Combined pre‐S deletion and core promoter mutations related to hepatocellular carcinoma: A nested case‐control study in China

Aim: To investigate the roles of biomedical factors, hepatitis B virus (HBV) DNA levels, genotypes, and specific viral mutation patterns on the progression of hepatocellular carcinoma (HCC) in Qidong, China. Methods: A total of 2387 males (aged 20–65 years) who were seropositive for the hepatitis B surface antigen (HBsAg), but had not been diagnosed with HCC, were recruited to a community‐based HCC screening study from August, 1996. Evaluation of virological parameters at recruitment was determined for 196 HCC patients during 10 years of follow‐up and 323 controls. Results: After adjustment for age at recruitment, history of cigarette smoking and alcohol consumption, alanine aminotransferase (ALT) elevation, alpha‐fetoprotein (AFP) levels >20 ng/mL, hepatitis B e antigen positive, HBV DNA levels ≥4.00 log₁₀ copies/mL, pre‐S deletion, T1653 mutation, T1762/A1764 double mutations, and T1766 and/or A1768 mutations were associated with subsequent risk of HCC. A significant biological gradient of HCC risk by HBV DNA levels from less than 2.69 log₁₀ copies/mL to 6.00 log₁₀ copies/mL or greater was observed. HBV with a complex mutation combination pattern (pre‐S deletion, T1762/A1764 double mutations, and T1766 and/or A1768 mutations) rather than a single mutation was associated with the development of HCC. The longitudinal observation demonstrated a gradual combination of pre‐S deletion, T1762/A1764 double mutations, and T1766 and/or A1768 mutations during the development of HCC. Conclusions: AFP levels >20 ng/mL, high HBV DNA levels, pre‐S deletion, and T1762/A1764 double mutations at recruitment were independent risk factors of HCC. Combination of pre‐S deletion and core promoter mutations increased the risk of HCC.