The effects of hepatitis B virus integration into the genomes of hepatocellular carcinoma patients
- Zhaoshi Jiang1,6,
- Suchit Jhunjhunwala1,6,
- Jinfeng Liu1,
- Peter M. Haverty1,
- Michael I. Kennemer2,
- Yinghui Guan3,
- William Lee1,
- Paolo Carnevali2,
- Jeremy Stinson3,
- Stephanie Johnson4,
- Jingyu Diao5,
- Stacy Yeung3,
- Adrian Jubb4,
- Weilan Ye3,
- Thomas D. Wu1,
- Sharookh B. Kapadia5,
- Frederic J. de Sauvage3,
- Robert C. Gentleman1,
- Howard M. Stern4,
- Somasekar Seshagiri3,
- Krishna P. Pant2,
- Zora Modrusan3,
- Dennis G. Ballinger2 and
- Zemin Zhang1,7
- 1Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA;
- 2Complete Genomics Inc., Mountain View, California 94043, USA;
- 3Department of Molecular Biology, Genentech Inc., South San Francisco, California 94080, USA;
- 4Department of Pathology, Genentech Inc., South San Francisco, California 94080, USA;
- 5Department of Microbial Pathogenesis, Genentech Inc., South San Francisco, California 94080, USA
Abstract
Hepatitis B virus (HBV) infection is a leading risk factor for hepatocellular carcinoma (HCC). HBV integration into the host genome has been reported, but its scale, impact and contribution to HCC development is not clear. Here, we sequenced the tumor and nontumor genomes (>80× coverage) and transcriptomes of four HCC patients and identified 255 HBV integration sites. Increased sequencing to 240× coverage revealed a proportionally higher number of integration sites. Clonal expansion of HBV-integrated hepatocytes was found specifically in tumor samples. We observe a diverse collection of genomic perturbations near viral integration sites, including direct gene disruption, viral promoter-driven human transcription, viral-human transcript fusion, and DNA copy number alteration. Thus, we report the most comprehensive characterization of HBV integration in hepatocellular carcinoma patients. Such widespread random viral integration will likely increase carcinogenic opportunities in HBV-infected individuals.
Footnotes
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↵7 Corresponding author.
E-mail zhang.zemin{at}gene.com.
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.133926.111.
- Received October 25, 2011.
- Accepted January 19, 2012.
- Copyright © 2012 by Cold Spring Harbor Laboratory Press
Freely available online through the Genome Research Open Access option.
