A GERMLINE SUBSTITUTION IN THE HUMAN MSH2 GENE IS ASSOCIATED WITH HIGH-GRADE DYSPLASIA AND CANCER IN ULCERATIVE-COLITIS

Background & Aims: The DNA mismatch repair gene human MSH2 shows a germline mutation in certain family members with hereditary nonpolyposis colorectal cancer. There is an increased risk of colorectal cancer in patients with ulcerative colitis (UC) with extensive disease of >8 years' duration; however, specific constitutional predisposing genetic abnormalities have not yet been identified. Methods: A germline human MSH2 abnormality was sought in patients with UC with high-grade dysplasia or carcinoma. Results: After direct sequencing of exon 13 and flanking regions of human MSH2, a germline T to C substitution was shown at the -6 intronic splice acceptor site of exon 13. This substitution was found in 14 of 53 patients with UC with high-grade dysplasia or carcinoma (26%) compared with 4 of 36 high-risk patients with UC without dysplasia or cancer (11%) (P less than or equal to 0.04) and in 7 of 80 healthy adult blood donors (9%) (P less than or equal to 0.003). The patients with UC who had the substitution were three times more likely to develop neoplasia than patients with UC who did not carry it. Conclusions: An intronic splice-site substitution in the human MSH2 gene is present in the general population but may predispose to cancer in the setting of UC.