Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma (original) (raw)

• Letter
• Published: 27 May 2012
• Hancheng Zheng5 na1,
• Shuyu Li6 na1,
• Ronghua Chen7 na1,
• Xiao Liu5 na1,
• Yingrui Li5,
• Nikki P Lee1,
• Wah H Lee4,
• Pramila N Ariyaratne4,
• Chandana Tennakoon2,3,
• Fabianus H Mulawadi4,
• Kwong F Wong1,8,9,10,
• Angela M Liu1,8,9,10,
• Ronnie T Poon1,
• Sheung Tat Fan1,
• Kwong L Chan1,
• Zhuolin Gong5,
• Yujie Hu5,
• Zhao Lin5,
• Guan Wang5,
• Qinghui Zhang5,
• Thomas D Barber6,
• Wen-Chi Chou6,
• Amit Aggarwal6,
• Ke Hao7,
• Wei Zhou7,
• Chunsheng Zhang7,
• James Hardwick7,11,
• Carolyn Buser7,
• Jiangchun Xu12,
• Zhengyan Kan12,
• Hongyue Dai7,
• Mao Mao11,12,
• Christoph Reinhard6,
• Jun Wang5,13,14 &
• …
• John M Luk1,8,9,10 nAff15

Nature Genetics volume 44, pages 765–769 (2012)Cite this article

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Abstract

To survey hepatitis B virus (HBV) integration in liver cancer genomes, we conducted massively parallel sequencing of 81 HBV-positive and 7 HBV-negative hepatocellular carcinomas (HCCs) and adjacent normal tissues. We found that HBV integration is observed more frequently in the tumors (86.4%) than in adjacent liver tissues (30.7%). Copy-number variations (CNVs) were significantly increased at HBV breakpoint locations where chromosomal instability was likely induced. Approximately 40% of HBV breakpoints within the HBV genome were located within a 1,800-bp region where the viral enhancer, X gene and core gene are located. We also identified recurrent HBV integration events (in ≥4 HCCs) that were validated by RNA sequencing (RNA-seq) and Sanger sequencing at the known and putative cancer-related TERT, MLL4 and CCNE1 genes, which showed upregulated gene expression in tumor versus normal tissue. We also report evidence that suggests that the number of HBV integrations is associated with patient survival.

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Acknowledgements

We gratefully acknowledge Y.-K. Mak and the clinical team of the Division of Hepatobiliary and Pancreatic Surgery (HBP) at Queen Mary Hospital. This study was funded by the Asian Cancer Research Group (ACRG), a not-for-profit organization formed by Eli Lilly, Merck and Pfizer. We thank S. Friend and G. Jin for initiating the establishment of ACRG. We are grateful to former and present members of ACRG, especially K. Blanchard, Y. Turpaz, J. Sedgwick, G. Tucker-Kellogg, G. Gilliland, P. Shaw, N. Gibson and S. Adams.

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Author notes

1. John M Luk
   Present address: Present address: Department of Oncology, Roche R&D Center (China) Ltd., Shanghai, China.,
2. Wing-Kin Sung, Hancheng Zheng, Shuyu Li, Ronghua Chen and Xiao Liu: These authors contributed equally to this work.

Authors and Affiliations

1. Department of Surgery, University of Hong Kong, Hong Kong
   Wing-Kin Sung, Nikki P Lee, Kwong F Wong, Angela M Liu, Ronnie T Poon, Sheung Tat Fan, Kwong L Chan & John M Luk
2. School of Computing, National University of Singapore (NUS), Singapore
   Wing-Kin Sung & Chandana Tennakoon
3. NUS Graduate School for Integrative Sciences & Engineering, National University of Singapore, Singapore
   Wing-Kin Sung & Chandana Tennakoon
4. Department of Computational & Systems Biology, Genome Institute of Singapore, Singapore
   Wing-Kin Sung, Wah H Lee, Pramila N Ariyaratne & Fabianus H Mulawadi
5. Beijing Genomics Institute, Shenzhen, China
   Hancheng Zheng, Xiao Liu, Yingrui Li, Zhuolin Gong, Yujie Hu, Zhao Lin, Guan Wang, Qinghui Zhang & Jun Wang
6. Eli Lilly & Co., Indianapolis, Indiana, USA
   Shuyu Li, Thomas D Barber, Wen-Chi Chou, Amit Aggarwal & Christoph Reinhard
7. Merck Research Laboratories, Boston, Massachusetts, USA
   Ronghua Chen, Ke Hao, Wei Zhou, Chunsheng Zhang, James Hardwick, Carolyn Buser & Hongyue Dai
8. Department of Pharmacology, NUS, Singapore
   Kwong F Wong, Angela M Liu & John M Luk
9. Department of Surgery, NUS, Singapore
   Kwong F Wong, Angela M Liu & John M Luk
10. Cancer Science Institute, NUS, Singapore
    Kwong F Wong, Angela M Liu & John M Luk
11. Asian Cancer Research Group, Inc., Wilmington, Delaware, USA
    James Hardwick & Mao Mao
12. Pfizer Oncology, San Diego, California, USA
    Jiangchun Xu, Zhengyan Kan & Mao Mao
13. Department of Biology, University of Copenhagen, Copenhagen, Denmark
    Jun Wang
14. The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
    Jun Wang

Authors

1. Wing-Kin Sung
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2. Hancheng Zheng
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3. Shuyu Li
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4. Ronghua Chen
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5. Xiao Liu
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6. Yingrui Li
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7. Nikki P Lee
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8. Wah H Lee
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9. Pramila N Ariyaratne
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10. Chandana Tennakoon
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11. Fabianus H Mulawadi
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12. Kwong F Wong
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13. Angela M Liu
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14. Ronnie T Poon
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15. Sheung Tat Fan
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16. Kwong L Chan
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17. Zhuolin Gong
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18. Yujie Hu
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19. Zhao Lin
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20. Guan Wang
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21. Qinghui Zhang
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22. Thomas D Barber
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23. Wen-Chi Chou
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24. Amit Aggarwal
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25. Ke Hao
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26. Wei Zhou
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27. Chunsheng Zhang
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28. James Hardwick
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29. Carolyn Buser
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30. Jiangchun Xu
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31. Zhengyan Kan
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32. Hongyue Dai
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33. Mao Mao
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34. Christoph Reinhard
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35. Jun Wang
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36. John M Luk
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Corresponding authors

Correspondence toChristoph Reinhard, Jun Wang or John M Luk.

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Sung, WK., Zheng, H., Li, S. et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma.Nat Genet 44, 765–769 (2012). https://doi.org/10.1038/ng.2295

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• Received: 23 January 2012
• Accepted: 30 April 2012
• Published: 27 May 2012
• Issue Date: July 2012
• DOI: https://doi.org/10.1038/ng.2295

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