MICROSATELLITE INSTABILITY AND MUTATION ANALYSIS OF HMSH2 AND HMLH1 IN PATIENTS WITH SPORADIC, FAMILIAL AND HEREDITARY COLORECTAL-CANCER

To date, at least four genes involved in DNA mismatch repair, hMSH2, h MLH1, hPMS1 and hPMS2, have been demonstrated to be altered in the ger mline of patients with hereditary nonpolyposis colorectal cancer (HNPC C). Additionally, defective mismatch repair is thought to account for the observation of microsatellite instability (MIN) in tumors from the se patients, The genetic defect responsible for the MIN(+) phenotype i n sporadic colorectal cancer, however, has yet to be clearly delineate d. In order to better understand the role of somatic and germline alte rations within hMSH2 and hMLH1 in the process of colorectal tumorigene sis, we examined the entire coding regions of both of these genes in s even patients with MIN(+) sporadic colorectal cancer, 19 patients with familial colorectal cancer, and 20 patients meeting the strict Amster dam criteria for HNPCC. Thirteen germline, two somatic, and four neutr al alterations were identified. The two somatic mutations occurred in patients having familial cancer, while the germline mutations were dis tributed among one sporadic (14%), three familial (16%), and nine HNPC C (45%) cases. All patients with identified mutations in the mismatch repair genes, whose tumors were available for analysis, demonstrated M IN. On the other hand, we could not identify mutations in the subset o f clinically defined HNPCC patients with MIN negative tumors nor in th e majority (6/7) of MIN(+) sporadic tumors.