Role of mismatch repair genes [h MLHI, h PMS1, h PMS2, GTBP/h MSH6, h MSH2] in the pathogenesis of hepatocellular carcinoma

ABSTRACT

DNA mismatch repair [MMR] is an important mechanism involved in maintaining fidelity of genomic DNA. Abnormalities in at least one of five MMR genes are implicated in the development of many cancers and the associated micro satellite instability [MSI]. By using a newly developed multiplex reverse transcription -PCR assay, the expression of the five known MMR [hMLH1, hPMS1, hPMS2, GTBP/hMSH6, hMSH2] were evaluated in 33 human HCC cases as well as 16 cases from the normal distant hepatic tissue samples [NDHT] were also evaluated. Twenty- five of them were associated with HCV infection. This was done in an attempt to determine the role of MMR genes in the development of HCC. The beta actin gene was used as an internal control for RNA degradation and DNA contamination and as well as a reference for quantifying the levels of their transcription. Out of the 33 studied HCC cases, 30 cases [90.9%] showed reduction in the expression of one or more of the 5 studied MMR genes. Reduced expression of hMSH2 was found in [71.9%], hMLH1 [53.3%], GTBP [51.1%], hPMS2 [33.3%] and hPMSI [6%]. Correlation analysis showed a strong significant correlation [P= 0.0069] between reduced expression of hPMS2 and GTBP [P=0.0034] as well as hPMS2 and non-cirrhosis [P=0.0197]. Chi-square analysis showed a significant correlation between reduced expression of hMLHl and grade II. On the other hand, 57.1%, 50%, 20%, 18.8% and 6% of the NDHT showed reduced expression of hMSH2, hMLHI, GTBP, hPMS2 and hPMSI respectively. Multivariate analysis showed significant correlation between HCC and hMSH2 [P= 0.008], hMLH1 [P=0.001] and GTBP [P=0.032], also between hPMS2, GTBP and HCC infected with HCV cases [P< 0.001, 0.002]. It could finally be concluded that reduced expression of hPMS2 is likely associated with growth advantage and stimulates proliferation changes that have encouraged malignant development in non- cirrhotic HCV infected patients via acquisition of more genetic damage and the MMR defects that occur at an early stage of hepatocarcinogenesis