GENETIC-LINKAGE ANALYSIS IN HEREDITARY NONPOLYPOSIS COLON-CANCER SYNDROME

Hereditary Non-polyposis Colon Cancer Syndrome (HNPCC) is the most com mon cause of familial colorectal cancer. Molecular genetic studies of HNPCC have shown evidence of locus heterogeneity, and mutations in fou r genes (hMSH2, hMLH1, hPMS1, and hPMS2) which encode components of th e mismatch enzyme repair system may cause HNPCC. To determine the exte nt and nature of locus heterogeneity in HNPCC, we performed genetic li nkage studies in 14 HNPCC families from eastern and north-western Engl and. Linkage to hMLH1 was excluded in six families, each of which were Likely to be linked to hMSH2 (lod score > 1.0 in each family and tota l lod score for all six families = 7.64). Linkage to hMSH2 was exclude d in three families, each of which were likely to be linked to kMLH1 ( led score > 1.0 in each family and total lod score at hMLH1 for all th ree families = 3.93). In the remaining five families linkage to hMSH2 or hMLH1 could not be excluded. These results confirm locus heterogene ity in HNPCC and suggest that, in the population studied, most large f amilies with HNPCC will have mutations in hMSH2 or hMLH1. We did not d etect any correlation between clinical phenotype and the genetic linka ge results, but a Muir-Torre syndrome family excluded from linkage to hMLH1 was likely to be linked to hMSH2 and showed microsatellite insta bility in a tumour from an affected relative.