EXCESS OF HMLH1 GERMLINE MUTATIONS IN SWISS FAMILIES WITH HEREDITARY NONPOLYPOSIS COLORECTAL-CANCER

Lynch syndrome, or hereditary non-polyposis colorectal cancer (HNPCC), is a consequence of a dominantly inherited susceptibility to accumula te somatic mutations. The disorder is manifested as a familial aggrega tion of colorectal cancers diagnosed at an early age and, to a lesser degree, of cancers of the endometrium, ovary, urinary tract, and organ s of the gastrointestinal tract other than the colon. In more than hal f of the HNPCC families investigated, the cancer predisposition has be en linked to germline mutations in one of the 2 genes hMLH1 or hMSH2, involved in post-replicative DNA-mismatch repair, Twenty-four Swiss fa milies affected with colorectal cancer were screened for germline muta tions in these 2 genes, and pathogenic mutations were identified in ov er 70% of the families fulfilling the Amsterdam criteria (AC), but in only 10% of the families not: completely fulfilling these criteria. On e of the reported mutations, discovered in an extended HNPCC kindred f rom the Swiss Alps, is shown to be a founding mutation. Unexpectedly, all the mutations identified are in the hMLH1 gene, where all but one are novel sequence alterations. Our data suggest that an unusually hig h proportion of Swiss HN PCC patients may harbour a germline mutation in the hNILH1 gene. (C) 1998R Wiley-Liss, Inc.