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Characterization of HPV and host genome interactions in primary head and neck cancers

2014-10-28 00:01:14

Proceedings of the National Academy of Sciences; 28 OCT 2014; DOI:10.1073/pnas.1416074111



Michael Parfenov, Chandra Sekhar Pedamallu, Nils Gehlenborg, Samuel S. Freeman, Ludmila Danilova, Christopher A. Bristow, Semin Lee, Angela G. Hadjipanayis, Elena V. Ivanova, Matthew D. Wilkerson, Alexei Protopopov, Lixing Yang, Sahil Seth, Xingzhi Song, Jiabin Tang, Xiaojia Ren, Jianhua Zhang, Angeliki Pantazi, Netty Santoso, Andrew W. Xu, Harshad Mahadeshwar, David A. Wheeler, Robert I. Haddad, Joonil Jung, Akinyemi I. Ojesina, Natalia Issaeva, Wendell G. Yarbrough, D. Neil Hayes, Jennifer R. Grandis, Adel K. El-Naggar, Matthew Meyerson, Peter J. Park, Lynda Chin, J. G. Seidman, Peter S. Hammerman, Raju Kucherlapati, the Cancer Genome Atlas Network



Significance



A significant proportion of head and neck cancer is driven by human papillomavirus (HPV) infection, and the expression of viral oncogenes is involved in the development of these tumors. However, the role of HPV integration in primary tumors beyond increasing the expression of viral oncoproteins is not understood. Here, we describe how HPV integration impacts the host genome by amplification of oncogenes and disruption of tumor suppressors as well as driving inter- and intrachromosomal rearrangements. Tumors that do and do not have HPV integrants display distinct gene expression profiles and DNA methylation patterns, which further support the view that the mechanisms by which tumors with integrated and nonintegrated HPV arise are distinct.



Abstract



Previous studies have established that a subset of head and neck tumors contains human papillomavirus (HPV) sequences and that HPV-driven head and neck cancers display distinct biological and clinical features. HPV is known to drive cancer by the actions of the E6 and E7 oncoproteins, but the molecular architecture of HPV infection and its interaction with the host genome in head and neck cancers have not been comprehensively described. We profiled a cohort of 279 head and neck cancers with next generation RNA and DNA sequencing and show that 35 (12.5%) tumors displayed evidence of high-risk HPV types 16, 33, or 35. Twenty-five cases had integration of the viral genome into one or more locations in the human genome with statistical enrichment for genic regions. Integrations had a marked impact on the human genome and were associated with alterations in DNA copy number, mRNA transcript abundance and splicing, and both inter- and intrachromosomal rearrangements. Many of these events involved genes with documented roles in cancer. Cancers with integrated vs. nonintegrated HPV displayed different patterns of DNA methylation and both human and viral gene expressions. Together, these data provide insight into the mechanisms by which HPV interacts with the human genome beyond expression of viral oncoproteins and suggest that specific integration events are an integral component of viral oncogenesis.



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Key Words



cancer | head and neck | papilloma virus | genome rearrangement | integration sites