SOMATIC MUTATIONS IN THE HMSH2 GENE IN MICROSATELLITE UNSTABLE COLORECTAL CARCINOMAS

Microsatellite instability is frequently seen in tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC). Germline mutat ions in the mismatch repair gene hMSH2 account for approximately 50% o f these cases. Tumors from sporadic cases also exhibit this microsatel lite instability phenotype, although at a lower frequency, and very fe w somatically derived mutations have so far been reported in such tumo rs. In this study DNA from 23 primary colorectal carcinomas (four fami lial and 19 sporadic cases) exhibiting microsatellite instability were screened for mutations in the hMSH2 gene using constant denaturant ge l electrophoresis (CDGE). Among the sporadic cases, five (26%) were fo und to have somatically derived mutations. One tumor revealed two diff erent mutations, possibly leading to a homozygous inactivation of the gene. One of the four familial cases was classified as having HNPCC, a nd a germline as well as a somatic mutation were found in this tumor. These results demonstrate that a considerable proportion of sporadic c olorectal cancers with microsatellite instability, have somatic mutati ons in the hMSH2 gene.