Background: Mutations in the hepatitis B virus (HBV) genome may influence the activity of liver disease. The aim of this study was to identify new viral variations associated with hepatocellular carcinoma (HCC). Methods: We carried out a comparison study on the complete sequence of HBV isolated from 20 HCC and 35 non-HCC patients in Qidong, China, an area with a high incidence of HCC. We compared the HBV sequences in a consecutive series of plasma samples from four HCC cases before and after the occurrence of HCC. In addition, we selected four mutations in the HBV core (C) gene to verify their relationships to HCC in an independent set of 103 HCC cases and 103 sex- and age-matched non-HCC controls. Results: The pre-S deletion and 12 point mutations, namely, the pre-S2 start codon mutation, T53C in the pre-S2 gene, T766A in the S gene, G1613A, C1653T, A1762T, G1764A in the X gene, and G1899A, C2002T, A2159G, A2189C, and G2203W (A or T) in the pre-C/C gene, showed close associations with HCC. In the validation study, A2159G, A2189C, and G2203W showed consistent associations with HCC by univariate analysis. Multivariate analysis showed that A2189C and G2203W were independent risk factors for HCC. The odds ratios (95% confidence interval) were 3.99 (1.61-9.92) and 9.70 (1.17-80.58), respectively, for A2189C and G2203W. Conclusions: These results implicate A2189C and G2203W as new predictive markers for HCC. Impact: The complete genome analysis of HBV provided pilot data for the identification of novel mutations that could serve as markers for HCC.
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