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

J Hepatol. 2006 Nov;45(5):646-53. doi: 10.1016/j.jhep.2006.06.018. Epub 2006 Aug 10.


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.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Asia, Southeastern
  • Carcinoma, Hepatocellular / virology*
  • Case-Control Studies
  • Cross-Sectional Studies
  • Enhancer Elements, Genetic*
  • Far East
  • Female
  • Genome, Viral / genetics*
  • Genotype
  • Hepatitis B Surface Antigens
  • Hepatitis B virus / genetics*
  • Hepatitis B virus / pathogenicity
  • Hepatitis B, Chronic / genetics
  • Hepatitis B, Chronic / virology*
  • Hong Kong
  • Humans
  • Japan
  • Liver Neoplasms / virology*
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Point Mutation / genetics
  • Promoter Regions, Genetic / genetics*


  • Hepatitis B Surface Antigens