the central nervous system, renal cell carcinoma, and pancreatic cysts (family VHL 42). HPO terms: retinal hemangioblastoma, hemangioblastoma, renal cell carcinoma, multiple pancreatic cysts. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C162W (c.486C>G) sequence variation in gene VHL/NCBI:7428 2609 check_entity AN5863-1 VHL C162W (c.486C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26763786 A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. This mutation was present in 1 individual of the 122 total number of variants captured in this population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C162W (c.486C>G) sequence variation in gene VHL/NCBI:7428 2609 check_entity AN5863-1 VHL C162W (c.486C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation (p.Cys162Trp), which was found in 2 individuals from France. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C162W (c.486C>G) sequence variation in gene VHL/NCBI:7428 2609 check_entity AN5863-1 VHL C162W (c.486C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11850829 36 VHL-related pheochromocytomas (from 21 patients) and 10 VHL-related CNS hemangioblastomas (from 6 patients) were studied using comparative genomic hybridization (CGH) to detect genetic imbalances. Patient IV with VHL-Associated hemangioblastoma was found with a germline missense mutation (c.486C>G) in the VHL gene. ACMG evidence codes: 'PP4' because the patients' phenotypes are highly specific for a disease with single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C162W (c.486C>G) sequence variation in gene VHL/NCBI:7428 2609 check_entity AN5863-1 VHL C162W (c.486C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1650 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C162W (c.486C>G) sequence variation in gene VHL/NCBI:7428 2609 check_entity AN5864-1 VHL C162Y (c.485G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:10761708 A previous study of 26 Japanese, VHL families was extended to 41 additional families. Germline mutations were detected in 55 of 77 Japanese families using SSCP, direct sequencing, and Southern Blot analysis of peripheral blood samples. The C162Y (c.485G>A) germline missense mutation of the VHL gene was found in a VHL patient with retinal angiomas, pancreatic cysts or tumor (unspecified), renal cell carcinoma, and pheochromocytoma (family ID 104). The variant was also found in a family of 4 individuals all presenting with CNS hemangioblastoma (family ID 11). This family was previously reported in PMID 8634692. This patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C162Y (c.485G>A) sequence variation in gene VHL/NCBI:7428 2610 check_entity AN5864-1 VHL C162Y (c.485G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12114495 A study of 34 Polish families revealed germline mutations in 30 families. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). This missense mutation was found in a VHL family of 5 affected patients (family no. 16). Four had retinal hemangioblastomas and 4 had hemangioblastomas of the central nervous system. Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). HPO terms: hemangioblastoma, retinal hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C162Y (c.485G>A) sequence variation in gene VHL/NCBI:7428 2610 check_entity AN5864-1 VHL C162Y (c.485G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C162Y (c.485G>A) sequence variation in gene VHL/NCBI:7428 2610 check_entity AN5864-1 VHL C162Y (c.485G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8634692 Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb), renal cell carcinoma (RCC), and pheochromocytoma was available. Case 11 had a p.Cys162Tyr (c.485G>A) mutation. 4 members were affected with CNS Hb (ACMG PP4). Other demographics of the members were not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C162Y (c.485G>A) sequence variation in gene VHL/NCBI:7428 2610 check_entity AN5864-1 VHL C162Y (c.485G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1700 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::C162Y (c.485G>A) sequence variation in gene VHL/NCBI:7428 2610 check_entity AN5865-1 VHL C162fs (c.483del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20846682 26 VHL patients, from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 1 patient from a single family was confirmed to have the above mutation. More specifically, this mutation causes the following protein change: C162AfsX8. Additional manifestations aside from pheochromocytoma are possible, but were not discussed. ACMG evidence codes: 'PVS1' because they observe a frameshift variant in a gene where loss of function is a known mechanism of disease. Relevant HPO terms: Pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.483del) sequence variation in gene VHL/NCBI:7428 2611 check_entity AN5865-1 VHL C162fs (c.483del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1911 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.483del) sequence variation in gene VHL/NCBI:7428 2611 check_entity AN5866-1 VHL C77_N78insL (c.230_231insTCT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This mutation was found in 2 Croatian, VHL type 1 family members (family VHL 26). Both have hemangioblastomas of the central nervous system, one has renal cell carcinoma, and one with pancreatic cysts. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.230_231insTCT) sequence variation in gene VHL/NCBI:7428 2612 check_entity AN5866-1 VHL C77_N78insL (c.230_231insTCT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11850829 36 VHL-related pheochromocytomas (from 21 patients) and 10 VHL-related CNS hemangioblastomas (from 6 patients) were studied using comparative genomic hybridization (CGH) to detect genetic imbalances. Patient III in VHL-Associated hemangioblastoma was found with germline insertion mutation (c.230insTCT) in the VHL gene. ACMG evidence codes: 'PP4' because the patients' phenotypes are highly specific for a disease with single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.230_231insTCT) sequence variation in gene VHL/NCBI:7428 2612 check_entity AN5866-1 VHL C77_N78insL (c.230_231insTCT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2965 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.230_231insTCT) sequence variation in gene VHL/NCBI:7428 2612 check_entity AN5867-1 VHL C77fs (c.228dup) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. This mutation causes a stop codon at amino acid 131 and was found in a VHL type 2 and a VHL type 1 patient (kindred no. 71, 85). A frameshift variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). Relevant HPO terms: Pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.228dup) sequence variation in gene VHL/NCBI:7428 2613 check_entity AN5867-1 VHL C77fs (c.228dup) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This frameshift mutation was found in 3 VHL type 1 families of 7 individuals total. Five patients had retinal angiomas, 3 had hemangioblastomas of the central nervous system, 3 had renal cell carcinoma and 2 had pheochromocytoma. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.228dup) sequence variation in gene VHL/NCBI:7428 2613 check_entity AN5867-1 VHL C77fs (c.228dup) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2008 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.228dup) sequence variation in gene VHL/NCBI:7428 2613 check_entity AN5868-1 VHL C77fs (c.230del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8634692 Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregared with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS Hb, RCC, and Pheo was available. Case 16 had p.Cys77fs mutation and one affected member with hemangioblastoma and renal cell carcinoma. ACMG PP4 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.230del) sequence variation in gene VHL/NCBI:7428 2614 check_entity AN5868-1 VHL C77fs (c.230del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:3114 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.230del) sequence variation in gene VHL/NCBI:7428 2614 check_entity AN5869-1 VHL D121G (c.362A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11409863 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This missense mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 105). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D121G (c.362A>G) sequence variation in gene VHL/NCBI:7428 2615 check_entity AN5869-1 VHL D121G (c.362A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D121G (c.362A>G) sequence variation in gene VHL/NCBI:7428 2615 check_entity AN5869-1 VHL D121G (c.362A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:14722919 'Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. This missense mutation was found in a 31 year old patient with retinal hemangioblastomas and renal cysts (patient no. F26). Patient had family history of pheochromocytomas and hemangioblastomas of the central nervous system. ACMG evidence code: ''flag for PP4'' because patients phenotype is highly specific for the disease.' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D121G (c.362A>G) sequence variation in gene VHL/NCBI:7428 2615 check_entity AN5869-1 VHL D121G (c.362A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1689 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D121G (c.362A>G) sequence variation in gene VHL/NCBI:7428 2615 check_entity AN5870-1 VHL D121_A122del (c.361_366del) VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 risk 34502-5 PubMed:7915601 Tumors from 98 patients with sporadic clear cell renal carcinoma (ccRC) were analyzed for VHL mutations and loss of heterozygosity (LOH). Somatic VHL variants were observed in 56 patients, and VHL LOH was observed in 98% of samples with VHL variants. VHL D121_A122del (c.361_366del) was found in a granular ccRC (sample UOK142, variant noted as 6 NT deletion, NT 574 because of differences in reference transcript). Authors noted that VHL variants were highly specific to ccRC and not found in the 12 other tumor types examined. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.361_366del) sequence variation in gene VHL/NCBI:7428 2616 check_entity AN5870-1 VHL D121_A122del (c.361_366del) VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 risk 34502-5 CIViC:2426 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.361_366del) sequence variation in gene VHL/NCBI:7428 2616 check_entity AN5871-1 VHL D126FS (c.375_376insC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21463266 In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This de novo frameshift mutation was found in a 24 yr old VHL patient with no family history and central nervous system and retinal hemangioblastomas (index case 107). This variant also potentially alters the beta domain of the VHL protein. ACMG codes as follows: Frameshift variant in a gene where loss-of-function is a known mechanism of disease (PVS1). De novo in a patient with the disease and no family history (PS2). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.375_376insC) sequence variation in gene VHL/NCBI:7428 2617 check_entity AN5871-1 VHL D126FS (c.375_376insC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1794 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.375_376insC) sequence variation in gene VHL/NCBI:7428 2617 check_entity AN5872-1 VHL D143fs (c.430delG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This mutation causes an early stop codon at position 158 and was found in a VHL type 1 family (lineage 119). Only moderate evidence for pathogenicity because protein length changes as a result of deletion in a nonrepeat region and stop-loss variant (ACMG code: PM4). Relevant HPO terms: hemangioblastoma, Renal cell carcinoma, Pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.430delG) sequence variation in gene VHL/NCBI:7428 2618 check_entity AN5872-1 VHL D143fs (c.430delG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1720 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.430delG) sequence variation in gene VHL/NCBI:7428 2618 check_entity AN5873-1 VHL D197FS (c.589delG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in a VHL type 1 family with 3 individuals, 1 with retinal angiomas and 1 with renal cell carcinoma. Supporting evidence of pathogenicity because of the introduction of a frame shift in a gene where loss of function is an established mechanism of disease (ACMG code: PVS1). HPO terms: retinal hemangioblastoma, renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.589delG) sequence variation in gene VHL/NCBI:7428 2619 check_entity AN5873-1 VHL D197FS (c.589delG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2017 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.589delG) sequence variation in gene VHL/NCBI:7428 2619 check_entity AN5874-1 VHL D92G (c.275A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D92G (c.275A>G) sequence variation in gene VHL/NCBI:7428 2620 check_entity AN5874-1 VHL D92G (c.275A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2322 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::D92G (c.275A>G) sequence variation in gene VHL/NCBI:7428 2620 check_entity AN5875-1 VHL Deletion VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26763786 A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. A complete deletion was present in 13 individuals of the 122 total number of variants captured in this population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene VHL/NCBI:7428 2621 check_entity AN5875-1 VHL Deletion VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2801 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::deletion sequence variation in gene VHL/NCBI:7428 2621 check_entity AN5876-1 VHL E160FS (c.479_480delAG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21463266 In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This frameshift mutation introduces a premature stop codon at amino acid 172 and was found in a 35 yr old VHL patient with hemangioblastomas of the central nervous system and clear cell renal cell carcinoma (index case 182). There is very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code : PVS1). Relevant HPO terms: hemangioblastoma, clear cell renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.479_480delAG) sequence variation in gene VHL/NCBI:7428 2622 check_entity AN5876-1 VHL E160FS (c.479_480delAG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 2 patients were found to have the above mutation. More specifically, this mutation causes the following protein change: E160AfsX12. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PVS1' because they observe a frameshift variant in a gene where loss of function is a known mechanism of disease . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.479_480delAG) sequence variation in gene VHL/NCBI:7428 2622 check_entity AN5876-1 VHL E160FS (c.479_480delAG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1795 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.479_480delAG) sequence variation in gene VHL/NCBI:7428 2622 check_entity AN5877-1 VHL E160fs (c.477del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This mutation causes a premature stop codon at amino acid 170 and was found in a VHL type 1 family (lineage 16). There is very strong evidence of pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.477del) sequence variation in gene VHL/NCBI:7428 2623 check_entity AN5877-1 VHL E160fs (c.477del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1974 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.477del) sequence variation in gene VHL/NCBI:7428 2623 check_entity AN5878-1 VHL E186* (c.556G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals .This nonsense mutation was found in a VHL type 1 family of 6 individuals (Family ID 3770 in publication). All 6 individuals were identified with cerebellar hemangioblastomas, 4 with retinal hemangioblastomas, and 5 with renal cell carcinoma. Supporting evidence of pathogenicity because of the introduction of an early stop codon in a gene where loss of function is an established mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E186* (c.556G>T) sequence variation in gene VHL/NCBI:7428 2624 check_entity AN5878-1 VHL E186* (c.556G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This nonsense mutation was found in a VHL type 1 family (lineage 78). Only moderate evidence for pathogenicity because protein length changes as a result of stop-loss variant (ACMG code: PM4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E186* (c.556G>T) sequence variation in gene VHL/NCBI:7428 2624 check_entity AN5878-1 VHL E186* (c.556G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1653 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E186* (c.556G>T) sequence variation in gene VHL/NCBI:7428 2624 check_entity AN5879-1 VHL E186K (c.556G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in 2 family members with VHL type 1 phenotype (Family ID 3736 in publication). One of 2 individuals were identified with retinal hemangioblastomas, one with cerebellar hemangioblastomas, and one with renal cell carcinoma. Only supporting evidence for pathogenicity because patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E186K (c.556G>A) sequence variation in gene VHL/NCBI:7428 2625 check_entity AN5879-1 VHL E186K (c.556G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1654 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E186K (c.556G>A) sequence variation in gene VHL/NCBI:7428 2625 check_entity AN5880-1 VHL E189fs (c.565del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17661816 Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This mutation causes an early stop codon at amino acid 201 and was found in a VHL type 1 patient with cerebellar hemangioblastomas and renal cysts (family no. 27). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.565del) sequence variation in gene VHL/NCBI:7428 2626 check_entity AN5880-1 VHL E189fs (c.565del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:24132471 Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. One patient was found with this frameshift mutation in the VHL gene. The patient was 30Y at the last follow-up and presented with: cerebellar hemangioblastoma and renal cysts. Family history was not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.565del) sequence variation in gene VHL/NCBI:7428 2626 check_entity AN5880-1 VHL E189fs (c.565del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1745 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.565del) sequence variation in gene VHL/NCBI:7428 2626 check_entity AN5881-1 VHL E46* (c.136G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12202531 A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations extracted from the French VHL database revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, this stop mutation (E46*) was found in a single patient with VHL retinal manifestation, which coincides with mutations confirmed to be associated with VHL type 1 in this study. No family information was provided. Only moderate evidence of pathogenicity since the protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants (AMCG code: PM4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E46* (c.136G>T) sequence variation in gene VHL/NCBI:7428 2627 check_entity AN5881-1 VHL E46* (c.136G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1609 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E46* (c.136G>T) sequence variation in gene VHL/NCBI:7428 2627 check_entity AN5882-1 VHL E52K (c.154G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12202531 A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, the missense mutation (E52K (c.154G>A)) was found in a single patient with no VHL retinal manifestation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E52K (c.154G>A) sequence variation in gene VHL/NCBI:7428 2628 check_entity AN5882-1 VHL E52K (c.154G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 1 patient (patient no. V285). No additional family members were screened. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E52K (c.154G>A) sequence variation in gene VHL/NCBI:7428 2628 check_entity AN5882-1 VHL E52K (c.154G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1610 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E52K (c.154G>A) sequence variation in gene VHL/NCBI:7428 2628 check_entity AN5883-1 VHL E55* (c.163G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:23298237 Genetic analysis of 7 Hungarian individuals from 5 unrelated families affected with type von Hippel-Lindau disease revealed 5 different mutations, 3 of which were novel. The mutations could not be found within 100 healthy controls. One germline truncation mutation was found in a 15-year-old male patient with bilateral renal cell carcinoma and retinal hemangioblastoma with serious retinal detachment. Neither of his parents displayed any mutations in the VHL gene indicating a de novo mutation. ACMG evidence codes: 'PS2' because they observe a de novo mutation (maternity and paternity confirmed), 'PP4' because the patient's phenotypes or family history are highly specific for a disease with single genetic etiology, 'PVS1' because they observe a nonsense variant in a gene where loss of function is a known mechanism of disease. Relevant HPO terms: Renal cell carcinoma, Retinal hemangioblastoma assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E55* (c.163G>T) sequence variation in gene VHL/NCBI:7428 2629 check_entity AN5883-1 VHL E55* (c.163G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1612 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E55* (c.163G>T) sequence variation in gene VHL/NCBI:7428 2629 check_entity AN5884-1 VHL E55= (c.165G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 c.165G>A results in synonymous change Glu55Glu. This is family V5 in the paper (VHL Type 1, no phechromocytoma). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E55= (c.165G>A) sequence variation in gene VHL/NCBI:7428 2630 check_entity AN5884-1 VHL E55= (c.165G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:772 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E55= (c.165G>A) sequence variation in gene VHL/NCBI:7428 2630 check_entity AN5885-1 VHL E55FS (c.163_164delGA) VHL NCBI:7428 gene renal cell carcinoma DOID:4450 risk 34502-5 PubMed:10408776 In a 54 year old male patient with sporadic renal cell carcinoma, VHL c.163_164delGA causing a p.Glu55 Stop at 130 frameshift mutation was observed. Loss of heterozygosity analysis was non-informative. This result suggests a potential oncogenic role for VHL c.163_164delGA in Renal Cell Carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.163_164delGA) sequence variation in gene VHL/NCBI:7428 2631 check_entity AN5885-1 VHL E55FS (c.163_164delGA) VHL NCBI:7428 gene renal cell carcinoma DOID:4450 risk 34502-5 CIViC:745 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.163_164delGA) sequence variation in gene VHL/NCBI:7428 2631 check_entity AN5886-1 VHL E55RfsTer11 (c.163delG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8956040 This is a frameshift mutation that results in a stop at codon 66. Family 3682 in this publication, variant segregates with disease. VHL Type 1 disease is reported: CNS tumors, retinal angioma, renal cell carcinoma but no pheochromocytoma assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.163delG) sequence variation in gene VHL/NCBI:7428 2632 check_entity AN5886-1 VHL E55RfsTer11 (c.163delG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:747 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.163delG) sequence variation in gene VHL/NCBI:7428 2632 check_entity AN5887-1 VHL E70* (c.208G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This nonsense mutation was found in a VHL type 1 family (lineage 179). This provides strong evidence of pathogenicity as it is a null variant in a gene where loss of function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E70* (c.208G>T) sequence variation in gene VHL/NCBI:7428 2633 check_entity AN5887-1 VHL E70* (c.208G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This nonsense mutation was found in a Filipino, VHL type 1 patient with hemangioblastomas of the central nervous system (family VHL 50). This study contains very strong evidence of pathogenicity in the form of a frameshift variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E70* (c.208G>T) sequence variation in gene VHL/NCBI:7428 2633 check_entity AN5887-1 VHL E70* (c.208G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PVS1' because they observe a nonsense variant in a gene where loss of function is a known mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E70* (c.208G>T) sequence variation in gene VHL/NCBI:7428 2633 check_entity AN5887-1 VHL E70* (c.208G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This nonsense variant was found in a VHL type 1 patient with CNS hemangioblastomas (family ID 4479). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E70* (c.208G>T) sequence variation in gene VHL/NCBI:7428 2633 check_entity AN5887-1 VHL E70* (c.208G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1710 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E70* (c.208G>T) sequence variation in gene VHL/NCBI:7428 2633 check_entity AN5888-1 VHL E70K (c.208G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 1 patient (patient no. V374). This patient was further described in Hes et al 2007 (family no. 5) to have bilateral, retinal hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E70K (c.208G>A) sequence variation in gene VHL/NCBI:7428 2634 check_entity AN5888-1 VHL E70K (c.208G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25562111 In the analysis of 63 clinically diagnosed VHL patients, 55 patients were found with pancreatic involvement. Genetic tests on 35 of 55 VHL patients revealed VHL variants in 28 patients. Of the 55 enrolled patients, hemangioblastomas of the central nervous system were previously documented in 47 patients, renal cell carcinoma in 25, and pheochromocytoma in 11 patients. This missense variant was found in 37-year-old female with reported VHL type 1 phenotype and pancreatic lesions (case no. 1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E70K (c.208G>A) sequence variation in gene VHL/NCBI:7428 2634 check_entity AN5888-1 VHL E70K (c.208G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25715769 A case report of a 74-year-old male with colorectal adenocarcinoma, clear cell renal cell carcinoma, and hemangioblastomas of the central nervous system. The spinal hemangioblastoma was histopathologically confirmed. Bilateral multifocal cerebellar hemangioblastomas were inferred on brain MRI. Family history included a mother with a brain tumor of unconfirmed pathology, 2 brothers with the E70K variant and renal cell carcinoma, and an asymptomatic son in his 40s who was also found to have this variant. ACMG evidence codes: 'PP1' because of cosegregation with disease in multiple affected family members in a gene known to cause the disease, 'PP4' because the patient's phenotype and family history are highly specific for a disease with a single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E70K (c.208G>A) sequence variation in gene VHL/NCBI:7428 2634 check_entity AN5888-1 VHL E70K (c.208G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:24132471 Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. One patient age 20Y at the last follow-up had retinal hemangioblastoma and a germline c.208G>A (p.Glu70Lys) mutation in the VHL gene. Family history was not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E70K (c.208G>A) sequence variation in gene VHL/NCBI:7428 2634 check_entity AN5888-1 VHL E70K (c.208G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:27439424 Thirteen unrelated Korean subjects and their family members were tested for VHL mutations with direct sequencing and multiplex ligation dependent probe amplification. Clinical manifestations and family histories were recorded for each subject. Genetic testing confirmed a c.208G>A missense mutation in members of family #2,3,4. Family #2; A 25-year-old male Korean proband presented with a central nervous system hemangioblastoma. This patient had no family history of VHL. Family #3; A 46-year-old female Korean proband presented with bilateral retinal hemangioblastomas. The patient's 19-year-old son was found to share her mutation, but did not exhibit and VHL symptoms at the time of the study. The proband had a sister with retinal hemangioblastoma, but she did not receive genetic testing. Family #4; A 20-year-old female Korean proband presented with bilateral retinal hemangioblastomas. The patient has a mother who had received treatment for retinal hemangioblastoma, but refused to undergo genetic analysis. No other VHL symptoms were observed in the proband or her mother. Suggested ACMG Code: 'PP4' because the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E70K (c.208G>A) sequence variation in gene VHL/NCBI:7428 2634 check_entity AN5888-1 VHL E70K (c.208G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25078357 Medical records of 26 patients with germline mutations of the VHL gene who had been diagnosed with VHL disease in Severance Hospital (Seoul, Republic of Korea) and Samsung Medical Center (Seoul, Republic of Korea) between 2003 and 2012 were reviewed. 9 unrelated patients diagnosed with Type 1 VHL disease shared the same VHL germline missense mutation (c.208G>A; p.Glu70Lys). The patients' phenotypes were as follows: 55 year old male with multiple CNS hemangioblastomas (patient 3), 55Y male with multiple CNS hemangioblastomas (Patient 4), 43Y male with multiple CNS hemangioblastomas (other phenotypic data not available, Patient 5), 11Y male with bilateral retinal hemangioblastoma (patient 6), 48Y female with CNS hemangioblastoma (Patient 7) , 64Y female with CNS hemangioblastoma (patient 8), 16Y F with retinal hemangioblastoma (Patient 9), 41Y female with CNS hemangioblastoma (patient 10). One patient has concurrent missense and splicing mutations (208G>A and IVS1+5G>C). 52 year old male with retinal hemangioblstoma. ACMG codes as follows: PM1 Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E70K (c.208G>A) sequence variation in gene VHL/NCBI:7428 2634 check_entity AN5888-1 VHL E70K (c.208G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1832 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E70K (c.208G>A) sequence variation in gene VHL/NCBI:7428 2634 check_entity AN5889-1 VHL E94* (c.280G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal hemangioblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This nonsense mutation was found in 2 VHL families with 6 patients altogether. All six had retinal hemangioblastomas and 2 had cerebellar hemangioblastomas. This study contains very strong evidence for pathogenicity in the form of a nonsense mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E94* (c.280G>T) sequence variation in gene VHL/NCBI:7428 2635 check_entity AN5889-1 VHL E94* (c.280G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12000816 Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This nonsense mutation was found in the VHL gene and one patient with pheochromocytoma. This study contains very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E94* (c.280G>T) sequence variation in gene VHL/NCBI:7428 2635 check_entity AN5889-1 VHL E94* (c.280G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11409863 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This nonsense mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 85). This study contains very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E94* (c.280G>T) sequence variation in gene VHL/NCBI:7428 2635 check_entity AN5889-1 VHL E94* (c.280G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12624160 Germline mutations were found in 20 Brazilian, VHL probands and their families. This nonsense mutation was found in a VHL type 1 family of 3 affected individuals. All three family members had retinal angiomas and 2 also had hemangioblastomas of the central nervous system (VHL family 4). A nonsense mutation in a gene where loss-of-function is a known mechanism of disease (PVS1). HPO terms: hemangioblastoma, retinal hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E94* (c.280G>T) sequence variation in gene VHL/NCBI:7428 2635 check_entity AN5889-1 VHL E94* (c.280G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:22133049 Case report of a female VHL patient presenting with spinal hemangioblastoma at the age of 32. Further workup showed the presence of pancreatic cysts and a history of spinal hemangioblastoma in the mother. Genetic testing confirmed the presence of the above mutation in the proband. There was no mention of genetic testing performed on her mother in this paper. ACMG evidence codes: 'PVS1' because they observe a nonsense variant in a gene where loss of function is a known mechanism of disease, 'PP4' because the patients' phenotypes or family history are highly specific for a disease with single genetic etiology. Relevant HPO terms: Spinal hemangioblastoma, Multiple pancreatic cysts. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E94* (c.280G>T) sequence variation in gene VHL/NCBI:7428 2635 check_entity AN5889-1 VHL E94* (c.280G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:22357542 Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This nonsense mutation was found in 2 unrelated families. One family of 3 had a asymptomatic 27-year-old female, a 27-year-old male with epididymal cystadenoma, and a 55-year old with hemangioblastomas of the central nervous system, renal cell carcinoma, and pancreatic cysts (proband no. 10). The other VHL family had 2 individuals with hemangioblastomas of the central nervous system (proband no. 11). ACMG codes as follows: A nonsense variant in a gene where loss-of-function is a known mechanism of disease (PSV1). Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E94* (c.280G>T) sequence variation in gene VHL/NCBI:7428 2635 check_entity AN5889-1 VHL E94* (c.280G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1670 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::E94* (c.280G>T) sequence variation in gene VHL/NCBI:7428 2635 check_entity AN5890-1 VHL E94FS (c.279delC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:10862095 This mutation was found in a 51 year old female with hemangioblastomas of the cerebellum, pancreatic cysts, and bilateral renal adenocarcinomas. Patient's mother died of a brain tumor. Mutation was not found in 55 normal individuals. This study contains very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.279delC) sequence variation in gene VHL/NCBI:7428 2636 check_entity AN5890-1 VHL E94FS (c.279delC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2003 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.279delC) sequence variation in gene VHL/NCBI:7428 2636 check_entity AN5891-1 VHL EXON 2-3 DELETION VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from Germany. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:2-3:deletion sequence variation in gene VHL/NCBI:7428 2637 check_entity AN5891-1 VHL EXON 2-3 DELETION VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1816 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:2-3:deletion sequence variation in gene VHL/NCBI:7428 2637 check_entity AN5892-1 VHL Exon 1 Deletion VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20151405 Mutation detected in one case. Case shows CNS hemangioblastoma. ACMG evidence codes: 'PVS1' for a single exon deletion, 'PP1' based on segregation results, 'PP4' because patients phenotypes are highly specific for a disease with single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:1:deletion sequence variation in gene VHL/NCBI:7428 2638 check_entity AN5892-1 VHL Exon 1 Deletion VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21972040 Germline mutation analysis of seven east-Chinese families revealed 6 mutations. This mutation was found two separate VHL families. One family contained a male VHL type 1 patient with hemangioblastomas of the central nervous system and a male asymptomatic patient (family A). The other family contained two male VHL type patients with hemangioblastomas of the central nervous system and 4 asymptomatic family members (family E). This study contains very strong evidence for pathogenicity in the form of a single exon deletion variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:1:deletion sequence variation in gene VHL/NCBI:7428 2638 check_entity AN5892-1 VHL Exon 1 Deletion VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from the Netherlands. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:1:deletion sequence variation in gene VHL/NCBI:7428 2638 check_entity AN5892-1 VHL Exon 1 Deletion VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:818 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:1:deletion sequence variation in gene VHL/NCBI:7428 2638 check_entity AN5893-1 VHL Exon 1-2 Deletion VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20151405 Mutation detected in one case. Case shows renal cell carcinoma. ACMG evidence codes:Mutation detected in one case. Case shows renal cell carcinoma. ACMG evidence codes: 'PVS1' based on deletion of exon 1+2, 'PP4' since the patients phenotypes are highly specific for a disease with single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:1-2:deletion sequence variation in gene VHL/NCBI:7428 2639 check_entity AN5893-1 VHL Exon 1-2 Deletion VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:819 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:1-2:deletion sequence variation in gene VHL/NCBI:7428 2639 check_entity AN5894-1 VHL Exon 1-3 Deletion VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20151405 Mutation detected in 4 separate cases. Two cases show CNS hemangioblastoma, pancreatic/hepatic/renal cysts, and renal cell carcinoma. One case shows CNS hemangioblastoma, pancreatic cysts, and Grawitz One shows CNS HB, pancreatic/renal cysts and retinal angioma. ACMG evidence codes: 'PVS1' based on deletion of all exons, 'PP1' based on segregation results, 'PP4' because the patients phenotypes are highly specific for a disease with single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:1-3:deletion sequence variation in gene VHL/NCBI:7428 2640 check_entity AN5894-1 VHL Exon 1-3 Deletion VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. Statistics of the VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 6 individuals from France, Germany, the Netherlands, or Spain. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:1-3:deletion sequence variation in gene VHL/NCBI:7428 2640 check_entity AN5894-1 VHL Exon 1-3 Deletion VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:817 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:1-3:deletion sequence variation in gene VHL/NCBI:7428 2640 check_entity AN5895-1 VHL Exon 2 Deletion VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:2:deletion sequence variation in gene VHL/NCBI:7428 2641 check_entity AN5895-1 VHL Exon 2 Deletion VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1814 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:2:deletion sequence variation in gene VHL/NCBI:7428 2641 check_entity AN5896-1 VHL Exon 3 Deletion VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:22357542 Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This mutation was found in 3 family members and an unrelated patient. All three family members had hemangioblastomas of the central nervous system (proband no. 13). The 32-year-old sister and 27-year-old proband had renal cell carcinoma and pancreatic cysts. The proband also had retinal angiomas. The unrelated, 45-year-old VHL patient had hemangioblastomas of the central nervous system and retina, renal cell carcinoma, and pancreatic cysts (proband no. 14). ACMG codes as follows: A single exon deletion variant in a gene where loss-of-function is known mechanism of disease (PSV1). Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:3:deletion sequence variation in gene VHL/NCBI:7428 2642 check_entity AN5896-1 VHL Exon 3 Deletion VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:28256701 A 33Y male presented with multiple bilateral renal masses, epididymis cyst, pancreatic cysts and renal cysts. The patient previously underwent resections of medullary hemangioblastoma and endolymphatic sac tumors. Genetic evaluation by MLPA revealed a germline deletion of exon 3 in the VHL gene, confirming the diagnosis of VHL disease. Family history was unremarkable, and both parents tested negative for the mutation, suggesting the mutation occurred de novo in the patient. ACMG: PVS1 exon deletion, PS2 de novo mutation confirmed absent in parents, PP4 phenotype specific for disease assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:3:deletion sequence variation in gene VHL/NCBI:7428 2642 check_entity AN5896-1 VHL Exon 3 Deletion VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26584481 A 22-year-old woman diagnosed in childhood with type IIb VHL, with known multiple retinal angiomas, pancreatic cysts, and spinal and cerebellar hemangioblastomas presented to the ER with signs of acute decompensated heart failure leading to the discovery of dilated left ventricle with severely depressed ejection fraction. Pheochromocytoma and clear cell renal carcinoma was also discovered at this time. Genetic analysis revealed a de novo germline exon 3 deletion mutation in the VHL gene, with no family history of disease. ACMG: PVS1, PS2, PP4 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:3:deletion sequence variation in gene VHL/NCBI:7428 2642 check_entity AN5896-1 VHL Exon 3 Deletion VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. Statistics of the VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 4 individuals from France, Germany, or Italy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:3:deletion sequence variation in gene VHL/NCBI:7428 2642 check_entity AN5896-1 VHL Exon 3 Deletion VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1815 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:3:deletion sequence variation in gene VHL/NCBI:7428 2642 check_entity AN5897-1 VHL F119L (c.357C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in a VHL type 2B family of 7 individuals (Family ID 4414 in publication). Two of seven individuals were identified with retinal hemangioblastomas, 3 with cerebellar hemangioblastomas, one with renal cell carcinoma, and one with pheochromocytomas. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F119L (c.357C>G) sequence variation in gene VHL/NCBI:7428 2643 check_entity AN5897-1 VHL F119L (c.357C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12000816 Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F119L (c.357C>G) sequence variation in gene VHL/NCBI:7428 2643 check_entity AN5897-1 VHL F119L (c.357C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11409863 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This missense mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 99). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F119L (c.357C>G) sequence variation in gene VHL/NCBI:7428 2643 check_entity AN5897-1 VHL F119L (c.357C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 2 patients were found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F119L (c.357C>G) sequence variation in gene VHL/NCBI:7428 2643 check_entity AN5897-1 VHL F119L (c.357C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1619 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F119L (c.357C>G) sequence variation in gene VHL/NCBI:7428 2643 check_entity AN5898-1 VHL F136C (c.407T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12000816 Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F136C (c.407T>G) sequence variation in gene VHL/NCBI:7428 2644 check_entity AN5898-1 VHL F136C (c.407T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20846682 26 VHL patients, from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 1 patient from a single family was confirmed to have the above mutation. Additional manifestations aside from pheochromocytoma are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F136C (c.407T>G) sequence variation in gene VHL/NCBI:7428 2644 check_entity AN5898-1 VHL F136C (c.407T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1690 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F136C (c.407T>G) sequence variation in gene VHL/NCBI:7428 2644 check_entity AN5899-1 VHL F136S (c.407T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Missense mutations were found to be more frequent among families affected by pheochromocytoma (VHL type 2) than in those which pheochromocytoma had not occurred (VHL type 1). This mutation was found in a VHL patient (kindred no. 27). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F136S (c.407T>C) sequence variation in gene VHL/NCBI:7428 2645 check_entity AN5899-1 VHL F136S (c.407T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting residue within the pVHL protein core, was found in 2 VHL families of 5 patients altogether. Three had retinal hemangioblastomas, 4 had cerebellar hemangioblastomas, 3 had renal cell carcinoma. ACMG codes as follows: supporting evidence for pathogenicity because of cosegregation of disease with multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F136S (c.407T>C) sequence variation in gene VHL/NCBI:7428 2645 check_entity AN5899-1 VHL F136S (c.407T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21463266 In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This missense mutation was found in a 30 yr old VHL patient with hemangioblastomas of the central nervous system (index case 207). ACMG codes as follows: Supporting evidence of pathogenicity because this is a missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F136S (c.407T>C) sequence variation in gene VHL/NCBI:7428 2645 check_entity AN5899-1 VHL F136S (c.407T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in two unrelated VHL type 1 patients (patient no. V53, V94). No unaffected individuals from either family were tested for this mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F136S (c.407T>C) sequence variation in gene VHL/NCBI:7428 2645 check_entity AN5899-1 VHL F136S (c.407T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12624160 Germline mutations were found in 20 Brazilian, VHL probands and their families. This missense mutation was found in a VHL type 1 family of 8 affected individuals (VHL family 12). Seven had hemangioblastomas of the central nervous system, one had retinal angiomas, and 2 had renal carcinoma. Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). HPO terms: hemangioblastoma, retinal hemangioblastoma, renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F136S (c.407T>C) sequence variation in gene VHL/NCBI:7428 2645 check_entity AN5899-1 VHL F136S (c.407T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:24132471 Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. One patient was found with this missense varaint in the VHL gene. The patient was 41Y at the last follow-up and presented with: cerebellar hemangioblastoma, spinal cord hemangioblastoma, renal cell carcinoma, renal cysts and pancreatic cysts. Family history was not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F136S (c.407T>C) sequence variation in gene VHL/NCBI:7428 2645 check_entity AN5899-1 VHL F136S (c.407T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26763786 A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. This mutation was present in 2 individuals of the 122 total number of variants captured in this population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F136S (c.407T>C) sequence variation in gene VHL/NCBI:7428 2645 check_entity AN5899-1 VHL F136S (c.407T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1677 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F136S (c.407T>C) sequence variation in gene VHL/NCBI:7428 2645 check_entity AN5900-1 VHL F76S (c.227T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in a VHL type 1 family (lineage 132). