Novel natural mutations in the hepatitis B virus reverse transcriptase domain associated with hepatocellular carcinoma.
OBJECTIVE
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.
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Yan
Y
Wu
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Yu
Y
Gan
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China.
Fumin
F
Gao
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Zhimei
Z
Zhao
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Yan
Y
Jin
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Yu
Y
Zhu
School of Basic Medical Sciences, Fudan University, Shanghai, China.
Zhihan
Z
Sun
School of Basic Medical Sciences, Fudan University, Shanghai, China.
Hao
H
Wu
Department of Etiology, Qidong Liver Cancer Institute/Qidong People's Hospital, Qidong, Jiangsu, China.
Taoyang
T
Chen
Department of Etiology, Qidong Liver Cancer Institute/Qidong People's Hospital, Qidong, Jiangsu, China.
Jinbing
J
Wang
Department of Etiology, Qidong Liver Cancer Institute/Qidong People's Hospital, Qidong, Jiangsu, China.
Yan
Y
Sun
Department of Etiology, Qidong Liver Cancer Institute/Qidong People's Hospital, Qidong, Jiangsu, China.
Chunsun
C
Fan
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Yongbing
Y
Xiang
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Gengsun
G
Qian
Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America.
John D
JD
Groopman
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Jianren
J
Gu
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Hong
H
Tu
D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D006528:Carcinoma, Hepatocellular / Q000209:etiology*; D016022:Case-Control Studies; D005260:Female; D006509:Hepatitis B / Q000150:complications* / Q000821:virology*; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D059645:Mutation Rate; D016017:Odds Ratio; D012194:RNA-Directed DNA Polymerase / Q000235:genetics*; D015203:Reproducibility of Results; D012307:Risk Factors; D019562:Viral Load
D012194:RNA-Directed DNA Polymerase