PMID- 10386556
OWN - NLM
STAT- MEDLINE
DCOM- 19990702
LR  - 20220311
IS  - 0098-7484 (Print)
IS  - 0098-7484 (Linking)
VI  - 281
IP  - 24
DP  - 1999 Jun 23-30
TI  - Novel hMLH1 and hMSH2 germline mutations in African Americans with colorectal
      cancer.
PG  - 2316-20
AB  - CONTEXT: Germline mutations of the DNA mismatch repair (MMR) genes hMLH1 and
      hMSH2 have been shown to cosegregate with the colorectal cancer phenotype in
      multiple hereditary nonpolyposis colorectal cancer (HNPCC) pedigrees. However,
      the frequency of these mutations among African American patients with colorectal 
      cancer is unknown. OBJECTIVE: To investigate the frequency of germline
      alterations of the DNA MMR genes hMLH1 and hMSH2 among African Americans affected
      by HNPCC and early-age onset colorectal cancer. DESIGN, SETTING, AND PATIENTS:
      Forty unrelated African American HNPCC and early-age onset colorectal cancer
      patients (8 women, 3 men) were identified from the cancer registry at a National 
      Cancer Institute-designated referral center, 11 of whom were available for and
      agreed to study participation from January 1997 to February 1998. The mean age of
      the subjects was 44 years. An additional 50 age- and sex-matched African
      Americans without personal or family history of colorectal, endometrial, ovarian,
      urinary tract, or upper gastrointestinal tract malignancy were also studied as a 
      polymorphism control population. In all subjects, genomic DNA was amplified by
      polymerase chain reaction for all hMLH1 and hMSH2 exons and screened using
      single-strand conformation polymorphism (SSCP) analysis. Samples demonstrating
      significant SSCP shifts underwent automated nucleotide sequencing analysis. MAIN 
      OUTCOME MEASURE: Frequency of hMLH1 and hMSH2 germline alterations in the
      affected and control subjects. RESULTS: Germline hMLH1 and hMSH2 mutations were
      detected in 3 (27%) of the African American colorectal cancer probands studied.
      Each mutation was novel. Two hMLH1 (an A-->T transversion at codon 26 and a
      GG-->AT substitution across codons 177 and 178) mutations and 1 hMSH2 mutation (a
      C-->T transition at codon 389) were identified in 3 female study subjects. Six
      other hMLH1 and hMSH2 alterations were detected but were presumed to be
      polymorphisms. Neither missense mutation (at codons 26 and 389) was detected in
      the control population. CONCLUSIONS: The results of our analysis support an
      association between the 3 mutations reported and predisposition to colorectal
      cancer. Further studies are needed to define DNA MMR gene-associated colorectal
      cancer in African Americans, an understudied population at increased risk of
      fatal colorectal cancer.
FAU - Weber, T K
AU  - Weber TK
AD  - Division of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, 
      USA. weber@sc3102.med.buffalo.edu
FAU - Chin, H M
AU  - Chin HM
FAU - Rodriguez-Bigas, M
AU  - Rodriguez-Bigas M
FAU - Keitz, B
AU  - Keitz B
FAU - Gilligan, R
AU  - Gilligan R
FAU - O'Malley, L
AU  - O'Malley L
FAU - Urf, E
AU  - Urf E
FAU - Diba, N
AU  - Diba N
FAU - Pazik, J
AU  - Pazik J
FAU - Petrelli, N J
AU  - Petrelli NJ
LA  - eng
GR  - P30 CA-16056/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - JAMA
JT  - JAMA
JID - 7501160
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Carrier Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (MLH1 protein, human)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - EC 3.6.1.3 (MSH2 protein, human)
RN  - EC 3.6.1.3 (MutL Protein Homolog 1)
RN  - EC 3.6.1.3 (MutS Homolog 2 Protein)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - Adult
MH  - Blacks/*genetics
MH  - Carrier Proteins
MH  - Colorectal Neoplasms/ethnology/*genetics
MH  - Colorectal Neoplasms, Hereditary Nonpolyposis/ethnology/*genetics
MH  - DNA Mutational Analysis
MH  - *DNA Repair
MH  - *DNA-Binding Proteins
MH  - Female
MH  - *Germ-Line Mutation
MH  - Humans
MH  - Male
MH  - MutL Protein Homolog 1
MH  - MutS Homolog 2 Protein
MH  - Neoplasm Proteins/*genetics
MH  - Nuclear Proteins
MH  - Polymerase Chain Reaction
MH  - Polymorphism, Genetic
MH  - Polymorphism, Single-Stranded Conformational
MH  - Proto-Oncogene Proteins/*genetics
EDAT- 1999/07/01 10:00
MHDA- 2001/08/14 10:01
CRDT- 1999/07/01 10:00
PHST- 1999/07/01 10:00 [pubmed]
PHST- 2001/08/14 10:01 [medline]
PHST- 1999/07/01 10:00 [entrez]
AID - jpc90024 [pii]
AID - 10.1001/jama.281.24.2316 [doi]
PST - ppublish
SO  - JAMA. 1999 Jun 23-30;281(24):2316-20. doi: 10.1001/jama.281.24.2316.