Association of colonic and endometrial carcinomas in Portuguese families with hereditary nonpolyposis colorectal carcinoma significantly increases the probability of detecting a pathogenic mutation in mismatch repair genes, primarily the MSH2 gene

BACKGROUND Hereditary nonpolyposis colorectal carcinoma (HNPCC) significantly raises the risk of developing colorectal carcinoma (CRC) and other extracolonic tumors. It is defined by the Amsterdam Criteria and is associated with germline mutations in mismatch repair genes, primarily MLH1 and MSH2. The objectives of the current study were to evaluate the presence of CRC (Type I) and other extracolonic tumors (Type II) in families with HNPCC and to analyze the findings for correlations with germline mutations in the MLH1 and MSH2 genes. METHODS Seventy families with an HNPCC diagnosis were analyzed. Denaturing gradient gel electrophoresis and direct sequencing were used for germline mutation analysis in the MLH1 and MSH2 genes. RESULTS Forty‐three of 70 families (61%) presented with HNPCC Type II. In 21 of 30 families that had a complete genetic diagnosis, 16 pathogenic germline mutations (7 MLH1 mutations and 9 MSH2 mutations) and 5 mutations of unknown pathogenecity (all MLH1 mutations) were found. In the remaining nine families, no mutations were detected. Unequivocally pathogenic mutations were far more common in families with HNPCC Type II compared with families that had CRC only (P = 0.01). Families with endometrial carcinoma presented with the greatest probability of mutational detection (P = 0.005). MLH1 was only gene affected in families with HNPCC Type I, whereas mutations in both MLH1 and MSH2 were found in families with HNPCC Type II (P = 0.04). However, the MSH2 gene was more frequently involved in families with HNPCC in which endometrial carcinoma was present (P = 0.005). CONCLUSIONS CRC and endometrial carcinoma were associated with a greater probability of detecting pathogenic mutations in mismatch repair genes, with MSH2 involvement predominating. The results support specific mutational screening strategies, based on observed phenotypes, for families with HNPCC. Cancer 2004. © 2004 American Cancer Society. Hereditary nonpolyposis colorectal carcinoma (HNPCC) is an autosomic disease that carries a high risk of developing colorectal carcinoma as well as other extracolonic tumors, including endometrial carcinoma. Mutations in MLH1 and MSH2 are found in a significant number of families. In the current study, the authors found that the presence of endometrial carcinoma in families with HNPCC conferred a significantly greater probability of detecting a pathogenic mutation, which may have important implications when referring patients for genetic t