Associations Between Hepatitis B Virus Mutations and the Risk of Hepatocellular Carcinoma: A Meta-Analysis (original) (raw)

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of cancer mortality. Most HCC cases (>80%) occur in either Eastern Asia or sub-Saharan Africa (1). Most HCCs occur in men and among people aged 75 years and older (1). Major risk factors for the development of HCC are chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), liver cirrhosis, exposure to aflatoxin B1, alcohol consumption, and diabetes. It has been estimated that 80% of HCC worldwide is etiologically associated with HBV (2). The double-stranded DNA genome of HBV contains four overlapping open reading frames that encode the surface protein (S), the core (nucleocapsid) protein core, a polymerase, and a multifunctional nonstructural protein called X. The PreS region (nucleotides 2854-155), which consists of the PreS1 and PreS2 domains, overlaps a region of the polymerase gene. The enhancer II (EnhII; nucleotides 1636-1744) and basal core promoter (BCP; nucleotides 1751-1769) regions overlap with the X gene (nucleotides 1374-1838). The precore region encodes the hepatitis B e antigen (HBeAg), which is used clinically as an indicator of active viral replication (3 , 4). Expression of HBeAg and a high serum level of HBV (ie, a viral load ≥ 10 000 copies per milliliter) are associated with an increased risk of HCC (5 , 6). Eight HBV genotypes (genotypes A-H) have been identifi ed based on a sequence divergence of greater than 8% over the entire HBV genome. Genotypes are further categorized into subgenotypes based on nucleotide sequence divergence between 4% and 8% (7). Patients who are infected with HBV genotypes that have