The role of hPMS1 and hPMS2 in predisposing to colorectal cancer

Hereditary nonpolyposis colorectal cancer (HNPCC) is attributable to a defi ciency of mismatch repair. Inactivation of DNA mismatch repair underlies th e genesis of microsatellite instability in colorectal cancer. Germline muta tions in three DNA mismatch repair genes, hMSH2, hMLH1, and hMSH6, have bee n found to segregate in HNPCC and HNPCC-like families. The two DNA mismatch repair genes hPMS1 and hPMS2 have also been suggested to predispose to HNP CC. In this study, 84 HNPCC and HNPCC-like kindreds without known mutations in the other three known DNA mismatch repair genes were screened for germl ine mutations in the hPMS1 or hPMS2 gene. No clear-cut pathogenic mutations were identified. Conversion technology was used to detect a large hMSH2 de letion in two affected members of the kindred in which the hPMS1 mutation w as originally reported, whereas the hRWS1 mutation was only present in one of these two individuals. Since the hPMS1 and hPMS2 genes were first report ed, germline mutations in hPMS2 have been demonstrated primarily in patient s with Turcot's syndrome. However, no mutation in any of the two genes has been found to segregate in HNPCC families. Until there is better evidence f or an increased colorectal cancer risk associated with germline mutations i n these genes, a conservative interpretation of the role of mutations in th ese genes is advised.