Specific mutations in enhancer II/core promoter of hepatitis B virus subgenotypes C1/C2 increase the risk of hepatocellular carcinoma.
OBJECTIVE
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.
Tanaka
Yasuhito
Y
Department of Clinical Molecular Informative Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Mukaide
Motokazu
M
Orito
Etsuro
E
Yuen
Man-Fung
MF
Ito
Kiyoaki
K
Kurbanov
Fuat
F
Sugauchi
Fuminaka
F
Asahina
Yasuhiro
Y
Izumi
Namiki
N
Kato
Michio
M
Lai
Ching-Lung
CL
Ueda
Ryuzo
R
Mizokami
Masashi
M
D000368:Aged; D001210:Asia, Southeastern; D006528:Carcinoma, Hepatocellular / Q000821:virology*; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D004742:Enhancer Elements, Genetic; D005202:Asia, Eastern; D005260:Female; D016679:Genome, Viral / Q000235:genetics*; D005838:Genotype; D006514:Hepatitis B Surface Antigens; D006515:Hepatitis B virus / Q000235:genetics* / Q000472:pathogenicity; D019694:Hepatitis B, Chronic / Q000235:genetics / Q000821:virology*; D006723:Hong Kong; D006801:Humans; D007564:Japan; D008113:Liver Neoplasms / Q000821:virology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D017354:Point Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*
D006514:Hepatitis B Surface Antigens