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F76S (c.227T>C) sequence variation in gene VHL/NCBI:7428 2646 check_entity AN5900-1 VHL F76S (c.227T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1711 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F76S (c.227T>C) sequence variation in gene VHL/NCBI:7428 2646 check_entity AN5901-1 VHL F76del (c.224_226delTCT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 This deletion mutation was found in two VHL type 1 families of 15 individuals altogether (Family IDs 2693 and 2956 in publication). Five of 7 individuals were identified with retinal hemangioblastomas, 8 with cerebellar hemangioblastomas, and 7 with renal cell carcinoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.224_226delTCT) sequence variation in gene VHL/NCBI:7428 2647 check_entity AN5901-1 VHL F76del (c.224_226delTCT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21463266 In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This deletion mutation was found in a 25 yr old VHL patient with multiple pancreatic cysts and hemangioblastomas of the central nervous system (index case 280). This study contains moderate support for pathogenicity because the protein length changes as a result changes as a result of in-frame deletions in a nonrepeat region (ACMG code: PM4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.224_226delTCT) sequence variation in gene VHL/NCBI:7428 2647 check_entity AN5901-1 VHL F76del (c.224_226delTCT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8641976 Blood samples from 5 Japanese families revealed 4 germline mutations. This mutation was found in a family of 3 individuals (Family B). Only one patient in this family developed symtoms, which included a brain stem hemangioblastoma and retinal angioma discovered at age 30. Parents of this individual showed no manifestations of VHL disease and were negative for bands via single-strand conformational polymorphism (SSCP) analysis where the proband showed extra bands. This study contains moderate evidence of pathogenicity because the protein length changes as a result of an in-frame deletion in a nonrepeat region (ACMG code: PM4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.224_226delTCT) sequence variation in gene VHL/NCBI:7428 2647 check_entity AN5901-1 VHL F76del (c.224_226delTCT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:10761708 A previous study of 26 Japanese, VHL families was extended to 41 additional families. Germline mutations were detected in 55 of 77 Japanese families. Renal cell carcinoma occurred predominantly in non-missense mutations predicted to lead to gross alteration or complete loss of the VHL protein. This mutation was found in a VHL type 1 patient with hemangioblastomas of the central nervous system, pancreatic cyst or tumor, and renal cell carcinoma (family ID 80). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.224_226delTCT) sequence variation in gene VHL/NCBI:7428 2647 check_entity AN5901-1 VHL F76del (c.224_226delTCT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11409863 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This mutation was found in 2 previously diagnosed VHL patients and a suspect VHL mutation carrier by DHPLC (family VHL 26, VHL 63, VHL 77). This variant results in an in frame deletion providing moderate evidence for pathogenicity (PM4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.224_226delTCT) sequence variation in gene VHL/NCBI:7428 2647 check_entity AN5901-1 VHL F76del (c.224_226delTCT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. More specifically, the mutation causes the following protein change: F76Cfs*83. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PVS1' because they observe a frameshift variant in a gene where loss of function is a known mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.224_226delTCT) sequence variation in gene VHL/NCBI:7428 2647 check_entity AN5901-1 VHL F76del (c.224_226delTCT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. This mutation was found in 2 VHL type 1 patients (kindred no. 48, 75). Only moderate support for pathogenicity because protein length changes as a result of in-frame deletion in a nonrepeat region (ACMG code: PM4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.224_226delTCT) sequence variation in gene VHL/NCBI:7428 2647 check_entity AN5901-1 VHL F76del (c.224_226delTCT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This mutation was found in 2 VHL type 1 families (lineages 136, 183). Only moderate evidence for pathogenicity because protein length changes as a result of in-frame deletion in a nonrepeat region (ACMG code: PM4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.224_226delTCT) sequence variation in gene VHL/NCBI:7428 2647 check_entity AN5901-1 VHL F76del (c.224_226delTCT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This mutation was found in a VHL type 1 patient (patient no. V67). Only moderate evidence of pathogenicity since the protein length changes as a result of an in-frame deletion in a nonrepeat region (AMCG code: PM4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.224_226delTCT) sequence variation in gene VHL/NCBI:7428 2647 check_entity AN5901-1 VHL F76del (c.224_226delTCT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:23143947 This paper reports on 4 Chinese kindreds with VHL. The VHL gene was screened using direct DNA sequencing and MLPA in 44 volunteers among the 4 families. The above mutation was found in 1 kindred; 10 members were tested and 3 were found to harbour the mutation. The 7 members without a mutation were asymptomatic, while the 3 members with a mutation had manifestations. In addition to the 3 members who tested positive, there were 2 additional members who displayed manifestations, but died before testing could be performed. Clinical manifestations in this kindred included: renal cell carcinoma, CNS hemangioblastoma, pancreatic cysts, renal cysts, and retinal hemangioblastoma. ACMG evidence codes: 'PP1' because of segregation results, 'PP4' because the patient's phenotypes or family history are highly specific for a disease with single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.224_226delTCT) sequence variation in gene VHL/NCBI:7428 2647 check_entity AN5901-1 VHL F76del (c.224_226delTCT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in 4 unrelated families of 8 individuals total. 5 individuals had retinal hemangioblastomas, 4 had hemangioblastomas of the cerebellum, and 3 had renal cell carcinoma. ACMG evidence codes: 'PM4' because they observe a protein length change as a result of an in-frame deletion in a nonrepeat region or stop-loss variants, 'PP4' because the patients' phenotypes or family history are highly specific for a disease with single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.224_226delTCT) sequence variation in gene VHL/NCBI:7428 2647 check_entity AN5901-1 VHL F76del (c.224_226delTCT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17661816 Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This mutation was found in 2 family members with retinal hemangioblastomas and renal cell carcinoma (family no. 25). One family member also had central nervous system hemangioblastoma. ACMG evidence codes: 'PM4' because they observe a protein length change as a result of an in-frame deletion in a nonrepeat region. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.224_226delTCT) sequence variation in gene VHL/NCBI:7428 2647 check_entity AN5901-1 VHL F76del (c.224_226delTCT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20151405 This study reports 1,548 germline and somatic mutations from 945 VHL families. Mutation was detected in a VHL kindred with hemangioblastomas of the central nervous system, retinal hemangioblastomas and Grawitz tumor (also known as RCC) (case no. 2034). Protein length changes as a result of an in-frame deletion in a nonrepeat region (ACMG code: PM4). Patient's phenotypes or family history are highly specific for a disease with a single genetic etiology (ACMG code: PP4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.224_226delTCT) sequence variation in gene VHL/NCBI:7428 2647 check_entity AN5901-1 VHL F76del (c.224_226delTCT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:22357542 Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This mutation was found in a 42-year-old VHL patient with hemangioblastomas of the central nervous system, renal cell carcinoma, and pancreatic cysts (proband no. 12). ACMG evidence codes: 'PP4' because the patient's phenotypes or family history are highly specific for a disease with single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.224_226delTCT) sequence variation in gene VHL/NCBI:7428 2647 check_entity AN5901-1 VHL F76del (c.224_226delTCT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation (p.Phe76del), which was found in 4 individuals from Germany or France. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.224_226delTCT) sequence variation in gene VHL/NCBI:7428 2647 check_entity AN5901-1 VHL F76del (c.224_226delTCT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26763786 A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. An in-frame deletion (TCT) at nucleotide 227 was present in 1 individual of the 122 total number of variants captured in this population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.224_226delTCT) sequence variation in gene VHL/NCBI:7428 2647 check_entity AN5901-1 VHL F76del (c.224_226delTCT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25078357 Medical records of 26 patients diagnosed with VHL disease in two Korean hospitals between 2003-2012 and harboring germline VHL mutations were retrospectively reviewed. One male patient diagnosed with Type 1 VHL disease at 23Y (Patient 14) presented with renal cell carcinoma, multiple CNS hemangioblastomas and other manifestations. He had a germline inframe deletion in the VHL gene (c.227delTCT) and a negative family history of VHL disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.224_226delTCT) sequence variation in gene VHL/NCBI:7428 2647 check_entity AN5901-1 VHL F76del (c.224_226delTCT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1964 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.224_226delTCT) sequence variation in gene VHL/NCBI:7428 2647 check_entity AN5902-1 VHL F76del (c.227_229del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:14722919 'Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. A mutation, F76del(c.227_229del) (noted as g.941_943delTCT in the paper originally) was found in a patient with cerebellar hemangioblastomas, renal cyst, and pancreatic cyst, the pateints age on onset was 31 years old. No family history was mentioned. ACMG evidence code: ''flag for PP4'' because patients phenotype is specific for the disease.' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.227_229del) sequence variation in gene VHL/NCBI:7428 2648 check_entity AN5902-1 VHL F76del (c.227_229del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8634692 Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregared with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS Hb, RCC, and Pheo was available. Case 2 had p.Phe76del mutation and one affected member with hemangioblastoma and renal cell carcinoma. ACMG PP4 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.227_229del) sequence variation in gene VHL/NCBI:7428 2648 check_entity AN5902-1 VHL F76del (c.227_229del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:3026 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.227_229del) sequence variation in gene VHL/NCBI:7428 2648 check_entity AN5903-1 VHL F76fs (c.223_224insT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:19270817 Germline VHL mutations were found in all Korean patients who fulfilled clinical criteria for VHL disease. No mutation of VHL was detected in other patients who did not meet clinical criteria. In all cases, samples from both parents were not available and evidence of de novo mutations could not further be evaluated. This variant is predicted to cause a frameshift and premature stop codon. This variant was found in a 24 year old Korean female with hemangioblastomas of the central nervous system and retinal hemangioblastomas (patient no. 4). There is very strong evidence of pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.223_224insT) sequence variation in gene VHL/NCBI:7428 2649 check_entity AN5903-1 VHL F76fs (c.223_224insT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1788 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.223_224insT) sequence variation in gene VHL/NCBI:7428 2649 check_entity AN5904-1 VHL F91* (c.272_273delinsAA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal hemangioblastoma and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. c.272T>A and 273C>A mutations (HGVS nomenclature as c.272_273delinsAA) leads to this this nonsense mutation which was found in a VHL with retinal hemangioblastomas and cerebellar hemangioblastomas. Only moderate evidence of pathogenicity since the protein length changes as a result of a stop-loss variant (ACMG code: PM4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F91* (c.272_273delinsAA) sequence variation in gene VHL/NCBI:7428 2650 check_entity AN5904-1 VHL F91* (c.272_273delinsAA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1769 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F91* (c.272_273delinsAA) sequence variation in gene VHL/NCBI:7428 2650 check_entity AN5905-1 VHL F91L (c.273C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in the germline of a male VHL patient (patient no. S3940) with apparently sporadic cerebellar hemangioblastoma diagnosed at 56Y old. No unaffected family members were tested. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F91L (c.273C>G) sequence variation in gene VHL/NCBI:7428 2651 check_entity AN5905-1 VHL F91L (c.273C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2170 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::F91L (c.273C>G) sequence variation in gene VHL/NCBI:7428 2651 check_entity AN5906-1 VHL G104= (c.312C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This silent variant was found in a VHL patient (patient no. V95). No unaffected family members were tested. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G104= (c.312C>G) sequence variation in gene VHL/NCBI:7428 2652 check_entity AN5906-1 VHL G104= (c.312C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2169 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G104= (c.312C>G) sequence variation in gene VHL/NCBI:7428 2652 check_entity AN5907-1 VHL G104A (c.311G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12202531 A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations extracted from the French VHL database revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, this missense mutation was found in a VHL patient with retinal hemangioblastomas. Other manifestations are not clearly stated. No family information or relation was provided. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G104A (c.311G>C) sequence variation in gene VHL/NCBI:7428 2653 check_entity AN5907-1 VHL G104A (c.311G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in the germline of a female patient (patient no. S6150) with apparently sporadic retinal hemangioblastoma diagnosed at 42Y old. No unaffected family members were tested. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G104A (c.311G>C) sequence variation in gene VHL/NCBI:7428 2653 check_entity AN5907-1 VHL G104A (c.311G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1919 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G104A (c.311G>C) sequence variation in gene VHL/NCBI:7428 2653 check_entity AN5908-1 VHL G104V (c.311G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:29789510 A healthy 21 year old woman presented with high blood pressure. She noted palpitations ongoing for 6 months prior. Her adrenal galnds were found to be normal via CT scan. A 2cm x 1.8cm x 1.5cm lesion close to costovertebral angle of third right thoracic vertebra was found via PET scan were histological findings found this to be consistent with paraganglioma. Blood samples for genomic DNA analysis were taken and screening for mutations in SDHA, SDHB, SDHC, SDHD, RET, SDHAF2, TMEM127, MAX, NF1, FH, MDH2, and EPAS1 genes was negative but she was positive for a heterozygous mutation in the VHL gene, c.311G > T (p.Gly104Val). This same variant was found in her 17 year-old sister and her mother but not in her father. Her mother refused a complete staging. The probands sister presented with a small retinal hemangioblastoma at this time. ACMG evidence codes: 'PM2' since this variant is absent from controls (gnomAD), 'PP1' since there is cosegregation with disease in multiple affected family members, 'PP2' since we have a missense variant in a gene where missense variants are a common mechanism of disease, 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G104V (c.311G>T) sequence variation in gene VHL/NCBI:7428 2654 check_entity AN5908-1 VHL G104V (c.311G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2301 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G104V (c.311G>T) sequence variation in gene VHL/NCBI:7428 2654 check_entity AN5909-1 VHL G114C (c.340G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. This mutation was found in 2 unrelated VHL families (kindred no. 40, 133). One was identified with pheochromocytoma, the other was unknown. Supporting evidence for pathogenicity because of a missense mutation in a gene where missense variants are a common mechanism of disease (ACMG code: PP2). Relevant HPO term: pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G114C (c.340G>T) sequence variation in gene VHL/NCBI:7428 2655 check_entity AN5909-1 VHL G114C (c.340G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Higher risk of pheochromocytoma was associated with missense mutations that result in substitution of a surface amino acid (p<=0.004) than for patients with missense mutations that disrupt the structural integrity of the VHL gene product (pVHL) or other loss of function mutations (either germline deletions or truncating mutations). This missense mutation, affecting residue within the pVHL protein core, was found in a VHL patient with cerebellar hemangioblastomas. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G114C (c.340G>T) sequence variation in gene VHL/NCBI:7428 2655 check_entity AN5909-1 VHL G114C (c.340G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1673 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G114C (c.340G>T) sequence variation in gene VHL/NCBI:7428 2655 check_entity AN5910-1 VHL G114R (c.340G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:19464396 43 Italian patients were molecularly analyzed for Von Hippel-Lindau disease based on clinical suspicion. 2 of the 43 patients (VHL-6 and -16) were found to have the above mutation. Clinical manifestations associated with this mutation include: CNS hemangioblastomas and pancreatic cysts. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G114R (c.340G>C) sequence variation in gene VHL/NCBI:7428 2656 check_entity AN5910-1 VHL G114R (c.340G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20846682 26 VHL patients from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 1 patient from a single family was confirmed to have the above mutation. Additional manifestations aside from pheochromocytoma are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G114R (c.340G>C) sequence variation in gene VHL/NCBI:7428 2656 check_entity AN5910-1 VHL G114R (c.340G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1733 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G114R (c.340G>C) sequence variation in gene VHL/NCBI:7428 2656 check_entity AN5911-1 VHL G114S (c.340G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G114S (c.340G>A) sequence variation in gene VHL/NCBI:7428 2657 check_entity AN5911-1 VHL G114S (c.340G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1902 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G114S (c.340G>A) sequence variation in gene VHL/NCBI:7428 2657 check_entity AN5912-1 VHL G114Vfs*45 (c.339delA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. Statistics of the VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from Germany. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.339delA) sequence variation in gene VHL/NCBI:7428 2658 check_entity AN5912-1 VHL G114Vfs*45 (c.339delA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2328 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.339delA) sequence variation in gene VHL/NCBI:7428 2658 check_entity AN5913-1 VHL G114dup (c.342dupGGT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). This mutation was found in 2 VHL type 1 family members with retinal angiomas and hemangioblastomas of the central nervous system. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.342dupGGT) sequence variation in gene VHL/NCBI:7428 2659 check_entity AN5913-1 VHL G114dup (c.342dupGGT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2005 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.342dupGGT) sequence variation in gene VHL/NCBI:7428 2659 check_entity AN5914-1 VHL G123fs (c.369_375delGACACAC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in a patient with no clinical manifestations of VHL disease as described in their supplemental table (retinal angioma, cerebellar hemangioblastoma, renal cell carcinoma, pheochromocytoma). There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.369_375delGACACAC) sequence variation in gene VHL/NCBI:7428 2660 check_entity AN5914-1 VHL G123fs (c.369_375delGACACAC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2011 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.369_375delGACACAC) sequence variation in gene VHL/NCBI:7428 2660 check_entity AN5915-1 VHL G144* (c.430G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This nonsense mutation was found in a VHL type 2 family (lineage 65). Only moderate evidence for pathogenicity because protein length changes as a result of stop-loss variant (ACMG code: PM4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G144* (c.430G>T) sequence variation in gene VHL/NCBI:7428 2661 check_entity AN5915-1 VHL G144* (c.430G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1726 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G144* (c.430G>T) sequence variation in gene VHL/NCBI:7428 2661 check_entity AN5916-1 VHL G144E (c.431G>A) VHL NCBI:7428 gene adrenal gland pheochromocytoma DOID:0050892 diagnostic 34502-5 PubMed:9663592 Screening of 68 patients, who had been operated on for apparently sporadic pheochromocytomas, for germline mutations in the VHL gene. This missense mutation was found in a 51 year-old female with unilateral, benign, adrenal pheochromocytoma (patient no. 48). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G144E (c.431G>A) sequence variation in gene VHL/NCBI:7428 2662 check_entity AN5916-1 VHL G144E (c.431G>A) VHL NCBI:7428 gene adrenal gland pheochromocytoma DOID:0050892 diagnostic 34502-5 CIViC:2166 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G144E (c.431G>A) sequence variation in gene VHL/NCBI:7428 2662 check_entity AN5917-1 VHL G144fs (c.429_439del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8634692 Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb) renal cell carcinoma (RCC), and pheochromocytoma was available. Case 26 had a G144fs (c.429_439del) frameshift mutation. 1 member was affected with retinal angioma, CNS hemangioblastoma, and renal cell carcinoma (ACMG PP4). Other demographics of the members were not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.429_439del) sequence variation in gene VHL/NCBI:7428 2663 check_entity AN5917-1 VHL G144fs (c.429_439del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:3116 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.429_439del) sequence variation in gene VHL/NCBI:7428 2663 check_entity AN5918-1 VHL G144fs (c.432insG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21972040 Germline mutation analysis of seven east-Chinese families revealed 6 mutations. This novel mutation was found in 2 male VHL type 1 family members with hemangioblastomas of the central nervous system (family B). Family also contained 5 asymptomatic individuals. This study contains very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.432insG) sequence variation in gene VHL/NCBI:7428 2664 check_entity AN5918-1 VHL G144fs (c.432insG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1825 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.432insG) sequence variation in gene VHL/NCBI:7428 2664 check_entity AN5919-1 VHL G93C (c.277G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12000816 Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G93C (c.277G>T) sequence variation in gene VHL/NCBI:7428 2665 check_entity AN5919-1 VHL G93C (c.277G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1884 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G93C (c.277G>T) sequence variation in gene VHL/NCBI:7428 2665 check_entity AN5920-1 VHL G93R (c.277G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11409863 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This missense mutation was found in a suspected VHL mutation carrier by DHPLC (family VHL 106). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G93R (c.277G>C) sequence variation in gene VHL/NCBI:7428 2666 check_entity AN5920-1 VHL G93R (c.277G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G93R (c.277G>C) sequence variation in gene VHL/NCBI:7428 2666 check_entity AN5920-1 VHL G93R (c.277G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1796 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G93R (c.277G>C) sequence variation in gene VHL/NCBI:7428 2666 check_entity AN5921-1 VHL G93S (c.277G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17661816 Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This mutation was found in 2 VHL type 2C family members (family no. 9), both with pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G93S (c.277G>A) sequence variation in gene VHL/NCBI:7428 2667 check_entity AN5921-1 VHL G93S (c.277G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12000816 Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and two patients with pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G93S (c.277G>A) sequence variation in gene VHL/NCBI:7428 2667 check_entity AN5921-1 VHL G93S (c.277G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:24132471 Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. Two patients were found with this missense mutation in the VHL gene. One patient was 35Y and the other was 60Y at last follow-up. Their phenotypes were grouped together: retinal hemangioblastoma, spinal cord hemangioblastoma, pheochromocytoma, renal cysts, and pancreatic cysts. Family history was not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G93S (c.277G>A) sequence variation in gene VHL/NCBI:7428 2667 check_entity AN5921-1 VHL G93S (c.277G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1735 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G93S (c.277G>A) sequence variation in gene VHL/NCBI:7428 2667 check_entity AN5922-1 VHL G93V (c.278G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12000816 Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G93V (c.278G>T) sequence variation in gene VHL/NCBI:7428 2668 check_entity AN5922-1 VHL G93V (c.278G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1885 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::G93V (c.278G>T) sequence variation in gene VHL/NCBI:7428 2668 check_entity AN5923-1 VHL G93_Y98del (c.275_292del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This mutation was found in VHL type 1 family (lineage 11). Only moderate evidence for pathogenicity because protein length changes as a result of in-frame deletion in a nonrepeat region (ACMG code: PM4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.275_292del) sequence variation in gene VHL/NCBI:7428 2669 check_entity AN5923-1 VHL G93_Y98del (c.275_292del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1973 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.275_292del) sequence variation in gene VHL/NCBI:7428 2669 check_entity AN5924-1 VHL H115P (c.344A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Higher risk of pheochromocytoma was associated with missense mutations that result in substitution of a surface amino acid (p<=0.004) than for patients with missense mutations that disrupt the structural integrity of the VHL gene product (pVHL) or other loss of function mutations (either germline deletions or truncating mutations). This missense mutation, affecting residue on the surface of pVHL, was found in a VHL type 1 patient with retinal hemangioblastomas and cerebellar hemangioblastomas. ACMG codes as follows: Supporting evidence of pathogenicity because missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H115P (c.344A>C) sequence variation in gene VHL/NCBI:7428 2670 check_entity AN5924-1 VHL H115P (c.344A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1761 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H115P (c.344A>C) sequence variation in gene VHL/NCBI:7428 2670 check_entity AN5925-1 VHL H115Q (c.345C>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in a VHL type 2B family of 12 individuals (Family ID 4486 in publication). All 12 family members identified with cerebellar hemangioblastomas, 2 of 12 family members with retinal hemangioblastomas, one with renal cell carcinoma and one with pheochromocytoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma, Renal cell carcinoma, Pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H115Q (c.345C>A) sequence variation in gene VHL/NCBI:7428 2671 check_entity AN5925-1 VHL H115Q (c.345C>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1618 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H115Q (c.345C>A) sequence variation in gene VHL/NCBI:7428 2671 check_entity AN5926-1 VHL H115Q (c.345C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 1 patient (patient no. V48). No unaffected family members were screened. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H115Q (c.345C>G) sequence variation in gene VHL/NCBI:7428 2672 check_entity AN5926-1 VHL H115Q (c.345C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12202531 A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations extracted from the French VHL database revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, this missense mutation (c.343C>T) was found in a VHL patient without retinal hemangioblastomas. Other manifestations are not clearly stated. No family information was provided. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H115Q (c.345C>G) sequence variation in gene VHL/NCBI:7428 2672 check_entity AN5926-1 VHL H115Q (c.345C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. The statistics of the VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H115Q (c.345C>G) sequence variation in gene VHL/NCBI:7428 2672 check_entity AN5926-1 VHL H115Q (c.345C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1833 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H115Q (c.345C>G) sequence variation in gene VHL/NCBI:7428 2672 check_entity AN5927-1 VHL H115R (c.344A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found in a German, VHL type 1 family of 2. Both patients had hemangioblastomas of the central nervous system, renal cell carcinoma, pancreatic cysts, and cystadenomas of the epididymis (family VHL 60). One patient also had retinal angiomas. This study contains supporting evidence of pathogenicity due to cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). HPO terms: papillary cystadenomas of the broad ligament. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H115R (c.344A>G) sequence variation in gene VHL/NCBI:7428 2673 check_entity AN5927-1 VHL H115R (c.344A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:22357542 Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This missense mutation was found in a 45-year-old VHL type 1 patient with hemangioblastomas of the central nervous system, renal cell carcinoma, and pancreatic cysts (proband no. 4) and no family history. HPO terms: hemangioblastoma, renal cell carcinoma, multiple pancreatic cysts. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H115R (c.344A>G) sequence variation in gene VHL/NCBI:7428 2673 check_entity AN5927-1 VHL H115R (c.344A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1876 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H115R (c.344A>G) sequence variation in gene VHL/NCBI:7428 2673 check_entity AN5928-1 VHL H115Y (c.343C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21463266 In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This missense mutation was found in a 36 yr old VHL patient with multiple pancreatic cysts as well as central nervous system and retinal hemangioblastomas (index case 118). ACMG codes as follows: Supporting evidence of pathogenicity because this is a missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H115Y (c.343C>T) sequence variation in gene VHL/NCBI:7428 2674 check_entity AN5928-1 VHL H115Y (c.343C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found in a German, VHL type 1 patient with retinal angiomas (family VHL 59). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H115Y (c.343C>T) sequence variation in gene VHL/NCBI:7428 2674 check_entity AN5928-1 VHL H115Y (c.343C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1797 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::H115Y (c.343C>T) sequence variation in gene VHL/NCBI:7428 2674 check_entity AN5929-1 VHL H115fs (c.344del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12624160 Germline mutations were found in 20 Brazilian, VHL probands and their families. This mutstaion was found in a VHL type 1 family of 3 affected individuals (VHL family 9). One had hemangioblastomas of the central nervous system, one with retinal angiomas, and one with renal carcinoma. ACMG codes as follows: A frameshift mutation in a gene where loss-of-function is a known mechanism of disease (PVS1). Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). HPO terms: hemangioblastoma, retinal hemangioblastoma, renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.344del) sequence variation in gene VHL/NCBI:7428 2675 check_entity AN5929-1 VHL H115fs (c.344del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1933 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.344del) sequence variation in gene VHL/NCBI:7428 2675 check_entity AN5930-1 VHL H125fs (c.374insA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in a VHL type 1 family of 3. One family member had retinal angiomas, one had hemangioblastomas of the central nervous system, and one had renal cell carcinoma. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.374insA) sequence variation in gene VHL/NCBI:7428 2676 check_entity AN5930-1 VHL H125fs (c.374insA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2012 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.374insA) sequence variation in gene VHL/NCBI:7428 2676 check_entity AN5931-1 VHL H191FS (c.571delC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This mutation causes a premature stop codon at amino acid 201 and was found in a VHL type 2B patient (patient no. V51). This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1) assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.571delC) sequence variation in gene VHL/NCBI:7428 2677 check_entity AN5931-1 VHL H191FS (c.571delC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1834 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.571delC) sequence variation in gene VHL/NCBI:7428 2677 check_entity AN5932-1 VHL I151F (c.451A>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:22357542 Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This missense mutation was found in a 43-year-old VHL type 1 patient with renal cell carcinoma, pancreatic cysts, an endolymphatic sac tumor, and an epididymal /ovarian cystadenoma (proband no. 5) and no family history. HPO terms: renal cell carcinoma, multiple pancreatic cysts, epididymal cysts, endolymphatic sac tumors. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I151F (c.451A>T) sequence variation in gene VHL/NCBI:7428 2678 check_entity AN5932-1 VHL I151F (c.451A>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2026 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I151F (c.451A>T) sequence variation in gene VHL/NCBI:7428 2678 check_entity AN5933-1 VHL I151M (c.453C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I151M (c.453C>G) sequence variation in gene VHL/NCBI:7428 2679 check_entity AN5933-1 VHL I151M (c.453C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1906 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I151M (c.453C>G) sequence variation in gene VHL/NCBI:7428 2679 check_entity AN5934-1 VHL I151T (c.452T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17661816 Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This mutation was detected in a VHL patient with cerebellar hemangioblastomas and renal cell carcinoma (family no. 11). Only supporting evidence for pathogenicity because Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology (ACMG code: PP4). Relevant HPO terms: Cerebellar hemangioblastoma, Renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I151T (c.452T>C) sequence variation in gene VHL/NCBI:7428 2680 check_entity AN5934-1 VHL I151T (c.452T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Higher risk of pheochromocytoma was associated with missense mutations that result in substitution of a surface amino acid (p<=0.004) than for patients with missense mutations that disrupt the structural integrity of the VHL gene product (pVHL) or other loss of function mutations (either germline deletions or truncating mutations). A missense mutation, affecting residue within the pVHL protein core, was found in 2 VHL families with 4 patients. Two had retinal hemangioblastomas. ACMG codes as follows: Supporting evidence of pathogenicity because a missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: Retinal hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I151T (c.452T>C) sequence variation in gene VHL/NCBI:7428 2680 check_entity AN5934-1 VHL I151T (c.452T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:10567493 A cohort of 141 patients with hemangioblastomas of the central nervous system was analyzed. 81 patients had germline mutations in the VHL gene. This missense mutation was found in one patient with hemangioblastomas of the central nervous system. No other phenotype described. HPO terms: hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I151T (c.452T>C) sequence variation in gene VHL/NCBI:7428 2680 check_entity AN5934-1 VHL I151T (c.452T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:28469506 A retrospective medical chart review was performed on patients referred to the genetics service. Two unrelated probands were genetically confirmed with a non-familial mutation at c.452T>C of the VHL gene. The first, a 30 year old male, presented with central nervous system hemangioblastoma, renal cell carcinoma, and a pancreatic cyst. The second, a 37 year old male, presented with central nervous system hemangioblastoma, renal cyst, pancreatic cyst, and epididymal cyst. Family histories are both negative. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I151T (c.452T>C) sequence variation in gene VHL/NCBI:7428 2680 check_entity AN5934-1 VHL I151T (c.452T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1747 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I151T (c.452T>C) sequence variation in gene VHL/NCBI:7428 2680 check_entity AN5935-1 VHL I180V (c.538A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Missense mutations were found to be more frequent among families affected by pheochromocytoma (VHL type 2) than in those which pheochromocytoma had not occurred (VHL type 1). This mutation was found in a VHL type 1 patient (kindred no. 79). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I180V (c.538A>G) sequence variation in gene VHL/NCBI:7428 2681 check_entity AN5935-1 VHL I180V (c.538A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1683 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::I180V (c.538A>G) sequence variation in gene VHL/NCBI:7428 2681 check_entity AN5936-1 VHL Intronic deletion (c.341-13delCGTTTCCAACAATTTCTCGGTGT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. This mutation was found in a VHL type 1 family of 3. All three family members had retinal angiomas. One also had renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.341-13delCGTTTCCAACAATTTCTCGGTGT) sequence variation in gene VHL/NCBI:7428 2682 check_entity AN5936-1 VHL Intronic deletion (c.341-13delCGTTTCCAACAATTTCTCGGTGT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2010 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.341-13delCGTTTCCAACAATTTCTCGGTGT) sequence variation in gene VHL/NCBI:7428 2682 check_entity AN5937-1 VHL K159fs (c.473dup) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This mutation causes a premature stop codon at amino acid 173 and was found in a VHL type 1 patient (patient no. V235). This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.473dup) sequence variation in gene VHL/NCBI:7428 2683 check_entity AN5937-1 VHL K159fs (c.473dup) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1748 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.473dup) sequence variation in gene VHL/NCBI:7428 2683 check_entity AN5938-1 VHL K159fs (c.474_476delGAAinsC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. VHL K159fs (c.474_476delGAAinsC) frameshift mutation was found in a VHL type 1 family of 5 individuals. Three had cerebellar hemangioblastomas and one had renal cell carcinoma. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.474_476delGAAinsC) sequence variation in gene VHL/NCBI:7428 2684 check_entity AN5938-1 VHL K159fs (c.474_476delGAAinsC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2013 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.474_476delGAAinsC) sequence variation in gene VHL/NCBI:7428 2684 check_entity AN5939-1 VHL K159fs (c.477_478insCA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12114495 A study of 34 Polish families revealed germline mutations in 30 families. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). This mutation was found in VHL patient with hemangioblastomas of the retina and central nervous system (family no. 14). This study contains very strong evidence of pathogenicity in the form of a frameshift variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). HPO terms: hemangioblastoma, retinal hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.477_478insCA) sequence variation in gene VHL/NCBI:7428 2685 check_entity AN5939-1 VHL K159fs (c.477_478insCA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1916 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.477_478insCA) sequence variation in gene VHL/NCBI:7428 2685 check_entity AN5940-1 VHL K196* (c.586A>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:19270817 Germline VHL mutations were found in all Korean patients who fulfilled clinical criteria for VHL disease. No mutation of VHL was detected in other patients who did not meet clinical criteria. In all cases, samples from both parents were not available and evidence of de novo mutations could not further be evaluated. This nonsense mutation was found in a 22 year old Korean female with hemangioblastomas of the central nervous system (patient no. 3). There is very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K196* (c.586A>T) sequence variation in gene VHL/NCBI:7428 2686 check_entity AN5940-1 VHL K196* (c.586A>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1789 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::K196* (c.586A>T) sequence variation in gene VHL/NCBI:7428 2686 check_entity AN5941-1 VHL K196fs (c.584_585delAG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in a VHL type 1 patient with retinal angiomas, hemangioblastomas of the central nervous system, and renal cell carcinoma. HPO terms: hemangioblastoma, retinal hemangioblastoma, renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.584_585delAG) sequence variation in gene VHL/NCBI:7428 2687 check_entity AN5941-1 VHL K196fs (c.584_585delAG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2016 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.584_585delAG) sequence variation in gene VHL/NCBI:7428 2687 check_entity AN5942-1 VHL L101G (c.301_302delinsGG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in a VHL type 1 family (lineage 103). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L101G (c.301_302delinsGG) sequence variation in gene VHL/NCBI:7428 2688 check_entity AN5942-1 VHL L101G (c.301_302delinsGG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1714 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L101G (c.301_302delinsGG) sequence variation in gene VHL/NCBI:7428 2688 check_entity AN5943-1 VHL L116V (c.346C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting residue with pVHL protein core, was detected in a VHL type 1 family with 3 affected individuals. All 3 patients had retinal angioma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L116V (c.346C>G) sequence variation in gene VHL/NCBI:7428 2689 check_entity AN5943-1 VHL L116V (c.346C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1696 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L116V (c.346C>G) sequence variation in gene VHL/NCBI:7428 2689 check_entity AN5944-1 VHL L118P (c.353T>C) VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 risk 34502-5 PubMed:7915601 Tumors from 98 patients with sporadic clear cell renal carcinoma (ccRC) were analyzed for VHL mutations and loss of heterozygosity (LOH). Somatic VHL variants were observed in 56 patients, and VHL LOH was observed in 98% of samples with VHL variants. VHL L118P (c.353T>C) was found in a granular ccRC (sample T36, variant location indicated at c.566 because of differences in reference transcript). Authors noted that VHL variants were highly specific to ccRC and not found in the 12 other tumor types examined. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L118P (c.353T>C) sequence variation in gene VHL/NCBI:7428 2690 check_entity AN5944-1 VHL L118P (c.353T>C) VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 risk 34502-5 CIViC:1674 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L118P (c.353T>C) sequence variation in gene VHL/NCBI:7428 2690 check_entity AN5944-2 VHL L118P (c.353T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Missense mutations were found to be more frequent among families affected by pheochromocytoma (VHL type 2) than in those which pheochromocytoma had not occurred (VHL type 1). This mutation was found in a VHL type 1 patient (kindred no. 19). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L118P (c.353T>C) sequence variation in gene VHL/NCBI:7428 2691 check_entity AN5944-2 VHL L118P (c.353T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting residue within the pVHL protein core, was found in 3 VHL families of 7 patients altogether. Six had retinal hemangioblastomas, one had renal cell carcinoma, 6 had cerebellar hemangioblastomas, and 4 pheochromocytoma. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: Renal cell carcinoma. retinal hemangioblastoma cerebellar hemangioblastoma, pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L118P (c.353T>C) sequence variation in gene VHL/NCBI:7428 2691 check_entity AN5944-2 VHL L118P (c.353T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in 3 VHL type 1 family members (patient no. V27). Ten unaffected family members were screened with no evidence of the L188P variant. This study contains strong evidence of pathogenicity for this variant because the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (ACMG code: PS4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L118P (c.353T>C) sequence variation in gene VHL/NCBI:7428 2691 check_entity AN5944-2 VHL L118P (c.353T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11409863 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This missense mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 94). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L118P (c.353T>C) sequence variation in gene VHL/NCBI:7428 2691 check_entity AN5944-2 VHL L118P (c.353T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20846682 26 VHL patients from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 1 patient from a single family was confirmed to have the above mutation. Additional manifestations aside from pheochromocytoma are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L118P (c.353T>C) sequence variation in gene VHL/NCBI:7428 2691 check_entity AN5944-2 VHL L118P (c.353T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8634692 Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors reported a nucleotide deletion (i.e. 566T>C) which coincides with legacy variant nomenclature (AF010238.1) and was mapped to c.353T>C (NM_000551.3). PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma, renal cell carcinoma (RCC), and pheochromocytoma was available. Case 46 had p.Leu117Pro (c.353T>C) mutation. 