Clinical utility of complex mutations in the core promoter and proximal precore regions of the hepatitis B virus genome.

The core promoter and proximal precore regions are the most complex portions of the hepatitis B virus (HBV) genome. These regions cooperatively regulate viral replication and differentially regulate the synthesis of the viral proteins E, core, and X. Multiple mutations in these regions are associated with the persistency of viral infection and the development of cirrhosis and hepatocellular carcinoma (HCC). In South Korea, nearly all HBVs are classified as HBV genotype C2; the majority of these viruses have the basal core promoter double mutation, a precore stop mutation, or both. These mutations may play a role in the alteration of viral and clinical features, and abundant and complex mutations are particularly prevalent in the core promoter and proximal precore regions. We previously demonstrated that the accumulation of ≥ 6 mutations at eight key nucleotides located in these regions (G1613A, C1653T, T1753V, A1762T, G1764A, A1846T, G1896A, and G1899A) is a useful marker to predict the development of HCC regardless of advanced liver disease. In addition, certain mutation combinations were predominant in cases with ≥ 4 mutations. In cases with ≤ 5 mutations, a low Hepatitis B e antigen titer (< 35 signal to noise ratio) was indicative of HCC risk. Viral mutation data of the single HBV genotype C2 suggest that the combined effect of the number and pattern of mutations in the core promoter and proximal precore regions is helpful in predicting HCC risk.