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, hMLH1,hPMS1 and hPMS2, have been demonstrated to be altered in the germline ofpatients with hereditary nonpolyposis colorectal cancer (HNPCC).Additionally, defective mismatch repair is thought to account for theobservation of microsatellite instability (MIN) in tumors from thesepatients. The genetic defect responsible for the MIN+ phenotype in sporadiccolorectal cancer, however, has yet to be clearly delineated. In order tobetter understand the role of somatic and germline alterations within hMSH2and hMLH1 in the process of colorectal tumorigenesis, we examined theentire coding regions of both of these genes in seven patients with MIN+sporadic colorectal cancer, 19 patients with familial colorectal cancer,and 20 patients meeting the strict Amsterdam criteria for HNPCC. Thirteengermline, two somatic, and four neutral alterations were identified. Thetwo somatic mutations occurred in patients having familial cancer, whilethe germline mutations were distributed among one sporadic (14%), threefamilial (16%), and nine HNPCC (45%) cases. All patients with identifiedmutations in the mismatch repair genes, whose tumors were available foranalysis, demonstrated MIN. On the other hand, we could not identifymutations in the subset of clinically defined HNPCC patients with MINnegative tumors nor in the majority (6/7) of MIN+ sporadic tumors.