Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancer

Hereditary nonpolyposis colorectal cancer (HNPCC) is a syndrome characteriz ed by familial predisposition to colorectal carcinoma and extracolonic canc ers of the gastrointestinal, urological, and female reproductive tracts. Th is dominant disorder is caused by germline defects in one of at least five DNA mismatch repair (MMR) genes: hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 (GTB P). Germline mutations of hMSH2 and hMLH1 are also frequently identified in families not fulfilling all the Amsterdam criteria, thereby demonstrating that the involvement of these genes is not confined to typical HNPCC. To ev aluate the respective involvement of the various MMR genes in typical and i ncomplete HNPCC syndromes, we have performed an analysis of the hMLH1, hMSH 2, hPMS1, hPMS2, and hMSH6 genes in a large series of French kindreds (n = 75) with colorectal tumors and/or aggregation of extracolonic cancers belon ging to the HNPCC spectrum. Mutational analysis has been performed in all f amilies, without preselection for the tumor phenotype. We have detected 26 pathogenic germline mutations of the hMLH1 and hMSH2 genes and several nove l variants of the hPMS1, hPMS2, and hMSH6 genes. Our data confirm that, reg ardless of the type of families and the tumor phenotype, hPMS1, hPMS2, and hMSH6 germline mutations are rare in familial aggregation of colorectal can cers. Furthermore, they suggest that the presence of multiple primary malig nancies in a single individual and the observation of extracolonic tumors i n relatives of a colorectal cancer patient should be included among the gui delines for referring patients for genetic testing.