Microsatellite instability and loss of fragile histidine triad in gallbladder carcinoma

Background and aim: Microsatellite instability and fragile histidine triad (FHIT) loss have been seen to be involved in gallbladder carcinogenesis. We studied expression loss of mismatch repair (MMR) proteins and loss of FHIT expression in gallbladder cancer by immunohistochemistry using antibodies against MLH1, MSH2 and MSH6 proteins. Methods: One hundred and two consecutive cases of gallbladder cancer were retrospectively collected and expression of MLH1, MSH2 and MSH6 and FHIT protein was studied. The expression pattern was correlated with various clinicopathologic parameters and survival. Results: Expression loss of MMR proteins was found in 52.9% and loss of FHIT expression was found in 45% cases of gallbladder cancer. Loss of FHIT expression was seen in 12% of dysplasia associated with carcinoma. Expression loss of MMR proteins was found in 16% of dysplasia associated with chronic cholecystitis and 32.6% of dysplasia associated with carcinoma. Expression loss of MMR proteins had significant positive correlation with tumor stage and had worse survival compared with patients with intact expression. Loss of FHIT expression was significantly correlated with both tumor grade and stage. Conclusions: Frequency of expression loss of MMR proteins and loss of FHIT expression increased from dysplasia to carcinoma suggesting that both these abnormalities have a role in pathogenesis and occur at an early stage in carcinogenesis of gallbladder. Fifty three percent of gallbladder cancer with expression loss of MMR proteins also showed loss of FHIT expression and were frequent in advanced stage disease suggesting that reduced FHIT expression may be correlated with expression loss of MMR proteins on immunohistochemistry.