GERMLINE HMSH2 AND HMLH1 GENE-MUTATIONS IN INCOMPLETE HNPCC FAMILIES

Hereditary non-polyposis colon cancer (HNPCC) is a common hereditary d isease characterized by a predisposition to an early onset of colorect al cancer. The majority of the HNPCC families carry germline mutations of either hMSH2 or hMLH1 genes, whereas germline mutations of hPMS1 a nd hPMS2 genes have rarely been observed. Almost all of the germline m utations reported so far concern typical HNPCC families. However, ther e are families that display aggregations of colon cancer even though t hey do not fulfil all HNPCC criteria (incomplete HNPCC families) as we ll as sporadic cases of early onset colon cancers that could be relate d to germline mutations of these genes. Therefore, we screened germlin e mutations of hMSH2 and hMLH1 genes in 3 groups of patients from Fran ce and Turkey: typical HNPCC (n = 3), incomplete HNPCC (n = 9) and you ng patients without apparent familial history (n = 7). By in vitro syn thesis of protein assay, heteroduplex analysis and direct genomic sequ encing, we identified 1 family with hMSH2 mutation and 5 families with hMLH1 mutations. Two of the 3 HNPCC families (66%) displayed hMLH1 ge rmline mutations. Interestingly, 4 of 9 families with incomplete HNPCC (44%) also displayed mutations of hMSH2 or hMLH1 genes. In contrast, no germline mutation of these genes was found in 7 young patients. Our results show that germline mutations of hMSH2 and hMLH1 genes contrib ute to a significant fraction of familial predisposition to colon canc er cases that do not fulfil all diagnostic criteria of HNPCC. (C) 1997 Wiley-Liss, Inc.