title: Novel hMLH1 and hMSH2 germline mutations in African Americans with colorectal cancer.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Division of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. weber@sc3102.med.buffalo.edu
authors.forename: T K
authors.initials: TK
authors.lastname: Weber
authors.forename: H M
authors.initials: HM
authors.lastname: Chin
authors.forename: M
authors.initials: M
authors.lastname: Rodriguez-Bigas
authors.forename: B
authors.initials: B
authors.lastname: Keitz
authors.forename: R
authors.initials: R
authors.lastname: Gilligan
authors.forename: L
authors.initials: L
authors.lastname: O'Malley
authors.forename: E
authors.initials: E
authors.lastname: Urf
authors.forename: N
authors.initials: N
authors.lastname: Diba
authors.forename: J
authors.initials: J
authors.lastname: Pazik
authors.forename: N J
authors.initials: NJ
authors.lastname: Petrelli
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D044383:Black People / Q000235:genetics*; D002352:Carrier Proteins; D015179:Colorectal Neoplasms / Q000208:ethnology / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000208:ethnology / Q000235:genetics*; D004252:DNA Mutational Analysis; D004260:DNA Repair; D004268:DNA-Binding Proteins; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D001741:Black or African American
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein