Novel natural mutations in the Hepatitis B Virus reverse transcriptase domain associated with hepatocellular carcinoma

Yan Wu, Yu Gan, Fumin Gao, Zhimei Zhao, Yan Jin, Yu Zhu, Zhihan Sun, Hao Wu, Taoyang Chen, Jinbing Wang, Yan Sun, Chunsun Fan, Yongbing Xiang, Gengsun Qian, John Davis Groopman, Jianren Gu, Hong Tu

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article numbere94864
JournalPLoS One
Volume9
Issue number5
DOIs
StatePublished - May 1 2014

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Hepatitis B virus
RNA-directed DNA polymerase
RNA-Directed DNA Polymerase
hepatoma
Viruses
Hepatocellular Carcinoma
mutation
Mutation
confidence interval
Genes
Confidence Intervals
carcinoma
Carcinoma
longitudinal studies
odds ratio
Longitudinal Studies
China
risk factors
genes
Odds Ratio

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Novel natural mutations in the Hepatitis B Virus reverse transcriptase domain associated with hepatocellular carcinoma. / Wu, Yan; Gan, Yu; Gao, Fumin; Zhao, Zhimei; Jin, Yan; Zhu, Yu; Sun, Zhihan; Wu, Hao; Chen, Taoyang; Wang, Jinbing; Sun, Yan; Fan, Chunsun; Xiang, Yongbing; Qian, Gengsun; Groopman, John Davis; Gu, Jianren; Tu, Hong.

In: PLoS One, Vol. 9, No. 5, e94864, 01.05.2014.

Research output: Contribution to journalArticle

Wu, Y, Gan, Y, Gao, F, Zhao, Z, Jin, Y, Zhu, Y, Sun, Z, Wu, H, Chen, T, Wang, J, Sun, Y, Fan, C, Xiang, Y, Qian, G, Groopman, JD, Gu, J & Tu, H 2014, 'Novel natural mutations in the Hepatitis B Virus reverse transcriptase domain associated with hepatocellular carcinoma', PLoS One, vol. 9, no. 5, e94864. https://doi.org/10.1371/journal.pone.0094864
Wu, Yan ; Gan, Yu ; Gao, Fumin ; Zhao, Zhimei ; Jin, Yan ; Zhu, Yu ; Sun, Zhihan ; Wu, Hao ; Chen, Taoyang ; Wang, Jinbing ; Sun, Yan ; Fan, Chunsun ; Xiang, Yongbing ; Qian, Gengsun ; Groopman, John Davis ; Gu, Jianren ; Tu, Hong. / Novel natural mutations in the Hepatitis B Virus reverse transcriptase domain associated with hepatocellular carcinoma. In: PLoS One. 2014 ; Vol. 9, No. 5.
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abstract = "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.",
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AU - Wu, Yan

AU - Gan, Yu

AU - Gao, Fumin

AU - Zhao, Zhimei

AU - Jin, Yan

AU - Zhu, Yu

AU - Sun, Zhihan

AU - Wu, Hao

AU - Chen, Taoyang

AU - Wang, Jinbing

AU - Sun, Yan

AU - Fan, Chunsun

AU - Xiang, Yongbing

AU - Qian, Gengsun

AU - Groopman, John Davis

AU - Gu, Jianren

AU - Tu, Hong

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N2 - 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.

AB - 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.

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