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 45 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.

Objective: To explore the relationship between the mutations in the reverse transcriptase(RT) domain of hepatitis B virus polymerase(HBV-P) gene and the occurrence and development of hepatocellular carcinoma(HCC). Methods: In this case-control study, the serum samples from 202 HCC patients and 202 chronic hepatitis B virus(CHB) carriers matching for age and gender were collected. The sequence of the RT domain of HBV-P gene was determined by direct sequencing following PCR amplifi cation. The relationship between the mutations in the RT domain of HBV-P gene and the occurrence and development of HCC was analyzed. Results: The T895A, A904T and C955T mutations in the RT domain of HBV-P gene were all signif icantly associated with HCC compared to non-HCC controls(P = 0.034, 47.5% vs 37.1%; P = 0.011, 5.4% vs 1.0%; P = 0.030, 5.4% vs 1.5%). Furthermore, the Logistic multivariate analysis showed that T895A was an independent risk factor for HCC [odds ratio(OR) = 2.230, 95% confi dence interval(CI): 1.230-4.044, P = 0.008]. A904T or C955T increased the risk of HCC occurrence either(OR = 6.523, 95% CI: 0.838-50.733; OR = 2.904,95% CI: 0.599-14.093), but it did not reach statistical signifi cance. The mutation rate of combined mutation occurrence either in A904 or C955T was 9.4% in HCC group and 2.5% in non-HCC controls(P = 0.003). The adjusted OR was 4.145(95% CI: 1.170-14.681), demonstrating its signif icant association with HCC(P = 0.028). Conclusion: The mutations in the RT domain of HBV-P gene are associated with the tumorigenesis of HCC.