Human papillomavirus (HPV) causes 5% of all cancers and frequently integrates into host chromosomes. The HPV oncoproteins E6 and E7 are necessary but insufficient for cancer formation, indicating that additional secondary genetic events are required. Here, we investigate potential oncogenic impacts of virus integration. Analysis of 105 HPV-positive oropharyngeal cancers by whole-genome sequencing detects virus integration in 77%, revealing five statistically significant sites of recurrent integration near genes that regulate epithelial stem cell maintenance (i.e., SOX2, TP63, FGFR, MYC) and immune evasion (i.e., CD274). Genomic copy number hyperamplification is enriched 16-fold near HPV integrants, and the extent of focal host genomic instability increases with their local density. The frequency of genes expressed at extreme outlier levels is increased 86-fold within ±150 kb of integrants. Across 95% of tumors with integration, host gene transcription is disrupted via intragenic integrants, chimeric transcription, outlier expression, gene breaking, and/or de novo expression of noncoding or imprinted genes. We conclude that virus integration can contribute to carcinogenesis in a large majority of HPV-positive oropharyngeal cancers by inducing extensive disruption of host genome structure and gene expression.
David E Symer 1, Keiko Akagi 2, Heather M Geiger 3, Yang Song 2, Gaiyun Li 2, Anne-Katrin Emde 3, Weihong Xiao 2, Bo Jiang 2, André Corvelo 3, Nora C Toussaint 3, Jingfeng Li 4, Amit Agrawal 5, Enver Ozer 5, Adel K El-Naggar 6, Zoe Du 1, Jitesh B Shewale 2, Birgit Stache-Crain 7, Mark Zucker 8, Nicolas Robine 3, Kevin R Coombes 8, Maura L Gillison 2
Affiliations
1Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
2Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
3New York Genome Center, New York, New York 10013, USA.
4Division of Medical Oncology, Department of Internal Medicine, Ohio State University, Columbus, Ohio 43210, USA.
5Department of Otolaryngology – Head and Neck Surgery, Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
6Division of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
7Complete Genomics, San Jose, California 95134, USA.
8Department of Biomedical Informatics, Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
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