MUTATIONAL ANALYSIS OF MLHI AND MSH2 IN 25 PROSPECTIVELY-ACQUIRED RER(+) ENDOMETRIAL CANCERS

Mutations in the DNA mismatch repair (MMR) genes MLH1 and MSH2 have be en linked to several human cancers which display the replication error (RER) phenotype. Germline mutations in these two genes have been impl icated in about 90% of families with hereditary nonpolyposis colorecta l cancer (HNPCC). A significant proportion of endometrial cancers, the second most common malignancy of the HNPCC syndrome, also exhibit RER . We screened 125 primary endometrial adenocarcinomas with seven micro satellite markers and identified 25 specimens with RER (20%). We used single-strand conformation variant analysis to search for mutations in MLH1 and MSH2. Direct sequencing of variants revealed only one germli ne mutation in MLH1 and a single somatic mutation in MSH2. However, si x previously unreported sequence polymorphisms in MLH1 were identified . Four of these polymorphisms show clear population-based differences in allele frequency. In addition, a highly informative marker for MLH1 was characterized. The low frequency of mutations in MLH1 and MSH2 in this large series of cancers suggests that other MMR genes are respon sible for the RER phenotype in endometrial cancers. (C) 1997 Wiley-Lis s, Inc.