1 member was affected with RCC. Other demographics of the members were not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L118P (c.353T>C) sequence variation in gene VHL/NCBI:7428 2691 check_entity AN5944-2 VHL L118P (c.353T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1674 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L118P (c.353T>C) sequence variation in gene VHL/NCBI:7428 2691 check_entity AN5945-1 VHL L118fs (c.352_353insA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This mutation causes stop codon at amino acid 131 and was found in a VHL type 1 family (lineage 13). This provides strong evidence of pathogenicity as it is a null variant in a gene where loss of function is a known mechanism of disease (ACMG code: PVS1). Relevant HPO terms: hemangioblastoma, Renal cell carcinoma, Pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.352_353insA) sequence variation in gene VHL/NCBI:7428 2692 check_entity AN5945-1 VHL L118fs (c.352_353insA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1717 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.352_353insA) sequence variation in gene VHL/NCBI:7428 2692 check_entity AN5946-1 VHL L128F (c.382C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20846682 26 VHL patients from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 1 patient from a single family was confirmed to have the above mutation. Additional manifestations aside from pheochromocytoma are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L128F (c.382C>T) sequence variation in gene VHL/NCBI:7428 2693 check_entity AN5946-1 VHL L128F (c.382C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2935 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L128F (c.382C>T) sequence variation in gene VHL/NCBI:7428 2693 check_entity AN5947-1 VHL L128R (c.383T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting residue within the pVHL protein core, was found in a VHL type 1 family with retinal hemangioblastomas and cerebellar hemangioblastomas. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: Cerebellar hemanioblastoma and retinal hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L128R (c.383T>G) sequence variation in gene VHL/NCBI:7428 2694 check_entity AN5947-1 VHL L128R (c.383T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:14722919 Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. This missense variant was found in a 22 year old patient with retinal and cerebellar hemangioblastomas, renal cysts, and pancreatic cysts (patient no. F41). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L128R (c.383T>G) sequence variation in gene VHL/NCBI:7428 2694 check_entity AN5947-1 VHL L128R (c.383T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1762 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L128R (c.383T>G) sequence variation in gene VHL/NCBI:7428 2694 check_entity AN5948-1 VHL L129P (c.386T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20846682 26 VHL patients from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 1 patient from a single family was confirmed to have the above mutation. Additional manifestations aside from pheochromocytoma are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L129P (c.386T>C) sequence variation in gene VHL/NCBI:7428 2695 check_entity AN5948-1 VHL L129P (c.386T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2381 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L129P (c.386T>C) sequence variation in gene VHL/NCBI:7428 2695 check_entity AN5949-1 VHL L129Q (c.386insAGA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This insertion mutation was detected in a VHL type 1 patient (family ID 4410 in publication) with retinal hemangioblastomas, cerebellar hemangioblastomas, and renal cell carcinoma. Only supporting evidence for pathogenicity because patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L129Q (c.386insAGA) sequence variation in gene VHL/NCBI:7428 2696 check_entity AN5949-1 VHL L129Q (c.386insAGA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1644 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L129Q (c.386insAGA) sequence variation in gene VHL/NCBI:7428 2696 check_entity AN5950-1 VHL L129fs (c.384delT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This mutation was found in 2 German, VHL type 1 family members with hemangioblastomas of the central nervous system, renal cell carcinoma, and pancreatic cysts (family VHL 44). This study contains very strong evidence of pathogenicity in the form of a frameshift variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.384delT) sequence variation in gene VHL/NCBI:7428 2697 check_entity AN5950-1 VHL L129fs (c.384delT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1872 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.384delT) sequence variation in gene VHL/NCBI:7428 2697 check_entity AN5951-1 VHL L135* (c.404T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This nonsense mutation was found in a VHL type 1 family of 6 individuals (family ID 3720). All 6 individuals were identified with cerebellar hemangioblastomas, 4 with angiomas and 3 with renal cell carcinoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L135* (c.404T>A) sequence variation in gene VHL/NCBI:7428 2698 check_entity AN5951-1 VHL L135* (c.404T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs in the VHL registries of the participating centers in Europe were identified and included in the International Endolymphatic Sac Tumor Registry. The statistics of this registry is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. Only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from Spain. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L135* (c.404T>A) sequence variation in gene VHL/NCBI:7428 2698 check_entity AN5951-1 VHL L135* (c.404T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1645 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L135* (c.404T>A) sequence variation in gene VHL/NCBI:7428 2698 check_entity AN5952-1 VHL L135fs (c.404del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. VHL L135FS (c.404del) results in a frameshift, an early stop codon at amino acid 158, and was found in a VHL family of 2, both with retinal hemangioblastomas and 1 with cerebellar hemangioblastomas. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.404del) sequence variation in gene VHL/NCBI:7428 2699 check_entity AN5952-1 VHL L135fs (c.404del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1782 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.404del) sequence variation in gene VHL/NCBI:7428 2699 check_entity AN5953-1 VHL L140fs (c.417_418delTC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. ACMG codes as follows. This mutation causes a premature stop codon at amino acid 142 and was found in a VHL type 1 patient and a VHL type 2B patient (patient no. V73, V80). A frameshift mutation in a gene where loss-of-function is a known mechanism of disease is strong evidence for pathogenicity (PVS1). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.417_418delTC) sequence variation in gene VHL/NCBI:7428 2700 check_entity AN5953-1 VHL L140fs (c.417_418delTC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1836 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.417_418delTC) sequence variation in gene VHL/NCBI:7428 2700 check_entity AN5954-1 VHL L153P (c.458T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21463266 In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This missense mutation was found in a 36 yr old VHL patient with multiple renal cysts as well as central nervous system and retinal hemangioblastoma (index case 191). ACMG codes as follows: Supporting evidence of pathogenicity because this is a missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: hemangioblastoma, retinal hemangioblastoma, multiple renal cysts assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L153P (c.458T>C) sequence variation in gene VHL/NCBI:7428 2701 check_entity AN5954-1 VHL L153P (c.458T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26763786 A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. This mutation was present in 1 individual of the 122 total number of variants captured in this population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L153P (c.458T>C) sequence variation in gene VHL/NCBI:7428 2701 check_entity AN5954-1 VHL L153P (c.458T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1799 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L153P (c.458T>C) sequence variation in gene VHL/NCBI:7428 2701 check_entity AN5955-1 VHL L153fs (c.457delC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma (VHL type 1) and 2 of 12 families with pheochromocytoma (VHL type 2). This mutation causes stop codon at amino acid 158 and was found in 2 unrelated VHL patients (kindred no. 41, 99). One patient did not have pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.457delC) sequence variation in gene VHL/NCBI:7428 2702 check_entity AN5955-1 VHL L153fs (c.457delC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This frameshift mutation causes an early stop codon at amino acid 158 and was found in 2 VHL families with 5 patients altogether. Three had retinal angiomas, 5 had cerebellar hemangioblastomas, and 2 had renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.457delC) sequence variation in gene VHL/NCBI:7428 2702 check_entity AN5955-1 VHL L153fs (c.457delC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1678 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.457delC) sequence variation in gene VHL/NCBI:7428 2702 check_entity AN5956-1 VHL L158P (c.473T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17661816 Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This mutation was found in 2 VHL family members with retinal hemangioblastomas (family no.13). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L158P (c.473T>C) sequence variation in gene VHL/NCBI:7428 2703 check_entity AN5956-1 VHL L158P (c.473T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in two VHL type 1 family members (patient no. V252). One unaffected individual family member did not have the L158P mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L158P (c.473T>C) sequence variation in gene VHL/NCBI:7428 2703 check_entity AN5956-1 VHL L158P (c.473T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs in the VHL registries of the participating centers in Europe were identified and included in the International Endolymphatic Sac Tumor Registry. The statistics of this registry is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. Only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L158P (c.473T>C) sequence variation in gene VHL/NCBI:7428 2703 check_entity AN5956-1 VHL L158P (c.473T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12202531 A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, the missense mutation (c.473T>C (p.Leu158Pro)) was found in a single patient with a VHL retinal hemangioma manifestation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L158P (c.473T>C) sequence variation in gene VHL/NCBI:7428 2703 check_entity AN5956-1 VHL L158P (c.473T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1614 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L158P (c.473T>C) sequence variation in gene VHL/NCBI:7428 2703 check_entity AN5957-1 VHL L158V (c.472C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Missense mutations were found to be more frequent among families affected by pheochromocytoma (VHL type 2) than in those which pheochromocytoma had not occurred (VHL type 1). This mutation was found in VHL type 1 patient (kindred no. 91). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L158V (c.472C>G) sequence variation in gene VHL/NCBI:7428 2704 check_entity AN5957-1 VHL L158V (c.472C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). This mutation was found in a VHL type 1 patient with retinal hemangioblastomas and cerebellar hemangioblastomas. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2).Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L158V (c.472C>G) sequence variation in gene VHL/NCBI:7428 2704 check_entity AN5957-1 VHL L158V (c.472C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L158V (c.472C>G) sequence variation in gene VHL/NCBI:7428 2704 check_entity AN5957-1 VHL L158V (c.472C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1679 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L158V (c.472C>G) sequence variation in gene VHL/NCBI:7428 2704 check_entity AN5958-1 VHL L158fs (c.471dupT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8956040 Germline mutation analysis of 469 VHL families reveled 300 mutations. The most common germline mutations were identified between codons 75-82, between codons 157-189 (Elongin binding domain) and at the splice site between exons 2 and 3. The association between mutations in codon 167 and pheochromocytoma was detected in all nationalities tested. This mutation was found in a VHL family (family ID 6BMS). No phenotype described. This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.471dupT) sequence variation in gene VHL/NCBI:7428 2705 check_entity AN5958-1 VHL L158fs (c.471dupT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1659 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.471dupT) sequence variation in gene VHL/NCBI:7428 2705 check_entity AN5959-1 VHL L163H (c.488T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L163H (c.488T>A) sequence variation in gene VHL/NCBI:7428 2706 check_entity AN5959-1 VHL L163H (c.488T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1909 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L163H (c.488T>A) sequence variation in gene VHL/NCBI:7428 2706 check_entity AN5960-1 VHL L169P (c.506T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting residue on the surface of pVHL, was found in a VHL type 1 family with retinal hemangioblastomas and renal cell carcinoma. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L169P (c.506T>C) sequence variation in gene VHL/NCBI:7428 2707 check_entity AN5960-1 VHL L169P (c.506T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21463266 In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This missense mutation was found in a 21 yr old VHL patient with retinal hemangioblastomas (index case 344). ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L169P (c.506T>C) sequence variation in gene VHL/NCBI:7428 2707 check_entity AN5960-1 VHL L169P (c.506T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26763786 A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. The c.506 T>C mutation was present in 1 individual of the 122 total number of variants captured in this population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L169P (c.506T>C) sequence variation in gene VHL/NCBI:7428 2707 check_entity AN5960-1 VHL L169P (c.506T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1763 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L169P (c.506T>C) sequence variation in gene VHL/NCBI:7428 2707 check_entity AN5961-1 VHL L178P (c.532C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. Statistics of the VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L178P (c.532C>T) sequence variation in gene VHL/NCBI:7428 2708 check_entity AN5961-1 VHL L178P (c.532C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2332 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L178P (c.532C>T) sequence variation in gene VHL/NCBI:7428 2708 check_entity AN5962-1 VHL L178P (c.533T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in 2 family members with VHL disease type 2A, who both had retinal hemangioblastomas and cerebellar hemangioblastomas (family ID 3786). One of 2 individuals carried pheochromocytomas as well. Mutation also found in 8 individuals with VHL type 1 phenotype (family IDs 3314, 4419, 4403, 3708). Three of 8 individuals were identified with retinal hemangioblastomas, 5 with cerebellar hemangioblastomas, and 2 with renal cell carcinoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L178P (c.533T>C) sequence variation in gene VHL/NCBI:7428 2709 check_entity AN5962-1 VHL L178P (c.533T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Missense mutations were found to be more frequent among families affected by pheochromocytoma (VHL type 2) than in those which pheochromocytoma had not occurred (VHL type 1). This mutation was found in a VHL type 1 patient (kindred no. 44). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L178P (c.533T>C) sequence variation in gene VHL/NCBI:7428 2709 check_entity AN5962-1 VHL L178P (c.533T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting residue on the surface of pVHL, was found in a VHL type 1 family of 3. All family members had retinal hemangioblastomas and cerebellar hemangioblastomas. Two had renal cell carcinoma. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma, Renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L178P (c.533T>C) sequence variation in gene VHL/NCBI:7428 2709 check_entity AN5962-1 VHL L178P (c.533T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21463266 In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This missense mutation was found in a 14 yr old VHL patient with retinal hemangioblastomas, multiple pancreatic cysts, pheochromocytoma, and multiple renal cysts (index case 160). This patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L178P (c.533T>C) sequence variation in gene VHL/NCBI:7428 2709 check_entity AN5962-1 VHL L178P (c.533T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L178P (c.533T>C) sequence variation in gene VHL/NCBI:7428 2709 check_entity AN5962-1 VHL L178P (c.533T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L178P (c.533T>C) sequence variation in gene VHL/NCBI:7428 2709 check_entity AN5962-1 VHL L178P (c.533T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8634692 Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregared with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS Hb, RCC, and Pheo was available. Case 34 had an c.533T>C mutation. 1 member was affected with RCC, CNS Hb, and retinal hemangioma (ACMG PP4). Other demographics of the members were not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L178P (c.533T>C) sequence variation in gene VHL/NCBI:7428 2709 check_entity AN5962-1 VHL L178P (c.533T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1624 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L178P (c.533T>C) sequence variation in gene VHL/NCBI:7428 2709 check_entity AN5963-1 VHL L178Q (c.533T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found in 2 German, VHL type 2 family members with retinal angiomas, hemangioblastomas of the central nervous system, and pheochromocytomas (family VHL 29). Each patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L178Q (c.533T>A) sequence variation in gene VHL/NCBI:7428 2710 check_entity AN5963-1 VHL L178Q (c.533T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11850829 36 VHL-related pheochromocytomas (from 21 patients) and 10 VHL-related CNS hemangioblastomas (from 6 patients) were studied using comparative genomic hybridization (CGH) to detect genetic imbalances. The study identified selective loss of chromosome 11 in pheochromocytomas associated with VHL. Patient XVII and XVIII in VHL-associated pheochromocytoma were found with a germline missense mutation (c.533T>A) in the VHL gene. ACMG evidence codes: 'PP4' because the patients' phenotypes are highly specific for a disease with single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L178Q (c.533T>A) sequence variation in gene VHL/NCBI:7428 2710 check_entity AN5963-1 VHL L178Q (c.533T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1873 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L178Q (c.533T>A) sequence variation in gene VHL/NCBI:7428 2710 check_entity AN5964-1 VHL L178R (c.533T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting residue on the surface of pVHL protein core, was found in a VHL type 1 patient with retinal hemanioblastomas and cerebellar hemangioblastomas. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: Cerebellar hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L178R (c.533T>G) sequence variation in gene VHL/NCBI:7428 2711 check_entity AN5964-1 VHL L178R (c.533T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:22357542 Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This missense mutation was found in a VHL family of 6 individuals (proband no. 7). A 62-year-old female carrying the mutation and a male with an unknown mutation had hemangioblastomas of the central nervous system (CNS). A 58-year-old male family member had retinal angiomas and renal cell carcinoma. The 60 year-old proband had CNS hemangioblastomas, retinal angiomas, renal cell carcinoma, and pancreatic cysts. Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L178R (c.533T>G) sequence variation in gene VHL/NCBI:7428 2711 check_entity AN5964-1 VHL L178R (c.533T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1764 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L178R (c.533T>G) sequence variation in gene VHL/NCBI:7428 2711 check_entity AN5965-1 VHL L184P (c.551T>C) VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 diagnostic 34502-5 PubMed:11505222 195 patients with sporadic clear cell renal cell carcinoma (sporadic CCRCC) were investigated for variants in the VHL gene, in order to determine the possible relationship between VHL mutations in CCRCC patients and polymorphisms in genes encoding enzymes involved in carcinogen metabolism. For each patient, fragments of tumor and non-tumoral kidney tissue were sampled, and DNA was extracted for analysis. PCR, SSCP (single strand conformation polymorphism,) and direct sequencing were used to investigate VHL variants. Tumor number 347 (a cytological grade 1 stage I tumor) was taken from a 60 year old female, and found to have the c.551T>C (p.L184P) somatic mutation in exon 3 of the VHL gene. No other phenotypic information was available for any of the patients included in this study. Relevant ACMG evidence codes: none. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L184P (c.551T>C) sequence variation in gene VHL/NCBI:7428 2712 check_entity AN5965-1 VHL L184P (c.551T>C) VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 diagnostic 34502-5 CIViC:1652 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L184P (c.551T>C) sequence variation in gene VHL/NCBI:7428 2712 check_entity AN5965-2 VHL L184P (c.551T>C) VHL NCBI:7428 gene renal cell carcinoma DOID:4450 diagnostic 34502-5 PubMed:7591282 In a study of 31 kidney tumors from France, 14 somatic VHL mutations were found. Most tumors were found to have heterozygous pattern of mutation likely due to contamination of renal cancer tissues with non-tumor cells. Genomic DNA was extracted from tumors, lymphocytes and cell lines using standard phenol/chloroform extraction or salt extraction protocols. Three sets of primers were designed to amplify the entire exons 2 and 3 and the last one third 3'-region of exon 1, the genotyping method used was PCR-SSCP (polymerase chain reaction-single-strand conformation polymorphism). A metastatic clear cell renal cell carcinoma sample (sample 3087) was obtained from a 68 year old male who was known to smoke one pack of cigarettes per day and had intense alcohol drinking habits. In this patient's tumor (sample 3087), a c.551T>C variant (noted in the paper as nucleotide 764) was identified as a somatic mutation, found only in the tumor. The second mutation, a C>G transversion, c.183C>G (p.P61=) (noted in the paper at nucleotide 396) was present in the non-tumor DNA, a germline synonymous mutation. The patient had no metastasis after nephrectomy and patients survival was >4 months. ACMG codes: none. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L184P (c.551T>C) sequence variation in gene VHL/NCBI:7428 2713 check_entity AN5965-2 VHL L184P (c.551T>C) VHL NCBI:7428 gene renal cell carcinoma DOID:4450 diagnostic 34502-5 CIViC:1652 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L184P (c.551T>C) sequence variation in gene VHL/NCBI:7428 2713 check_entity AN5965-3 VHL L184P (c.551T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL affected families, germline mutations in the VHL gene were identified in 85 of the families. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals, however it seems unaffected family members were not tested genetically for the mutations. Mutations in the VHL gene were detected by SSCP and DNA sequencing. Haplotypes were determined with four microsatellite polymorphic probes. The missense mutation L184P (c.551T>C) (In the paper noted as nucleotide position 764 and codon position 255 due to old reference transcript), was found in 2 individuals in family 3708. Both individuals were identified with renal cell carcinoma and one also presented with a CNS hemangioblastoma. Additional information regarding the family information, including a pedigree, were not provided. ACMG evidence codes: 'flag for PP4' since the patients phenotype and family history is consistent with VHL, 'flag for PP1' because there is co-segregation of variant with the phenotype in two members of the family. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L184P (c.551T>C) sequence variation in gene VHL/NCBI:7428 2714 check_entity AN5965-3 VHL L184P (c.551T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 93 families that fulfilled the clinical criteria of VHL disease were assessed for germline mutations in the VHL gene, and mutations were found in all affected family members. The c.551T>C (p.L184P) mutation was found in a family (Lineage 14) in which members were clinically diagnosed with VHL presenting without pheochromocytoma (VHL type 1), however, no further phenotypic information about specific patients was provided. This mutation was recorded as c.764T>C in the paper, due to the use of an older VHL reference transcript (AF010238.1). Genomic DNA was extracted from whole blood for analysis. Polymorphisms in the VHL gene were detected by southern blotting, and were further investigated by PCR and Sanger sequencing. Partial and total deletions of the VHL gene were investigated by southern blot. Relevant ACMG codes include: PP4, because the patient’s phenotype is highly specific for a disease with a single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L184P (c.551T>C) sequence variation in gene VHL/NCBI:7428 2714 check_entity AN5965-3 VHL L184P (c.551T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:14722919 Thirty-five unrelated patients suspected of having von Hippel-Lindau disease had genomic DNA from peripheral blood leukocytes analyzed using sequence analysis of the coding region for VHL / Southern blot analyses. 32 VHL gene variants were found in 35 patients. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered, although this only reached significance when combining data from other studies (p=0.101 for present study; p=0.0086 for present study + other study data). This missense variant was found in a patient with spinal and cerebellar hemangioblastomas, retinal hemangioblastomas, pancreatic cysts, renal cysts, and cysts of the broad ligament (patient no. F43). The patient was 27 years old. ACMG PP4 as patient's phenotypes are highly specific for VHL disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L184P (c.551T>C) sequence variation in gene VHL/NCBI:7428 2714 check_entity AN5965-3 VHL L184P (c.551T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:18474773 Of 14 patients with retinal vascular proliferation and known family history of VHL disease, 12 patients were enrolled in an approved study protocol at the National Cancer Institute. 11 of these patients underwent genetic testing and were found to have mutations in the VHL gene. Patient 1 presented with retinal capillary hemangioblastoma (RCH) in her left eye at age the age of 13, which was treated with radiation. At age 62 years, this eye had good visual acuity (20/20) without any RCHs. As of her last visit, patient 1 also presented with abnormalities in the CNS, pancreas and kidney. She was found to have the L184P (c.551T>C) mutation. Her last known age was 69 years old. ACMG evidence codes: 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L184P (c.551T>C) sequence variation in gene VHL/NCBI:7428 2714 check_entity AN5965-3 VHL L184P (c.551T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1652 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L184P (c.551T>C) sequence variation in gene VHL/NCBI:7428 2714 check_entity AN5966-1 VHL L184R (c.551T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21463266 In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This missense mutation was found in a 44 yr old VHL patient with clear cell renal cell carcinoma as well as central nervous system and retinal hemangioblastomas (index case 363). ACMG codes as follows: Supporting evidence of pathogenicity because this is a missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L184R (c.551T>G) sequence variation in gene VHL/NCBI:7428 2715 check_entity AN5966-1 VHL L184R (c.551T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26763786 A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. The c.551 T>G mutation was present in 1 individual of the 122 total number of variants captured in this population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L184R (c.551T>G) sequence variation in gene VHL/NCBI:7428 2715 check_entity AN5966-1 VHL L184R (c.551T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1684 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L184R (c.551T>G) sequence variation in gene VHL/NCBI:7428 2715 check_entity AN5967-1 VHL L188P (c.563T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in a VHL type 2 family (lineage 73). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L188P (c.563T>C) sequence variation in gene VHL/NCBI:7428 2716 check_entity AN5967-1 VHL L188P (c.563T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 1 patient (patient no. V269). Five unaffected family members were negative for the L188P variant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L188P (c.563T>C) sequence variation in gene VHL/NCBI:7428 2716 check_entity AN5967-1 VHL L188P (c.563T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1728 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L188P (c.563T>C) sequence variation in gene VHL/NCBI:7428 2716 check_entity AN5968-1 VHL L188Q (c.563T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense variant was found in 2 family members with VHL type 1 phenotype (family ID 3513). Both individuals were identified with cerebellar hemangioblastomas and renal cell carcinoma. One also had angiomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L188Q (c.563T>A) sequence variation in gene VHL/NCBI:7428 2717 check_entity AN5968-1 VHL L188Q (c.563T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1737 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L188Q (c.563T>A) sequence variation in gene VHL/NCBI:7428 2717 check_entity AN5969-1 VHL L188R (c.563T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21463266 In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This novel, missense mutation was found in a 48 yr old VHL patient with multiple renal cysts and hemangioblastomas of the central nervous system (index case 109). This variant potentially alters the alpha domain core of the VHL protein. ACMG codes as follows: Supporting evidence of pathogenicity because this is a missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L188R (c.563T>G) sequence variation in gene VHL/NCBI:7428 2718 check_entity AN5969-1 VHL L188R (c.563T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26763786 A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. The c.563 T>G mutation was present in 3 individuals of the 122 total number of variants captured in this population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L188R (c.563T>G) sequence variation in gene VHL/NCBI:7428 2718 check_entity AN5969-1 VHL L188R (c.563T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1800 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L188R (c.563T>G) sequence variation in gene VHL/NCBI:7428 2718 check_entity AN5970-1 VHL L188V (c.562C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12000816 Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L188V (c.562C>G) sequence variation in gene VHL/NCBI:7428 2719 check_entity AN5970-1 VHL L188V (c.562C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11850829 36 VHL-related pheochromocytomas (from 21 patients) and 10 VHL-related CNS hemangioblastomas (from 6 patients) were studied using comparative genomic hybridization (CGH) to detect genetic imbalances. The study identified selective loss of chromosome 11 in pheochromocytomas associated with VHL. Patient XVI, XX and XXI in VHL-associated pheochromocytoma were found with germline missense mutation (c.562C>G) in the VHL gene. ACMG evidence codes: 'PP4' because the patients' phenotypes are highly specific for a disease with single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L188V (c.562C>G) sequence variation in gene VHL/NCBI:7428 2719 check_entity AN5970-1 VHL L188V (c.562C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1712 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L188V (c.562C>G) sequence variation in gene VHL/NCBI:7428 2719 check_entity AN5971-1 VHL L188fs (c.562delC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in 2 family members with renal cell carcinomas. One relative also had retinal angiomas, while the other had hemangioblastomas of the central nervous system. HPO terms: retinal hemangioblastoma, hemangioblastoma, renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.562delC) sequence variation in gene VHL/NCBI:7428 2720 check_entity AN5971-1 VHL L188fs (c.562delC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2015 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.562delC) sequence variation in gene VHL/NCBI:7428 2720 check_entity AN5972-1 VHL L198Q (c.593T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12000816 Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L198Q (c.593T>A) sequence variation in gene VHL/NCBI:7428 2721 check_entity AN5972-1 VHL L198Q (c.593T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 2 patients were found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L198Q (c.593T>A) sequence variation in gene VHL/NCBI:7428 2721 check_entity AN5972-1 VHL L198Q (c.593T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1886 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L198Q (c.593T>A) sequence variation in gene VHL/NCBI:7428 2721 check_entity AN5973-1 VHL L85P (c.254T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11409863 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This missense mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 66). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L85P (c.254T>C) sequence variation in gene VHL/NCBI:7428 2722 check_entity AN5973-1 VHL L85P (c.254T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1896 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L85P (c.254T>C) sequence variation in gene VHL/NCBI:7428 2722 check_entity AN5974-1 VHL L89P (c.266T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Missense mutations were found to be more frequent among families affected by pheochromocytoma (VHL type 2) than in those which pheochromocytoma had not occurred (VHL type 1). This mutation was found in VHL type 1 patient (kindred no. 59). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L89P (c.266T>C) sequence variation in gene VHL/NCBI:7428 2723 check_entity AN5974-1 VHL L89P (c.266T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting residue within the pVHL protein core, was found in a VHL type 1 patient with retinal hemangioblastomas, cerebellar hemangioblastomas, and renal cell carcinoma. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L89P (c.266T>C) sequence variation in gene VHL/NCBI:7428 2723 check_entity AN5974-1 VHL L89P (c.266T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found in a German, VHL type 1 family of 11. Three patients had retinal angiomas, 7 hand hemangioblastomas of the central nervous system, 7 had renal cell carcinoma, and 6 had pancreatic cysts (family VHL 3). This study contains supporting evidence of pathogenicity due to cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L89P (c.266T>C) sequence variation in gene VHL/NCBI:7428 2723 check_entity AN5974-1 VHL L89P (c.266T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L89P (c.266T>C) sequence variation in gene VHL/NCBI:7428 2723 check_entity AN5974-1 VHL L89P (c.266T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L89P (c.266T>C) sequence variation in gene VHL/NCBI:7428 2723 check_entity AN5974-1 VHL L89P (c.266T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1669 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::L89P (c.266T>C) sequence variation in gene VHL/NCBI:7428 2723 check_entity AN5975-1 VHL Loss VHL NCBI:7428 gene renal carcinoma DOID:4451 risk 34502-5 PubMed:16341243 Preclinical studies linking the efficacy of mTOR inhibitor CCI-779 to VHL loss in vitro and in mouse models of kidney cancer. VHL-deficient tumors were more sensitive to mTOR inhibition than VHL-proficient tumors. Growth arrest caused by CCI-779 correlated with a block in translation of HIF1A mRNA. Expression of a VHL-resistant HIF1A cDNA lacking the 5' untranslated region rescued tumor growth. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition VHL Loss [biomarker_term_in_review] 2724 not_mapped AN5975-1 VHL Loss VHL NCBI:7428 gene renal carcinoma DOID:4451 risk 34502-5 CIViC:432 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition VHL Loss [biomarker_term_in_review] 2724 not_mapped AN5976-1 VHL Loss-of-function VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 prognostic 34502-5 PubMed:11793370 In patients with renal clear cell carcinoma, patients with loss of function VHL mutations had shorter tumor-specific survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition VHL Loss-of-function [biomarker_term_in_review] 2725 not_mapped AN5976-1 VHL Loss-of-function VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 prognostic 34502-5 CIViC:159 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition VHL Loss-of-function [biomarker_term_in_review] 2725 not_mapped AN5977-1 VHL M1? (c.1-1_20del21) VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 risk 34502-5 PubMed:15932632 This variant was detected in a single case with clear-cell renal cell carcinoma. The tumor had two somatic variants (c.1-1_20del21 and c.291_310del20). Either of these variants is predicted to be quite deleterious. While they were observed in a somatic context in an RCC, we can infer that they could be predisposing for VHL in a germline context. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M1? (c.1-1_20del21) sequence variation in gene VHL/NCBI:7428 2726 check_entity AN5977-1 VHL M1? (c.1-1_20del21) VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 risk 34502-5 CIViC:821 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M1? (c.1-1_20del21) sequence variation in gene VHL/NCBI:7428 2726 check_entity AN5978-1 VHL M1? (c.3G>A) VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 risk 34502-5 PubMed:11505222 Mutation detected in one case. Case shows clear-cell renal cell carcinoma. This case also harbored a second somatic variant in VHL: 209-210delAG (Stop130). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M1? (c.3G>A) sequence variation in gene VHL/NCBI:7428 2727 check_entity AN5978-1 VHL M1? (c.3G>A) VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 risk 34502-5 CIViC:822 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::M1? (c.3G>A) sequence variation in gene VHL/NCBI:7428 2727 check_entity AN5979-1 VHL M1FS (c.1_17del17) VHL NCBI:7428 gene chromophobe renal cell carcinoma DOID:4471 risk 34502-5 PubMed:15932632 This somatic mutation was detected in two samples from a single patient with chromophobe renal cell carcinoma (a 74 year old male). The tumor also harbored a silent T157= (c.471T>A) somatic variant. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.1_17del17) sequence variation in gene VHL/NCBI:7428 2728 check_entity AN5979-1 VHL M1FS (c.1_17del17) VHL NCBI:7428 gene chromophobe renal cell carcinoma DOID:4471 risk 34502-5 CIViC:820 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.1_17del17) sequence variation in gene VHL/NCBI:7428 2728 check_entity AN5980-1 VHL M54IFS (c.162_166delGGAGG) VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 risk 34502-5 PubMed:8187067 A study of sporadic renal cell carcinoma identified this frameshift confirmed somatic variant along with LOH of the VHL gene in a case with clear cell renal carcinoma (case #152 in the study). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.162_166delGGAGG) sequence variation in gene VHL/NCBI:7428 2729 check_entity AN5980-1 VHL M54IFS (c.162_166delGGAGG) VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 risk 34502-5 CIViC:807 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.162_166delGGAGG) sequence variation in gene VHL/NCBI:7428 2729 check_entity AN5981-1 VHL M54fs (c.161dup) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). This mutation was found in 2 VHL type 1 family members with cerebellar hemangioblastomas. ACMG codes as follows: Protein length changes as a result of insertion in a nonrepeat region and stop-loss variant (PM4). Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). Relevant HPO terms: Cerebellar hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.161dup) sequence variation in gene VHL/NCBI:7428 2730 check_entity AN5981-1 VHL M54fs (c.161dup) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This mutation causes a premature stop codon at amino acid 131 and was found in a VHL type 2A patient (patient no. V69). This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.161dup) sequence variation in gene VHL/NCBI:7428 2730 check_entity AN5981-1 VHL M54fs (c.161dup) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1765 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.161dup) sequence variation in gene VHL/NCBI:7428 2730 check_entity AN5982-1 VHL Mutation VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 prognostic 34502-5 PubMed:18464292 In patients with renal clear cell carcinoma, patients with VHL mutations had longer cancer-specific survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene VHL/NCBI:7428 2731 check_entity AN5982-1 VHL Mutation VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 prognostic 34502-5 PubMed:23620406 In renal clear cell carcinoma, patients with VHL mutations did not have a significant impact on cancer specific survival. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene VHL/NCBI:7428 2731 check_entity AN5982-1 VHL Mutation VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 prognostic 34502-5 CIViC:160 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene VHL/NCBI:7428 2731 check_entity AN5982-2 VHL Mutation VHL NCBI:7428 gene renal cell carcinoma DOID:4450 risk 34502-5 PubMed:23881929 VHL mutations were evaluated in 78 tumors samples of patients with metastatic RCC treated with pazopanib as part of a clinical trial. Overall, 87% had one VHL mutation, 12% showed promoter hypermethylation, and 6 patients had both. 8 patients exhibited neither mutation nor methylation of VHL. There was no correlation between VHL status and overall response rate or progression free survival under pazopanib therapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene VHL/NCBI:7428 2732 check_entity AN5982-2 VHL Mutation VHL NCBI:7428 gene renal cell carcinoma DOID:4450 risk 34502-5 PubMed:28103578 A meta-analysis to evaluate the association between the VHL alteration and clinical outcomes in patients with RCC. There were six studies including a total of 633 patients: 244 patients who received anti-VEGF therapy in the predictive value analysis and 419 in the prognostic value analysis. 410 (61.8%) had VHL alteration. The meta-analysis showed no association between the VHL gene alteration and ORR or PFS, as well as no correlation to OS. VEGFR inhibition included: Sunitinib, Sorafenib, Axitinib, Pazopanib, Bevacizumab. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene VHL/NCBI:7428 2732 check_entity AN5982-2 VHL Mutation VHL NCBI:7428 gene renal cell carcinoma DOID:4450 risk 34502-5 PubMed:26951309 A randomized, open-label phase 2 study, encompassing 85 patients, to compare the efficacy of dual PIK3/mTOR Inhibitor Apitolisib and mTORC1 inhibitor Everolimus in patients who progressed on or after antiangiogenetic therapy (VEGFR). There was a trend towards association between deleterious VHL alterations and progression-free-survival in the Everolimus arm only. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene VHL/NCBI:7428 2732 check_entity AN5982-2 VHL Mutation VHL NCBI:7428 gene renal cell carcinoma DOID:4450 risk 34502-5 CIViC:160 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::mutation sequence variation in gene VHL/NCBI:7428 2732 check_entity AN5983-1 VHL N131K (c.393C>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 2A patient (patient no. V233). A single unaffected family member available for screening did not have the N131K mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N131K (c.393C>A) sequence variation in gene VHL/NCBI:7428 2733 check_entity AN5983-1 VHL N131K (c.393C>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N131K (c.393C>A) sequence variation in gene VHL/NCBI:7428 2733 check_entity AN5983-1 VHL N131K (c.393C>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1829 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N131K (c.393C>A) sequence variation in gene VHL/NCBI:7428 2733 check_entity AN5984-1 VHL N131S (c.392A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:10761708 A previous study of 26 Japanese, VHL families was extended to 41 additional families. Germline mutations were detected in 55 of 77 Japanese families using SSCP, direct sequencing, and Southern Blot analysis of peripheral blood samples. The N131S (c.392A>G) missense mutation was found in 1 VHL type 2 family with both family members having retinal angiomas and pheochromocytomas (family ID 87). 1/2 individuals had hemangioblastomas of the central nervous system and 1/2 had pancreatic cysts or tumor (unspecified). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N131S (c.392A>G) sequence variation in gene VHL/NCBI:7428 2734 check_entity AN5984-1 VHL N131S (c.392A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1877 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N131S (c.392A>G) sequence variation in gene VHL/NCBI:7428 2734 check_entity AN5985-1 VHL N131T (c.392A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in a VHL type 1 family (lineage 86). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N131T (c.392A>C) sequence variation in gene VHL/NCBI:7428 2735 check_entity AN5985-1 VHL N131T (c.392A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from Germany. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N131T (c.392A>C) sequence variation in gene VHL/NCBI:7428 2735 check_entity AN5985-1 VHL N131T (c.392A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2453 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N131T (c.392A>C) sequence variation in gene VHL/NCBI:7428 2735 check_entity AN5986-1 VHL N131fs (c.390_391del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma (VHL type 1) and 2 of 12 families with pheochromocytoma (VHL type 2). This mutation causes stop codon at amino acid 133 and was found in VHL type 1 patient (kindred no. 64). This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.390_391del) sequence variation in gene VHL/NCBI:7428 2736 check_entity AN5986-1 VHL N131fs (c.390_391del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Higher risk of pheochromocytoma was associated with missense mutations that result in substitution of a surface amino acid (p<=0.004) than for patients with missense mutations that disrupt the structural integrity of the VHL gene product (pVHL) or other loss of function mutations (either germline deletions or truncating mutations). Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This frameshift mutation causes an early stop codon at amino acid 133 and was found in a VHL patient with cerebellar hemangioblastomas. This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). Relevant HPO terms: Cerebellar hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.390_391del) sequence variation in gene VHL/NCBI:7428 2736 check_entity AN5986-1 VHL N131fs (c.390_391del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1676 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.390_391del) sequence variation in gene VHL/NCBI:7428 2736 check_entity AN5987-1 VHL N150S (c.449A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25586603 This is a case report on a 9-month-old female with polycythemia. The patient carries a de novo nonsense mutation [Q145* (c.433C>T)] and this paternally inherited, missense mutation. The authors of this paper believed this missense mutation was the cause of the aforementioned clinical manifestations. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N150S (c.449A>G) sequence variation in gene VHL/NCBI:7428 2737 check_entity AN5987-1 VHL N150S (c.449A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2038 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N150S (c.449A>G) sequence variation in gene VHL/NCBI:7428 2737 check_entity AN5988-1 VHL N150fs (c.445_458del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. More specifically, this mutation causes the following protein change: N150SfsX19. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PVS1' because they observe a frameshift variant in a gene where loss of function is a known mechanism of disease. Relevant HPO terms: Neuroendocrine neoplasm. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.445_458del) sequence variation in gene VHL/NCBI:7428 2738 check_entity AN5988-1 VHL N150fs (c.445_458del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1905 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.445_458del) sequence variation in gene VHL/NCBI:7428 2738 check_entity AN5989-1 VHL N150fs (c.447del) VHL NCBI:7428 gene renal carcinoma DOID:4451 risk 34502-5 PubMed:7915601 Tumors from 98 patients with sporadic clear cell renal carcinoma (ccRC) were analyzed for VHL mutations and loss of heterozygosity (LOH). Somatic VHL variants were observed in 56 patients, and VHL LOH was observed in 98% of samples with VHL variants. VHL N150fs (c.447del) was found in a ccRC (sample T683, variant noted as c.659del because of differences in reference transcript). Authors noted that VHL variants were highly specific to ccRC and not found in the 12 other tumor types examined. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.447del) sequence variation in gene VHL/NCBI:7428 2739 check_entity AN5989-1 VHL N150fs (c.447del) VHL NCBI:7428 gene renal carcinoma DOID:4451 risk 34502-5 CIViC:2434 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.447del) sequence variation in gene VHL/NCBI:7428 2739 check_entity AN5990-1 VHL N150fs (c.449del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This mutation causes a stop codon at amino acid 158. Mutation also found in 3 family members with VHL type 1 phenotype (family ID 3575). Two of 3 members carried retinal hemangioblastomas, one carried cerebellar hemangioblastomas and one with renal cell carcinoma. Supporting evidence of pathogenicity because of the introduction of an early stop codon in a gene where loss of function is an established mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.449del) sequence variation in gene VHL/NCBI:7428 2740 check_entity AN5990-1 VHL N150fs (c.449del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1646 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.449del) sequence variation in gene VHL/NCBI:7428 2740 check_entity AN5991-1 VHL N78H (c.232A>C) VHL NCBI:7428 gene renal cell carcinoma DOID:4450 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting a residue within the pVHL protein core, was found in 2 VHL family members. Both had retinal angiomas and cerebellar hemangioblastomas. One had renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N78H (c.232A>C) sequence variation in gene VHL/NCBI:7428 2741 check_entity AN5991-1 VHL N78H (c.232A>C) VHL NCBI:7428 gene renal cell carcinoma DOID:4450 diagnostic 34502-5 CIViC:1630 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N78H (c.232A>C) sequence variation in gene VHL/NCBI:7428 2741 check_entity AN5991-2 VHL N78H (c.232A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was detected in a type 1 VHL patient (family ID 4389) with retinal hemangioblastomas, cerebellar hemangioblastomas, and renal cell carcinoma. Only supporting evidence for pathogenicity because patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N78H (c.232A>C) sequence variation in gene VHL/NCBI:7428 2742 check_entity AN5991-2 VHL N78H (c.232A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Missense mutations were found to be more frequent among families affected by pheochromocytoma (VHL type 2) than in those in which pheochromocytoma had not occurred (VHL type1). This mutation was found in a VHL type 1 patient (kindred no. 34). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N78H (c.232A>C) sequence variation in gene VHL/NCBI:7428 2742 check_entity AN5991-2 VHL N78H (c.232A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8641976 Blood samples from 5 Japanese families revealed 4 germline mutations. This missense mutation was found in a family of five individuals. Only one VHL patient was identified with hemangioblastomas of the cerebellum and spinal cord, retinal angiomas, and renal cysts (family A). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N78H (c.232A>C) sequence variation in gene VHL/NCBI:7428 2742 check_entity AN5991-2 VHL N78H (c.232A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1630 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N78H (c.232A>C) sequence variation in gene VHL/NCBI:7428 2742 check_entity AN5992-1 VHL N78I (c.233A>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12114495 A study of 34 Polish families revealed germline mutations in 30 families. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). This missense mutation was found in a VHLD family of 4 affected patients (family no. 10). All 4 patients had retinal hemangioblastomas, 3 had hemangioblastomas of the central nervous system, and one had renal cell carcinoma. Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). HPO terms: retinal hemangioblastoma, hemangioblastoma, renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N78I (c.233A>T) sequence variation in gene VHL/NCBI:7428 2743 check_entity AN5992-1 VHL N78I (c.233A>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1913 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N78I (c.233A>T) sequence variation in gene VHL/NCBI:7428 2743 check_entity AN5993-1 VHL N78S (c.233A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in 3 family members with VHL type 1 phenotype (family ID 4327). All 3 individuals carried cerebellar hemangioblastomas and one also carried renal cell carcinoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N78S (c.233A>G) sequence variation in gene VHL/NCBI:7428 2744 check_entity AN5993-1 VHL N78S (c.233A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of VHL gene product (pVHL). Missense mutation, affecting an amino acid within pVHL protein core, was found in 6 VHL type 1 families with 12 affected individuals altogether. Nine of 12 patients had retinal angioma, 5 had cerebellar hemangioblastoma, and 2 had renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N78S (c.233A>G) sequence variation in gene VHL/NCBI:7428 2744 check_entity AN5993-1 VHL N78S (c.233A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17661816 Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This missense mutation was detected in a VHL type 1 patient with cerebellar hemangioblastoma, renal cysts and pancreatic cysts (family no. 6). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N78S (c.233A>G) sequence variation in gene VHL/NCBI:7428 2744 check_entity AN5993-1 VHL N78S (c.233A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:19464396 43 Italian patients were molecularly analyzed for Von Hippel-Lindau disease based on clinical suspicion. 2 of the 43 patients were found to have the above mutation. Clinical manifestations associated with this mutation include: CNS hemangioblastomas, pancreatic cysts, and retinal hemangioblastomas. ACMG evidence codes: 'PP2' because they observe a missense variant in gene where missense variants are common mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N78S (c.233A>G) sequence variation in gene VHL/NCBI:7428 2744 check_entity AN5993-1 VHL N78S (c.233A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found in a German, VHL type 1 family of 6. Each patient had hemangioblastomas of the central nervous system and 4 had cystadenomas of the epididymis (family VHL 51). This study contains supporting evidence of pathogenicity due to cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). HPO terms: papillary cystadenomas of the broad ligament. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N78S (c.233A>G) sequence variation in gene VHL/NCBI:7428 2744 check_entity AN5993-1 VHL N78S (c.233A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12114495 A study of 34 Polish families revealed germline mutations in 30 families. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). This missense mutation was found in a VHL patient and 2 VHL family members. The single patient had hemangioblastomas of the central nervous system and retina (family no. 8). One of the family members had retinal hemangioblastomas and the other had renal cell carcinoma (family no. 9). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N78S (c.233A>G) sequence variation in gene VHL/NCBI:7428 2744 check_entity AN5993-1 VHL N78S (c.233A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26984080 A male patient with Type 1 VHL disease presented with vision loss and retinal angiomatosis in the right eye at 19Y, left retinal angiomatosis at 23Y as well as CNS hemangioblastomas, neuroendocrine tumor of the pancreas which metastases to the liver, and renal tumors at 25Y. Patient was found to carry c.233A>G (p.Asn78Ser) mutation in the VHL gene. Patient had a positive family history of VHL clinical manifestations, although the genotype of affected family members was not confirmed. His mother presented with pancreatic and renal cysts at 37Y and retinal angiomatosis at 47Y. Patient's grandmother suffered from loss of vision in her 30s, and renal cancer and brain tumour at 58Y. ACMG: PP2, PP4 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N78S (c.233A>G) sequence variation in gene VHL/NCBI:7428 2744 check_entity AN5993-1 VHL N78S (c.233A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation (p.Asn78Ser), which was found in 2 individuals, one from Germany and the other from Japan. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N78S (c.233A>G) sequence variation in gene VHL/NCBI:7428 2744 check_entity AN5993-1 VHL N78S (c.233A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11850829 36 VHL-related pheochromocytomas (from 21 patients) and 10 VHL-related CNS hemangioblastomas (from 6 patients) were studied using comparative genomic hybridization (CGH) to detect genetic imbalances. Patient II in VHL-Associated hemangioblastoma was found with germline missense mutation (c.233A>G) in the VHL gene. ACMG evidence codes: 'PP4' because the patients' phenotypes are highly specific for a disease with single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N78S (c.233A>G) sequence variation in gene VHL/NCBI:7428 2744 check_entity AN5993-1 VHL N78S (c.233A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8634692 Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb) renal cell carcinoma (RCC), and pheochromocytoma was available. Case 9 had p.Asn78Ser (c.233A>G) mutation. Three members were affected, and all had retinal capillary hemangioma and CNS hemangioblastoma. Other demographics of the members were not described. ACMG PP4 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N78S (c.233A>G) sequence variation in gene VHL/NCBI:7428 2744 check_entity AN5993-1 VHL N78S (c.233A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12202531 A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, the missense mutation (c.233A>G (p.Asn78Ser)) was found in 2 patients total - 1 of which is stated to have retinal HBs and the other is said to not. Other manifestations are possible but not clear. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N78S (c.233A>G) sequence variation in gene VHL/NCBI:7428 2744 check_entity AN5993-1 VHL N78S (c.233A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1631 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N78S (c.233A>G) sequence variation in gene VHL/NCBI:7428 2744 check_entity AN5994-1 VHL N78T (c.233A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in 3 family members with VHL type 1 phenotype (family ID 3101). One of 3 members carried retinal hemangioblastomas and 2 carried cerebellar hemangioblastomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N78T (c.233A>C) sequence variation in gene VHL/NCBI:7428 2745 check_entity AN5994-1 VHL N78T (c.233A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1632 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N78T (c.233A>C) sequence variation in gene VHL/NCBI:7428 2745 check_entity AN5995-1 VHL N7D (c.19A>G) VHL NCBI:7428 gene renal cell carcinoma DOID:4450 risk 34502-5 PubMed:11536052 A somatic mutation (N7D) detected in one case, a 79ya patient with renal cell carcinoma (case '1VT'). The patient had a second in-frame deletion of 5 amino acids (41-45), but the author speculate that it could be an inherited polymorphism. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N7D (c.19A>G) sequence variation in gene VHL/NCBI:7428 2746 check_entity AN5995-1 VHL N7D (c.19A>G) VHL NCBI:7428 gene renal cell carcinoma DOID:4450 risk 34502-5 CIViC:823 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::N7D (c.19A>G) sequence variation in gene VHL/NCBI:7428 2746 check_entity AN5996-1 VHL Null (Large deletion) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8634692 Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregared with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS Hb, RCC, and Pheo was available. Case 20, 23, and 30 were found with complete VHL deletions. Phenotypes found in the patients included RCC, retinal capillary hemangioma and hemangioblastoma (ACMG PP4). Other demographics of the members were not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::null:(large:deletion) sequence variation in gene VHL/NCBI:7428 2747 check_entity AN5996-1 VHL Null (Large deletion) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 6 patients were found to have the large germline deletions in the VHL gene. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP4' because phenotype consistent with VHL disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::null:(large:deletion) sequence variation in gene VHL/NCBI:7428 2747 check_entity AN5996-1 VHL Null (Large deletion) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2058 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::null:(large:deletion) sequence variation in gene VHL/NCBI:7428 2747 check_entity AN5997-1 VHL Null (Partial deletion of Exons 2 & 3) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20846682 26 VHL patients from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 3 patients from 3 families were confirmed to have the above mutation. Additional manifestations aside from pheochromocytoma are possible, but were not discussed. ACMG evidence codes: 'PVS1' because they observe a multiexon deletion variant in a gene where loss of function is a known mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::null:(partial:deletion:of:exons:2:&:3) sequence variation in gene VHL/NCBI:7428 2748 check_entity AN5997-1 VHL Null (Partial deletion of Exons 2 & 3) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1912 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::null:(partial:deletion:of:exons:2:&:3) sequence variation in gene VHL/NCBI:7428 2748 check_entity AN5998-1 VHL P102fs (c.305delC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12624160 Germline mutations were found in 20 Brazilian, VHL probands and their families. This mutation causes a premature stop codon at amino acid 142 and was found in a VHL type 1 patient with hemangioblastomas of the central nervous system (VHL family 6). This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). HPO terms: hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.305delC) sequence variation in gene VHL/NCBI:7428 2749 check_entity AN5998-1 VHL P102fs (c.305delC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1934 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.305delC) sequence variation in gene VHL/NCBI:7428 2749 check_entity AN5999-1 VHL P103FS (c.309_310delTG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal hemangioblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This frameshift mutation causes an early stop codon at amino acid 130 and was found in a VHL type 1 family of 16 patients. Six patients had retinal hemangioblastomas, 10 had cerebellar hemangioblastomas, and 2 had renal cell carcinoma. This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.309_310delTG) sequence variation in gene VHL/NCBI:7428 2750 check_entity AN5999-1 VHL P103FS (c.309_310delTG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1671 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.309_310delTG) sequence variation in gene VHL/NCBI:7428 2750 check_entity AN6000-1 VHL P138R (c.413C>G) VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 risk 34502-5 PubMed:7915601 Tumors from 98 patients with sporadic clear cell renal carcinoma (ccRC) were analyzed for VHL mutations and loss of heterozygosity (LOH). Somatic VHL variants were observed in 56 patients, and VHL LOH was observed in 98% of samples with VHL variants. P138R (c.413C>G) was found in a granular ccRC (sample UOK102, variant location indicated at NT 626 because of differences in reference transcript). Authors noted that VHL variants were highly specific to ccRC and not found in the 12 other tumor types examined. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P138R (c.413C>G) sequence variation in gene VHL/NCBI:7428 2751 check_entity AN6000-1 VHL P138R (c.413C>G) VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 risk 34502-5 CIViC:2313 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P138R (c.413C>G) sequence variation in gene VHL/NCBI:7428 2751 check_entity AN6001-1 VHL P138T (c.412C>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21463266 In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This novel, missense mutation was found in a 21 yr old VHL patient with retinal hemangioblastomas and pheochromocytoma (index case 115). This variant potentially alters the beta domain core of the VHL protein. ACMG codes as follows: Supporting evidence of pathogenicity because this is a missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P138T (c.412C>A) sequence variation in gene VHL/NCBI:7428 2752 check_entity AN6001-1 VHL P138T (c.412C>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26763786 A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. This mutation was present in 5 individuals of the 122 total number of variants captured in this population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P138T (c.412C>A) sequence variation in gene VHL/NCBI:7428 2752 check_entity AN6001-1 VHL P138T (c.412C>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1804 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P138T (c.412C>A) sequence variation in gene VHL/NCBI:7428 2752 check_entity AN6002-1 VHL P146fs (c.437del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12624160 Germline mutations were found in 20 Brazilian, VHL probands and their families. This mutation causes a premature stop codon at amino acid 158 and was found in a VHL type 1 patient with hemangioblastomas of the central nervous system, retinal angiomas, and renal carcinoma (VHL family 13). This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). HPO terms: hemangioblastoma, retinal hemangioblastoma, renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.437del) sequence variation in gene VHL/NCBI:7428 2753 check_entity AN6002-1 VHL P146fs (c.437del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1931 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.437del) sequence variation in gene VHL/NCBI:7428 2753 check_entity AN6003-1 VHL P154= (c.462A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This silent mutation was found in two VHL type 2A family members (patient no. V78). Two unaffected family members did not harbor this synonymous mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P154= (c.462A>C) sequence variation in gene VHL/NCBI:7428 2754 check_entity AN6003-1 VHL P154= (c.462A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:24132471 Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. One patient was found with this missense varaint in the VHL gene. The patient was 71Y at the last follow-up and presented with: cerebellar hemangioblastoma, pheochromocytoma, and renal cysts. Family history was not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P154= (c.462A>C) sequence variation in gene VHL/NCBI:7428 2754 check_entity AN6003-1 VHL P154= (c.462A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26763786 A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. This mutation was present in 2 individuals of the 122 total number of variants captured in this population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P154= (c.462A>C) sequence variation in gene VHL/NCBI:7428 2754 check_entity AN6003-1 VHL P154= (c.462A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1838 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P154= (c.462A>C) sequence variation in gene VHL/NCBI:7428 2754 check_entity AN6004-1 VHL P154L (c.461C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Missense mutations were found to be more frequent among families affected by pheochromocytoma (VHL type 2) than in those which pheochromocytoma had not occurred (VHL type 1). This mutation was found in VHL type 2 patient (kindred no. 49). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P154L (c.461C>T) sequence variation in gene VHL/NCBI:7428 2755 check_entity AN6004-1 VHL P154L (c.461C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Higher risk of pheochromocytoma was associated with missense mutations that result in substitution of a surface amino acid (p<=0.004) than for patients with missense mutations that disrupt the structural integrity of the VHL gene product (pVHL) or other loss of function mutations (either germline deletions or truncating mutations). This missense mutation is within the protein core and was found in a VHL family with 6 patients. One patient had retinal hemangioblastomas, 2 had cerebellar hemangioblastomas, 3 had renal cell carcinoma, 2 had pheochromocytoma. Only supporting evidence of pathogenicity because of cosegregation of disease with multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P154L (c.461C>T) sequence variation in gene VHL/NCBI:7428 2755 check_entity AN6004-1 VHL P154L (c.461C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P154L (c.461C>T) sequence variation in gene VHL/NCBI:7428 2755 check_entity AN6004-1 VHL P154L (c.461C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 2 individuals from Germany. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P154L (c.461C>T) sequence variation in gene VHL/NCBI:7428 2755 check_entity AN6004-1 VHL P154L (c.461C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1658 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P154L (c.461C>T) sequence variation in gene VHL/NCBI:7428 2755 check_entity AN6005-1 VHL P154fs (c.462delA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. Mutation causes a stop codon at amino acid 158. This mutation was also found in 4 family members with VHL type 1 phenotype (family ID 3616). Two of 4 members carried retinal hemangioblastomas and 2 with renal cell carcinoma. Supporting evidence of pathogenicity because of the introduction of an early stop codon in a gene where loss of function is an established mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.462delA) sequence variation in gene VHL/NCBI:7428 2756 check_entity AN6005-1 VHL P154fs (c.462delA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1647 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.462delA) sequence variation in gene VHL/NCBI:7428 2756 check_entity AN6006-1 VHL P25L (c.74C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12114495 Mutation was detected in three unaffected members of Polish VHL families. Described as being in the non-conserved portion of the VHL coding region where mutations are not typically seen according to these authors. Possibly benign but appears to have fairly low global mutation allele frequency. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P25L (c.74C>T) sequence variation in gene VHL/NCBI:7428 2757 check_entity AN6006-1 VHL P25L (c.74C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:824 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P25L (c.74C>T) sequence variation in gene VHL/NCBI:7428 2757 check_entity AN6007-1 VHL P40fs (c.118ins) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma (VHL type 1) and 2 of 12 families with pheochromocytoma (VHL type 2). This mutation was found in a VHL type 1 patient (kindred no. 46). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.118ins) sequence variation in gene VHL/NCBI:7428 2758 check_entity AN6007-1 VHL P40fs (c.118ins) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1966 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.118ins) sequence variation in gene VHL/NCBI:7428 2758 check_entity AN6008-1 VHL P59fs (c.173_174insC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:19270817 Mutation was detected using direct sequencing/MLPA in and 18Y old female patient referred to Samsung Medical Center, Seoul, Korea. Patient shows CNS hemangioblastoma and was positive for 'other' phenotypes which included either pancreatic neuroendocrine tumors, renal cysts, pancreatic cysts, or central nervous system tumors. ACMG evidence codes: 'PVS1' because the variant is an early frameshift and 'PP4' because the patients phenotypes and family history are highly specific for a disease with single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.173_174insC) sequence variation in gene VHL/NCBI:7428 2759 check_entity AN6008-1 VHL P59fs (c.173_174insC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:825 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.173_174insC) sequence variation in gene VHL/NCBI:7428 2759 check_entity AN6009-1 VHL P59fs (c.176delC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal hemangioblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This frameshift mutation, affecting residue within the pVHL protein core, was found in a VHL type 1 family of 5 patients. Three had retinal hemangioblastomas, 4 had cerebellar hemangioblastomas, and 2 had renal cell carcinoma. This mutation also causes an early stop codon at amino acid 66. ACMG codes as follows: Protein length changes as a result of in-frame deletions in a nonrepeat region and stop-loss variant (PM4). Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma, Renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.176delC) sequence variation in gene VHL/NCBI:7428 2760 check_entity AN6009-1 VHL P59fs (c.176delC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1805 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.176delC) sequence variation in gene VHL/NCBI:7428 2760 check_entity AN6010-1 VHL P61FS (c.182_185delCCGT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in a VHL patient with retinal angiomas and hemangioblastomas of the central nervous system. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.182_185delCCGT) sequence variation in gene VHL/NCBI:7428 2761 check_entity AN6010-1 VHL P61FS (c.182_185delCCGT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2021 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.182_185delCCGT) sequence variation in gene VHL/NCBI:7428 2761 check_entity AN6011-1 VHL P61fs (c.183insC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11409863 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This mutation was detected in a previously diagnosed VHL patient by DHPLC (VHL 73). This frameshift mutation provides strong evidence of pathogenicity (PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.183insC) sequence variation in gene VHL/NCBI:7428 2762 check_entity AN6011-1 VHL P61fs (c.183insC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1890 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.183insC) sequence variation in gene VHL/NCBI:7428 2762 check_entity AN6012-1 VHL P71fs (c.211insT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This mutation was found in a VHL type 1 patient (patient no. V96). This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.211insT) sequence variation in gene VHL/NCBI:7428 2763 check_entity AN6012-1 VHL P71fs (c.211insT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1831 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.211insT) sequence variation in gene VHL/NCBI:7428 2763 check_entity AN6013-1 VHL P81S (c.241C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found in a German, VHL type 1 patient with hemangioblastomas of the central nervous system, renal cell carcinoma, and pancreatic cysts (family VHL 23). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P81S (c.241C>T) sequence variation in gene VHL/NCBI:7428 2764 check_entity AN6013-1 VHL P81S (c.241C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:24132471 Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. Two patients were found with this missense mutation in the VHL gene. One patient was 34Y and the other was 59Y at last follow-up. Their phenotypes were grouped together: retinal hemangioblastoma, cerebellar hemangioblastoma, spinal cord hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumour, pheochromocytoma, and renal cysts. Family history was not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P81S (c.241C>T) sequence variation in gene VHL/NCBI:7428 2764 check_entity AN6013-1 VHL P81S (c.241C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8634692 Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregared with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS Hb, RCC, and Pheo was available. Case 37 had p.Pro81Ser mutation. One member was affected with hemangioblastoma. Other demographics of the members were not described. ACMG PP4 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P81S (c.241C>T) sequence variation in gene VHL/NCBI:7428 2764 check_entity AN6013-1 VHL P81S (c.241C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1713 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P81S (c.241C>T) sequence variation in gene VHL/NCBI:7428 2764 check_entity AN6014-1 VHL P86A (c.256C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from Italy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P86A (c.256C>G) sequence variation in gene VHL/NCBI:7428 2765 check_entity AN6014-1 VHL P86A (c.256C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1635 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P86A (c.256C>G) sequence variation in gene VHL/NCBI:7428 2765 check_entity AN6015-1 VHL P86L (c.257C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in two VHL type 1 families of 12 individuals altogether (family IDs 2612 and 3568). Nine of 12 individuals were identified with cerebellar hemangioblastomas, 6 with retinal hemangioblastomas, and 6 with renal cell carcinoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma, Renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P86L (c.257C>T) sequence variation in gene VHL/NCBI:7428 2766 check_entity AN6015-1 VHL P86L (c.257C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting residue within the pVHL protein core, was found in a VHL patient with retinal hemangioblastomas and cerebellar hemangioblastomas. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P86L (c.257C>T) sequence variation in gene VHL/NCBI:7428 2766 check_entity AN6015-1 VHL P86L (c.257C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8634692 Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma, renal cell carcinoma, and pheochromocytoma was available. Case 39 had p.Pro86Leu (c.257C>T) mutation. One member was affected with retinal angioma. Other demographics of the members were not described. ACMG PP4 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P86L (c.257C>T) sequence variation in gene VHL/NCBI:7428 2766 check_entity AN6015-1 VHL P86L (c.257C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1636 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P86L (c.257C>T) sequence variation in gene VHL/NCBI:7428 2766 check_entity AN6016-1 VHL P86R (c.257C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in a VHL type 1 family (lineage 128). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P86R (c.257C>G) sequence variation in gene VHL/NCBI:7428 2767 check_entity AN6016-1 VHL P86R (c.257C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting residue within the pVHL protein core, was found in a VHL type 1 family with retinal hemangiolastomas and renal cell carcinoma. Only supporting evidence of pathogenicity because of cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). Relevant HPO terms: retinal hemangioblastoma and renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P86R (c.257C>G) sequence variation in gene VHL/NCBI:7428 2767 check_entity AN6016-1 VHL P86R (c.257C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1725 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P86R (c.257C>G) sequence variation in gene VHL/NCBI:7428 2767 check_entity AN6017-1 VHL P86S (c.256C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting residue within the pVHL protein core, was found in a VHL patient with cerebellar hemangioblastomas. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: Cerebellar hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P86S (c.256C>T) sequence variation in gene VHL/NCBI:7428 2768 check_entity AN6017-1 VHL P86S (c.256C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in 3 VHL type 2B family members (patient no. V11). One unaffected family member was negative for the P86S mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P86S (c.256C>T) sequence variation in gene VHL/NCBI:7428 2768 check_entity AN6017-1 VHL P86S (c.256C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:22357542 Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline variants. VHL P86S (c.256C>T) was found in a type 2B VHL patient (proband no. 2). The 33-year-old proband had retinal angiomas, renal cell carcinoma, pancreatic cysts, and pheochromocytoma. The proband's 8-year-old daughter also carried this variant but had no clinical manifestations of VHL disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P86S (c.256C>T) sequence variation in gene VHL/NCBI:7428 2768 check_entity AN6017-1 VHL P86S (c.256C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P86S (c.256C>T) sequence variation in gene VHL/NCBI:7428 2768 check_entity AN6017-1 VHL P86S (c.256C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:18580449 Among patients prospectively followed by the members of the French VHL Study Group, 35 consecutive patients with well-documented endocrine pancreatic tumour (20 women and 15 men; median age,37 [21Y-57] years) were included. All 35 patients had VHL germline mutations and were assessed for the presence of pheochromocytoma and renal carcinoma in addition to pancreatic tumours. The presence of other phenotypes was not described. DNA was isolated from peripheral blood lymphocytes and mutations were detected using direct sequencing of the 3 exons of VHL and/or southern blot analysis. A germline missense mutation (c.256C>T) was found in 3 patients, 2 of which were related. Patient No 7 from family 503 presented with pancreatic endocrine tumour, pheochromocytoma, and renal carcinoma and patient No 15 from family 503 presented with pancreatic endocrine tumour. Their familial relation was not described. Patient No. 27 from family 11 also had the same mutation and presented with pancreatic endocrine tumour, pheochromocytoma, and renal carcinoma. The patients' phenotypes are highly specific to VHL disease (ACMG PP4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P86S (c.256C>T) sequence variation in gene VHL/NCBI:7428 2768 check_entity AN6017-1 VHL P86S (c.256C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8634692 Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb) renal cell carcinoma (RCC), and pheochromocytoma was available. Case 42 had p.Pro86Ser (c.256C>T) mutation. One member was affected with hemangioblastoma, retinal angioma, and RCC. Other demographics of the members were not described. ACMG PP4 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P86S (c.256C>T) sequence variation in gene VHL/NCBI:7428 2768 check_entity AN6017-1 VHL P86S (c.256C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1778 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::P86S (c.256C>T) sequence variation in gene VHL/NCBI:7428 2768 check_entity AN6018-1 VHL P86fs (c.254_255insC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This frameshift mutation was found in 3 family members with VHL type 1 phenotype (family ID 3312). All 3 individuals carried retinal hemangioblastomas, 2 of 3 carried cerebellar hemangioblastomas and one carried renal cell carcinoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.254_255insC) sequence variation in gene VHL/NCBI:7428 2769 check_entity AN6018-1 VHL P86fs (c.254_255insC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1634 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.254_255insC) sequence variation in gene VHL/NCBI:7428 2769 check_entity AN6019-1 VHL Q132* (c.394C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This nonsense mutation was found in a German, VHL type 1 patient with retinal angiomas, hemangioblastomas of the central nervous system, and pancreatic cysts (family VHL 30). This study contains very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q132* (c.394C>T) sequence variation in gene VHL/NCBI:7428 2770 check_entity AN6019-1 VHL Q132* (c.394C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PVS1' because they observe a nonsense variant in a gene where loss of function is a known mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q132* (c.394C>T) sequence variation in gene VHL/NCBI:7428 2770 check_entity AN6019-1 VHL Q132* (c.394C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1870 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q132* (c.394C>T) sequence variation in gene VHL/NCBI:7428 2770 check_entity AN6020-1 VHL Q132P (c.395A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting a residue on surface of pVHL, was found in a VHL family with retinal angiomas, cerebellar hemangioblastomas, and renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q132P (c.395A>C) sequence variation in gene VHL/NCBI:7428 2771 check_entity AN6020-1 VHL Q132P (c.395A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11148816 41 non-related patients with retinal capillary hemangioma presenting in the Benjamin Franklin University Eye Clinic between 1988 to 1999 Germany were evaluated for the presence of other VHL lesions. VHL disease was diagnosed in 33 patients based on the presence of other severe VHL lesions (spinal hemangioblastoma, cerebellar hemangioblastoma, renal cysts, pancreatic cyst, renal carcinoma, and pheochromocytoma), molecular genetic testing, and/or family history. VHL germline mutations were identified in 27 out of 29 VHL families screened with molecular genetics. One patient with VHL-related retinal capillary hemangioma was found to have germline missense VHL Q132P (c.395A>C). 3 other affected relatives were also evaluated. It's unclear which other VHL-related lesions were identified in this patient. ACMG evidence codes: 'PP4' because the patients' phenotypes and family history are highly specific for a disease with single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q132P (c.395A>C) sequence variation in gene VHL/NCBI:7428 2771 check_entity AN6020-1 VHL Q132P (c.395A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2001 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q132P (c.395A>C) sequence variation in gene VHL/NCBI:7428 2771 check_entity AN6021-1 VHL Q145* (c.433C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21972040 Germline mutation analysis of seven east-Chinese families revealed 6 mutations. This nonsense mutation was found in two separate families. One female VHL type 1 patient with hemangioblastomas of the central nervous system and an asymptomatic son (family D). Two male VHL type 1 family members with hemangioblastomas of the central nervous system and pancreatic cysts (family F). This study contains very strong evidence for pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q145* (c.433C>T) sequence variation in gene VHL/NCBI:7428 2772 check_entity AN6021-1 VHL Q145* (c.433C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25586603 This is a case report on a 9-month-old female with polycythemia. The patient carries a paternally inherited missense mutation (EID5799) and this de novo, nonsense mutation. ACMG codes as follows: A nonsense mutation in a gene where loss-of-function is a known mechanism of disease (PVS1). Assumed de novo, but without confirmation of paternity and maternity (PM6). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q145* (c.433C>T) sequence variation in gene VHL/NCBI:7428 2772 check_entity AN6021-1 VHL Q145* (c.433C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1759 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q145* (c.433C>T) sequence variation in gene VHL/NCBI:7428 2772 check_entity AN6022-1 VHL Q164* (c.490C>T) VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 risk 34502-5 PubMed:7915601 Tumors from 98 patients with sporadic clear cell renal cell carcinoma (ccRCC) were analyzed for VHL mutations and loss of heterozygosity (LOH). Somatic VHL variants were observed in 56 patients, and VHL LOH was observed in 98% of samples with VHL variants. VHL Q164* (c.490C>T) was found in a granular ccRC (sample UOK161, variant location indicated as c.703 because of differences in reference transcript). Authors noted that VHL variants were highly specific to ccRC and not found in the 12 other tumor types examined. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q164* (c.490C>T) sequence variation in gene VHL/NCBI:7428 2773 check_entity AN6022-1 VHL Q164* (c.490C>T) VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 risk 34502-5 CIViC:1721 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q164* (c.490C>T) sequence variation in gene VHL/NCBI:7428 2773 check_entity AN6022-2 VHL Q164* (c.490C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This nonsense mutation was found in a VHL type 1 family (lineage 141). This provides strong evidence of pathogenicity as it is a null variant in a gene where loss of function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q164* (c.490C>T) sequence variation in gene VHL/NCBI:7428 2774 check_entity AN6022-2 VHL Q164* (c.490C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17661816 Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This mutation was found in a VHL type 1 patient with cerebellar hemangioblastomas, epididymal cyst, and renal cell carcinoma (family no. 21). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q164* (c.490C>T) sequence variation in gene VHL/NCBI:7428 2774 check_entity AN6022-2 VHL Q164* (c.490C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This nonsense mutation was found in an Iranian, VHL type 1 patient with retinal angiomas, hemangioblastomas of the central nervous system, renal cell carcinoma, pancreatic cysts, and pancreatic islet cell tumors (family VHL 65). This study contains very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q164* (c.490C>T) sequence variation in gene VHL/NCBI:7428 2774 check_entity AN6022-2 VHL Q164* (c.490C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12000816 Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This nonsense mutation was found in the VHL gene and one patient with pheochromocytoma. This study contains very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q164* (c.490C>T) sequence variation in gene VHL/NCBI:7428 2774 check_entity AN6022-2 VHL Q164* (c.490C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1721 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q164* (c.490C>T) sequence variation in gene VHL/NCBI:7428 2774 check_entity AN6023-1 VHL Q164L (c.491A>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from Germany. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q164L (c.491A>T) sequence variation in gene VHL/NCBI:7428 2775 check_entity AN6023-1 VHL Q164L (c.491A>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1955 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q164L (c.491A>T) sequence variation in gene VHL/NCBI:7428 2775 check_entity AN6024-1 VHL Q164R (c.491A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). This missense mutation was found in a VHL patient with retinal hemangioblastomas and pheochromocytoma. Relevant HPO terms: Retinal hemangioblastoma, Pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q164R (c.491A>G) sequence variation in gene VHL/NCBI:7428 2776 check_entity AN6024-1 VHL Q164R (c.491A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20583150 A 2.75 year old patient (32 month-old girl) presented with a pheochromocytoma. Genetic sequencing revealed a c.491A>G (p.Gln164Arg) heterozygous germline mutation in exon 3 of the VHL gene. Sequencing of her mother, father, a sibling, and her paternal grandparents revealed that the mutation was present only in her father, and was de-novo in her father. Upon screening, her father (a 31 year old male) presented with a retinal angioma, an adenoma of right adrenal gland, a right-sided renal cyst, an epidydymal cyst, a contrast-enhancing lesion in the pancreas, and bilateral pheochromocytomas. ACMG evidence codes: 'PP1'- Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease, and 'PP4'- patients' phenotypes or family history are highly specific for a disease with a single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q164R (c.491A>G) sequence variation in gene VHL/NCBI:7428 2776 check_entity AN6024-1 VHL Q164R (c.491A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1732 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q164R (c.491A>G) sequence variation in gene VHL/NCBI:7428 2776 check_entity AN6025-1 VHL Q195* (c.583C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. This mutation was found in a VHL type 1 patient (kindred no. 21). This study contains very strong evidence for pathogenicity in the form of a nonsense mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q195* (c.583C>T) sequence variation in gene VHL/NCBI:7428 2777 check_entity AN6025-1 VHL Q195* (c.583C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17661816 Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This mutation was found in 2 VHL type 2A family members (family no. 23). Both had retinal hemangioblastomas, one had cerebellar hemangioblastomas, and one had pheochromocytoma. Only supportive evidence for pathogenicity because patient’s phenotype or family history is highly specific for a disease with a single genetic etiology (ACMG code: PP4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q195* (c.583C>T) sequence variation in gene VHL/NCBI:7428 2777 check_entity AN6025-1 VHL Q195* (c.583C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This nonsense mutation was found in 2 VHL families with 9 patients altogether. Eight had retinal hemangioblastoma, one had cerebellar hemangioblastomas, 3 had renal cell carcinoma, and 5 had pheochromcytoma. This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q195* (c.583C>T) sequence variation in gene VHL/NCBI:7428 2777 check_entity AN6025-1 VHL Q195* (c.583C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This nonsense mutation was found in 2 German, VHL type 1 family members with retinal angiomas and hemangioblastomas of the central nervous system (family VHL 56). This study contains very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q195* (c.583C>T) sequence variation in gene VHL/NCBI:7428 2777 check_entity AN6025-1 VHL Q195* (c.583C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12000816 Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This nonsense mutation was found in the VHL gene and one patient with pheochromocytoma. This study contains very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q195* (c.583C>T) sequence variation in gene VHL/NCBI:7428 2777 check_entity AN6025-1 VHL Q195* (c.583C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PVS1' because they observe a nonsense variant in a gene where loss of function is a known mechanism of disease . