Novel Natural Mutations in the Hepatitis B Virus Reverse Transcriptase Domain Associated with Hepatocellular Carcinoma

BACKGROUND/AIM: Hepatitis B Virus (HBV) mutations play a role in the development of hepatocellular carcinoma (HCC). However, the association between HBV polymerase gene mutations and HCC has not been reported. In this study, we conducted a multi-stage study to identify HCC-related mutations in the reverse transcriptase (RT) domain of the HBV polymerase gene. METHODS: A total of 231 HCCs and 237 non-HCC controls from Qidong, China, were included in this study. The entire sequence of HBV RT was first compared between 29 HCC and 35 non-HCC cases, and candidate mutations were then evaluated in two independent validation sets. RESULTS: There were 15 candidate mutations identified from the discovery set, with A799G and T1055A being consistently associated with HCC across all studies. A pooled analysis of samples revealed that A799G, A987G, and T1055A were independent risk factors for HCC, with adjusted odds ratios of 5.53 [95% confidence interval (CI), 1.69–18.10], 4.20 (95%CI, 1.15–15.35), and 3.78 (95%CI, 1.45–9.86), respectively. A longitudinal study showed that these mutations were detectable 4–5 years prior to HCC diagnosis. CONCLUSIONS: Our study provides evidence the first that HBV RT contains naturally occurring mutations that can be used as predictive markers for HCC.