Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability
- Keiko Akagi1,2,3,10,
- Jingfeng Li1,2,3,10,
- Tatevik R. Broutian2,4,
- Hesed Padilla-Nash5,
- Weihong Xiao2,4,
- Bo Jiang2,4,
- James W. Rocco6,7,
- Theodoros N. Teknos8,
- Bhavna Kumar8,
- Danny Wangsa5,
- Dandan He1,2,3,
- Thomas Ried5,
- David E. Symer1,2,3,4,9,11,12 and
- Maura L. Gillison2,4,11,12
- 1Human Cancer Genetics Program, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA;
- 2Viral Oncology Program, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA;
- 3Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio 43210, USA;
- 4Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
- 5Cancer Genomics Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20814, USA;
- 6Center for Cancer Research and Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
- 7Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 8Department of Otolaryngology–Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, USA;
- 9Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio 43210, USA
Abstract
Genomic instability is a hallmark of human cancers, including the 5% caused by human papillomavirus (HPV). Here we report a striking association between HPV integration and adjacent host genomic structural variation in human cancer cell lines and primary tumors. Whole-genome sequencing revealed HPV integrants flanking and bridging extensive host genomic amplifications and rearrangements, including deletions, inversions, and chromosomal translocations. We present a model of “looping” by which HPV integrant-mediated DNA replication and recombination may result in viral–host DNA concatemers, frequently disrupting genes involved in oncogenesis and amplifying HPV oncogenes E6 and E7. Our high-resolution results shed new light on a catastrophic process, distinct from chromothripsis and other mutational processes, by which HPV directly promotes genomic instability.
Footnotes
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↵12 Corresponding authors
E-mail david.symer{at}osumc.edu
E-mail maura.gillison{at}osumc.edu
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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.164806.113.
- Received August 7, 2013.
- Accepted October 17, 2013.
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 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.
