Specific mutations in enhancer II/core promoter of hepatitis B virus subgenotypes C1/C2 increase the risk of hepatocellular carcinoma

Background/Aims Hepatitis B virus genotype C (HBV/C) has been classified into two geographically distinct subgenotypes; HBV/C1/Cs (Southeast Asia) and HBV/C2/Ce (East Asia). Methods Viral differences in enhancer II/core promoter and precore regions between the subgenotypes and their association with hepatocellular carcinoma (HCC) were assessed in a matched cross-sectional control study of 118 carriers (from Hong Kong) with HBV/C1/Cs (48.0 years, 81% male, 40% HBeAg+, 44% HCC) and 210 HBV/C2/Ce (172 from Japan, 38 from Hong Kong) (50.2 years, 78% male, 30% HBeAg+, 46% HCC). Results Univariate analyses showed that mutation V1753 was predictive for HCC among HBeAg-positive-C1/Cs-carriers (P = 0.0055), and T1653 among HBeAg-positive-C2/Ce-carriers (P = 0.018), and T1653 or V1753 or T1762/A1764 among HBeAg-negative-C2/Ce-carriers (P < 0.05). In the multivariate analysis on all HBV/C subjects, independent predictive factors for HCC were subgenotype C2/Ce (odds ratio, 4.21; 95% confidence interval, 1.07–16.23), T1653 (3.64; 1.93–6.86), V1753 (3.07; 1.66–5.65) and T1762/A1764 (2.58; 1.21–5.49) mutations, age ( 50 years), gender (male) and HBeAg (positive). Conclusions Our data indicate that T1653 and/or V1753 mutations in addition to T1762/A1764 are differently associated with HCC in context of HBeAg status among HBV/C1/Cs and C2/Ce-carriers. HBV/C subgenotypes have specific mutation patterns, which is probably responsible for increased carcinogenesis of HBV/C2/Ce.