ALTERED EXPRESSION OF HMSH2 AND HMLH1 IN TUMORS WITH MICROSATELLITE INSTABILITY AND GENETIC ALTERATIONS IN MISMATCH REPAIR GENES

date, at least four genes involved in DNA mismatch repair (MMR) have b een demonstrated to be altered in the germline of patients with heredi tary nonpolyposis colon cancer: hMSH2, hMLH1, hPMS1, and hPMS2. Additi onally, loss of MMR function has been demonstrated to lead to the phen omenon of microsatellite instability (MIN) in tumors from these patien ts. In this study, we have examined the protein expression pattern of hMSH2 and hMLH1 by immunohistochemistry in paraffin-embedded turners f rom 7 patients with MIN+ sporadic cancer, 13 patients with familial co lorectal cancer, and 12 patients meeting the strict Amsterdam criteria for hereditary nonpolyposis colon cancer. The relationship between th e expression of these two gene products, the presence of germline or s omatic mutations, and the presence of tumor MIN was examined. Nineteen of the 18 tumors studied demonstrated MIN, whereas mutations in hMLH1 and hMSH2 were detected in 6 and 2 patients, respectively. Of the eig ht MIN+/mutation+ cases, the absence of protein expression was observe d for the corresponding gene product in ail but one case (missense mut ation in hMLH1). However, seven MIN+/mutation- cases also showed no ex pression of either hMLH1 (n = 5), hMSH2 (n = 1), or both (n = 1), wher eas four MIN+/mutation- cases demonstrated normal expression for both. None of the MIN-/mutation- cases (n = 5) demonstrated an altered expr ession pattern for either protein. These data suggest that examination of protein expression by immunohistochemistry may he a rapid method f ur prescreening tumors for mutations in the MMR genes.