Helal TEA, Khamis NS, El-Sharkawy TM, Nada OH, Radwan NA. Immunohistochemical expression of mismatch repair genes (hMSH2 and hMLH1) in hepatocellular carcinoma in Egypt. APMIS 2010; 118: 934–40. Egypt has the highest prevalence rate of hepatitis C virus (HCV) infection in the world. HCV contributes to the development of about 70% of hepatocellular carcinoma (HCC) cases. Understanding the molecular basis of hepatocarcinogenesis is important for planning the therapeutic regimen for HCC patients. To clarify the possible role of mismatch repair (MMR) genes in HCV-related HCC, we studied 50 HCV-related HCC specimens (28 of which were with adjacent non-cancerous cirrhotic liver tissue, ANCLT) and 30 specimens of chronic liver disease (CLD) with no evidence of HCC. All cases were examined immunohistochemically to demonstrate the protein expression of hMSH2 and hMLH1. Thirty-two (64%) and 35 (70%) of the HCC cases revealed reduced expression of hMSH2 and hMLH1, respectively. Reduced expression of both the proteins was obtained in 26 (52%) of the HCC cases. The expression of hMSH2 and hMLH1 was reduced in 53.6% and 64.3% of ANCLT cases, respectively, with no significant difference between HCC and ANCLT. All 30 specimens of CLD had preserved expression of hMSH2 and hMLH1. Multivariate analysis showed that the reduced expression of hMSH2 or hMLH1 was significantly associated with higher grades of the tumor (p = 0.002 and 0.02, respectively).The relationships of these MMR genes with other clinicopathologic factors were not significant. Reduced expression of hMSH2 and hMLH1 in both HCC and ANCLT suggests that this event occurs at early stages of HCV-related hepatocarcinogenesis. Moreover, the significant association between reduced expression of both MMR genes and poor histologic grades of the tumor claims that these proteins are involved in the process of cancer progression.