A virome-wide clonal integration analysis platform for discovering cancer viral etiology
- Xun Chen1,
- Jason Kost1,
- Arvis Sulovari1,
- Nathalie Wong2,
- Winnie S. Liang3,
- Jian Cao4,5 and
- Dawei Li1,6,7
- 1Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont 05405, USA;
- 2Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong 999077, P.R. China;
- 3Translational Genomics Research Institute, Phoenix, Arizona 85004, USA;
- 4Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08903, USA;
- 5Department of Medicine, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08903, USA;
- 6Neuroscience, Behavior, and Health Initiative, University of Vermont, Burlington, Vermont 05405, USA;
- 7Department of Computer Science, University of Vermont, Burlington, Vermont 05405, USA
Abstract
Oncoviral infection is responsible for 12%–15% of cancer in humans. Convergent evidence from epidemiology, pathology, and oncology suggests that new viral etiologies for cancers remain to be discovered. Oncoviral profiles can be obtained from cancer genome sequencing data; however, widespread viral sequence contamination and noncausal viruses complicate the process of identifying genuine oncoviruses. Here, we propose a novel strategy to address these challenges by performing virome-wide screening of early-stage clonal viral integrations. To implement this strategy, we developed VIcaller, a novel platform for identifying viral integrations that are derived from any characterized viruses and shared by a large proportion of tumor cells using whole-genome sequencing (WGS) data. The sensitivity and precision were confirmed with simulated and benchmark cancer data sets. By applying this platform to cancer WGS data sets with proven or speculated viral etiology, we newly identified or confirmed clonal integrations of hepatitis B virus (HBV), human papillomavirus (HPV), Epstein-Barr virus (EBV), and BK Virus (BKV), suggesting the involvement of these viruses in early stages of tumorigenesis in affected tumors, such as HBV in TERT and KMT2B (also known as MLL4) gene loci in liver cancer, HPV and BKV in bladder cancer, and EBV in non-Hodgkin's lymphoma. We also showed the capacity of VIcaller to identify integrations from some uncharacterized viruses. This is the first study to systematically investigate the strategy and method of virome-wide screening of clonal integrations to identify oncoviruses. Searching clonal viral integrations with our platform has the capacity to identify virus-caused cancers and discover cancer viral etiologies.
Footnotes
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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.242529.118.
- Received July 31, 2018.
- Accepted March 11, 2019.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