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q195* (c.583C>T) sequence variation in gene VHL/NCBI:7428 2777 check_entity AN6025-1 VHL Q195* (c.583C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:23298237 Genetic analysis of 7 Hungarian individuals from 5 unrelated families affected with von Hippel-Lindau disease revealed 5 different mutations, 3 of which were novel. All 7 patients were found to have Type 1 VHL disease. The mutations could not be found within 100 healthy controls. The above mutation was found in 1 member of a single family. The patient developed retinal and cerebellar hemangioblastoma. ACMG evidence codes: 'PP4' because the patient's phenotypes or family history are highly specific for a disease with single genetic etiology, 'PVS1' because they observe a nonsense variant in a gene where loss of function is a known mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q195* (c.583C>T) sequence variation in gene VHL/NCBI:7428 2777 check_entity AN6025-1 VHL Q195* (c.583C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26763786 A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. The c.583 C>T mutation was present in 2 individuals of the 122 total number of variants captured in this population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q195* (c.583C>T) sequence variation in gene VHL/NCBI:7428 2777 check_entity AN6025-1 VHL Q195* (c.583C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 2 individuals from France. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q195* (c.583C>T) sequence variation in gene VHL/NCBI:7428 2777 check_entity AN6025-1 VHL Q195* (c.583C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1686 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q195* (c.583C>T) sequence variation in gene VHL/NCBI:7428 2777 check_entity AN6026-1 VHL Q73* (c.217C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This nonsense mutation was found in a VHL type 1 family of 7 individuals (family ID 2753). Six of 7 individuals were identified with retinal hemangioblastomas, 3 with cerebellar hemangioblastomas and one with renal cell carcinoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q73* (c.217C>T) sequence variation in gene VHL/NCBI:7428 2778 check_entity AN6026-1 VHL Q73* (c.217C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal hemangioblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This nonsense mutation was found in 3 VHL families with 9 patients altogether. Seven had retinal hemangioblastomas, 3 had cerebellar hemangioblastomas, and 5 had renal cell carcinoma. Only moderate evidence of pathogenicity since the protein length changes as a result of a stop-loss variants (ACMG code: PM4). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma, Renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q73* (c.217C>T) sequence variation in gene VHL/NCBI:7428 2778 check_entity AN6026-1 VHL Q73* (c.217C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This mutation was found in a VHL type 1 patient (patient no. V64). This study contains very strong evidence for pathogenicity in the form of a nonsense mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q73* (c.217C>T) sequence variation in gene VHL/NCBI:7428 2778 check_entity AN6026-1 VHL Q73* (c.217C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1628 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q73* (c.217C>T) sequence variation in gene VHL/NCBI:7428 2778 check_entity AN6027-1 VHL Q73FS (c.217delC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12114495 A study of 34 Polish families revealed germline mutations in 30 families. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). This mutation was found in a VHL patient with hemangioblastomas of the central nervous system and retina (family no. 4). This study contains very strong evidence of pathogenicity in the form of a frameshift variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). HPO terms: hemangioblastoma, retinal hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.217delC) sequence variation in gene VHL/NCBI:7428 2779 check_entity AN6027-1 VHL Q73FS (c.217delC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1917 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.217delC) sequence variation in gene VHL/NCBI:7428 2779 check_entity AN6028-1 VHL Q73fs (c.214insGCCC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This frameshift mutation was found in a VHL type 1 family of 3. All three had retinal angiomas and hemangioblastomas of the cerebellum. One also had renal cell carcinoma. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.214insGCCC) sequence variation in gene VHL/NCBI:7428 2780 check_entity AN6028-1 VHL Q73fs (c.214insGCCC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2007 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.214insGCCC) sequence variation in gene VHL/NCBI:7428 2780 check_entity AN6029-1 VHL Q96* (c.286C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This nonsense mutation was found in a VHL type 1 family (lineage 48). Only moderate evidence for pathogenicity because protein length changes as a result of stop-loss variant (ACMG code: PM4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q96* (c.286C>T) sequence variation in gene VHL/NCBI:7428 2781 check_entity AN6029-1 VHL Q96* (c.286C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This mutation was found in a VHL type 1 patient (patient no. V77). This study contains very strong evidence for pathogenicity in the form of a nonsense mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q96* (c.286C>T) sequence variation in gene VHL/NCBI:7428 2781 check_entity AN6029-1 VHL Q96* (c.286C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:14722919 Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. This nonsense mutation was found in a patient with retinal hemangioblastoma (patient no. F66). Patient has family history of pancreatic cysts. This study contains very strong evidence for pathogenicity in the form of a nonsense mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q96* (c.286C>T) sequence variation in gene VHL/NCBI:7428 2781 check_entity AN6029-1 VHL Q96* (c.286C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1724 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q96* (c.286C>T) sequence variation in gene VHL/NCBI:7428 2781 check_entity AN6030-1 VHL Q96_P97delinsH (c.288_290del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8634692 Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma, renal cell carcinoma (RCC), and pheochromocytoma was available. Case 25 had c.288delGCC mutation resulting in the replacement of Q96 and P97 with H. 1 member was affected with retinal angioma and RCC (ACMG PP4). Other demographics of the members were not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.288_290del) sequence variation in gene VHL/NCBI:7428 2782 check_entity AN6030-1 VHL Q96_P97delinsH (c.288_290del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:3115 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.288_290del) sequence variation in gene VHL/NCBI:7428 2782 check_entity AN6031-1 VHL R107G (c.319C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12000816 Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R107G (c.319C>G) sequence variation in gene VHL/NCBI:7428 2783 check_entity AN6031-1 VHL R107G (c.319C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1883 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R107G (c.319C>G) sequence variation in gene VHL/NCBI:7428 2783 check_entity AN6032-1 VHL R107H (c.320G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12202531 A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations extracted from the French VHL database revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, this mutation was found in a 1 patient, without retinal hemangioblastomas, but other manifestations are not clearly stated. No family information or relation was provided. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R107H (c.320G>A) sequence variation in gene VHL/NCBI:7428 2784 check_entity AN6032-1 VHL R107H (c.320G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1920 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R107H (c.320G>A) sequence variation in gene VHL/NCBI:7428 2784 check_entity AN6033-1 VHL R107P (c.320G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in a VHL type 1 family (lineage 76). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R107P (c.320G>C) sequence variation in gene VHL/NCBI:7428 2785 check_entity AN6033-1 VHL R107P (c.320G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1716 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R107P (c.320G>C) sequence variation in gene VHL/NCBI:7428 2785 check_entity AN6034-1 VHL R108dup (c.322_324dup) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11409863 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 86). Protein length changes as a result of in-frame insertion in a nonrepeat region (ACMG code: PM4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.322_324dup) sequence variation in gene VHL/NCBI:7428 2786 check_entity AN6034-1 VHL R108dup (c.322_324dup) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1897 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.322_324dup) sequence variation in gene VHL/NCBI:7428 2786 check_entity AN6035-1 VHL R113* (c.337C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This nonsense mutation was found in a VHL type 1 family (lineage 81). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R113* (c.337C>T) sequence variation in gene VHL/NCBI:7428 2787 check_entity AN6035-1 VHL R113* (c.337C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21463266 In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This nonsense mutation was found in a 23 year old VHL patient with no family history and hemangioblastomas of the central nervous system (index case 77). There is very strong evidence for pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R113* (c.337C>T) sequence variation in gene VHL/NCBI:7428 2787 check_entity AN6035-1 VHL R113* (c.337C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This mutation was found in a VHL type 1 patient (patient V59). This study contains very strong evidence for pathogenicity in the form of a nonsense mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R113* (c.337C>T) sequence variation in gene VHL/NCBI:7428 2787 check_entity AN6035-1 VHL R113* (c.337C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations using SSCP analysis of PCR products by peripheral blood. The R113* (c.337C>T) mutation was detected in the patient, referred to in the paper by R113* (c.550C>T) due to a difference in transcript sequence. This nonsense mutation was found in a German, VHL type 1 family (family VHL 55). Two patients were identified with retinal angiomas and hemangioblastomas of the central nervous system. This study contains very strong evidence of pathogenicity in the form of a nonsense mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R113* (c.337C>T) sequence variation in gene VHL/NCBI:7428 2787 check_entity AN6035-1 VHL R113* (c.337C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:10761708 A previous study of 26 Japanese, VHL families was extended to 41 additional families. Germline mutations were detected in 55 of 77 Japanese families, using SSCP, direct sequencing, and Southern Blot analysis of peripheral blood samples. Renal cell carcinoma occurred predominantly in non-missense mutations predicted to lead to gross alteration or complete loss of the VHL protein. This stop-gain mutation, c.337C>T (stated as c.550C>T in the paper which used the Latif sequence as reference), was found in a VHL type 2 patient, who was previously diagnosed with VHL type 1. The patient had a hemangioblastoma of the central nervous system, pancreatic cysts, renal cell carcinoma, and pheochromocytoma (family ID 47). This study contains very strong evidence for pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R113* (c.337C>T) sequence variation in gene VHL/NCBI:7428 2787 check_entity AN6035-1 VHL R113* (c.337C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R113* (c.337C>T) sequence variation in gene VHL/NCBI:7428 2787 check_entity AN6035-1 VHL R113* (c.337C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12202531 A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, the missense mutation (c.337C>T (p.Arg113Ter)) was found in 2 patients stated to have retinal HBs. Other manifestations are possible but not clear. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R113* (c.337C>T) sequence variation in gene VHL/NCBI:7428 2787 check_entity AN6035-1 VHL R113* (c.337C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1672 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R113* (c.337C>T) sequence variation in gene VHL/NCBI:7428 2787 check_entity AN6036-1 VHL R113FS (c.337delC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in a patient with retinal hemangioblastomas. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.337delC) sequence variation in gene VHL/NCBI:7428 2788 check_entity AN6036-1 VHL R113FS (c.337delC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2019 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.337delC) sequence variation in gene VHL/NCBI:7428 2788 check_entity AN6037-1 VHL R120G (c.358A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21463266 In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This missense mutation was found in a 24 year old VHL patient with hemangioblastomas of the central nervous system, retinal hemangioblastomas, pancreatic cysts, clear cell renal cell carcinoma, and multiple renal cysts (index case 100). ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology (PP4)Relevant HPO terms: Renal cell carcinoma, hemangioblastoma, retinal hemangioblastoma, pheochromocytoma, multiple pancreatic cysts and multiple renal cysts. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R120G (c.358A>G) sequence variation in gene VHL/NCBI:7428 2789 check_entity AN6037-1 VHL R120G (c.358A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:24132471 Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. One patient was found with this missense varaint in the VHL gene. The patient was 15Y at the last follow-up and presented with: spinal cord hemangioblastoma. Family history was not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R120G (c.358A>G) sequence variation in gene VHL/NCBI:7428 2789 check_entity AN6037-1 VHL R120G (c.358A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from Italy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R120G (c.358A>G) sequence variation in gene VHL/NCBI:7428 2789 check_entity AN6037-1 VHL R120G (c.358A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1790 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R120G (c.358A>G) sequence variation in gene VHL/NCBI:7428 2789 check_entity AN6038-1 VHL R120fs (c.358_359insAC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8634692 Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb) renal cell carcinoma (RCC), and pheochromocytoma was available. Case 14 had p.Arg120fs ( c.358insAC) mutation. 2 members were affected with renal cell carcinoma (ACMG PP4). Other demographics of the members were not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.358_359insAC) sequence variation in gene VHL/NCBI:7428 2790 check_entity AN6038-1 VHL R120fs (c.358_359insAC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:3113 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.358_359insAC) sequence variation in gene VHL/NCBI:7428 2790 check_entity AN6039-1 VHL R161* (c.481C>T) VHL NCBI:7428 gene renal cell carcinoma DOID:4450 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This nonsense mutation was found in 2 unrelated, German families. One VHL type 1 family of 2 affected individuals had one patient with retinal angiomas, 2 with hemangioblastomas of the central nervous system, one with renal cell carcinoma, one with pancreatic cysts, and one with cystadenomas of the epididymis (family VHL 32). Another VHL type 1 family of 3 affected individuals had 3 patients with retinal angiomas, one with hemangioblastomas of the central nervous system, 2 with renal cell carcinoma, one with pancreatic cysts, and one with cystadenomas of the epididymis (family VHL 49). ACMG codes as follows: A nonsense mutation in a gene where loss-of-function is a known mechanism of disease (PVS1). Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). HPO terms: papillary cystadenomas of the broad ligament. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161* (c.481C>T) sequence variation in gene VHL/NCBI:7428 2791 check_entity AN6039-1 VHL R161* (c.481C>T) VHL NCBI:7428 gene renal cell carcinoma DOID:4450 diagnostic 34502-5 CIViC:1680 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161* (c.481C>T) sequence variation in gene VHL/NCBI:7428 2791 check_entity AN6039-2 VHL R161* (c.481C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This nonsense mutation was found in 3 VHL type 1 families and one VHL type 2 family (lineages 184, 93, 22, 92). Only moderate evidence for pathogenicity because protein length changes as a result of stop-loss variant (ACMG code: PM4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161* (c.481C>T) sequence variation in gene VHL/NCBI:7428 2792 check_entity AN6039-2 VHL R161* (c.481C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This mutation was found in 2 unrelated VHL type 1 patients (patient V3, V46). ACMG codes as follows: A null, nonsense mutation in a gene where loss-of-function is a known mechanism of disease (PVS1). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161* (c.481C>T) sequence variation in gene VHL/NCBI:7428 2792 check_entity AN6039-2 VHL R161* (c.481C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12114495 A study of 34 Polish families revealed germline mutations in 30 families. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). This nonsense mutation was found in a VHL patient with hemangioblastomas of the central nervous system and retina, and renal cell carcinoma (family no. 15). This study contains very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161* (c.481C>T) sequence variation in gene VHL/NCBI:7428 2792 check_entity AN6039-2 VHL R161* (c.481C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20151405 This study reports 1,548 germline and somatic mutations from 945 VHL families. This nonsense mutation was found in a VHL patient with retinal angiomas and pancreatic cysts (case no. 306). There is very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161* (c.481C>T) sequence variation in gene VHL/NCBI:7428 2792 check_entity AN6039-2 VHL R161* (c.481C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:14722919 'Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. This nonsense variant was found in a 20 year old patient with retinal and cerebellar hemangioblastomas and pancreatic cysts (patient no. F9). ACMG codes: ''flag for PP4'' since patients phenotype is specific for gene.' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161* (c.481C>T) sequence variation in gene VHL/NCBI:7428 2792 check_entity AN6039-2 VHL R161* (c.481C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:28630796 A case report of a 32 year old male patient presenting with bilateral retinal hemangioblastoma, loss of vision in the left eye, and a history of cerebral hemangioblastoma revealed a R161X mutation in VHL. Two family members (daughter and sister) were confirmed to heterozygously harbor R161X. The patient's 12 year old daughter had no clinical presentations. The patient's sister had an optic nerve head hemangioblastoma in the left eye, peripheral temporal retina hemangioblastoma in left eye, and cystic lesions in the pancreas and kidney. The patient's mother was recalled to have advanced unilateral vision loss and dying due to renal cancer, but no genetic confirmation of VHL mutation status could be completed. ACMG codes: PVS1 (nonsense variant where LOF is a known mechanism of disease), PP4 (patient's phenotype and family history is specific for a disease with a single genetic etiology) assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161* (c.481C>T) sequence variation in gene VHL/NCBI:7428 2792 check_entity AN6039-2 VHL R161* (c.481C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:27617348 A retrospective cohort study was conducted at a public children’s hospital (Buenos Aires, Argentina). Eligible patients were all index cases with clinical diagnosis or clinical suspicion of type 1 VHL referred for genetic testing from 2003 to 2015. A nonsense germline mutation c.481C>T resulting in p.R161* was confirmed in 4 patients, all of which fulfilled the requirements for diagnosis of type 1 VHL, and none of which had family history of VHL disease. Patient #1 was clinically diagnosed at age 13, and presented with retinal angioma (16Y) and endolymphatic sac tumors (13Y). Patient #3 was diagnosed at age 20Y, and presented with CNS hemangioblastoma at 20Y, 25Y, 26Y, clear cell renal cancer at 27Y, pancreatic cysts at 25Y, renal cysts at 25Y, and epididymal cysts at 31Y. Patient #4 was diagnosed at 21Y and presented with CNS hemangioblastoma at 22Y, retinal angioma at 21Y, pancreatic cysts at 23Y, and epididymal cysts since birth. Patient #9 was diagnosed at 25Y and presented with CNS hemangioblastoma at 22Y, clear cell renal cell carcinoma at 22Y, renal cysts at 22Y, and pancreatic cysts at 22Y. ACMG: PVS1 (nonsense variant in gene where LOF is a known mechanism of disease), PM6 (mutations assumed de novo, without confirmation). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161* (c.481C>T) sequence variation in gene VHL/NCBI:7428 2792 check_entity AN6039-2 VHL R161* (c.481C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26763786 A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. This mutation was present in 2 individuals of the 122 total number of variants captured in this population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161* (c.481C>T) sequence variation in gene VHL/NCBI:7428 2792 check_entity AN6039-2 VHL R161* (c.481C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 3 individuals from France or Argentina. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161* (c.481C>T) sequence variation in gene VHL/NCBI:7428 2792 check_entity AN6039-2 VHL R161* (c.481C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11148816 41 non-related patients with retinal capillary hemangioma presenting in the Benjamin Franklin University Eye Clinic between 1988 to 1999 Germany were evaluated for the presence of other VHL lesions. VHL disease was diagnosed in 33 patients based on the presence of other severe VHL lesions (spinal hemangioblastoma, cerebellar hemangioblastoma, renal cysts, pancreatic cyst, renal carcinoma, and pheochromocytoma), molecular genetic testing, and/or family history. VHL germline mutations were identified in 27 out of 29 VHL families screened with molecular genetics. Two patients with VHL-related retinal capillary hemangioma were found to have germline missense VHL R161* (c.481C>T). 1 other affected relative was also evaluated for one of the patients. Other VHL lesions harbored by the patients were not specified. ACMG evidence codes: 'PP4' because the patients' phenotypes and family history are highly specific for a disease with single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161* (c.481C>T) sequence variation in gene VHL/NCBI:7428 2792 check_entity AN6039-2 VHL R161* (c.481C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12202531 A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, the missense mutation (c.481C>T (p.Arg161Ter)) was found in 8 patients total - 3 of which are stated to have retinal HBs and 5 are said to not. Other manifestations are possible but not clear. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161* (c.481C>T) sequence variation in gene VHL/NCBI:7428 2792 check_entity AN6039-2 VHL R161* (c.481C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1680 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161* (c.481C>T) sequence variation in gene VHL/NCBI:7428 2792 check_entity AN6040-1 VHL R161= (c.481C>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:22357542 Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This silent mutation was found in a 34-year-old VHL patient with hemangioblastomas of the central nervous system, renal cell carcinoma, and pancreatic cysts (proband no. 15). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161= (c.481C>A) sequence variation in gene VHL/NCBI:7428 2793 check_entity AN6040-1 VHL R161= (c.481C>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2024 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161= (c.481C>A) sequence variation in gene VHL/NCBI:7428 2793 check_entity AN6041-1 VHL R161G (c.481C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found in a German, VHL type 2B family. Only one patient was identified with retinal angiomas, hemangioblastomas of the central nervous system, pheochromocytoma, and renal cell carcinoma. This patient's phenotype is highly specific for a disease with a single etiology (ACMG code: PP4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161G (c.481C>G) sequence variation in gene VHL/NCBI:7428 2794 check_entity AN6041-1 VHL R161G (c.481C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26763786 A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. This mutation was present in 2 individuals of the 122 total number of variants captured in this population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161G (c.481C>G) sequence variation in gene VHL/NCBI:7428 2794 check_entity AN6041-1 VHL R161G (c.481C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1791 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161G (c.481C>G) sequence variation in gene VHL/NCBI:7428 2794 check_entity AN6042-1 VHL R161P (c.482G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12000816 Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161P (c.482G>C) sequence variation in gene VHL/NCBI:7428 2795 check_entity AN6042-1 VHL R161P (c.482G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1731 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161P (c.482G>C) sequence variation in gene VHL/NCBI:7428 2795 check_entity AN6043-1 VHL R161Q (c.482G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was detected in a VHL type 2B patient with retinal hemangioblastoma, renal cell carcinoma, and pheochromocytoma (family ID 4422). Only supporting evidence for pathogenicity because patient's phenotyoe is highly specific for a disease with a single genetic etiology (ACMG code: PP4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161Q (c.482G>A) sequence variation in gene VHL/NCBI:7428 2796 check_entity AN6043-1 VHL R161Q (c.482G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in a VHL type 2 family (lineage 3). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161Q (c.482G>A) sequence variation in gene VHL/NCBI:7428 2796 check_entity AN6043-1 VHL R161Q (c.482G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting a residue on surface of pVHL protein core, was found in 2 VHL type 2C families with 4 patients altogether. All 4 patients had pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161Q (c.482G>A) sequence variation in gene VHL/NCBI:7428 2796 check_entity AN6043-1 VHL R161Q (c.482G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21463266 In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This missense mutation was found in a 8 year old VHL patient with pheochromocytoma (index case 244). ACMG codes as follows: Supporting evidence of pathogenicity because this is a missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161Q (c.482G>A) sequence variation in gene VHL/NCBI:7428 2796 check_entity AN6043-1 VHL R161Q (c.482G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in 3 unrelated VHL type 2A patients (patients V32, V60, V97). This study contains strong evidence of pathogenicity for this variant because the prevalence of the variant in affected individuals is significantly increased compared with the prevalence In controls (ACMG code: PS4). An additional 0, 4 or 1 unaffected family members, respectively, were negative for the R161Q mutation across the 3 families described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161Q (c.482G>A) sequence variation in gene VHL/NCBI:7428 2796 check_entity AN6043-1 VHL R161Q (c.482G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12000816 Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and two patients with pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161Q (c.482G>A) sequence variation in gene VHL/NCBI:7428 2796 check_entity AN6043-1 VHL R161Q (c.482G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 5 patients were found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161Q (c.482G>A) sequence variation in gene VHL/NCBI:7428 2796 check_entity AN6043-1 VHL R161Q (c.482G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20846682 26 VHL patients, from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 1 patient from a single family was confirmed to have the above mutation. Additional manifestations aside from pheochromocytoma are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161Q (c.482G>A) sequence variation in gene VHL/NCBI:7428 2796 check_entity AN6043-1 VHL R161Q (c.482G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:29662268 A 12 year old Japanese female confirmed with the germline VHL mutation (c.482G>A) presented with pheochromocytoma. It was found that neither of her parents harboured this variation, confirming that she had a de novo mutation. The paper concluded that weight loss could be indicative of pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161Q (c.482G>A) sequence variation in gene VHL/NCBI:7428 2796 check_entity AN6043-1 VHL R161Q (c.482G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11850829 36 VHL-related pheochromocytomas (from 21 patients) and 10 VHL-related CNS hemangioblastomas (from 6 patients) were studied using comparative genomic hybridization (CGH) to detect genetic imbalances. The study identified selective loss of chromosome 11 in pheochromocytomas associated with VHL. Patient XIX with VHL-associated pheochromocytoma was found with a germline missense mutation (c.482G>A) in the VHL gene. ACMG evidence codes: 'PP4' because the patients' phenotypes are highly specific for a disease with single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161Q (c.482G>A) sequence variation in gene VHL/NCBI:7428 2796 check_entity AN6043-1 VHL R161Q (c.482G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1622 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R161Q (c.482G>A) sequence variation in gene VHL/NCBI:7428 2796 check_entity AN6044-1 VHL R167L (c.500G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21463266 In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. A novel, missense mutation, was found in 57 year old and 31 year old patients with hemangioblastomas of the central nervous system, retinal hemangioblastomas and pheochromocytoma (index cases 24, 232). This mutation was predicted to alter the linker region between beta and alpha domains of VHL protein. ACMG codes as follows: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before (PM5). Patient's phenotype is highly specific for a disease with a single genetic etiology (PP4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167L (c.500G>T) sequence variation in gene VHL/NCBI:7428 2797 check_entity AN6044-1 VHL R167L (c.500G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26763786 A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. The c.500 G>T mutation was present in 3 individuas of the 122 total number of variants captured in this population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167L (c.500G>T) sequence variation in gene VHL/NCBI:7428 2797 check_entity AN6044-1 VHL R167L (c.500G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1792 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167L (c.500G>T) sequence variation in gene VHL/NCBI:7428 2797 check_entity AN6045-1 VHL R167P (c.500G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167P (c.500G>C) sequence variation in gene VHL/NCBI:7428 2798 check_entity AN6045-1 VHL R167P (c.500G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2331 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167P (c.500G>C) sequence variation in gene VHL/NCBI:7428 2798 check_entity AN6046-1 VHL R167Q (c.500G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in six VHL type 2 families (including one family with 9 affected individuals) and one VHL type 1 family totaling 23 individuals altogether (family IDs 4421, 3718, 3767, 3493, 3731, 3517, 3739). Twelve of 23 individuals had retinal hemangioblastomas, 12 carried cerebellar hemangioblastomas, 8 carried renal cell carcinoma and 12 carried pheochromocytomas. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167Q (c.500G>A) sequence variation in gene VHL/NCBI:7428 2799 check_entity AN6046-1 VHL R167Q (c.500G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in six VHL type 2 families (lineages 100, 42, 44, 88, 105, 135). Only supporting evidence for pathogenicity because patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167Q (c.500G>A) sequence variation in gene VHL/NCBI:7428 2799 check_entity AN6046-1 VHL R167Q (c.500G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 1 patient and two VHL type 2B patients (patient no. V322, V36, V262). This study contains strong evidence of pathogenicity for this variant because the prevalence of the variant in affected individuals is significantly increased compared with the prevalence In controls (ACMG code: PS4). No additional family members were screened in all 3 cases. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167Q (c.500G>A) sequence variation in gene VHL/NCBI:7428 2799 check_entity AN6046-1 VHL R167Q (c.500G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found in a German, VHL type 2B family with 5 affected individuals (family VHL 43). Each patient had retinal angiomas, 2 had hemangioblastomas of the central nervous system, and 2 had renal cell carcinoma. The patients phenotype and family history are highly specific for a disease with a single gene etiology (ACMG code: PP4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167Q (c.500G>A) sequence variation in gene VHL/NCBI:7428 2799 check_entity AN6046-1 VHL R167Q (c.500G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:10761708 A previous study of 26 Japanese, VHL families was extended to 41 additional families. Germline mutations were detected in 55 of 77 Japanese families using SSCP, direct sequencing, and Southern Blot analysis of peripheral blood samples. This missense mutation, c.500G>A (reported as 713G>A in the paper which used the Latif sequence as reference) was found in 3 unrelated VHL families (Family ID 5, 77, 79). Family 5 was previously reported in paper 8634692. In family 5, there were two patients who both presented with hemangioblastoma and retinal capillary hemangioma but only one patient had renal cell carcinoma. In the VHL family of 3, one affected individual had hemangioblastomas of the central nervous system, one had retinal angiomas, two had pancreatic cysts, and one had pheochromocytoma (family ID 77). The unrelated, VHL type 2 patient had retinal angiomas and pheochromocytoma (family ID 79). ACMG codes as follows: Cosegregation with the disease in multiple affected family members in a gene definitively known to cause the disease (PP1). Patient's phenotype is highly specific for a disease with a single genetic etiology (PP4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167Q (c.500G>A) sequence variation in gene VHL/NCBI:7428 2799 check_entity AN6046-1 VHL R167Q (c.500G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12000816 Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167Q (c.500G>A) sequence variation in gene VHL/NCBI:7428 2799 check_entity AN6046-1 VHL R167Q (c.500G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 4 patients were found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167Q (c.500G>A) sequence variation in gene VHL/NCBI:7428 2799 check_entity AN6046-1 VHL R167Q (c.500G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20846682 26 VHL patients from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 12 patients from 4 families were confirmed to have the above mutation. Additional manifestations aside from pheochromocytoma are possible, but were not discussed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167Q (c.500G>A) sequence variation in gene VHL/NCBI:7428 2799 check_entity AN6046-1 VHL R167Q (c.500G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12114495 A study of 34 Polish families revealed germline mutations in 30 families. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). Arg167Trp and Arg167Gln mutations conferred a high (62%) risk for pheochromocytoma. Pheochromocytoma was diagnosed in all families with Arg167Gln mutation. This missense mutation was found in a VHL patient with retinal hemangioblastomas and pheochromocytoma (family no. 17). This mutation was also found in a VHL family of 8 affected patients (family no. 18). Seven had retinal hemangioblastomas, six had hemangioblastomas of the central nervous system, and 2 had pheochromocytoma. Cosegregation of the disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167Q (c.500G>A) sequence variation in gene VHL/NCBI:7428 2799 check_entity AN6046-1 VHL R167Q (c.500G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12624160 Germline mutations were found in 20 Brazilian, VHL probands and their families. This missense mutation was found in a VHL type 2 family of 4 affected individuals (VHL family 16). Two patients had hemangioblastomas of the central nervous system and three had pheochromocytoma. ACMG codes as follows: Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167Q (c.500G>A) sequence variation in gene VHL/NCBI:7428 2799 check_entity AN6046-1 VHL R167Q (c.500G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:29396065 A case report of a 51Y male patient presenting with headaches and a family history of VHL disease revealed multiple CNS hemangioblastomas, bilateral clear cell renal cell carcinomas, pheochromocytoma, and a pancreatic neuroendocrine tumor. A germline mutation of p.Arg167Trp was confirmed in the patient's VHL gene. ACMG: PP4 as patients phenotype and family history are highly specific for a disease with a single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167Q (c.500G>A) sequence variation in gene VHL/NCBI:7428 2799 check_entity AN6046-1 VHL R167Q (c.500G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:24132471 Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. Eleven patients were found with this missense varaint in the VHL gene. The ages of the patient was represented as a range, 21-65Y. The phenotypes were presented together: retinal hemangioblastoma, cerebellar hemangioblastoma, spinal cord hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumour, phenchromocytoma, renal cysts, and pancreatic cysts. Family history was not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167Q (c.500G>A) sequence variation in gene VHL/NCBI:7428 2799 check_entity AN6046-1 VHL R167Q (c.500G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26763786 A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. This mutation was present in 9 individuals of the 122 total number of variants captured in this population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167Q (c.500G>A) sequence variation in gene VHL/NCBI:7428 2799 check_entity AN6046-1 VHL R167Q (c.500G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 4 individuals from France or Italy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167Q (c.500G>A) sequence variation in gene VHL/NCBI:7428 2799 check_entity AN6046-1 VHL R167Q (c.500G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8634692 Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb), renal cell carcinoma (RCC), and pheochromocytoma was available. Case 5 had an R167Q (c.500G>A) mutation. 2 members were affected: 1 had RCC, CNS Hb, and retinal hemangioma. The other had CNS Hb and retinal hemangioma. (ACMG PP4) Other demographics of the members were not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167Q (c.500G>A) sequence variation in gene VHL/NCBI:7428 2799 check_entity AN6046-1 VHL R167Q (c.500G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12202531 A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, the missense mutation (c.500G>A (p.Arg167Gln)) was found in 10 patients total - 3 of which are stated to have retinal HBs and 7 are said to not. Other manifestations are possible but not clear. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167Q (c.500G>A) sequence variation in gene VHL/NCBI:7428 2799 check_entity AN6046-1 VHL R167Q (c.500G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1615 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167Q (c.500G>A) sequence variation in gene VHL/NCBI:7428 2799 check_entity AN6047-1 VHL R167W (c.499C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in four VHL type 2 families of 51 individuals altogether (family IDs 2338, 3490, 4477, 4405). 36 of 51 individuals had retinal hemangioblastomas, 17 had cerebellar hemangioblastomas, 16 with renal cell carcinoma, and 36 with pheochromocytomas. This mutation was also detected in a VHL type 1 patient with angiomas (family ID 3699). Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167W (c.499C>T) sequence variation in gene VHL/NCBI:7428 2800 check_entity AN6047-1 VHL R167W (c.499C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in six VHL type 2 families (lineages 202, 47, 102, 106, 153, 109). Two of these families (47 and 109) were previously reported in Chen et al 1995 or Zbar et al 1996. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167W (c.499C>T) sequence variation in gene VHL/NCBI:7428 2800 check_entity AN6047-1 VHL R167W (c.499C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21463266 In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This missense mutation was found in five VHL patients. The 13 yr old patient had pheochromocytoma (PH) (index case 164). The 25 yr old patient had pheochromocytoma and multiple renal cysts (index case 260). The 27 yr old patient had pheochromocytoma, hemangioblastomas of the central nervous system (CNS) and retinal hemangioblastoma (index case 6). The 30 yr old patient had CNS hemangioblastomas and pheochromocytoma (index case 217). The 33 yr old patient had retinal hemangioblastomas and multiple renal cysts (index case 44). Only supporting evidence for pathogenicity because patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167W (c.499C>T) sequence variation in gene VHL/NCBI:7428 2800 check_entity AN6047-1 VHL R167W (c.499C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 2A patient, a VHL type 2B patient and a family with 5 VHL type 2B patients (patient no. V30, V23, V1). This study contains strong evidence of pathogenicity for this variant because the prevalence of the variant in affected individuals is significantly increased compared with the prevalence In controls (ACMG code: PS4). The first two individuals had no family screened but 14 unaffected family members showed no evidence of this mutation in the family with 5 mutation-positive affected members. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167W (c.499C>T) sequence variation in gene VHL/NCBI:7428 2800 check_entity AN6047-1 VHL R167W (c.499C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:10761708 A previous study of 26 Japanese, VHL families was extended to 41 additional families. Germline mutations were detected in 55 of 77 Japanese families using SSCP, direct sequencing, and Southern Blot analysis of peripheral blood samples. This missense mutation was found in 4 unrelated VHL families. Family 19: 1 individual presenting with pheochromocytoma, renal cell carcinoma, CNS hemangioblastoma and retinal angioma. Family 31: pheochromocytoma (2/2), CNS hemangioblastoma (2/2) and renal cell carcinoma (1/2). Family 66: pheochromocytoma (1/2), CNS hemangioblastoma (1/2) and renal cell carcinoma (1/2). Family 102: pheochromocytoma (2/2), CNS hemangioblastoma (1/2) and retinal angioma (1/2). Patients from families 19 and 31 were previously published in PMID 8634692. ACMG codes as follows: Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). Patient's phenotype is highly specific for a disease with a single genetic etiology (PP4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167W (c.499C>T) sequence variation in gene VHL/NCBI:7428 2800 check_entity AN6047-1 VHL R167W (c.499C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 7 patients were found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167W (c.499C>T) sequence variation in gene VHL/NCBI:7428 2800 check_entity AN6047-1 VHL R167W (c.499C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20846682 26 VHL patients from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 2 patients from 2 families were confirmed to have the above mutation. Additional manifestations aside from pheochromocytoma are possible, but were not discussed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167W (c.499C>T) sequence variation in gene VHL/NCBI:7428 2800 check_entity AN6047-1 VHL R167W (c.499C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12624160 Germline mutations were found in 20 Brazilian, VHL probands and their families. This missense mutation was found in 2 affected family members with pheochromocytoma (VHL family 15). One also had hemangioblastomas of the central nervous system. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167W (c.499C>T) sequence variation in gene VHL/NCBI:7428 2800 check_entity AN6047-1 VHL R167W (c.499C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:22357542 Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This missense mutation was found in 4 VHL family members (proband no. 6). The 65-year-old father had renal cell carcinoma; The 37-year old sister had pancreatic cysts and the 33-year old sister had retinal angiomas. The 38-year-old proband had hemangioblastomas of the central nervous system, renal cell carcinoma, pancreatic cysts, and epididymal cystadenoma. Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167W (c.499C>T) sequence variation in gene VHL/NCBI:7428 2800 check_entity AN6047-1 VHL R167W (c.499C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12000816 Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and six patients with pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167W (c.499C>T) sequence variation in gene VHL/NCBI:7428 2800 check_entity AN6047-1 VHL R167W (c.499C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:24132471 Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. One patient was found with this missense varaint in the VHL gene. The patient was 43Y at the last follow-up and presented with: retinal hemangioblastoma, spinal cord hemangioblastoma, renal cell carcinoma, pheochromocytoma, and renal cysts. Family history was not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167W (c.499C>T) sequence variation in gene VHL/NCBI:7428 2800 check_entity AN6047-1 VHL R167W (c.499C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 3 individuals each from France, UK, and Germany. