tribution of hMSH2 and hMLH1 to the HNPCC phenotype and suggest that in the majority of Eastern United States HNPCC kindreds

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant cancer syndrome characterized by early age of onset colorectal cancer(mean45 years)as well as endometrial,urinarytract,and upper gastrointestinal adenocarcinomas. The HNPCC phenotype has been shown to segregate with germline mutations in the human homologues of the DNA mismatch repair genes MSH2, MLHJ, PMSJ, and PMS2. How ever, the majority of published DNA mismatch repair gene mutation surveys associated with HNPCC kindreds report multiple levels of prese lection, including 2p and 3p chromosomal linkage analysis and the eval uation of microsatellite instability of proband colorectal cancers prior to mutation analysis. For this reason, the concise contribution of each of the known DNA mismatch repair genes to the HNPCC phenotype remains unknown. We report the results of a genomic DNA-based analysis of hMSH2 and hMLH1 germline mutations in 32 unrelated Eastern United States HNPCC kindreds. These families were selected for study on the basis of phenotype only. We Identified three hMSH2 and six hMLH1 mutations in eight families, for a positive mutation rate of 25%. Two mutations were identified in one of the families. Four of the mutations detected have not been reported in the literature previously. One of the mutation-positive families is African American; the others were of Euro pean-American ancestry. These results provide a clarification of the con tribution of hMSH2 and hMLH1 to the HNPCC phenotype and suggest that in the majority of Eastern United States HNPCC kindreds selected by phenotype alone, the molecular genetic basis for the disease remains unknown.