MUTATIONAL ANALYSIS OF MISMATCH REPAIR GENES, HMLH1 AND HMSH2, IN SPORADIC ENDOMETRIAL CARCINOMAS WITH MICROSATELLITE INSTABILITY

Microsatellite instability, monitored by replication error (RER), has been observed in both sporadic and hereditary types of endometrial car cinoma. In the hereditary tumors, this instability is considered to be caused by a germline defect in the DNA mismatch-repair system. We pre viously reported that nearly one-quarter of sporadic endometrial carci nomas examined revealed an RER-positive phenotype at multiple microsat ellite loci. To investigate the role of genetic alterations of DNA mis match-repair genes in sporadic endometrial carcinomas, we screened 18 RER (+) endometrial carcinomas for mutations of hMLH1 and hMSH2. Altho ugh we found no germline mutations, we detected two somatic mutations of hMLH1 in a single endometrial cancer; these two mutations had occur red on different alleles, suggesting that two separate mutational even ts had affected both copies of hMLH1 in this particular tumor. These d ata implied that mutations of hMLH1 or hMSH2 play limited roles in the development of sporadic endometrial carcinomas, and that the tumors w ith genetic instability might have alterations of other mismatch-repai r genes, such as hPMS1 and hPMS2, or of unknown genes related to the m ismatch repair system.