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167W (c.499C>T) sequence variation in gene VHL/NCBI:7428 2800 check_entity AN6047-1 VHL R167W (c.499C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:16042317 The 10 1/2 year old patient was diagnosed with adrenal incidentaloma. He had intermittent abdominal pain for 6 months. His blood pressure was normal. A CT scan showed a left adrenal solid tumor (3x3cm) with no calcifications and I-MIBG scintiography was normal. He underwent an adrenalectomy. He was found to have a point mutation in exon 3 (Arg167Trp) but neither parent had this mutation. Brain and spinal cord MRI, ophthalmoscopy, whole body CT scan and ultrasonography of the testes, showed no abnormalities. ACMG evidence codes: 'PS2' since both parents are tested and do not present with the variant (de novo), 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167W (c.499C>T) sequence variation in gene VHL/NCBI:7428 2800 check_entity AN6047-1 VHL R167W (c.499C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21382250 Patients' records in a tertiary care university hospital were reviewed. Fifty-four Black patients presenting with phaeochromocytoma between 1980 and 2009 were included. Two patients had VHL syndrome (submitted for publication). The second diagnosis of VHL syndrome was made in the pregnant woman (Case 9) who had bilateral adrenal phaeochromocytomas. There were no clinical features of VHL syndrome; however, MRI showed a haemangioblastoma in the cervical spine. Genetic testing revealed a missense mutation (c.499C>T) in the VHL gene, located on chromosome 3p26-p25. Her 6-year-old daughter screened positive for the mutation; her 8-year-old son was negative. Both mother and daughter will be investigated further and monitored long-term. ACMG PP4 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167W (c.499C>T) sequence variation in gene VHL/NCBI:7428 2800 check_entity AN6047-1 VHL R167W (c.499C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8634692 Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb) renal cell carcinoma (RCC), and pheochromocytoma was available. Case 19 had an R167W (c.499C>T) mutation. 1 member was affected with RCC, pheochromocytoma, CNS Hb, and retinal hemangioma (ACMG PP4). Other demographics of the members were not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167W (c.499C>T) sequence variation in gene VHL/NCBI:7428 2800 check_entity AN6047-1 VHL R167W (c.499C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1623 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R167W (c.499C>T) sequence variation in gene VHL/NCBI:7428 2800 check_entity AN6048-1 VHL R176fs (c.526del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal hemangioblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. VHL R176fs (c.526del) causes a frameshift, an early stop codon at amino acid 201, and was found in two VHL families of 3 patients. One patient had retinal hemangioblastomas, three had cerebellar hemangioblastomas, and one had renal cell carcinoma. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.526del) sequence variation in gene VHL/NCBI:7428 2801 check_entity AN6048-1 VHL R176fs (c.526del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1656 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.526del) sequence variation in gene VHL/NCBI:7428 2801 check_entity AN6049-1 VHL R177* (c.529A>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20518900 14 Chinese patients from 10 VHL Type I families were diagnosed with Von Hippel-Lindau disease based on clinical criteria. Germline mutations were identified in 7/10 families. In all 14 patients, the first manifestation of VHL disease was a central nervous system hemangioblastoma. Their mean age of neurological symptom onset was 24.5 years (range: 12–58 years). Genetic testing demonstrated that Patient 10 (from family VI) and Patient 11 (from family VII) carried this mutation. Patient 10 was reported to have a retinal hemangioblastoma, and patient 11 had a pancreatic tumor. ACMG evidence codes: 'PP4' because the patients' phenotypes and family history are highly specific for a disease with single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R177* (c.529A>T) sequence variation in gene VHL/NCBI:7428 2802 check_entity AN6049-1 VHL R177* (c.529A>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1703 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R177* (c.529A>T) sequence variation in gene VHL/NCBI:7428 2802 check_entity AN6050-1 VHL R177fs (c.528del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal hemangioblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. VHL R177fs (c.528del) causes a frameshift, a stop codon at amino acid 201, and was found in a VHL family of 7, 3 with cerebellar hemangioblastomas and 3 with renal cell carcinoma. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.528del) sequence variation in gene VHL/NCBI:7428 2803 check_entity AN6050-1 VHL R177fs (c.528del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. This mutation was found in a VHL type 1 family (kindred no. 54). This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.528del) sequence variation in gene VHL/NCBI:7428 2803 check_entity AN6050-1 VHL R177fs (c.528del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1783 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.528del) sequence variation in gene VHL/NCBI:7428 2803 check_entity AN6051-1 VHL R177ins (c.531insCTGAGAGTAAAGCCTGAA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This in-frame insertion mutation was found in 3 VHL type 1 family members (kindred no, V31), but not found in 3 unaffected family members. No specific VHL manifestations were discussed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.531insCTGAGAGTAAAGCCTGAA) sequence variation in gene VHL/NCBI:7428 2804 check_entity AN6051-1 VHL R177ins (c.531insCTGAGAGTAAAGCCTGAA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2057 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.531insCTGAGAGTAAAGCCTGAA) sequence variation in gene VHL/NCBI:7428 2804 check_entity AN6052-1 VHL R200W (c.598C>T) VHL NCBI:7428 gene familial erythrocytosis 2 DOID:0060474 risk 34502-5 PubMed:27518686 Homozygous VHL R200W mutations result in a rare congenital polycythemia known as Chuvash polycythemia. Treatment of 3 patients with this disease with the JAK1/2 inhibitor ruxolitinib led to symptomatic and hematologic improvements in all patients through 21-78 weeks of treatment. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R200W (c.598C>T) sequence variation in gene VHL/NCBI:7428 2805 check_entity AN6052-1 VHL R200W (c.598C>T) VHL NCBI:7428 gene familial erythrocytosis 2 DOID:0060474 risk 34502-5 CIViC:627 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R200W (c.598C>T) sequence variation in gene VHL/NCBI:7428 2805 check_entity AN6053-1 VHL R60FS (c.179delG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation causes a premature stop codon at amino acid 66 and was found in a VHL type 1 patient (patient no. V9). This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.179delG) sequence variation in gene VHL/NCBI:7428 2806 check_entity AN6053-1 VHL R60FS (c.179delG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1840 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.179delG) sequence variation in gene VHL/NCBI:7428 2806 check_entity AN6054-1 VHL R64P (c.191G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17661816 Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This missense mutation was found in a VHL type 2B family of 6 patients with the mutation, but incomplete penetrance (family no. 1; pedigree in Figure 2). A 59 yo carrier had no VHL manifestations but 2 unaffected children without the mutation and 2 children with the mutation, 1 with pheochromocytoma aged 32 and a 40 yo with no clinical manifestations. The 59 year old also had an affected family with the mutation - a parent (renal cell carcinoma) and a affected sibling (pheochromocytoma) and their child (paraganglioma) - and 4 unaffected siblings without the mutation. Only supporting evidence for pathogenicity because of cosegregation of the disease with multiple affected family in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R64P (c.191G>C) sequence variation in gene VHL/NCBI:7428 2807 check_entity AN6054-1 VHL R64P (c.191G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1743 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R64P (c.191G>C) sequence variation in gene VHL/NCBI:7428 2807 check_entity AN6055-1 VHL R69fs (c.204insG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21972040 Germline mutation analysis of seven east-Chinese families revealed 6 mutations. This mutation was found in a VHL type 1 male patient with hemangioblastomas of the central nervous system, retinal angiomas, and renal cell carcinomas (family G). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.204insG) sequence variation in gene VHL/NCBI:7428 2808 check_entity AN6055-1 VHL R69fs (c.204insG) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1824 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.204insG) sequence variation in gene VHL/NCBI:7428 2808 check_entity AN6056-1 VHL R79P (c.236G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Missense mutations were found to be more frequent among families affected by pheochromocytoma (VHL type 2) than in those in which pheochromocytoma had not occurred (VHL type 1). This mutation was found in a VHL patient (kindred no. 150). The presence of pheochromocytoma was not indicated. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R79P (c.236G>C) sequence variation in gene VHL/NCBI:7428 2809 check_entity AN6056-1 VHL R79P (c.236G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1667 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R79P (c.236G>C) sequence variation in gene VHL/NCBI:7428 2809 check_entity AN6057-1 VHL R79_S80del (c.236_241delGCAGTC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from Germany. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.236_241delGCAGTC) sequence variation in gene VHL/NCBI:7428 2810 check_entity AN6057-1 VHL R79_S80del (c.236_241delGCAGTC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2321 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.236_241delGCAGTC) sequence variation in gene VHL/NCBI:7428 2810 check_entity AN6058-1 VHL R82P (c.245G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12202531 A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations extracted from the French VHL database revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, this mutation was found in 3 VHL patients. 1 member was said to have retinal hemangioblastomas, while the other 2 were said not to have this phenotype. Other manifestations are not clearly stated. No family information or relation was provided. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R82P (c.245G>C) sequence variation in gene VHL/NCBI:7428 2811 check_entity AN6058-1 VHL R82P (c.245G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in 3 VHL type 2B family members (kindred no. V12), but not in 7 unaffected family members. ACMG evidence codes: 'PP2' because they observe a missense variant in gene where missense variants are common mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R82P (c.245G>C) sequence variation in gene VHL/NCBI:7428 2811 check_entity AN6058-1 VHL R82P (c.245G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1856 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R82P (c.245G>C) sequence variation in gene VHL/NCBI:7428 2811 check_entity AN6059-1 VHL R82_V84del (c.243_251del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma (VHL type 1) and 2 of 12 families with pheochromocytoma (VHL type 2). This mutation was found in a VHL type 1 patient (kindred no. 35). Only moderate support for pathogenicity because protein length changes as a result of in-frame deletions in a nonrepeat region (ACMG code: PM4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.243_251del) sequence variation in gene VHL/NCBI:7428 2812 check_entity AN6059-1 VHL R82_V84del (c.243_251del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). This mutation was found in a VHL type 1 family of 5 individuals. Four family members had retinal angiomas and 3 had hemangioblastomas of the central nervous system. Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). HPO terms: retinal hemangioblastoma, hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.243_251del) sequence variation in gene VHL/NCBI:7428 2812 check_entity AN6059-1 VHL R82_V84del (c.243_251del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1965 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.243_251del) sequence variation in gene VHL/NCBI:7428 2812 check_entity AN6060-1 VHL R82_V84del (c.244_252del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This in-frame deletion was found in a VHL type 1 family of 6 individuals (family ID 3177). Four of 6 individuals were identified with angiomas and 3 had CNS hemangioblastomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.244_252del) sequence variation in gene VHL/NCBI:7428 2813 check_entity AN6060-1 VHL R82_V84del (c.244_252del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2140 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.244_252del) sequence variation in gene VHL/NCBI:7428 2813 check_entity AN6061-1 VHL Rearrangement VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:24132471 Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. One patient was found with a VHL rearrangment determined by a southern blot. The patient was 25Y at the last follow-up and presented with: retinal hemangioblastoma, cerebellar hemangioblastoma, spinal cord hemangioblastoma, renal cysts and pancreatic cysts. Family history was not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene VHL/NCBI:7428 2814 check_entity AN6061-1 VHL Rearrangement VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26763786 A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. A rearrangement mutation was present in 4 individuals of the 122 total number of variants captured in this population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene VHL/NCBI:7428 2814 check_entity AN6061-1 VHL Rearrangement VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2312 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::rearrangement sequence variation in gene VHL/NCBI:7428 2814 check_entity AN6062-1 VHL S111C (c.330_331delinsTT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in a VHL type 2 family (lineage 174). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S111C (c.330_331delinsTT) sequence variation in gene VHL/NCBI:7428 2815 check_entity AN6062-1 VHL S111C (c.330_331delinsTT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1729 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S111C (c.330_331delinsTT) sequence variation in gene VHL/NCBI:7428 2815 check_entity AN6063-1 VHL S111C (c.331A>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12202531 A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations extracted from the French VHL database revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, this mutation was found in 3 VHL patients. All 3 members were said to have retinal hemangioblastomas, while other manifestations are not clearly stated. No family information or relation was provided. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S111C (c.331A>T) sequence variation in gene VHL/NCBI:7428 2816 check_entity AN6063-1 VHL S111C (c.331A>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. Statistics of the VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S111C (c.331A>T) sequence variation in gene VHL/NCBI:7428 2816 check_entity AN6063-1 VHL S111C (c.331A>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1921 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S111C (c.331A>T) sequence variation in gene VHL/NCBI:7428 2816 check_entity AN6064-1 VHL S111FS (c.331delA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This frameshift mutation was detected in a VHL type 1 patient with cerebellar hemangioblastomas (family ID 3669). Only supporting evidence for pathogenicity because the patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). Relevant HPO terms: Cerebellar hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.331delA) sequence variation in gene VHL/NCBI:7428 2817 check_entity AN6064-1 VHL S111FS (c.331delA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1638 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.331delA) sequence variation in gene VHL/NCBI:7428 2817 check_entity AN6065-1 VHL S111N (c.332G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in a VHL type 1 family of 4 individuals (family ID 3315). One of the 4 individuals was identified with retinal hemangioblastomas, 2 with cerebellar hemangioblastomas and 2 with renal cell carcinoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S111N (c.332G>A) sequence variation in gene VHL/NCBI:7428 2818 check_entity AN6065-1 VHL S111N (c.332G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. Statistics of the VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 2 individuals from the UK. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S111N (c.332G>A) sequence variation in gene VHL/NCBI:7428 2818 check_entity AN6065-1 VHL S111N (c.332G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1639 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S111N (c.332G>A) sequence variation in gene VHL/NCBI:7428 2818 check_entity AN6066-1 VHL S111R (c.333C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was detected in a VHL type 1 patient with cerebellar hemangioblastomas (family ID 4401). Only supporting evidence for pathogenicity because patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S111R (c.333C>G) sequence variation in gene VHL/NCBI:7428 2819 check_entity AN6066-1 VHL S111R (c.333C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12114495 A study of 34 Polish families revealed germline mutations in 30 families. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). This missense mutation was found in a VHL patient with hemangioblastomas of the central nervous system and retina (family no. 12). HPO terms: hemangioblastoma, retinal hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S111R (c.333C>G) sequence variation in gene VHL/NCBI:7428 2819 check_entity AN6066-1 VHL S111R (c.333C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1640 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S111R (c.333C>G) sequence variation in gene VHL/NCBI:7428 2819 check_entity AN6067-1 VHL S183* (c.548C>A) VHL NCBI:7428 gene renal cell carcinoma DOID:4450 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This nonsense mutation was found in 3 Italian, VHL type 1 family members. Two had retinal angiomas, 2 had hemangioblastomas of the central nervous system, 2 had renal cell carcinoma, and all three had pancreatic cysts. This study contains very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S183* (c.548C>A) sequence variation in gene VHL/NCBI:7428 2820 check_entity AN6067-1 VHL S183* (c.548C>A) VHL NCBI:7428 gene renal cell carcinoma DOID:4450 diagnostic 34502-5 CIViC:1660 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S183* (c.548C>A) sequence variation in gene VHL/NCBI:7428 2820 check_entity AN6067-2 VHL S183* (c.548C>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PVS1' because they observe a nonsense variant in a gene where loss of function is a known mechanism of disease . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S183* (c.548C>A) sequence variation in gene VHL/NCBI:7428 2821 check_entity AN6067-2 VHL S183* (c.548C>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26763786 A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. The c.548 C>A mutation was present in 3 individuals of the 122 total number of variants captured in this population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S183* (c.548C>A) sequence variation in gene VHL/NCBI:7428 2821 check_entity AN6067-2 VHL S183* (c.548C>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1660 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S183* (c.548C>A) sequence variation in gene VHL/NCBI:7428 2821 check_entity AN6068-1 VHL S65* (c.194C>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This nonsense mutation found in VHL type 1 family (lineage 80). This provides strong evidence of pathogenicity as it is a null variant in a gene where loss of function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65* (c.194C>A) sequence variation in gene VHL/NCBI:7428 2822 check_entity AN6068-1 VHL S65* (c.194C>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11409863 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This nonsense mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 83). This study contains very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65* (c.194C>A) sequence variation in gene VHL/NCBI:7428 2822 check_entity AN6068-1 VHL S65* (c.194C>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1687 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65* (c.194C>A) sequence variation in gene VHL/NCBI:7428 2822 check_entity AN6069-1 VHL S65A (c.193T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12000816 Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65A (c.193T>G) sequence variation in gene VHL/NCBI:7428 2823 check_entity AN6069-1 VHL S65A (c.193T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1887 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65A (c.193T>G) sequence variation in gene VHL/NCBI:7428 2823 check_entity AN6070-1 VHL S65FS (c.194delC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in a VHL type 2 family of 7 individuals. Three family members had retinal angiomas, 2 had hemangioblastomas of the cerebellum, 2 had renal cell carcinoma, and one had pheochromocytoma. ACMG codes as follows: A frameshift variant in a gene where loss-of-function is known mechanism of disease (PSV1). Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.194delC) sequence variation in gene VHL/NCBI:7428 2824 check_entity AN6070-1 VHL S65FS (c.194delC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2006 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.194delC) sequence variation in gene VHL/NCBI:7428 2824 check_entity AN6071-1 VHL S65L (c.194C>T) VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 risk 34502-5 PubMed:11505222 This study analyzed tumor and non-tumor kidney tissue from 195 unrelated patients with sporadic clear cell renal cell carcinoma (CCRCC) for a relationship between VHL variants in sporadic CCRCC and 'genotypes for genes encoding several carcinogen-metabolizing enzymes.' This missense variant was found in a 68 year-old male (tumour 311). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65L (c.194C>T) sequence variation in gene VHL/NCBI:7428 2825 check_entity AN6071-1 VHL S65L (c.194C>T) VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 risk 34502-5 CIViC:1664 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65L (c.194C>T) sequence variation in gene VHL/NCBI:7428 2825 check_entity AN6071-2 VHL S65L (c.194C>T) VHL NCBI:7428 gene renal carcinoma DOID:4451 risk 34502-5 PubMed:7915601 Tumors from 110 patients with sporadic renal carcinoma were analyzed for VHL mutations and loss of heterozygosity. 56 of the 98 samples from sporadic, clear cell renal carcinoma patients were identified with VHL somatic mutations; Loss of heterozygosity was observed in 97% of those samples. This missense mutation was found in one of the clear cell renal carcinoma cell lines (sample UOK164). No phenotype described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65L (c.194C>T) sequence variation in gene VHL/NCBI:7428 2826 check_entity AN6071-2 VHL S65L (c.194C>T) VHL NCBI:7428 gene renal carcinoma DOID:4451 risk 34502-5 CIViC:1664 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65L (c.194C>T) sequence variation in gene VHL/NCBI:7428 2826 check_entity AN6071-3 VHL S65L (c.194C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. This mutation was found in a VHL type 1 patient (kindred no. 52). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65L (c.194C>T) sequence variation in gene VHL/NCBI:7428 2827 check_entity AN6071-3 VHL S65L (c.194C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17661816 Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This mutation was found in a VHL type 1 patient with cerebellar hemangioblastomas, renal cell carcinoma, renal cysts, epididymal cyst, and pancreatic cysts (family no. 2). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65L (c.194C>T) sequence variation in gene VHL/NCBI:7428 2827 check_entity AN6071-3 VHL S65L (c.194C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. This missense mutation was found in 4 VHL families of 11 patients altogether. Ten had retinal hemangioblastomas, 4 had cerebellar hemangioblastomas, and 2 had renal cell carcinoma. ACMG codes as follows: supporting evidence for pathogenicity because of cosegregation of disease with multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). Two other amino acid changes at this site were also reported in this publication in association with disease (S65W and S65P). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma, Renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65L (c.194C>T) sequence variation in gene VHL/NCBI:7428 2827 check_entity AN6071-3 VHL S65L (c.194C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 2 patient (patient no. V209). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65L (c.194C>T) sequence variation in gene VHL/NCBI:7428 2827 check_entity AN6071-3 VHL S65L (c.194C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12114495 A study of 34 Polish families revealed germline mutations in 30 families. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). This missense mutation was found in a single VHL patient and 2 VHL families with multiple affected individuals. The patient had hemangioblastomas of the central nervous system (family no. 1). A VHL family of 4 affected individuals had one patient with retinal hemangioblastomas, 3 with hemangioblastomas of the central nervous system, and one with renal cell carcinoma (family no. 2). A VHL family of 12 individuals had 10 with retinal hemangioblastomas, 3 with renal cell carcinoma, and 12 with hemangioblastomas of the central nervous system (family no. 3). Supporting evidence of pathogenicity since there is cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). HPO terms: hemangioblastoma, retinal hemangioblastoma, renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65L (c.194C>T) sequence variation in gene VHL/NCBI:7428 2827 check_entity AN6071-3 VHL S65L (c.194C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:14722919 Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. This germline missense mutation was found in a 25 year old patient with cerebellar hemangioblastomas, and clear cell renal carcinoma (patient no. F62). The patient's family history was negative for VHL features. This evidence supports the following ACMG Code: PP4- Patient's phenotype is specific for a disease with a single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65L (c.194C>T) sequence variation in gene VHL/NCBI:7428 2827 check_entity AN6071-3 VHL S65L (c.194C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:28379443 Thirty-two surgically resected HB specimens from 28 patients treated at the University of Tokyo Hospital between 1995 and 2012 were analyzed retrospectively. Of the 32 specimens, 11 were VHL-related HBs from 7 patients, and 21 were sporadic HBs from 21 patients. One of the 7 VHL patients was a female patient with a c.194C>T (p.Ser65Leu) mutation in the VHL gene. She developed a CNS hemangioblastoma in the cerebellum at 19Y. It is unclear whether she had germline testing. However, the patient met clinical criteria for VHL (Losner et al., 2003). Interestingly, the HB from this patient was noted to have LOH of chromosome 3p. No other phenotypic information was available. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65L (c.194C>T) sequence variation in gene VHL/NCBI:7428 2827 check_entity AN6071-3 VHL S65L (c.194C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25834951 This retrospective study of 52 Danish patients with genetically confirmed VHL mutations analyzed the results of each individual's VHL-related examinations and manifestations diagnosed up to the time of study inclusion. All patients were enrolled in the Danish vHL surveillance program. Data was collected through detailed interviews and subsequent evaluation of each subject’s clinical, radiographic, and histological records. Genetic testing confirmed a germline VHL mutation at c.194C>T in four patients. Associated phenotypes, demographic, and family history is unknown. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65L (c.194C>T) sequence variation in gene VHL/NCBI:7428 2827 check_entity AN6071-3 VHL S65L (c.194C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26308528 A retrospective study reviewed cases of 23 patients with advanced and complicated VHL eye disease who underwent pars plana vitrectomy in the years 1999 to 2012. These inidiviuals were part of 223 VHL patients consulted at the International Hereditary Cancer Center and Polish VHL Registry. 22/23 patients received genetic molecular testing to identify germline mutations in the VHL gene. 24 eyes from 23 patients were studied. Patient #6 (35 years old) had the p.Ser65Leu (c.194C>T) mutation and a previous history of HbCNS and RCC. Patient # 16 (44 year old) also had this mutation, and had a previous history of HbCNS and RCC. Patient # 17 (20 year old) had this mutation, and had a previous history of HbCNS. Since patients were listed 'by eye' it is impossible to determine whether the three patients listed above actually represent 2 or 3 unique patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65L (c.194C>T) sequence variation in gene VHL/NCBI:7428 2827 check_entity AN6071-3 VHL S65L (c.194C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:23797736 240 ccRCC specimens were genetically analyzed. 3 specimens (ccRCC-58, ccRCC-154, ccRCC-238) from 3 different patients were confirmed to carry the p.Ser65Leu; c.194C>T mutation. The mutation was found to be germline in one male patient, age 27, who had contralateral kidney cancer. Family history and patient demographics are unknown. This patient was the source of ccRCC-238. This evidence supports AMCG code 'PM2' - Absent from controls (i.e. gnomAD). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65L (c.194C>T) sequence variation in gene VHL/NCBI:7428 2827 check_entity AN6071-3 VHL S65L (c.194C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:28388566 A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. A mutation c.194C>T (p.Ser65Leu) was found in 3 families (#4, #5, #6) with 11 genetically confirmed patients and 13 affected members in total. From family #4: one male patient presented with renal cell carcinoma at 33Y and pancreatic cysts or tumors at 33Y (mutation confirmed). From family #5: male proband with CNS haemangioblastoma at 21Y and multpile pancreatic cysts or tumours at 30Y (mutation confirmed), grandfather with CNS haemangioblastoma at 30Y (mutation status unknown), father with CNS haemangioblastoma at 36Y (mutation status unknown), and uncle with CNS haemangioblastoma at 33Y (mutation status unknown). From family #6: female proband with RCC at 36Y who then developed PCT at 37Y (mutation confirmed); daughter confirmed with the mutation but no manifestations and age unknown; mother with CNS hemangioblastoma diagnosed at 59Y (mutation confirmed); uncle 1 with CNS hemangioblastoma at 45Y, renal cell carcinoma at 59Y, and multiple pancreatic cysts or tumours at 65Y (mutation confirmed); son of uncle 1 with CNS hemangioblastoma at 22Y (mutation status unknown); Uncle 2 with CNS hemangioblastoma at 51Y, renal cell carcinoma at 51Y, and pancreatic cysts or tumours at 51Y (mutation status unknown); 1st son of uncle 2 with CNS hemangioblastoma at 22Y, renal cell carcinoma at 30Y, and pancreatic cysts or tumours at 31Y (mutation confirmed); 2nd son of uncle 2 with mutation confirmed but no manifestations and age unknown; granddaughter of uncle 2 with mutation confirmed but no manifestations and age unknown; Uncle 3 with multiple pancreatic cysts or tumours at 49Y (mutation confirmed); Aunt with CNS hemangioblastoma at 53Y and retinal angioma at 53Y (mutation confirmed). This evidence supports the following ACMG Codes: PP4 - the patient's phenotype and family history are highly specific for a disease with single genetic etiology, PP1- Co-segregation with disease in multiple affected family members (.e. family #6), PM2 - Absent from controls (i.e. gnomAD) assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65L (c.194C>T) sequence variation in gene VHL/NCBI:7428 2827 check_entity AN6071-3 VHL S65L (c.194C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1664 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65L (c.194C>T) sequence variation in gene VHL/NCBI:7428 2827 check_entity AN6072-1 VHL S65P (c.193T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). This missense mutation was found in a VHL patient with retinal hemangioblastomas and cerebellar hemangioblastomas. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65P (c.193T>C) sequence variation in gene VHL/NCBI:7428 2828 check_entity AN6072-1 VHL S65P (c.193T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1779 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65P (c.193T>C) sequence variation in gene VHL/NCBI:7428 2828 check_entity AN6073-1 VHL S65W (c.194C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in a VHL type 1 family of four individuals (family ID 4325). Three of 4 individuals were identified with retinal hemangioblastomas and one with cerebellar hemangioblastomas. Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65W (c.194C>G) sequence variation in gene VHL/NCBI:7428 2829 check_entity AN6073-1 VHL S65W (c.194C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. This mutation was found in a VHL type 1 patient (kindred no. 25). Supporting evidence for pathogenicity because of a missense mutation in a gene where missense variants are a common mechanism of disease (ACMG code: PP2). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65W (c.194C>G) sequence variation in gene VHL/NCBI:7428 2829 check_entity AN6073-1 VHL S65W (c.194C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8730290 In a study of 138 unrelated VHL families, 109 germline mutations were found. Missense mutations were more frequently found in families with pheochromocytoma. Deletions. Nonsense, and frameshift mutations were more frequently found in families without pheochromocytoma. Large deletions and mutations predicted to cause truncated protein were associated with lower risk pheochromocytoma. This missense mutation was found in one of the VHL families (family ID 39). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65W (c.194C>G) sequence variation in gene VHL/NCBI:7428 2829 check_entity AN6073-1 VHL S65W (c.194C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17661816 Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This missense mutation was detected in a VHL type 1 patient with retinal and cerebellar hemangioblastoma, renal cell carcinoma, and renal and pancreatic cysts (family no. 3). ACMG codes: PP4. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65W (c.194C>G) sequence variation in gene VHL/NCBI:7428 2829 check_entity AN6073-1 VHL S65W (c.194C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in a VHL type 1 family (lineage 53). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65W (c.194C>G) sequence variation in gene VHL/NCBI:7428 2829 check_entity AN6073-1 VHL S65W (c.194C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Higher risk of pheochromocytoma was associated with missense mutations that result in substitution of a surface amino acid (p<=0.004) than for patients with missense mutations that disrupt the structural integrity of the VHL gene product (pVHL) or other loss of function mutations (either germline deletions or truncating mutations). A missense mutation, affecting residue within the pVHL protein core, was found in a VHL family with 8 affected individuals including 6 with retinal hemangioblastomas, 5 with cerebellar hemangioblastomas, and 1 with renal cell carcinoma. ACMG codes as follows: supporting evidence for pathogenicity because of cosegregation of disease with multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65W (c.194C>G) sequence variation in gene VHL/NCBI:7428 2829 check_entity AN6073-1 VHL S65W (c.194C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21463266 In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, and none were present in 200 unaffected control individuals. This missense variant was found in a 33 yr old VHL patient with pancreatic cyst or tumour, renal cystic lesion and CNS hemangioblastoma (index case 214). ACMG codes as follows: supporting evidence of pathogenicity because Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology (PP4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65W (c.194C>G) sequence variation in gene VHL/NCBI:7428 2829 check_entity AN6073-1 VHL S65W (c.194C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20518900 14 Chinese patients from 10 families were diagnosed with Von Hippel-Lindau disease based on clinical criteria. Genetic testing demonstrated 2 members (Patient 1 and 2) of a single family (Family I) harbored the above mutation. Clinical manifestations in this family included: CNS hemangioblastoma and retinal hemangioblastoma. ACMG evidence codes: PP4 - because the patients' phenotypes and family history are highly specific for a disease with single genetic etiology; PP1 - cosegregation with disease in multiple affected family members in a gene definitively known to cause disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65W (c.194C>G) sequence variation in gene VHL/NCBI:7428 2829 check_entity AN6073-1 VHL S65W (c.194C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:22156657 The study looked to evaluate growth kinetic in VHL-associated renal cell carcinoma. Of the 64 VHL patients with renal involvement, 61 were confirmed to have a germline variant. This variant was identified in one patient (Patient #3 - supplementary table). Clinical manifestations included renal cell carcinoma; other manifestations were not discussed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65W (c.194C>G) sequence variation in gene VHL/NCBI:7428 2829 check_entity AN6073-1 VHL S65W (c.194C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:23384228 A case report of a Chinese family with mosaic VHL is described. The proband first came to medical attention with bilateral renal cell carcinoma, renal cysts, and pancreatic cysts. However, she initially tested negative for VHL. Her daughter presented with spinal hemangioblastoma, and upon genetic testing was found to have the above mutation. The probands' DNA was reexamined and was determined to harbour the above mutation in approximately 18% of peripheral leukocytes. ACMG evidence codes: 'PP4' because the patient's phenotypes or family history are highly specific for a disease with single genetic etiology, 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65W (c.194C>G) sequence variation in gene VHL/NCBI:7428 2829 check_entity AN6073-1 VHL S65W (c.194C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:22357542 Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This missense mutation was found in a 40 year old type 1 VHL patient with hemangioblastomas of the central nervous system, renal cell carcinoma, and pancreatic cysts (proband no. 1) but no family history. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65W (c.194C>G) sequence variation in gene VHL/NCBI:7428 2829 check_entity AN6073-1 VHL S65W (c.194C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:28650583 37 Danish patients diagnosed with VHL before 18 years from a prospective cohort study from Denmark's National vHL Research Database (Binderup et al., 2013) were assessed. Two families (Family ID 9 and 13) were found with a germline missense mutation in the VHL gene (S65W; c.194C>G). Family ID9 had 3 patients: Patient 1 and 2 were both diagnosed at 0Y and had no manifestations by the end of the study at 5Y and 10Y respectively. Patient 3 was diagnosed at 16Y and developed 2 CNS hemangioblastomas at 16Y and 2 pancreatic cysts at 16Y. Family ID13 had 1 patient who was diagnosed at age 13Y and had 8 retinal hemangioblastomas at 13Y, 16Y, 17Y, and 18Y, 1 pancreatic cyst at 17Y, and 1 CNS hemangioblastoma at 17Y. ACMG codes: PM1, PM5, PS3; and PP5. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65W (c.194C>G) sequence variation in gene VHL/NCBI:7428 2829 check_entity AN6073-1 VHL S65W (c.194C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26622630 A 33 year old Asian male patient presented with advanced bilateral multicentric renal carcinoma. Genetic testing confirmed a de novo missense variant at c.194C>G of the VHL gene. The patient was diagnosed with an epididymal cyst at age 23, bilateral retinal angiomatosis at age 26, and bilateral clear cell renal cell carcinoma at age 33. ACMG codes:PM1; PM5; and PP4. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65W (c.194C>G) sequence variation in gene VHL/NCBI:7428 2829 check_entity AN6073-1 VHL S65W (c.194C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25834951 The national cohort study describes how the rate of new tumor development varies through the lifetimes of VHL patients and how it is influenced by age and genotype. This study included 52 VHL mutation carriers who were retrospectively followed for a total of 799 person-years. From birth to current age, 581 manifestations were diagnosed during 2,583 examinations in the study subjects. Genetic testing confirmed a germline variant at c.194C>G of the VHL gene in two patients. Detailed phenotype, demographic, and family history information was not available for the 2 patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65W (c.194C>G) sequence variation in gene VHL/NCBI:7428 2829 check_entity AN6073-1 VHL S65W (c.194C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:28388566 A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. The c.194C>G (p.Ser65Trp) variant was found in a 48Y patient with RCC and multiple pancreatic cysts or tumours, and his son who had a CNS hemangioblastoma at 22Y. The patient's mother and brother had CNS hemangioblastomas at age 61 and 33 respectively, although genotypic confirmation was not available. This variant was also found in an unrelated woman with CNS hemangioblastoma diagnosed at age 34Y, and renal cell carcinoma and multiple pancreatic cysts or tumours diagnosed at age 37Y. ACMG codes: PM2 -absent from controls in GnomAD; PP4 - patient's phenotype or FHx is highly specific for a disease with a single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65W (c.194C>G) sequence variation in gene VHL/NCBI:7428 2829 check_entity AN6073-1 VHL S65W (c.194C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1663 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S65W (c.194C>G) sequence variation in gene VHL/NCBI:7428 2829 check_entity AN6074-1 VHL S68P (c.202T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17661816 Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This mutation was detected in a VHL family with 2 individuals with retinal hemangioblastomas (family no. 4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S68P (c.202T>C) sequence variation in gene VHL/NCBI:7428 2830 check_entity AN6074-1 VHL S68P (c.202T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1749 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S68P (c.202T>C) sequence variation in gene VHL/NCBI:7428 2830 check_entity AN6075-1 VHL S68W (c.203C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12000816 Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S68W (c.203C>G) sequence variation in gene VHL/NCBI:7428 2831 check_entity AN6075-1 VHL S68W (c.203C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1888 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S68W (c.203C>G) sequence variation in gene VHL/NCBI:7428 2831 check_entity AN6076-1 VHL S72P (c.214T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting residue on the surface of pVHL, was found in two VHL families of 4 patients altogether. One patient had retinal hemagioblastomas and two had cerebellar hemangioblastomas. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S72P (c.214T>C) sequence variation in gene VHL/NCBI:7428 2832 check_entity AN6076-1 VHL S72P (c.214T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1780 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S72P (c.214T>C) sequence variation in gene VHL/NCBI:7428 2832 check_entity AN6077-1 VHL S72fs (c.214del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal hemangioblastoma and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation causes a frameshift, an early stop codon at amino acid 158, and was found in a VHL family with 3 affected members: 2 had retinal hemangioblastoma, 2 had cerebellar hemangioblastomas, and 1 had renal cell carcinoma. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.214del) sequence variation in gene VHL/NCBI:7428 2833 check_entity AN6077-1 VHL S72fs (c.214del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1692 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.214del) sequence variation in gene VHL/NCBI:7428 2833 check_entity AN6078-1 VHL S80I (c.239G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was detected in a type 1 VHL patient with retinal hemangioblastomas and cerebellar hemangioblastomas (family ID 3630). Only supporting evidence for pathogenicity because patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S80I (c.239G>T) sequence variation in gene VHL/NCBI:7428 2834 check_entity AN6078-1 VHL S80I (c.239G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11409863 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This missense mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 104). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S80I (c.239G>T) sequence variation in gene VHL/NCBI:7428 2834 check_entity AN6078-1 VHL S80I (c.239G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1633 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S80I (c.239G>T) sequence variation in gene VHL/NCBI:7428 2834 check_entity AN6079-1 VHL S80N (c.239G>A) VHL NCBI:7428 gene renal cell carcinoma DOID:4450 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found in a Slovakian, VHL type 1 family of 13 affected individuals. Seven had retinal angiomas, 7 had hemangioblastomas of the central nervous system, 5 had renal cell carcinoma, one had pancreatic cysts, and one had pancreatic islet cell tumors (family VHL 39). This study contains supporting evidence for pathogenicity due to cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S80N (c.239G>A) sequence variation in gene VHL/NCBI:7428 2835 check_entity AN6079-1 VHL S80N (c.239G>A) VHL NCBI:7428 gene renal cell carcinoma DOID:4450 diagnostic 34502-5 CIViC:1750 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S80N (c.239G>A) sequence variation in gene VHL/NCBI:7428 2835 check_entity AN6079-2 VHL S80N (c.239G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in two VHL type 1 family members (patient no. V19). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S80N (c.239G>A) sequence variation in gene VHL/NCBI:7428 2836 check_entity AN6079-2 VHL S80N (c.239G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12000816 Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S80N (c.239G>A) sequence variation in gene VHL/NCBI:7428 2836 check_entity AN6079-2 VHL S80N (c.239G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11409863 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This missense mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 82). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S80N (c.239G>A) sequence variation in gene VHL/NCBI:7428 2836 check_entity AN6079-2 VHL S80N (c.239G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1750 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S80N (c.239G>A) sequence variation in gene VHL/NCBI:7428 2836 check_entity AN6080-1 VHL S80R (c.238A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 1 patient (patient no. V259). This S80R variant was not detected in 2 unaffected family members. An additional 2 unrelated, affected individuals had the similar S80N missense mutation in this study. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S80R (c.238A>C) sequence variation in gene VHL/NCBI:7428 2837 check_entity AN6080-1 VHL S80R (c.238A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12202531 Study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. This missense mutation was found in a VHL patient with retinal hemangioblastomas. