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Thomas K. Weber, MD; Hyung-Min Chin, MD; Miguel Rodriguez-Bigas, MD; Bernadette Keitz, BA; Rebecca Gilligan, MBBS; Linda O'Malley, RN; Edwin Urf, BS; Nazli Diba, BS; James Pazik, BSc; Nicholas J. Petrelli, MD

JAMA. 1999;281:2316-2320.

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 AT transversion at codon 26 and a GGAT substitution across codons 177 and 178) mutations and 1 hMSH2 mutation (a CT 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.

Author Affiliations: Division of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY (Drs Weber, Rodriguez-Bigas, and Petrelli, and Mss Keitz, O'Malley, and Diba, and Messrs Urf and Pazik); Department of Surgery, St Vincent's Hospital, Catholic University Medical College, Suwon, Korea (Dr Chin); and Faculty of Medicine, University of Manchester, Manchester, England (Dr Gilligan).

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