Associations Between Hepatitis B Virus Mutations and the Risk of Hepatocellular Carcinoma: A Meta-Analysis

BACKGROUND: The association between hepatitis B virus (HBV) mutations and hepatocarcinogenesis remains controversial because of conflicting data in the literature. We conducted a meta-analysis of case–control and cohort studies to examine HBV PreS, enhancer II (EnhII), basal core promoter (BCP), and precore mutations in relation to the risk of hepatocellular carcinoma (HCC). METHODS: We searched databases for studies of these associations that were published in English or Chinese up to August 31, 2008. HBV mutation–specific odds ratios and relative risks were pooled by use of a random-effects model and stratified by potential confounders. All statistical tests were two-sided. RESULTS: Of the 43 studies included in this meta-analysis, 40 used a case–control design. The 43 studies evaluated a total of 11 582 HBV-infected participants, of whom 2801 had HCC. Statistically significant summary odds ratios of HCC were obtained for any PreS mutation (3.77, 95% confidence interval [CI] = 2.57 to 5.52), C1653T in EnhII (2.76, 95% CI = 2.09 to 3.64), T1753V (2.35, 95% CI = 1.63 to 3.40), and A1762T/G1764A in BCP (3.79, 95% CI = 2.71 to 5.29). PreS mutations were more strongly associated with an increased risk of HCC in subjects who were infected with HBV genotype C than in those who were infected with HBV genotype B, whereas the opposite was true for A1762T/G1764A. C1653T, T1753V, and A1762T/G1764A were more strongly associated with an increased risk of HCC in hepatitis B e antigen (HBeAg)–positive subjects than in HBeAg-negative subjects. PreS mutations, C1653T, T1753V, and A1762T/G1764A accumulated during the progression of chronic HBV infection from the asymptomatic carrier state to HCC (P(trend) < .001 for each mutation). PreS mutations, C1653T, C1653T + T1753V, and A1762T/G1764A-based combinations of mutations had specificities greater than 80% for the prediction of HCC. The precore mutations G1896A and C1858T were not associated with the risk of HCC, regardless of HBeAg status and HBV genotype. CONCLUSIONS: HBV PreS mutations, C1653T, T1753V, and A1762T/G1764A are associated with an increased risk of HCC. These mutations alone and in combination may be predictive for hepatocarcinogenesis.