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S80R (c.238A>C) sequence variation in gene VHL/NCBI:7428 2837 check_entity AN6080-1 VHL S80R (c.238A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12624160 Germline mutations were found in 20 Brazilian, VHL probands and their families. This missense mutation was found in a VHL type 1 family of 10 affected individuals (VHL family 2). Seven had hemangioblastomas of the central nervous system, 3 had retinal angiomas, and 3 had renal carcinoma. Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S80R (c.238A>C) sequence variation in gene VHL/NCBI:7428 2837 check_entity AN6080-1 VHL S80R (c.238A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1839 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S80R (c.238A>C) sequence variation in gene VHL/NCBI:7428 2837 check_entity AN6081-1 VHL S80R (c.240T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Missense mutations were found to be more frequent among families affected by pheochromocytoma (VHL type 2) than in those which pheochromocytoma had not occurred (VHL type 1). This mutation was found in a VHL type 1 patient (kindred no. 103). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S80R (c.240T>G) sequence variation in gene VHL/NCBI:7428 2838 check_entity AN6081-1 VHL S80R (c.240T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S80R (c.240T>G) sequence variation in gene VHL/NCBI:7428 2838 check_entity AN6081-1 VHL S80R (c.240T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1668 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::S80R (c.240T>G) sequence variation in gene VHL/NCBI:7428 2838 check_entity AN6082-1 VHL S80fs (c.239del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8634692 Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb) renal cell carcinoma (RCC), and pheochromocytoma was available. Case 22 had p.Ser80fs (c.239del) mutation. One member was affected with retinal capillary hemangioma and hemangioblastoma (ACMG PP4). Other demographics of the members were not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.239del) sequence variation in gene VHL/NCBI:7428 2839 check_entity AN6082-1 VHL S80fs (c.239del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2384 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.239del) sequence variation in gene VHL/NCBI:7428 2839 check_entity AN6083-1 VHL Splice Region (c.340+5G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21972040 Germline mutation analysis of seven east-Chinese families revealed 6 mutations. This splice-site alteration was found in two VHL type 2A female family members with hemangioblastomas of the central nervous system. Mutation was also found in a male VHL type 2A family member with hemangioblastomas of the central nervous system and pheochromocytomas (family C). This study contains very strong evidence for pathogenicity in the form of a splice-site variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.340+5G>C) sequence variation in gene VHL/NCBI:7428 2840 check_entity AN6083-1 VHL Splice Region (c.340+5G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1980 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.340+5G>C) sequence variation in gene VHL/NCBI:7428 2840 check_entity AN6084-1 VHL Splice Region (c.463+8C>T) VHL NCBI:7428 gene adrenal gland pheochromocytoma DOID:0050892 diagnostic 34502-5 PubMed:9663592 Screening of 68 patients, who had been operated on for apparently sporadic pheochromocytomas, for germline mutations in the VHL gene. This splice variant causes a premature stop codon at amino acid 66 and was found in a 33 year-old male with unilateral, benign, adrenal pheochromocytoma (patient no. 54). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.463+8C>T) sequence variation in gene VHL/NCBI:7428 2841 check_entity AN6084-1 VHL Splice Region (c.463+8C>T) VHL NCBI:7428 gene adrenal gland pheochromocytoma DOID:0050892 diagnostic 34502-5 CIViC:2168 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.463+8C>T) sequence variation in gene VHL/NCBI:7428 2841 check_entity AN6085-1 VHL Splice Site (c.340+1G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17661816 Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This mutation was detected in a VHL patient with renal cell carcinoma (family no. 31). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.340+1G>A) sequence variation in gene VHL/NCBI:7428 2842 check_entity AN6085-1 VHL Splice Site (c.340+1G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20518900 14 Chinese patients from 10 families were diagnosed with Von Hippel-Lindau disease based on clinical criteria. Genetic testing demonstrated 1 member of a single family harbored the above mutation. Clinical manifestations in this family included: CNS hemangioblastoma. ACMG evidence codes: 'PVS1' because they observe a canonical +1 splice site variant in a gene where loss of function is a known mechanism of disease. Relevant HPO terms: Hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.340+1G>A) sequence variation in gene VHL/NCBI:7428 2842 check_entity AN6085-1 VHL Splice Site (c.340+1G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:23298237 Genetic analysis of 7 Hungarian individuals from 5 unrelated families affected with von Hippel-Lindau disease revealed 5 different mutations, 3 of which were novel. The mutations could not be found within 100 healthy controls. The above mutation was found in 2 members (father and daughter) of a single family. The mutation was absent in two healthy family members. The mutation destroys the conserved intronic donor splice site and likely leads to premature protein termination (G114Dfs*6). The 12-year-old daughter had retinal and spinal hemangioblastoma, while the 34-year-old father had retinal, spinal, and cerebellar hemangioblastoma, and bilateral clear cell renal cell carcinoma. ACMG evidence codes: 'PVS1' because they observe a canonical +1 splice site variant in a gene where loss of function is a known mechanism of disease, 'PP4' because the patient's phenotypes or family history are highly specific for a disease with single genetic etiology, 'PP1' because of segregation results. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.340+1G>A) sequence variation in gene VHL/NCBI:7428 2842 check_entity AN6085-1 VHL Splice Site (c.340+1G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25952756 A study describing phenotypic and genotypic characteristics of VHL in an Indian population of 31 subjects, from 15 families diagnosed with VHL. Multi-cystic pancreas and CNS hemangioblastomas were the most common manifestations in this population. This splice site mutation was found in a VHL family of 8 individuals(family ID AD). 3 family members had renal cell carcinoma, 4 had hemangioblastomas of the central nervous system, 7 had multi-cystic pancreatic lesions, and 1 had retinal hemangioblastomas. ACMG codes as follows: A splice-site variant in a gene where loss-of-function is a known mechanism of disease (PVS1), patient's phenotypes or family history are highly specific for a disease with single genetic etiology (PP4), cosegregation with the disease in multiple affected family members in a gene definitively known to cause the disease (PP1). Relevant HPO terms: Hemangioblastoma, Retinal hemangioblastoma, Renal cell carcinoma, Multiple pancreatic cysts. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.340+1G>A) sequence variation in gene VHL/NCBI:7428 2842 check_entity AN6085-1 VHL Splice Site (c.340+1G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:24132471 Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. One patient was found with this splice varaint in the VHL gene. The patient was 32Y at the last follow-up and presented with: retinal hemangioblastoma, cerebellar hemangioblastoma, spinal cord hemangioblastoma, renal cell carcinoma, renal cysts and pancreatic cysts. Family history was not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.340+1G>A) sequence variation in gene VHL/NCBI:7428 2842 check_entity AN6085-1 VHL Splice Site (c.340+1G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11148816 41 non-related patients with retinal capillary hemangioma presenting in the Benjamin Franklin University Eye Clinic between 1988 to 1999 Germany were evaluated for the presence of other VHL lesions. VHL disease was diagnosed in 33 patients based on the presence of other severe VHL lesions (spinal hemangioblastoma, cerebellar hemangioblastoma, renal cysts, pancreatic cyst, renal carcinoma, and pheochromocytoma), molecular genetic testing, and/or family history. VHL germline mutations were identified in 27 out of 29 VHL families screened with molecular genetics. One patient with VHL-related retinal angiomatosis was found to have germline splicing (c.340+1G>A) mutation in the VHL gene. The other VHL lesions harbored by this patient were not specified. ACMG evidence codes: 'PP4' because the patient's phenotype is highly specific for a disease with single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.340+1G>A) sequence variation in gene VHL/NCBI:7428 2842 check_entity AN6085-1 VHL Splice Site (c.340+1G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1990 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.340+1G>A) sequence variation in gene VHL/NCBI:7428 2842 check_entity AN6086-1 VHL Splice Site (c.341-2A>C) VHL NCBI:7428 gene renal cell carcinoma DOID:4450 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. This mutation was found in a VHL type 2 patient with retinal angiomas, hemangioblastomas of the central nervous system, renal cell carcinoma, and pheochromocytoma. There is very strong evidence for pathogenicity in the form of a splice-site variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.341-2A>C) sequence variation in gene VHL/NCBI:7428 2843 check_entity AN6086-1 VHL Splice Site (c.341-2A>C) VHL NCBI:7428 gene renal cell carcinoma DOID:4450 diagnostic 34502-5 CIViC:2009 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.341-2A>C) sequence variation in gene VHL/NCBI:7428 2843 check_entity AN6086-2 VHL Splice Site (c.341-2A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17661816 Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This splice mutation was found in VHL patient with hemangioblastomas of the retina and central nervous system, renal cell carcinoma, and pancreatic cysts (family no. 32). ACMG evidence codes: 'PSV1' because they observe a splice-site variant in a gene where loss-of-function is known mechanism of disease, 'PP4' because the patients' phenotypes or family history are highly specific for a disease with single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.341-2A>C) sequence variation in gene VHL/NCBI:7428 2844 check_entity AN6086-2 VHL Splice Site (c.341-2A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2009 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.341-2A>C) sequence variation in gene VHL/NCBI:7428 2844 check_entity AN6087-1 VHL Splice Site (c.463+1G>C) VHL NCBI:7428 gene renal cell carcinoma DOID:4450 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This splice mutation was found in a German, VHL type 1 patient with retinal angiomas, hemangioblastomas of the central nervous system, renal cell carcinoma, and pancreatic cysts (family VHL 45). This study contains very strong evidence of pathogenicity in the form of a canonical +1 splice site variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.463+1G>C) sequence variation in gene VHL/NCBI:7428 2845 check_entity AN6087-1 VHL Splice Site (c.463+1G>C) VHL NCBI:7428 gene renal cell carcinoma DOID:4450 diagnostic 34502-5 CIViC:1874 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.463+1G>C) sequence variation in gene VHL/NCBI:7428 2845 check_entity AN6088-1 VHL Splice Site (c.463+2T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This splice mutation was found in a Croatian, VHL type 1 family of 3. Each individual had retinal angiomas, one had hemangioblastomas of the central nervous system, one had renal cell carcinoma, and one had pancreatic cysts (family VHL 7). This study contains very strong evidence of pathogenicity in the form of a canonical +2 splice site variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.463+2T>C) sequence variation in gene VHL/NCBI:7428 2846 check_entity AN6088-1 VHL Splice Site (c.463+2T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:22156657 64 VHL patients with renal involvement were analyzed. 61 of the 64 patients had a known germline mutation. The above mutation was found in 2 patients. Clinical manifestations included renal cell carcinoma; other manifestations are possible, but not discussed. ACMG evidence codes: 'PSV1' because they observe a canonical +2 splice site variant in a gene where loss of function is a known mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.463+2T>C) sequence variation in gene VHL/NCBI:7428 2846 check_entity AN6088-1 VHL Splice Site (c.463+2T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:24132471 Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. One patient was found with this splice varaint in the VHL gene. The patient was 31Y at the last follow-up and presented with: retinal hemangioblastoma, cerebellar hemangioblastoma, spinal cord hemangioblastoma, renal cell carcinoma, and renal cysts. Family history was not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.463+2T>C) sequence variation in gene VHL/NCBI:7428 2846 check_entity AN6088-1 VHL Splice Site (c.463+2T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 2 individuals from Germany. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.463+2T>C) sequence variation in gene VHL/NCBI:7428 2846 check_entity AN6088-1 VHL Splice Site (c.463+2T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1951 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.463+2T>C) sequence variation in gene VHL/NCBI:7428 2846 check_entity AN6089-1 VHL Splice Site (c.464-1G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This splice mutation was found in a German, VHL type 1 patient with hemangioblastomas of the central nervous system (family VHL 48). This study contains very strong evidence of pathogenicity in the form of a canonical -1 splice site variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.464-1G>A) sequence variation in gene VHL/NCBI:7428 2847 check_entity AN6089-1 VHL Splice Site (c.464-1G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1850 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.464-1G>A) sequence variation in gene VHL/NCBI:7428 2847 check_entity AN6090-1 VHL Splice Site (c.464-1G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in 2 unrelated VHL families with 4 individuals total. Three had hemangioblastomas of the cerebellum, 4 had retinal angiomas, and 2 had renal cell carcinoma. There is very strong evidence for pathogenicity in the form of a splice-site variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.464-1G>C) sequence variation in gene VHL/NCBI:7428 2848 check_entity AN6090-1 VHL Splice Site (c.464-1G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1953 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.464-1G>C) sequence variation in gene VHL/NCBI:7428 2848 check_entity AN6091-1 VHL Splice Site (c.464-1G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8641976 Blood samples from 5 Japanese families revealed 4 germline mutations. This mutation was found in a family of 10 individuals. Three VHL patients were identified with hemangioblastomas of the central nervous system and retinal angiomas (family C). The eldest patient also had renal cell carcinoma (listed as C-1 in publication). This study contains very strong evidence of pathogenicity in the form of a canonical -1 splice site mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.464-1G>T) sequence variation in gene VHL/NCBI:7428 2849 check_entity AN6091-1 VHL Splice Site (c.464-1G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma (VHL type 1) and 2 of 12 families with pheochromocytoma (VHL type 2). This splice mutation was found in a VHL type 1 patient (kindred no. 143). This study contains very strong evidence for pathogenicity in the form of a canonical -1 splice site mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.464-1G>T) sequence variation in gene VHL/NCBI:7428 2849 check_entity AN6091-1 VHL Splice Site (c.464-1G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1866 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.464-1G>T) sequence variation in gene VHL/NCBI:7428 2849 check_entity AN6092-1 VHL Splice Site (c.464-2A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 2 patients were found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.464-2A>G) sequence variation in gene VHL/NCBI:7428 2850 check_entity AN6092-1 VHL Splice Site (c.464-2A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. This splice mutation was found in a VHL type 1 family of 3 individuals. One family member had retinal angiomas and 2 had hemangioblastomas of the central nervous system. There is very strong evidence for pathogenicity in the form of a splice-site variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). HPO terms: retinal hemangioblastoma, hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.464-2A>G) sequence variation in gene VHL/NCBI:7428 2850 check_entity AN6092-1 VHL Splice Site (c.464-2A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This splice mutation was found in a German, VHL type 1 family. Only one affected patient was identified with retinal angiomas, hemangioblastomas of the central nervous system, renal cell carcinoma, pancreatic cysts and cystadenomas of the epididymis. (family VHL 31). HPO terms: hemangioblastomas, retinal hemangioblastomas, renal cell carcinoma, multiple pancreatic cysts, papillary cystadenomas of the broad ligament. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.464-2A>G) sequence variation in gene VHL/NCBI:7428 2850 check_entity AN6092-1 VHL Splice Site (c.464-2A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1954 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.464-2A>G) sequence variation in gene VHL/NCBI:7428 2850 check_entity AN6093-1 VHL Splice Site (c.464-2A>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This splice mutation was found in a German, VHL type 1 family. Only one affected patient was identified with hemangioblastomas of the central nervous system, renal cell carcinoma, and pancreatic cysts. (family VHL 57). This study contains very strong evidence of pathogenicity in the form of a canonical -2 splice variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.464-2A>T) sequence variation in gene VHL/NCBI:7428 2851 check_entity AN6093-1 VHL Splice Site (c.464-2A>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1868 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.464-2A>T) sequence variation in gene VHL/NCBI:7428 2851 check_entity AN6094-1 VHL T105P (c.313A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in VHL type 1 family (lineage 208). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T105P (c.313A>C) sequence variation in gene VHL/NCBI:7428 2852 check_entity AN6094-1 VHL T105P (c.313A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in 14 VHL type 1 family members (patient no. V8). This study contains supporting evidence of pathogenicity due to cosegregation with disease in multiple affected family members (14 affected, 13 unaffected) in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T105P (c.313A>C) sequence variation in gene VHL/NCBI:7428 2852 check_entity AN6094-1 VHL T105P (c.313A>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1715 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T105P (c.313A>C) sequence variation in gene VHL/NCBI:7428 2852 check_entity AN6095-1 VHL T133fs (c.397del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This mutation causes an early stop codon at position 158 and was found in a VHL type 1 family (lineage 64). This provides strong evidence of pathogenicity as it is a null variant in a gene where loss of function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.397del) sequence variation in gene VHL/NCBI:7428 2853 check_entity AN6095-1 VHL T133fs (c.397del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.397del) sequence variation in gene VHL/NCBI:7428 2853 check_entity AN6095-1 VHL T133fs (c.397del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1719 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.397del) sequence variation in gene VHL/NCBI:7428 2853 check_entity AN6096-1 VHL T152fs (c.455insA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. This mutation was found in a VHL type 1 patient (kindred no. 151). This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.455insA) sequence variation in gene VHL/NCBI:7428 2854 check_entity AN6096-1 VHL T152fs (c.455insA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. VHL T152fs (c.455insA) was found in a VHL patient with retinal angiomas. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.455insA) sequence variation in gene VHL/NCBI:7428 2854 check_entity AN6096-1 VHL T152fs (c.455insA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1967 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.455insA) sequence variation in gene VHL/NCBI:7428 2854 check_entity AN6097-1 VHL T157I (c.470C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This mutation was found in 2 family members with VHL disease (family ID 4402). One carried pheochromocytoma and both carried retinal hemangioblastoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T157I (c.470C>T) sequence variation in gene VHL/NCBI:7428 2855 check_entity AN6097-1 VHL T157I (c.470C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 2A patient (patient no. V240). No unaffected family members were tested. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T157I (c.470C>T) sequence variation in gene VHL/NCBI:7428 2855 check_entity AN6097-1 VHL T157I (c.470C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26763786 A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. This mutation was present in 2 individuals of the 122 total number of variants captured in this population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T157I (c.470C>T) sequence variation in gene VHL/NCBI:7428 2855 check_entity AN6097-1 VHL T157I (c.470C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs in the VHL registries of the participating centers in Europe were identified and included in the International Endolymphatic Sac Tumor Registry. The statistics of this registry is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. Only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from Italy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T157I (c.470C>T) sequence variation in gene VHL/NCBI:7428 2855 check_entity AN6097-1 VHL T157I (c.470C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8634692 Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma, renal cell carcinoma (RCC), and pheochromocytoma was available. Case 45 had a p.Thr157Ile (c.470C>T) mutation. 2 members were affected: one had RCC and the other had RCC and pheochromocytoma (ACMG PP4). Other demographics of the members were not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T157I (c.470C>T) sequence variation in gene VHL/NCBI:7428 2855 check_entity AN6097-1 VHL T157I (c.470C>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1621 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::T157I (c.470C>T) sequence variation in gene VHL/NCBI:7428 2855 check_entity AN6098-1 VHL T157fs (c.472ins) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. This mutation was found in a VHL type 1 patient (kindred no. 76). This study contains very strong evidence for pathogenicity in the form of a frameshift mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). However, the bases inserted were not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.472ins) sequence variation in gene VHL/NCBI:7428 2856 check_entity AN6098-1 VHL T157fs (c.472ins) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1968 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.472ins) sequence variation in gene VHL/NCBI:7428 2856 check_entity AN6099-1 VHL T202fs (c.606insA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in a patient with hemangioblastomas of the central nervous system. ACMG evidence codes: 'PVS1' because they observe a frameshift variant in a gene where loss-of-function is known mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.606insA) sequence variation in gene VHL/NCBI:7428 2857 check_entity AN6099-1 VHL T202fs (c.606insA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2018 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.606insA) sequence variation in gene VHL/NCBI:7428 2857 check_entity AN6100-1 VHL V130L (c.388G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 1 patient (patient no. V91). No unaffected family members were tested. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V130L (c.388G>C) sequence variation in gene VHL/NCBI:7428 2858 check_entity AN6100-1 VHL V130L (c.388G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:14722919 Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. This missense mutation was found in a 26 year old patient with cerebellar hemangioblastomas and a pancreatic cyst (patient no. F2). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V130L (c.388G>C) sequence variation in gene VHL/NCBI:7428 2858 check_entity AN6100-1 VHL V130L (c.388G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1846 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V130L (c.388G>C) sequence variation in gene VHL/NCBI:7428 2858 check_entity AN6101-1 VHL V155E (c.464T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). This missense mutation was found in a VHL type 2B family with retinal hemangioblastomas, cerebellar hemangioblastomas, and pheochromocytoma. ACMG codes as follows: Supporting evidence of pathogenicity because Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma, Pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V155E (c.464T>A) sequence variation in gene VHL/NCBI:7428 2859 check_entity AN6101-1 VHL V155E (c.464T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1785 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V155E (c.464T>A) sequence variation in gene VHL/NCBI:7428 2859 check_entity AN6102-1 VHL V155G (c.464T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26763786 A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations was presented. This mutation was present in 2 individuals of the 122 total number of variants captured in this population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V155G (c.464T>G) sequence variation in gene VHL/NCBI:7428 2860 check_entity AN6102-1 VHL V155G (c.464T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1810 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V155G (c.464T>G) sequence variation in gene VHL/NCBI:7428 2860 check_entity AN6103-1 VHL V155L (c.463G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12202531 A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations extracted from the French VHL database revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, this mutation was found in 2 VHL patients. 1 member was said to have retinal hemangioblastomas, while the other was said not to have this phenotype. Other manifestations are not clearly stated. No family information or relation was provided. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V155L (c.463G>C) sequence variation in gene VHL/NCBI:7428 2861 check_entity AN6103-1 VHL V155L (c.463G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1922 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V155L (c.463G>C) sequence variation in gene VHL/NCBI:7428 2861 check_entity AN6104-1 VHL V166A (c.497T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:24132471 Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. One patient was found with this missense varaint in the VHL gene. The patient was 27Y at the last follow-up and presented with: pancreatic neuroendocrine tumour and pheochromocytoma. Family history was not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V166A (c.497T>C) sequence variation in gene VHL/NCBI:7428 2862 check_entity AN6104-1 VHL V166A (c.497T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2310 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V166A (c.497T>C) sequence variation in gene VHL/NCBI:7428 2862 check_entity AN6105-1 VHL V166D (c.497T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in 2 family members with VHL type 1 phenotype (family ID 4480). Both individuals were identified with cerebellar hemangioblastomas and one with retinal hemangioblastoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V166D (c.497T>A) sequence variation in gene VHL/NCBI:7428 2863 check_entity AN6105-1 VHL V166D (c.497T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1651 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V166D (c.497T>A) sequence variation in gene VHL/NCBI:7428 2863 check_entity AN6106-1 VHL V166F (c.496G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). A missense mutation, affecting surface residue of pVHL protein core, was found in 2 VHL type 2A families with 5 affected individuals altogether. Two of 5 patients had retinal angioma, 2 had cerebellar hemangioblastoma, and 4 had pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V166F (c.496G>T) sequence variation in gene VHL/NCBI:7428 2864 check_entity AN6106-1 VHL V166F (c.496G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 2A patient (patient no. V49). This variant was not found in 8 unaffected family members and previously reported in patients with VHL. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V166F (c.496G>T) sequence variation in gene VHL/NCBI:7428 2864 check_entity AN6106-1 VHL V166F (c.496G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1701 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V166F (c.496G>T) sequence variation in gene VHL/NCBI:7428 2864 check_entity AN6107-1 VHL V170D (c.509T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8730290 In a study of 138 unrelated VHL families, 109 germline mutations were found. Missense mutations were more frequently found in families with pheochromocytoma (PC). Deletions. Nonsense, and frameshift mutations were more frequently found in families without PC. Large deletions and mutations predicted to cause truncated protein were associated with lower risk of PC. This missense mutation was found in a VHL family (family ID 77). No phenotype described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V170D (c.509T>A) sequence variation in gene VHL/NCBI:7428 2865 check_entity AN6107-1 VHL V170D (c.509T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17661816 Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This missense mutation was identified in 14 VHL patients (family no. 18). Six had retinal hemangioblastoma, 9 had cerebellar hemangioblastoma, 7 had renal cell carcinoma, 8 had renal cysts, 4 had pheochromocytoma, and 5 had pancreatic cysts. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V170D (c.509T>A) sequence variation in gene VHL/NCBI:7428 2865 check_entity AN6107-1 VHL V170D (c.509T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8956040 Germline mutation analysis of 469 VHL families reveled 300 mutations. The most common germline mutations were identified between codons 75-82, between codons 157-189 (Elongin binding domain) and at the splice site between exons 2 and 3. The association between mutations in codon 167 and pheochromocytoma was detected in all nationalities tested. This missense mutation was found in a VHL type 2 family (family ID R-D). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V170D (c.509T>A) sequence variation in gene VHL/NCBI:7428 2865 check_entity AN6107-1 VHL V170D (c.509T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9681858 20 patients from 6 families in the Netherlands were analyzed for Von Hippel Lindau manifestations. 1 family consisting of 12 members had the above mutation. Manifestations in this family included: renal cell carcinoma, cerebellar hemangioblastoma, pancreatic cyst, retinal hemangioblastoma, and pheochromocytoma. ACMG evidence codes: 'PP1' based on segregation results, 'PP2' because they observe a missense variant in gene where missense variants are common mechanism of disease, 'PP4' because the patients phenotypes and family history are highly specific for a disease with single genetic etiology. Relevant HPO terms: Renal cell carcinoma, Cerebellar hemangioblastoma, Multiple pancreatic cysts, Retinal hemangioblastoma, Pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V170D (c.509T>A) sequence variation in gene VHL/NCBI:7428 2865 check_entity AN6107-1 VHL V170D (c.509T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:24132471 Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. 15 patients were found with this missense varaint in the VHL gene. The ages of the patients were represented as a range, 16-71Y (mean 45). The phenotypes were presented together: retinal hemangioblastoma, cerebellar hemangioblastoma, spinal cord hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumour, phenchromocytoma, renal cysts, and pancreatic cysts. Family history was not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V170D (c.509T>A) sequence variation in gene VHL/NCBI:7428 2865 check_entity AN6107-1 VHL V170D (c.509T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1702 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V170D (c.509T>A) sequence variation in gene VHL/NCBI:7428 2865 check_entity AN6108-1 VHL V170F (c.508G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. This mutation was found in a VHL type 2 patient (kindred no. 26). Supporting evidence of pathogenicity because of a missense mutation in a gene in which missense variants are a common mechanism of disease. Relevant HPO terms: Pheochomocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V170F (c.508G>T) sequence variation in gene VHL/NCBI:7428 2866 check_entity AN6108-1 VHL V170F (c.508G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1682 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V170F (c.508G>T) sequence variation in gene VHL/NCBI:7428 2866 check_entity AN6109-1 VHL V170G (c.509T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Higher risk of pheochromocytoma was associated with missense mutations that result in substitution of a surface amino acid (p<=0.004) than for patients with missense mutations that disrupt the structural integrity of the VHL gene product (pVHL) or other loss of function mutations (either germline deletions or truncating mutations). A missense mutation, affecting residue on the surface of pVHL, was found in a VHL family of 4, 3 with retinal hemangioblastomas, 1 with renal cell carcinoma, and 1 with pheochromocytoma. ACMG codes as follows: supporting evidence for pathogenicity because of cosegregation of disease with multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). Supporting evidence of pathogenicity because missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V170G (c.509T>G) sequence variation in gene VHL/NCBI:7428 2867 check_entity AN6109-1 VHL V170G (c.509T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 1 patient (patient no. V81). No unaffected family members were tested but this mutation was reported in other unrelated patients previously. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V170G (c.509T>G) sequence variation in gene VHL/NCBI:7428 2867 check_entity AN6109-1 VHL V170G (c.509T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:26763786 A prospective study followed 128 participants affected by VHL syndrome for 12 years in Padova, Italy. Individual patient data was not available, but frequency of specific mutations presented. The c.509 T>G mutation was present in 3 individuals of the 122 total number of variants captured in this population. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V170G (c.509T>G) sequence variation in gene VHL/NCBI:7428 2867 check_entity AN6109-1 VHL V170G (c.509T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1811 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V170G (c.509T>G) sequence variation in gene VHL/NCBI:7428 2867 check_entity AN6110-1 VHL V181fs (c.540_543del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This mutation causes an early stop codon at amino acid 200 and was found in a VHL type 1 family (lineage 25). Only moderate evidence for pathogenicity because protein length changes as a result of deletions in a nonrepeat region and stop-loss variant (ACMG code: PM4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.540_543del) sequence variation in gene VHL/NCBI:7428 2868 check_entity AN6110-1 VHL V181fs (c.540_543del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1723 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.540_543del) sequence variation in gene VHL/NCBI:7428 2868 check_entity AN6111-1 VHL V194fs (c.581_582del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11409863 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 79). This study contains very strong evidence of pathogenicity in the form of a frameshift variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.581_582del) sequence variation in gene VHL/NCBI:7428 2869 check_entity AN6111-1 VHL V194fs (c.581_582del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1853 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.581_582del) sequence variation in gene VHL/NCBI:7428 2869 check_entity AN6112-1 VHL V62Cfs*5 (c.180del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This frameshift mutation was found in a VHL type 1 family of 8 individuals (family ID 3563). Two of 8 individuals were identified with retinal hemangioblastomas, 3 with cerebellar hemangioblastomas and 3 with renal cell carcinoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.180del) sequence variation in gene VHL/NCBI:7428 2870 check_entity AN6112-1 VHL V62Cfs*5 (c.180del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:3053 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.180del) sequence variation in gene VHL/NCBI:7428 2870 check_entity AN6113-1 VHL V66Gfs*89 (c.197_209del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.197_209del) sequence variation in gene VHL/NCBI:7428 2871 check_entity AN6113-1 VHL V66Gfs*89 (c.197_209del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2320 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.197_209del) sequence variation in gene VHL/NCBI:7428 2871 check_entity AN6114-1 VHL V66del (c.197_220del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This mutation was found in a VHL type 1 patient (patient no. V287). Only moderate evidence of pathogenicity since the protein length changes as a result of an in-frame deletion in a nonrepeat region (AMCG code: PM4). One unaffected family member was tested and negative for this mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.197_220del) sequence variation in gene VHL/NCBI:7428 2872 check_entity AN6114-1 VHL V66del (c.197_220del) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1975 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.197_220del) sequence variation in gene VHL/NCBI:7428 2872 check_entity AN6115-1 VHL V74G (c.221T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found in 2 unrelated, German families. The VHL type 1 family of 4 affected individuals had 2 patients with retinal angiomas, 5 with hemangioblastomas of the central nervous system, and one with renal cell carcinoma (family VHL 53). The VHL type 2B family of 3 affected individuals had one patient with retinal angioma, 3 with hemangioblastomas of the central nervous system, one with pheochromocytoma, one with renal cell carcinoma, one with pancreatic cysts, and one with cystadenomas of the epididymis (family VHL 9). This study contains supporting evidence of pathogenicity due to cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). HPO terms: papillary cystadenomas of the broad ligament assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V74G (c.221T>G) sequence variation in gene VHL/NCBI:7428 2873 check_entity AN6115-1 VHL V74G (c.221T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11409863 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This missense mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 92). This was the same missense mutation as was described in the previously published Glavač et al. (1996) study included in this study (VHL 9 and 53). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V74G (c.221T>G) sequence variation in gene VHL/NCBI:7428 2873 check_entity AN6115-1 VHL V74G (c.221T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V74G (c.221T>G) sequence variation in gene VHL/NCBI:7428 2873 check_entity AN6115-1 VHL V74G (c.221T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1875 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V74G (c.221T>G) sequence variation in gene VHL/NCBI:7428 2873 check_entity AN6116-1 VHL V84L (c.250G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11409863 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This nonsense mutation was found in a suspect VHL mutation carrier by DHPLC (family VHL 110). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V84L (c.250G>T) sequence variation in gene VHL/NCBI:7428 2874 check_entity AN6116-1 VHL V84L (c.250G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:24877602 A case report of African American twin sisters with VHL type 2C is presented. 1 twin presented at the age of 16 with unilateral vision loss determined to be caused by a Rathke's cleft cyst. Further imaging identified bilateral pheochromocytoma. The other twin presented with pheochromocytoma at the age of 7. Radiological studies identified a similar sellar lesion to the Rathke's cleft cyst found in twin 1. Genetic testing discovered the above mutation in both twins. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V84L (c.250G>T) sequence variation in gene VHL/NCBI:7428 2874 check_entity AN6116-1 VHL V84L (c.250G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1691 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V84L (c.250G>T) sequence variation in gene VHL/NCBI:7428 2874 check_entity AN6117-1 VHL V84M (c.250G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:22438210 This study examined 182 patients with non-syndromic pheochromocytoma or paraganglioma for the presence of VHL mutations. VHL mutations were found in 3 of the 182 patients. The above mutation was found in 1 patient with pheochromocytoma. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V84M (c.250G>A) sequence variation in gene VHL/NCBI:7428 2875 check_entity AN6117-1 VHL V84M (c.250G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1977 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::V84M (c.250G>A) sequence variation in gene VHL/NCBI:7428 2875 check_entity AN6118-1 VHL V87fs (c.259_260insA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:24132471 Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. One patient was found with this insertion in the VHL gene. The patient was 42Y at the last follow-up and presented with: retinal hemangioblastoma, cerebellar hemangioblastoma, spinal cord hemangioblastoma, renal cell carcinoma, renal cysts and pancreatic cysts. Family history was not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.259_260insA) sequence variation in gene VHL/NCBI:7428 2876 check_entity AN6118-1 VHL V87fs (c.259_260insA) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2305 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.259_260insA) sequence variation in gene VHL/NCBI:7428 2876 check_entity AN6119-1 VHL W117C (c.351G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in a VHL type 1 family of 10 individuals (family ID 1239). Seven of 10 individuals were identified with cerebellar hemangioblastomas and renal cell carcinoma. One identified with retinal hemangioblastomas. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::W117C (c.351G>T) sequence variation in gene VHL/NCBI:7428 2877 check_entity AN6119-1 VHL W117C (c.351G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in 2 VHL type 1 families (lineage 83 and 146). Family 146 was previously described in another publication. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::W117C (c.351G>T) sequence variation in gene VHL/NCBI:7428 2877 check_entity AN6119-1 VHL W117C (c.351G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in 4 VHL type 1 family members (patient no. V13). This study contains supporting evidence of pathogenicity for this variant due to cosegregation of disease with multiple family members (4 affected, 4 unaffected) in a gene definitively known to cause disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::W117C (c.351G>T) sequence variation in gene VHL/NCBI:7428 2877 check_entity AN6119-1 VHL W117C (c.351G>T) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1643 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::W117C (c.351G>T) sequence variation in gene VHL/NCBI:7428 2877 check_entity AN6120-1 VHL W117fs (c.349dup) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. More specifically, the mutation causes the following protein change W117LfsX1. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PVS1' because they observe a frameshift variant in a gene where loss of function is a known mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.349dup) sequence variation in gene VHL/NCBI:7428 2878 check_entity AN6120-1 VHL W117fs (c.349dup) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1903 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.349dup) sequence variation in gene VHL/NCBI:7428 2878 check_entity AN6121-1 VHL W8* (c.24G>A) VHL NCBI:7428 gene renal cell carcinoma DOID:4450 risk 34502-5 PubMed:11536052 'A single case (70 year-old named ''3GT'' in this study) with sporadic grade 3 renal cell carcinoma was observed with both W8* and G44D somatic variants.' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::W8* (c.24G>A) sequence variation in gene VHL/NCBI:7428 2879 check_entity AN6121-1 VHL W8* (c.24G>A) VHL NCBI:7428 gene renal cell carcinoma DOID:4450 risk 34502-5 CIViC:1268 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::W8* (c.24G>A) sequence variation in gene VHL/NCBI:7428 2879 check_entity AN6122-1 VHL W88* (c.263G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:22357542 Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This nonsense mutation was found in 2 unrelated VHL type 1 families. One family had a 32-year-old with hemangioblastomas of the central nervous system, renal cell carcinoma, pancreatic cysts, and epididymal cystadenoma with an 8-year-old asymptomatic son (proband no. 8). The other family had a 39-year-old with renal cell carcinoma and pancreatic cysts and their 81-year-old mother with CNS hemangioblastomas (proband no. 9). There is very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::W88* (c.263G>A) sequence variation in gene VHL/NCBI:7428 2880 check_entity AN6122-1 VHL W88* (c.263G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2027 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::W88* (c.263G>A) sequence variation in gene VHL/NCBI:7428 2880 check_entity AN6123-1 VHL W88* (c.264G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal hemangoblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This nonsense mutation was found in a VHL family with 3 affected members, 1 had retinal hemangioblastomas, 1 had cerebellar hemangioblastomas, 2 had renal cell carcinoma, and 1 had pheochromocytoma. There is very strong evidence for pathogenicity in the form of a nonsense variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::W88* (c.264G>A) sequence variation in gene VHL/NCBI:7428 2881 check_entity AN6123-1 VHL W88* (c.264G>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1784 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::W88* (c.264G>A) sequence variation in gene VHL/NCBI:7428 2881 check_entity AN6124-1 VHL W88FS (c.263_265delGGCinsTT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12114495 A study of 34 Polish families revealed germline mutations in 30 families. