Somatic mutation of hPMS2 as a possible cause of sporadic human colon cancer with microsatellite instability

Inactivation of DIVA-mismatch repair underlies the genesis of microsatellit e unstable (MSI) colon cancers. hPMS2 is one of several genes encoding comp onents of the DNA-mismatch repair complex, and germline hPMS2 mutations hav e been found in a fem kindreds with hereditary nonpolyposis colorectal carc inoma (HNPCC), in whom hereditary MSI colon cancers develop. Ho tr ever, mi ce bearing null hPMS2 genes do not develop colon cancers and hPMS2 mutation s in sporadic human colon cancers have not been described, Here we report t hat in Vaco481 colon cancer the hPMS2 gene is inactivated by somatic mutati ons of both hPMS2 alleles, The cell line derived from this tumor is functio nally deficient in DNA mismatch repair. This deficiency can be biochemicall y complemented by addition of a purified hMLH1-hPMS2 (hMutL alpha) complex, The hPMS2 deficient Vaco481 cancer cell line demonstrates microsatellite i nstability, an elevated HPRT gene mutation rate, and resistance to the cyto toxicity of the alkylator MNNG. We conclude that somatic inactivation of hP MS2 can play a role in development of sporadic MSI colon cancer expressing the full range of cancer phenotypes associated with inactivation of the mis match repair system.