Alcohol, cofactors and the genetics of hepatocellular carcinoma

Heavy alcohol consumption, chronic infection with the hepatitis B virus (HBV) or the hepatitis C virus (HCV), tobacco smoking, and diabetes are risk factors for hepatocellular carcinoma (HCC). In the Los Angeles Non-Asian MCC Study, heavy alcohol intake was shown to exhibit synergistic effects with viral hepatitis (HBV, HCV) and diabetes in the causation of MCC among individuals with joint exposures. Although chronic infection with HBV is recognized as the most important causal factor for MCC in humans, only a minority of HBV carriers eventually develop MCC, suggesting the presence of important cofactors in HBV-related MCC. In the Guangxi/China MCC Study, a 20-fold difference in MCC risk was observed between individuals possessing the least versus the most favorable cytokine genotypes for hepatitis B viral clearance. Experimental studies have indicated an important role for one-carbon metabolism in MCC development. In both the Los Angeles and Guangxi studies, low-activity genotypes (reduced enzymatic activities) of methylenetet-rahydrofolate reductase (MTHFR) and high-activity genotypes (enhanced enzymatic activities) of thymidylate synthase (TYMS), both of which discourage the misincorporation of uracil into DNA, were shown to be associated with a reduced risk for MCC.