Excess of hMLH1 germline mutations in Swiss families with hereditary non-polyposis colorectal cancer.

Lynch syndrome, or hereditary non-polyposis colorectal cancer (HNPCC), is a consequence of a dominantly inherited susceptibility to accumulate somatic mutations. The disorder is manifested as a familial aggregation of colorectal cancers diagnosed at an early age and, to a lesser degree, of cancers of the endometrium, ovary, urinary tract, and organs of the gastrointestinal tract other than the colon. In more than half of the HNPCC families investigated, the cancer predisposition has been linked to germline mutations in one of the 2 genes hMLHI or hMSH2, involved in post-replicative DNA-mismatch repair. Twenty-four Swiss families affected with colorectal cancer were screened for germline mutations in these 2 genes, and pathogenic mutations were identified in over 70% of the families fulfilling the Amsterdam criteria (AC), but in only 10% of the families not completely fulfilling these criteria. One of the reported mutations, discovered in an extended HNPCC kindred from the Swiss Alps, is shown to be a founding mutation. Unexpectedly, all the mutations identified are in the hMLHI gene, where all but one are novel sequence alterations. Our data suggest that an unusually high proportion of Swiss HNPCC patients may harbour a germline mutation in the hMLHI gene.