PMID- 10036184
OWN - NLM
STAT- MEDLINE
DCOM- 19990505
LR  - 20111117
IS  - 0888-7543 (Print)
IS  - 0888-7543 (Linking)
VI  - 56
IP  - 1
DP  - 1999 Feb 15
TI  - A physical, transcript, and deletion map of chromosome region 12p12.3 flanked by 
      ETV6 and CDKN1B: hypermethylation of the LRP6 CpG island in two leukemia patients
      with hemizygous del(12p).
PG  - 40-50
AB  - FISH analyses and loss of heterozygosity studies have delineated a commonly
      deleted region in hematological malignancies flanked by ETV6 and CDKN1B on
      chromosome 12p12.3. The same chromosomal region is also a target for deletions in
      certain solid tumors. As an initial step toward the cloning of a potential tumor 
      suppressor gene at 12p12.3, we mapped the ETV6-CDKN1B region physically using
      bacterial artificial chromosome (BAC) and P1-derived clone (PAC) contigs. The
      1.2-Mb high-resolution, contiguous map extends from D12S1095 to D12S929 and
      consists of 19 PACs and 20 BACs. Pulsed-field gel electrophoresis experiments
      confirmed the integrity of the clone-based map and identified six CpG islands in 
      the region. A transcript map was generated by performing hybridization selection 
      experiments with the genomic clones, by evaluating known 12p ESTs for their
      presence in the contig, and by sequence analysis of CpG islands in the region.
      Altogether evidence was gathered for the presence of the recently published LRP6 
      gene and at least seven other new genes in this chromosomal region. The CLAPS3
      gene, mapped between D12S391 and D12S358, was reassigned to chromosome 5 since
      genomic sequencing demonstrated the chromosome 12p sequence to be a pseudogene.
      Polymorphic CA repeats were identified approximately every 100 kb, which will
      support future analysis of loss of heterozygosity in tumors. Fluorescence in situ
      hybridization analysis of leukemia patients with del(12p) further refined the
      commonly deleted segment to 600 kb between ETV6 and D12S358, which apparently
      excludes CDKN1B. Methylation changes of the CpG islands in the ETV6-CDKN1B
      interval were assessed by Southern analysis for leukemia patients with hemizygous
      12p deletions. A "de novo" methylation was detected only at the LRP6 CpG island
      in 2 of 22 leukemia patients tested and was confirmed by methylation-sensitive
      PCR and sequencing. The genomic structure of LRP6 was elucidated to allow
      screening for inactivating mutations, but only intragenic polymorphisms were
      identified. Hypermethylation of CpG islands associated with gene promoters is
      reported as a common mechanism for gene silencing and tumor suppressor
      inactivation. Therefore the consequences of the LRP6 CpG island methylation and
      its role in the observed phenotype need further investigation.
CI  - Copyright 1999 Academic Press.
FAU - Baens, M
AU  - Baens M
AD  - Human Genome Laboratory, Center for Human Genetics-Flanders Interuniversity
      Institute for Biotechnology, Leuven, Belgium.
FAU - Wlodarska, I
AU  - Wlodarska I
FAU - Corveleyn, A
AU  - Corveleyn A
FAU - Hoornaert, I
AU  - Hoornaert I
FAU - Hagemeijer, A
AU  - Hagemeijer A
FAU - Marynen, P
AU  - Marynen P
LA  - eng
SI  - GENBANK/AF090125
SI  - GENBANK/AF090126
SI  - GENBANK/AF090127
SI  - GENBANK/AF090128
SI  - GENBANK/AF090129
SI  - GENBANK/AF090130
SI  - GENBANK/AF090131
SI  - GENBANK/AF090132
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Genomics
JT  - Genomics
JID - 8800135
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (DNA, Complementary)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (ETS translocation variant 6 protein)
RN  - 0 (LRP6 protein, human)
RN  - 0 (Low Density Lipoprotein Receptor-Related Protein-6)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 0 (Proto-Oncogene Proteins c-ets)
RN  - 0 (Receptors, LDL)
RN  - 0 (Repressor Proteins)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27)
SB  - IM
MH  - *Cell Cycle Proteins
MH  - Chromosome Banding
MH  - Chromosome Deletion
MH  - Chromosome Mapping
MH  - Chromosomes, Human, Pair 12/*genetics
MH  - CpG Islands/*genetics
MH  - Cyclin-Dependent Kinase Inhibitor p27
MH  - DNA, Complementary
MH  - DNA-Binding Proteins/*genetics
MH  - Exons
MH  - Expressed Sequence Tags
MH  - Female
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Introns
MH  - Leukemia/*genetics
MH  - Low Density Lipoprotein Receptor-Related Protein-6
MH  - Male
MH  - Methylation
MH  - Microsatellite Repeats
MH  - Microtubule-Associated Proteins/*genetics
MH  - Physical Chromosome Mapping
MH  - Polymorphism, Genetic
MH  - Proto-Oncogene Proteins c-ets
MH  - Receptors, LDL/*genetics
MH  - *Repressor Proteins
MH  - Transcription Factors/*genetics
MH  - *Tumor Suppressor Proteins
EDAT- 1999/02/26 00:00
MHDA- 1999/02/26 00:01
CRDT- 1999/02/26 00:00
PHST- 1999/02/26 00:00 [pubmed]
PHST- 1999/02/26 00:01 [medline]
PHST- 1999/02/26 00:00 [entrez]
AID - S0888-7543(98)95685-3 [pii]
AID - 10.1006/geno.1998.5685 [doi]
PST - ppublish
SO  - Genomics. 1999 Feb 15;56(1):40-50. doi: 10.1006/geno.1998.5685.