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). This mutation was found in a VHL patient with hemangioblastomas of the central nervous system and retina (family no. 11). This study contains very strong evidence of pathogenicity in the form of a frameshift variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). HPO terms: hemangioblastoma, retinal hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.263_265delGGCinsTT) sequence variation in gene VHL/NCBI:7428 2882 check_entity AN6124-1 VHL W88FS (c.263_265delGGCinsTT) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1915 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.263_265delGGCinsTT) sequence variation in gene VHL/NCBI:7428 2882 check_entity AN6125-1 VHL W88R (c.262T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in 3 family members with VHL type 1 phenotype (family ID 1255). All 3 individuals carried cerebellar hemangioblastomas and retinal hemangioblastomas. Two of 3 also carried renal cell carcinoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma, Renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::W88R (c.262T>A) sequence variation in gene VHL/NCBI:7428 2883 check_entity AN6125-1 VHL W88R (c.262T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. This missense mutation, affecting residue on the surface of pVHL, was found in a VHL type 1 patient with retinal hemangioblastoms, cerebellar hemangioblastomas, and renal cell carcinoma. ACMG codes as follows: Supporting evidence of pathogenicity because of a missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease (PP2). Relevant HPO terms: Cerebellar hemangioblastoma, Retinal hemangioblastoma, Renal cell carcinoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::W88R (c.262T>A) sequence variation in gene VHL/NCBI:7428 2883 check_entity AN6125-1 VHL W88R (c.262T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1637 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::W88R (c.262T>A) sequence variation in gene VHL/NCBI:7428 2883 check_entity AN6126-1 VHL W88R (c.262T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12624160 Germline mutations were found in 20 Brazilian, VHL probands and their families. This missense mutation was found in 2 VHL family members (VHL family 3). One had hemangioblastomas of the central nervous system and the other had retinal angiomas. HPO terms: hemangioblastoma, retinal hemangioblastoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::W88R (c.262T>C) sequence variation in gene VHL/NCBI:7428 2884 check_entity AN6126-1 VHL W88R (c.262T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1932 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::W88R (c.262T>C) sequence variation in gene VHL/NCBI:7428 2884 check_entity AN6127-1 VHL W88S (c.263G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 1 patient (patient no. V266). No unaffected family members were evaluated. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::W88S (c.263G>C) sequence variation in gene VHL/NCBI:7428 2885 check_entity AN6127-1 VHL W88S (c.263G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8634692 Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors used the 284 codon ORF previously described by Latif et al., 1993 and this notation was converted to NP_000542. PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregared with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS Hb, RCC, and Pheo was available. Case 8 had p.Trp88Ser mutation. 5 members were affected with renal cell carcinoma. Other demographics of the members were not described. ACMG PP4 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::W88S (c.263G>C) sequence variation in gene VHL/NCBI:7428 2885 check_entity AN6127-1 VHL W88S (c.263G>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1842 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::W88S (c.263G>C) sequence variation in gene VHL/NCBI:7428 2885 check_entity AN6128-1 VHL W88fs (c.261dup) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17661816 Molecular analysis of VHL gene in 146 probands, 103 with and 43 without a positive family history, resulted in the detection of 43 germline VHL mutations. Majority of mutations were found in patients with classic or multi-organ manifestations of VHL disease, but mutations were also found in patients with limited or single-organ manifestations of VHL disease. Follow-up of families with germline mutations and limited VHL manifestations was recommended. This variant was detected in a VHL type 1 patient with cerebellar hemangioblastoma, retinal hemangioblastomas, and renal cell carcinoma (family no. 28). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.261dup) sequence variation in gene VHL/NCBI:7428 2886 check_entity AN6128-1 VHL W88fs (c.261dup) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2172 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.261dup) sequence variation in gene VHL/NCBI:7428 2886 check_entity AN6129-1 VHL Y112* (c.336C>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This nonsense mutation was found in a VHL type 1 patient and familiy of 4 individuals (family IDs 3759 and 3760). Four of 5 individuals were identified with angiomas, 2 with cerebellar hemangioblastomas, and one with renal cell carcinoma. ACMG codes as follows: Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). Patient's phenotype is highly specific for a disease with a single genetic etiology (PP4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y112* (c.336C>A) sequence variation in gene VHL/NCBI:7428 2887 check_entity AN6129-1 VHL Y112* (c.336C>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1642 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y112* (c.336C>A) sequence variation in gene VHL/NCBI:7428 2887 check_entity AN6130-1 VHL Y112H (c.334T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20846682 26 VHL patients from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 1 patient from a single family was confirmed to have the above mutation. Additional manifestations aside from pheochromocytoma are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y112H (c.334T>C) sequence variation in gene VHL/NCBI:7428 2888 check_entity AN6130-1 VHL Y112H (c.334T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1741 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y112H (c.334T>C) sequence variation in gene VHL/NCBI:7428 2888 check_entity AN6131-1 VHL Y156* (c.468T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This mutation was found in a VHL type 1 patient (patient no. V41). This study contains very strong evidence for pathogenicity in the form of a nonsense mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y156* (c.468T>G) sequence variation in gene VHL/NCBI:7428 2889 check_entity AN6131-1 VHL Y156* (c.468T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1844 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y156* (c.468T>G) sequence variation in gene VHL/NCBI:7428 2889 check_entity AN6132-1 VHL Y156C (c.467A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 1 patient (patient no. V265). One unaffected family member was negative for this mutation. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y156C (c.467A>G) sequence variation in gene VHL/NCBI:7428 2890 check_entity AN6132-1 VHL Y156C (c.467A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12000816 Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and two patients with pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y156C (c.467A>G) sequence variation in gene VHL/NCBI:7428 2890 check_entity AN6132-1 VHL Y156C (c.467A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 1 patient was found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y156C (c.467A>G) sequence variation in gene VHL/NCBI:7428 2890 check_entity AN6132-1 VHL Y156C (c.467A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:24132471 Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. Seven patients were found with this missense varaint in the VHL gene. The ages of the patients was represented as a range 7-88 (mean 45). Phenotypes were grouped together: phenochromocytoma and renal cysts, although it is unclear if only one of the seven patients had renal cysts. Family history was not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y156C (c.467A>G) sequence variation in gene VHL/NCBI:7428 2890 check_entity AN6132-1 VHL Y156C (c.467A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1822 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y156C (c.467A>G) sequence variation in gene VHL/NCBI:7428 2890 check_entity AN6133-1 VHL Y156D (c.466T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This missense mutation was found in a VHL type 2B patient (patient no.V87). No unaffected family members were evaluated. An additional type 1 patient had a similar missense mutation (Y156C, patient no. V265). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y156D (c.466T>G) sequence variation in gene VHL/NCBI:7428 2891 check_entity AN6133-1 VHL Y156D (c.466T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12202531 A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations extracted from the French VHL database revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, this mutation (c.466T>G) was found in a VHL patient without retinal hemangioblastomas. Other manifestations are not clearly stated. No family information was provided. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y156D (c.466T>G) sequence variation in gene VHL/NCBI:7428 2891 check_entity AN6133-1 VHL Y156D (c.466T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1843 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y156D (c.466T>G) sequence variation in gene VHL/NCBI:7428 2891 check_entity AN6134-1 VHL Y156N (c.466T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12000816 Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y156N (c.466T>A) sequence variation in gene VHL/NCBI:7428 2892 check_entity AN6134-1 VHL Y156N (c.466T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1889 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y156N (c.466T>A) sequence variation in gene VHL/NCBI:7428 2892 check_entity AN6135-1 VHL Y175* (c.525C>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y175* (c.525C>A) sequence variation in gene VHL/NCBI:7428 2893 check_entity AN6135-1 VHL Y175* (c.525C>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1808 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y175* (c.525C>A) sequence variation in gene VHL/NCBI:7428 2893 check_entity AN6136-1 VHL Y175* (c.525C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829912 Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. This mutation was found in a VHL type 1 patient (patient no. V63). This study contains very strong evidence for pathogenicity in the form of a nonsense mutation in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y175* (c.525C>G) sequence variation in gene VHL/NCBI:7428 2894 check_entity AN6136-1 VHL Y175* (c.525C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:11409863 43 unrelated VHL patients with previously sequenced VHL germline mutations and 36 suspected VHL mutation carriers were subject to denaturing high performance liquid chromatography (DHPLC) mutation screening. This nonsense mutation was found in a previously diagnosed VHL patient by DHPLC (family VHL 103). This study contains very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y175* (c.525C>G) sequence variation in gene VHL/NCBI:7428 2894 check_entity AN6136-1 VHL Y175* (c.525C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from France. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y175* (c.525C>G) sequence variation in gene VHL/NCBI:7428 2894 check_entity AN6136-1 VHL Y175* (c.525C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12202531 A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations extracted from the French VHL database meeting diagnostic criteria of VHL disease revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, the missense mutation (c.525C>G (p.Tyr175Ter)) was found in 7 patients total - 3 of which are stated to have retinal HBs and 4 are said to not. Other manifestations are possible but not clear. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y175* (c.525C>G) sequence variation in gene VHL/NCBI:7428 2894 check_entity AN6136-1 VHL Y175* (c.525C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1845 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y175* (c.525C>G) sequence variation in gene VHL/NCBI:7428 2894 check_entity AN6137-1 VHL Y175* (c.525delC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal angiomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in 2 family members. One family member had retinal angiomas and the other had hemangioblastomas of the central nervous system. There is very strong evidence for pathogenicity in the form of a frameshift variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y175* (c.525delC) sequence variation in gene VHL/NCBI:7428 2895 check_entity AN6137-1 VHL Y175* (c.525delC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2014 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y175* (c.525delC) sequence variation in gene VHL/NCBI:7428 2895 check_entity AN6138-1 VHL Y175C (c.524A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:14722919 Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. This missense mutation was found in a 32 year old patient with unilateral pheochromocytoma (patient no. F15). The patient also had a family history of pheochromocytoma. ACMG evidence codes: none assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y175C (c.524A>G) sequence variation in gene VHL/NCBI:7428 2896 check_entity AN6138-1 VHL Y175C (c.524A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1943 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y175C (c.524A>G) sequence variation in gene VHL/NCBI:7428 2896 check_entity AN6139-1 VHL Y175D (c.523T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This missense mutation was found in a VHL type 1 family (lineage 7). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y175D (c.523T>G) sequence variation in gene VHL/NCBI:7428 2897 check_entity AN6139-1 VHL Y175D (c.523T>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1722 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y175D (c.523T>G) sequence variation in gene VHL/NCBI:7428 2897 check_entity AN6140-1 VHL Y175N (c.523T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:14722919 'Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. This missense mutation (Y175N (c.523T>A)) was found in a 32 year old patient with retinal hemangioblastomas and pheochromocytomas (patient no. F11). ACMG evidence code: ''flag for PP4'' because patients phenotype is highly specific for the disease.' assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y175N (c.523T>A) sequence variation in gene VHL/NCBI:7428 2898 check_entity AN6140-1 VHL Y175N (c.523T>A) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1942 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y175N (c.523T>A) sequence variation in gene VHL/NCBI:7428 2898 check_entity AN6141-1 VHL Y185* (c.555C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:9829911 Germline mutations were found in all 93 families that fulfilled clinical criteria of VHL disease. Mutations predicted to inactivate the VHL protein were associated with renal cell carcinoma and hemangioblastomas of the central nervous system (VHL type 1); mutations predicted to produce full length VHL proteins were associated with pheochromocytoma (VHL type 2). This nonsense mutation was found in a VHL type 1 family (lineage 50). Only moderate evidence for pathogenicity because protein length changes as a result of stop-loss variant (ACMG code: PM4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y185* (c.555C>G) sequence variation in gene VHL/NCBI:7428 2899 check_entity AN6141-1 VHL Y185* (c.555C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:17024664 Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Age-related risks of retinal hemangiobastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. This mutation was found in 3 VHL families with 4 patients altogether. All four had retinal hemangioblastomas and cerebellar hemangioblastomas. Two had renal cell carcinoma. There is very strong evidence for pathogenicity in the form of a nonsense variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PVS1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y185* (c.555C>G) sequence variation in gene VHL/NCBI:7428 2899 check_entity AN6141-1 VHL Y185* (c.555C>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1685 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y185* (c.555C>G) sequence variation in gene VHL/NCBI:7428 2899 check_entity AN6142-1 VHL Y98C (c.293A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:21463266 In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. This missense mutation was found in a 30 yr old VHL patient with retinal hemangioblastomas and pheochromocytoma (index case 183). ACMG codes as follows: Supporting evidence of pathogenicity because Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology (PP4). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y98C (c.293A>G) sequence variation in gene VHL/NCBI:7428 2900 check_entity AN6142-1 VHL Y98C (c.293A>G) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1809 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y98C (c.293A>G) sequence variation in gene VHL/NCBI:7428 2900 check_entity AN6143-1 VHL Y98FS (c.291_310del20) VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 risk 34502-5 PubMed:15932632 This variant was detected in a single case with clear-cell renal cell carcinoma. The tumor had two somatic variants (c.1-1_20del21 and c.291_310del20). Either of these variants is predicted to be quite deleterious. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.291_310del20) sequence variation in gene VHL/NCBI:7428 2901 check_entity AN6143-1 VHL Y98FS (c.291_310del20) VHL NCBI:7428 gene clear cell renal cell carcinoma DOID:4467 risk 34502-5 CIViC:826 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.291_310del20) sequence variation in gene VHL/NCBI:7428 2901 check_entity AN6144-1 VHL Y98FS (c.291delC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:24396697 A case report of a female Korean patient with VHL. She presented initially with gestational diabetes mellitus, and on routine abdominal scan displayed renal and pancreatic cysts. Family history demonstrated 2 family members with features consistent with VHL (cerebellar hemangioblastoma), which prompted genetic testing. Molecular analysis revealed the presence of the above mutation. Subsequently, she developed spinal hemangioblastoma and clear cell renal cell carcinoma. ACMG evidence codes: 'PP4' because the patient's phenotype or family history is highly specific for a disease with a single genetic etiology, 'PVS1' because they observe a frameshift variant in a gene where loss of function is a known mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.291delC) sequence variation in gene VHL/NCBI:7428 2902 check_entity AN6144-1 VHL Y98FS (c.291delC) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2036 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::(c.291delC) sequence variation in gene VHL/NCBI:7428 2902 check_entity AN6145-1 VHL Y98H (c.292T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7728151 In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. Missense mutation found in two VHL type 2A families of 55 individuals altogether (family IDs 3476, 3127). 26 of 55 individuals were identified with retinal hemangioblastomas, 5 with cerebellar hemangioblastomas, and 30 with pheochromocytomas. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y98H (c.292T>C) sequence variation in gene VHL/NCBI:7428 2903 check_entity AN6145-1 VHL Y98H (c.292T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7987306 An investigation of 94 VHL patients without large deletions for intragenic mutations revealed 40 different mutations in 55 unrelated individuals. In all patients with multiple affected family members the missense mutation segregated with the disease. This mutation was found in a VHL family (kindred no. 22). Incidence of pheochromocytoma was unknown. Supporting evidence for pathogenicity because of a missense mutation in a gene where missense variants are a common mechanism of disease (ACMG code: PP2). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y98H (c.292T>C) sequence variation in gene VHL/NCBI:7428 2903 check_entity AN6145-1 VHL Y98H (c.292T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:8707293 Of 65 VHL families from central Europe, 53 were identified with germline mutations. This missense mutation was found 3 unrelated, German families, 2 of which had been previously described (Neumann et al. 1995). The newly-identified VHL type 2 patient had retinal angiomas and pheochromocytoma (family VHL 54). As previously described, one VHL type 2A family of 52 affected individuals had 26 patients with retinal angiomas, 6 with hemangioblastomas of the central nervous system, and 41 with pheochromocytoma (family VHL*). A VHL type 1 family of 3 had 2 patients with retinal angiomas and one with renal cell carcinoma (family VHL 47). This study contains supporting evidence for pathogenicity due to cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y98H (c.292T>C) sequence variation in gene VHL/NCBI:7428 2903 check_entity AN6145-1 VHL Y98H (c.292T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:12000816 Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). This missense mutation was found in the VHL gene and one patient with pheochromocytoma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y98H (c.292T>C) sequence variation in gene VHL/NCBI:7428 2903 check_entity AN6145-1 VHL Y98H (c.292T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20660572 53 patients with a molecularly confirmed VHL mutation and a pancreatic neuroendocrine tumor were collected from the German NET-Registry and the German VHL-registry. 2 patients were found to have the above mutation. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease . assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y98H (c.292T>C) sequence variation in gene VHL/NCBI:7428 2903 check_entity AN6145-1 VHL Y98H (c.292T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:20846682 26 VHL patients from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 1 patient from a single family was confirmed to have the above mutation. Additional manifestations aside from pheochromocytoma are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y98H (c.292T>C) sequence variation in gene VHL/NCBI:7428 2903 check_entity AN6145-1 VHL Y98H (c.292T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25883647 Genetic analysis of 21 patients with known germline mutations in an inherited pheochromocytoma/paraganglioma gene, ten of which were in the VHL gene. This missense mutation was found in 8 unrelated patients with pheochromocytoma (tumor IDs P5, P6, P7, P8, P9, P10, P11, P12). ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y98H (c.292T>C) sequence variation in gene VHL/NCBI:7428 2903 check_entity AN6145-1 VHL Y98H (c.292T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:25867206 Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. statistics of the VHL subgroup is as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation, which was found in 1 individual from Germany. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y98H (c.292T>C) sequence variation in gene VHL/NCBI:7428 2903 check_entity AN6145-1 VHL Y98H (c.292T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:7759077 Peripheral blood from 116 VHL-affected patients in an interrelated group of 14 German and 2 American families with common ancestry was tested for mutations of the VHL gene, revealing a c.292T>C mutation leading to a p.Tyr89His missense protein change. Among these 116 affected patients, 116 retinal angiomas, 17 CNS hemangioblastomas, 73 pheochromocytomas, and 4 renal cell carcinomas were noted. ACMG evidence codes: 'PP1', with the allele significant cosegregation with the disease in family members for a gene known to cause the described syndrome, and 'PP4' because the patients' phenotypes or family histories are highly specific for a disease with a single genetic etiology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y98H (c.292T>C) sequence variation in gene VHL/NCBI:7428 2903 check_entity AN6145-1 VHL Y98H (c.292T>C) VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:1617 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Y98H (c.292T>C) sequence variation in gene VHL/NCBI:7428 2903 check_entity AN6146-1 VHL c.128-?_250+? mutation VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:15709172 Eleven RCCs and 16 renal cysts from eight patients with VHL were analyzed. All patients had known germline VHL mutations. One male patient had a germline deletion (c.128−?_250+?) in the VHL gene and presented with bilateral RCC and cysts, CNS hemangioblastoma, and pancreatic cysts. Family history was not described for the patient. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.128-?_250+?:mutation sequence variation in gene VHL/NCBI:7428 2904 check_entity AN6146-1 VHL c.128-?_250+? mutation VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2246 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::c.128-?_250+?:mutation sequence variation in gene VHL/NCBI:7428 2904 check_entity AN6147-1 VHL c.341-59_341-14del VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:24132471 Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. Two patients were found with this deletion in the VHL gene. One patient was 33Y and the other was 67Y at the last follow-up. The phenotypes of the patients were presented together: retinal hemangioblastoma, cerebellar hemangioblastoma, renal cell carcinoma, pheochromocytoma, renal cysts and pancreatic cysts. Family history was not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition VHL c.341-59_341-14del [biomarker_term_in_review] 2905 not_mapped AN6147-1 VHL c.341-59_341-14del VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2308 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition VHL c.341-59_341-14del [biomarker_term_in_review] 2905 not_mapped AN6148-1 VHL c.−213− ?_463 ?del VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 PubMed:24132471 Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. Four patients were found with this deletion in the VHL gene. Their age at last follow-up was presented as a range, 38Y-48Y and their phenotypes were grouped together: retinal hemangioblastoma, cerebellar hemangioblastoma, spinal cord hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumour, renal cysts, pancreatic cysts. Family history was not described. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition VHL c.−213− ?_463 ?del [biomarker_term_in_review] 2906 not_mapped AN6148-1 VHL c.−213− ?_463 ?del VHL NCBI:7428 gene von Hippel-Lindau disease DOID:14175 diagnostic 34502-5 CIViC:2304 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition VHL c.−213− ?_463 ?del [biomarker_term_in_review] 2906 not_mapped AN6149-1 VPS37A Underexpression VPS37A NCBI:137492 gene ovarian cancer DOID:2394 risk PubMed:22016507 Vps37A-deficient ovarian cancer cells become irresponsive to inhibition by the therapeutic antibody cetuximab in-vitro. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene VPS37A/NCBI:137492 2907 AN6149-1 VPS37A Underexpression VPS37A NCBI:137492 gene ovarian cancer DOID:2394 risk CIViC:842 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:decreased;aspect_type:expression Decreased expression of gene VPS37A/NCBI:137492 2907 AN6150-1 WEE1 RS3910384 mutation WEE1 NCBI:7465 gene lung non-small cell carcinoma DOID:3908 risk PubMed:26057002 The presence of the WEE1 polymorphism rs3910384 correlated with OS and PFS of NSCLC patients treated with platinum-based chemotherapy. Especially the combination of two DNA-damaging agents was associated with efficacy. 663 patients were tested. The authors showed that rs3910384 is closely linked with the putative functional WEE1 promoter at SNPs rs6486433, rs3763869 and rs3763868. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS3910384 sequence variation in gene WEE1/NCBI:7465 2908 check_entity AN6150-1 WEE1 RS3910384 mutation WEE1 NCBI:7465 gene lung non-small cell carcinoma DOID:3908 risk CIViC:327 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::RS3910384 sequence variation in gene WEE1/NCBI:7465 2908 check_entity AN6151-1 WT1 Exon 7 Mutation WT1 NCBI:7490 gene acute myeloid leukemia DOID:9119 prognostic;risk 21742-2 PubMed:18591546 WT1 mutations were associated with an inferior response to induction chemotherapy with a higher rate of resistant disease in young (15-60+, median 45) patients with cytogenetically normal AML. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:7:mutation sequence variation in gene WT1/NCBI:7490 2909 check_entity AN6151-1 WT1 Exon 7 Mutation WT1 NCBI:7490 gene acute myeloid leukemia DOID:9119 prognostic;risk 21742-2 PubMed:19221039 No differences in relapse-free or overall survival were identified between young (16-60) patients with or without WT1 mutations (69% exon 7, 15% exon 9) in cytogenetically normal AML. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:7:mutation sequence variation in gene WT1/NCBI:7490 2909 check_entity AN6151-1 WT1 Exon 7 Mutation WT1 NCBI:7490 gene acute myeloid leukemia DOID:9119 prognostic;risk 21742-2 PubMed:19536888 Mutations in WT1 were associated with increased risk of recurrence in young patients (15-50) with cytogenetically normal AML. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:7:mutation sequence variation in gene WT1/NCBI:7490 2909 check_entity AN6151-1 WT1 Exon 7 Mutation WT1 NCBI:7490 gene acute myeloid leukemia DOID:9119 prognostic;risk 21742-2 PubMed:18559874 WT mutations were associated with shorter overall and disease free survival in a cohort of cytogenetically normal, young (<60) AML patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:7:mutation sequence variation in gene WT1/NCBI:7490 2909 check_entity AN6151-1 WT1 Exon 7 Mutation WT1 NCBI:7490 gene acute myeloid leukemia DOID:9119 prognostic;risk 21742-2 CIViC:129 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:7:mutation sequence variation in gene WT1/NCBI:7490 2909 check_entity AN6152-1 WT1 Exon 9 Mutation WT1 NCBI:7490 gene acute myeloid leukemia DOID:9119 prognostic 21742-2 PubMed:19221039 Rates of complete remission and refractory disease are not different in patients with WT1 mutations (69% exon 7, 15% exon 9) than those without in young (16-60) patients with cytogenetically normal AML. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:9:mutation sequence variation in gene WT1/NCBI:7490 2910 check_entity AN6152-1 WT1 Exon 9 Mutation WT1 NCBI:7490 gene acute myeloid leukemia DOID:9119 prognostic 21742-2 PubMed:18559874 WT1 mutations were associated with shorter overall and disease free survival in a cohort of cytogenetically normal, young (<60) AML patients. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:9:mutation sequence variation in gene WT1/NCBI:7490 2910 check_entity AN6152-1 WT1 Exon 9 Mutation WT1 NCBI:7490 gene acute myeloid leukemia DOID:9119 prognostic 21742-2 CIViC:130 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_II::exon:9:mutation sequence variation in gene WT1/NCBI:7490 2910 check_entity AN6153-1 WWTR1 WWTR1::CAMTA1 mutation WWTR1 NCBI:25937 gene malignant epithelioid hemangioendothelioma DOID:0080190 diagnostic PubMed:21584898 Performed a systematic molecular analysis of 17 epithelioid hemangioendothelioma (EHE) and compared to 13 epithelioid hemangiomas, five epithelioid angiosarcomas, and four epithelioid sarcoma-like EHE. A FISH positional cloning strategy, and RT-PCR analysis identified WWTR1-CAMTA1 in all EHE cases and none of the other benign or malignant epithelioid vascular tumors examined. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::WWTR1::CAMTA1 sequence variation in gene WWTR1/NCBI:25937 2911 check_entity AN6153-1 WWTR1 WWTR1::CAMTA1 mutation WWTR1 NCBI:25937 gene malignant epithelioid hemangioendothelioma DOID:0080190 diagnostic CIViC:723 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::WWTR1::CAMTA1 sequence variation in gene WWTR1/NCBI:25937 2911 check_entity AN6154-1 XRCC1 Q399R mutation XRCC1 NCBI:7515 gene cervical cancer DOID:4362 risk PubMed:16875718 The XRCC1 R399Q variant was correlated with increased response to platinum-based neoadjuvant chemotherapy in patients with cervical cancer. Tumor samples from 36 patients with Stage IB or IIA bulky (greater than 4 cm in size) cervical carcinomas were used in this study. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q399R sequence variation in gene XRCC1/NCBI:7515 2912 check_entity AN6154-1 XRCC1 Q399R mutation XRCC1 NCBI:7515 gene cervical cancer DOID:4362 risk CIViC:257 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q399R sequence variation in gene XRCC1/NCBI:7515 2912 check_entity AN6154-2 XRCC1 Q399R mutation XRCC1 NCBI:7515 gene lung non-small cell carcinoma DOID:3908 prognostic PubMed:22551904 The XRCC1 R399Q variant was significantly correlated with higher overall survival in non-small cell lung carcinoma (NSCLC) patients treated with gemcitabine and platinum. 62 patients with either Stage IIIB or Stage IV NSCLC were used for this study. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q399R sequence variation in gene XRCC1/NCBI:7515 2913 check_entity AN6154-2 XRCC1 Q399R mutation XRCC1 NCBI:7515 gene lung non-small cell carcinoma DOID:3908 prognostic CIViC:257 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::Q399R sequence variation in gene XRCC1/NCBI:7515 2913 check_entity AN6155-1 XRCC1 R194W mutation XRCC1 NCBI:7515 gene lung non-small cell carcinoma DOID:3908 risk PubMed:19157633 The XRCC1 R194W variant was shown to be correlated with increased chance of response to platinum-based chemotherapy in Stage IV Non-small Cell Lung Carcinoma (NSCLC). 82 patients with Stage IV NSCLC who had not previously been treated with chemotherapy were used in this study. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R194W sequence variation in gene XRCC1/NCBI:7515 2914 check_entity AN6155-1 XRCC1 R194W mutation XRCC1 NCBI:7515 gene lung non-small cell carcinoma DOID:3908 risk CIViC:245 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::R194W sequence variation in gene XRCC1/NCBI:7515 2914 check_entity AN6156-1 YAP1 YAP1::TFE3 mutation YAP1 NCBI:10413 gene malignant epithelioid hemangioendothelioma DOID:0080190 diagnostic;risk PubMed:23737213 This study by Antonescu, et al. (2013) included 10 cases with a diagnosis of epithelioid hemangioendothelioma (EHE), which showed unusual morphologic features such as abundant eosinophilic cytoplasm, mature vascular channel formation and were negative for WWTR1 and CAMTA1 rearrangements by FISH. Patients ranged in age from 14 to 50 years. RNA sequencing identified a YAP1::TFE3 fusion transcript, and RT-PCR confirmed the fusion transcript of YAP1 exon 1 to exon 4 of TFE3. All 10 cases investigated by FISH showed TFE3 break-apart signal, and 8 of the 10 also showed YAP1 rearrangement. A control group of similar tumor types which included 18 epithelioid hemangiomas, 9 pseudomyogenic HE, and 3 epithelioid angiosarcomas showed no TFE3 rearrangements suggesting the YAP1::TFE3 is specific for this subgroup of epithelioid hemangioendothelioma. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::YAP1::TFE3 sequence variation in gene YAP1/NCBI:10413 2915 check_entity AN6156-1 YAP1 YAP1::TFE3 mutation YAP1 NCBI:10413 gene malignant epithelioid hemangioendothelioma DOID:0080190 diagnostic;risk PubMed:37810439 This 2023 study included 29 epithelioid hemangioendothelioma (EHE) cases, with the median patient age of 53 years. Eleven of the 29 tumors had a targeted sequencing panel which identified the WWTR1::CAMTA1 fusion in 9 (81%) patients and the YAP1::TFE3 fusion in 2 (19%) patients. The authors state that no single specific morphological feature was defining EHE but a constellation of features and the molecular studies could provide assurance of the diagnosis. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::YAP1::TFE3 sequence variation in gene YAP1/NCBI:10413 2915 check_entity AN6156-1 YAP1 YAP1::TFE3 mutation YAP1 NCBI:10413 gene malignant epithelioid hemangioendothelioma DOID:0080190 diagnostic;risk PubMed:34381186 This 2021 paper by Dermawan, et al. included 24 cases of YAP1::TFE3 fusion-positive epithelioid hemangioendotheliomas (EHE), with an age range of 20 to 78 years old. All cases were confirmed by molecular testing to harbor YAP1::TFE3 gene fusions, 88% with YAP1 exon 1 fused to TFE3 exon 4 and 12% with YAP1 exon 1 fused to TFE3 exon 6. The predicted fusion protein contains the TEAD binding site of YAP1 (located in exon 1), which is essential for tethering the protein to genes to activate transcription, and swaps the YAP1 transactivating domain for the basic helix-loop-helix and leucine zipper domains of TFE3. Thus the fusion protein acts as a transcription factor that utilizes the transactivating domains and nuclear localization sequences of TFE3 and binds DNA through the TEAD binding site on YAP1, resulting in a constitutively active chimeric transcription factor. YAP1 and WWTR1 (TAZ) are highly homologous transcriptional co-regulators that are downstream nuclear effectors of the Hippo signaling pathway. In EHE with WWTR1::CAMTA1 gene fusion, WWTR1::CAMTA1 acts as a constitutively active form of TAZ. Thus the a YAP-like transcriptional program in YAP1::TFE3 fused EHE, is considered analogous to WWTR1::CAMTA1 EHE (PMID: 33913810). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::YAP1::TFE3 sequence variation in gene YAP1/NCBI:10413 2915 check_entity AN6156-1 YAP1 YAP1::TFE3 mutation YAP1 NCBI:10413 gene malignant epithelioid hemangioendothelioma DOID:0080190 diagnostic;risk CIViC:4622 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::YAP1::TFE3 sequence variation in gene YAP1/NCBI:10413 2915 check_entity AN6157-1 YWHAE YWHAE::NUTM2 mutation YWHAE NCBI:7531 gene kidney clear cell sarcoma DOID:4880 diagnostic PubMed:22294382 In this 2012 study O’Meara et al. included 51 clear cell sarcoma of kidney (CCSK). Using an index CCSK with the t(10;17)(q22;p13) identified by cytogenetics, they were able to map the breakpoints and identified the gene fusion transcript YHWAE::FAM22, currently known as YHWAE::NUTM2. Using RT-PCR they screened an additional 50 samples. Overall, fusion positive transcripts of YHWAE::NUTM2 were detected in 7/51 (14%) cases. Ages of the patients ranged from 0 to 6 years. This rearrangement produces an in-frame YWHAE::NUTM2 fusion transcript, comprising exons 1–5 of YWHAE and exons 2–7 of NUTM2. Of the 3 cases with RNA sufficient to sequence the entire coding region, the YWHAE fusion partner was identified as either NUTM2B (FAM22B) or NUTM2E (FAM22E). None of the transcript-positive cases presented with stage I disease, suggesting the fusion may be associated with poorer outcome. Tumor cellularity was significantly higher in the cases that were transcript-positive. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::YWHAE::NUTM2 sequence variation in gene YWHAE/NCBI:7531 2916 check_entity AN6157-1 YWHAE YWHAE::NUTM2 mutation YWHAE NCBI:7531 gene kidney clear cell sarcoma DOID:4880 diagnostic PubMed:32364435 In this 2020 study Kenny et al. included 68 cases of clear cell sarcoma of the kidney (CCSK). Using RT-PCR with RNA extracted from FFPE tumour tissue they detected a YWHAE::NUTM2 fusion transcript in 1/68 (1.5%) of cases. The majority of cases (54/68, 79%) had a BCOR ITD which is mutually exclusive with the YWHAE::NUTM2 fusion. The group generated a cell line model system in which inducible expression of YWHAE::NUTM2 could be used to identify reliable immunohistochemical markers. The study concluded that reliance on a single marker in CCSK is not ideal and suggested BCOR, TLE1 and CCND1 could be useful as a group of markers, with the YWHAE::NUTM2 case as well as BCOR-ITD cases staining strongly for all three of these markers, while 63 control samples from tumor types often considered in the differential diagnosis were negative or weakly staining. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::YWHAE::NUTM2 sequence variation in gene YWHAE/NCBI:7531 2916 check_entity AN6157-1 YWHAE YWHAE::NUTM2 mutation YWHAE NCBI:7531 gene kidney clear cell sarcoma DOID:4880 diagnostic PubMed:27000436 In this 2016 study Kenny et al. included 159 cases of clear cell sarcoma of the kidney (CCSK). RNA was extracted from either snap-frozen or FFPE tumour tissue samples and real-time PCR used to identify YWHAE::NUTM2 fusions. Of the 102 cases tested, 2 (2%) were positive for the YWHAE::NUTM2 fusion transcript. The two cases were both aged less than a year (mean of 9 months), both male, and disease stage II or III/IV. The YWHAE::NUTM2 fusion transcript is present in only a minority of CCSKs, however the observation of the same rearrangement in high-grade endometrial stromal sarcoma, suggests this translocation is oncogenic. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::YWHAE::NUTM2 sequence variation in gene YWHAE/NCBI:7531 2916 check_entity AN6157-1 YWHAE YWHAE::NUTM2 mutation YWHAE NCBI:7531 gene kidney clear cell sarcoma DOID:4880 diagnostic CIViC:4879 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::YWHAE::NUTM2 sequence variation in gene YWHAE/NCBI:7531 2916 check_entity AN6158-1 ZEB1 Expression ZEB1 NCBI:6935 gene mantle cell lymphoma DOID:0050746 risk PubMed:24013721 Downregulation of ZEB1 expression in mantle cell lymphoma cell lines and mouse xenografts led to enhanced sensitivity towards treatment with doxorubicin, cytarabin and gemcitabine. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene ZEB1/NCBI:6935 2917 AN6158-1 ZEB1 Expression ZEB1 NCBI:6935 gene mantle cell lymphoma DOID:0050746 risk CIViC:372 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;aspect_type:expression Presence of expression of gene ZEB1/NCBI:6935 2917 AN6159-1 ZFTA MN1::ZFTA mutation ZFTA NCBI:65998 gene supratentorial ependymoma, ZFTA fusion–positive DOID:0081252 diagnostic PubMed:34389065 In an analysis of 13 cases of supratentorial tumors with ZFTA rearrangements without RELA involvement, all were found to have DNA methylation profiles similar to ZFTA::RELA supratentorial ependymoma. The underlying ZFTA rearrangements included 3 ZFTA::NCOA1 fusions, 4 ZFTA::NCOA2 fusions, 3 ZFTA::MALM2 fusions, 1 novel MN1::ZFTA fusion, and a truncated ZFTA product. The MN1::ZFTA was found in a 41 year old male and consisted of MN1 with 3 transactivation domains at the N terminus and the 4 zinc finger C2H2 domains of ZFTA at the C terminus. Interestingly, this had astroblastoma-like histology and epigenetically clustered with ZFTA::RELA supratentorial ependymoma rather than high-grade neuroepithelial tumor with MN1 alteration (HGNET-MN1). assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::MN1::ZFTA sequence variation in gene ZFTA/NCBI:65998 2918 check_entity AN6159-1 ZFTA MN1::ZFTA mutation ZFTA NCBI:65998 gene supratentorial ependymoma, ZFTA fusion–positive DOID:0081252 diagnostic CIViC:4563 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::MN1::ZFTA sequence variation in gene ZFTA/NCBI:65998 2918 check_entity AN6160-1 ZFTA ZFTA::MAML2 mutation ZFTA NCBI:65998 gene supratentorial ependymoma, ZFTA fusion–positive DOID:0081252 diagnostic PubMed:34389065 In an analysis of 13 cases of supratentorial tumors with ZFTA rearrangements without RELA involvement, all were found to have DNA methylation profiles similar to ZFTA::RELA supratentorial ependymoma. The underlying ZFTA rearrangements included 3 ZFTA::NCOA1 fusions, 4 ZFTA::NCOA2 fusions, 3 ZFTA::MALM2 fusions, 1 novel MN1::ZFTA fusion, and a truncated ZFTA product. The 3 ZFTA::MAML2 in-frame fusions contained 4 of the zinc finger C2H2 domains of ZFTA at the N-terminus fused to variable proportions of MAML2, all of which included the transactivation domain of MAML2. Two of these had astroblastoma-like histology and the third had more classic EPN-like histology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ZFTA::MAML2 sequence variation in gene ZFTA/NCBI:65998 2919 check_entity AN6160-1 ZFTA ZFTA::MAML2 mutation ZFTA NCBI:65998 gene supratentorial ependymoma, ZFTA fusion–positive DOID:0081252 diagnostic CIViC:4562 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ZFTA::MAML2 sequence variation in gene ZFTA/NCBI:65998 2919 check_entity AN6161-1 ZFTA ZFTA::NCOA1 mutation ZFTA NCBI:65998 gene supratentorial ependymoma, ZFTA fusion–positive DOID:0081252 diagnostic PubMed:34389065 In an analysis of 13 cases of supratentorial glial tumors with ZFTA rearrangements without RELA involvement, all were found to have DNA methylation profiles similar to ZFTA::RELA supratentorial ependymoma. The underlying ZFTA rearrangements included 3 ZFTA::NCOA1 fusions, 4 ZFTA::NCOA2 fusions, 3 ZFTA::MALM2 fusions, 1 novel MN1::ZFTA fusion, and a truncated ZFTA product. Of the 3 ZFTA::NCOA1 in-frame fusions identified, 2 contained 4 zinc finger C2H2 domains of ZFTA at the N-terminus fused to 2 transactivation domains and the histone acetyl transferase domains of NCOA1 at the C terminus. The third only contained 1 zinc finger C2H2 domain of ZFTA fused to 2 transactivation domains and the histone acetyl transferase domains of NCOA1. Of note, the 1 case with only 1 zinc finger domain had a sarcoma-like histology rather than the more classic EPN-like histology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ZFTA::NCOA1 sequence variation in gene ZFTA/NCBI:65998 2920 check_entity AN6161-1 ZFTA ZFTA::NCOA1 mutation ZFTA NCBI:65998 gene supratentorial ependymoma, ZFTA fusion–positive DOID:0081252 diagnostic CIViC:4560 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ZFTA::NCOA1 sequence variation in gene ZFTA/NCBI:65998 2920 check_entity AN6162-1 ZFTA ZFTA::NCOA2 mutation ZFTA NCBI:65998 gene supratentorial ependymoma, ZFTA fusion–positive DOID:0081252 diagnostic PubMed:34389065 In an analysis of 13 cases of supratentorial glial tumors with ZFTA rearrangements without RELA involvement, all were found to have DNA methylation profiles similar to ZFTA::RELA supratentorial ependymoma. The underlying ZFTA rearrangements included 3 ZFTA::NCOA1 fusions, 4 ZFTA::NCOA2 fusions, 3 ZFTA::MALM2 fusions, 1 novel MN1::ZFTA fusion, and a truncated ZFTA product. Of the 4 ZFTA::NCOA2 in-frame fusions identified, 2 contained 4 zinc finger C2H2 domains of ZFTA at the N-terminus fused to 2 transactivation domains of NCOA2 at the C terminus and 2 contained 1 zinc finger C2H2 domain of ZFTA fused to 2 transactivation domains of NCOA2 at the C terminus. Of note, the 2 cases with only 1 zinc finger domain had a sarcoma-like histology. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ZFTA::NCOA2 sequence variation in gene ZFTA/NCBI:65998 2921 check_entity AN6162-1 ZFTA ZFTA::NCOA2 mutation ZFTA NCBI:65998 gene supratentorial ependymoma, ZFTA fusion–positive DOID:0081252 diagnostic CIViC:4561 assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition change_type:presence of;mod_type:sequence variation Presence of bmkb_I::ZFTA::NCOA2 sequence variation in gene ZFTA/NCBI:65998 2921 check_entity AN6163-1 ZFTA ZFTA::RELA Methylation Profile ZFTA NCBI:65998 gene supratentorial ependymoma, ZFTA fusion–positive DOID:0081252 prognostic PubMed:37287693 An international multi-institutional study identified108 patients with a methylation profile of supratentorial ependymoma, ZFTA fusion-positive, by whole genome DNA methylation profiling. The study found a 5-year and 10-year PFS of 65% and 63%, with a 5-year and 10-year OS of 87% and 37% respectively. This was is in contrast to a seminal publication in ependymoma prognosis (PMID: 25965575, EID8628), which suggested that supratentorial ependymoma, RELA fusion-positive, (now classified as 'supratentorial ependyoma, ZFTA fusion-positive'), had a poorer prognosis as compared with other ependymoma subtypes. The current study findings were comparable to more recent studies showing similar improved survival outcomes in this ependymoma subtype. Additionally, the study demonstrated a trend towards improved PFS with gross total resection vs subtotal resection (68.1% vs. 53% (P = .06)), with no surival benefit conferred by chemotherapy. assessed_biomarker_entity;assessed_biomarker_entity_id;biomarker;condition ZFTA ZFTA::RELA Methylation Profile [biomarker_term_in_review] 2922 not_mapped AN6163-1 ZFTA ZFTA::RELA Methylation Profile ZFTA NCBI:65998 gene supratentorial ependymoma, ZFTA fusion–positive DOID:0081252 prognostic PubMed:30976811 In a series of 54 cases of ependymoma diagnosed in children