Combinations of eight key mutations in the X/preC region and genomic activity of hepatitis B virus are associated with hepatocellular carcinoma

Accumulation of eight key mutations located in the X/preC regions of the hepatitis B virus (HBV) genome (G1613A, C1653T, T1753V, A1762T, G1764A, A1846T, G1896A and G1899A) is a risk marker for the development of hepatocellular carcinoma (HCC). In this study, we analysed the 8 key mutations in 442 serum samples collected from 310 non-HCC and 132 HCC patients to identify the combinations linked to HCC. After the patients were stratified according to the age groups and mutation combinations, clinical parameters were compared between the HCC and the non-HCC groups. Analyses were focused on patient ≥40 years of age infected by HBV genotype C with A1762T and G1764A mutations in the basal core promoter region (BCP double mutation). In patients with ≥6 mutations, the combination of [G1613A + C1653T + A1846T + G1896A] mutations was closely linked to HCC, whereas no specific single or double mutation combination was associated with HCC. In patients with ≤5 mutations, HBeAg and HBV DNA serum titres were lower in the HCC group than those in the non-HCC group. Unlike the number of mutations, no specific combination correlated with advanced clinical stage in HCC. Of the BCP double mutation-based HBV mutant types, combinations of ≥6 mutations that include G1613A + C1653T + A1846T + G1896A, and combinations of ≤5 mutations with reduced HBeAg production, may be more specific indicators of HCC risk than only the number of mutations or any specific combination(s).