ABSENCE OF MUTATIONS IN DNA MISMATCH REPAIR GENES IN SPORADIC ENDOMETRIAL TUMORS WITH MICROSATELLITE INSTABILITY

DNA mismatch repair genes have been reported to play a role in the pat hogenesis of hereditary nonpolyposis colorectal cancer (HNPCC), Mutati ons of DNA mismatch repair genes have accounted for 90% of HNPCC-relat ed colon and endometrial tumors. These mutations have been associated with microsatellite instability (MIN), Because endometrial cancer (EC) is the most common extracolonic malignancy associated with HNPCC, we hypothesized that similar molecular alterations may occur in sporadic endometrial tumors exhibiting MIN. Mutational analysis of the MSH2 and MLH1 genes was undertaken in sporadic EC that demonstrate MIN to dete rmine the role of these genes in the pathogenesis of sporadic ECs. Est ablished microsatellite markers were used to determine the incidence o f MIN from 28 patients with sporadic EC, MIN was observed in 32% (9 of 28) of the tumor specimens analyzed, Mutational analysis of MSH2 and MLH1 genes was performed by immunohistochemical analysis and direct se quencing of tumor specimens that exhibited MIN, All 28 tumor specimens exhibited strong nuclear staining with both MSH2 and MLH1 antibodies, suggesting the absence of mutations. Sequencing of all exons of both the MSH2 and MLH1 genes in the nine MIN-positive tumor specimens demon strated no mutations, We conclude that the MSH2 and MLH1 genes do not play a role in the pathogenesis of sporadic endometrial cancer.