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Proc Natl Acad Sci U S A. 2014 Oct 28;111(43):15544-9. doi: 10.1073/pnas.1416074111. Epub 2014 Oct 13.

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

Collaborators (340)

Ally A, Balasundaram M, Birol I, Bowlby R, Butterfield YS, Carlsen R, Cheng D, Chu A, Dhalla N, Guin R, Holt RA, Jones SJ, Lee D, Li HI, Marra MA, Mayo M, Moore RA, Mungall AJ, Robertson AG, Schein JE, Sipahimalani P, Tam A, Thiessen N, Wong T, Protopopov A, Santoso N, Lee S, Parfenov M, Zhang J, Mahadeshwar HS, Tang J, Ren X, Seth S, Haseley P, Zeng D, Yang L, Xu AW, Song X, Pantazi A, Bristow C, Hadjipanayis A, Seidman J, Chin L, Park PJ, Kucherlapati R, Akbani R, Casasent T, Liu W, Lu Y, Mills G, Motter T, Weinstein J, Diao L, Wang J, Fan YH, Liu J, Wang K, Auman JT, Balu S, Bodenheimer T, Buda E, Hayes DN, Hoadley KA, Hoyle AP, Jefferys SR, Jones CD, Kimes PK, Marron JS, Meng S, Mieczkowski PA, Mose LE, Parker JS, Perou CM, Prins JF, Roach J, Shi Y, Simons JV, Singh D, Soloway MG, Tan D, Veluvolu U, Walter V, Waring S, Wilkerson MD, Wu J, Zhao N, Cherniack AD, Hammerman PS, Tward AD, Pedamallu CS, Saksena G, Jung J, Ojesina AI, Carter SL, Zack TI, Schumacher SE, Beroukhim R, Freeman SS, Meyerson M, Cho J, Chin L, Getz G, Noble MS, DiCara D, Zhang H, Heiman DI, Gehlenborg N, Voet D, Lin P, Frazer S, Stojanov P, Liu Y, Zou L, Kim J, Lawrence MS, Sougnez C, Lichtenstein L, Cibulskis K, Lander E, Gabriel SB, Muzny D, Doddapaneni H, Kovar C, Reid J, Morton D, Han Y, Hale W, Chao H, Chang K, Drummond JA, Gibbs RA, Kakkar N, Wheeler D, Xi L, Ciriello G, Ladanyi M, Lee W, Ramirez R, Sander C, Shen R, Sinha R, Weinhold N, Taylor BS, Aksoy BA, Dresdner G, Gao J, Gross B, Jacobsen A, Reva B, Schultz N, Sumer SO, Sun Y, Chan T, Morris L, Stuart J, Benz S, Ng S, Benz C, Yau C, Baylin SB, Cope L, Danilova L, Herman JG, Bootwalla M, Maglinte DT, Laird PW, Triche T Jr, Weisenberger DJ, Van Den Berg DJ, Agrawal N, Bishop J, Boutros PC, Bruce JP, Byers LA, Califano J, Carey TE, Chen Z, Cheng H, Chiosea SI, Cohen E, Diergaarde B, Egloff AM, El-Naggar AK, Ferris RL, Frederick MJ, Grandis JR, Guo Y, Haddad RI, Hammerman PS, Harris T, Hayes DN, Hui AB, Lee JJ, Lippman SM, Liu FF, McHugh JB, Myers J, Ng PK, Perez-Ordonez B, Pickering CR, Prystowsky M, Romkes M, Saleh AD, Sartor MA, Seethala R, Seiwert TY, Si H, Tward AD, Van Waes C, Waggott DM, Wiznerowicz M, Yarbrough W, Zhang J, Zuo Z, Burnett K, Crain D, Gardner J, Lau K, Mallery D, Morris S, Paulauskis J, Penny R, Shelton C, Shelton T, Sherman M, Yena P, Black AD, Bowen J, Frick J, Gastier-Foster JM, Harper HA, Lichtenberg TM, Ramirez NC, Wise L, Zmuda E, Baboud J, Jensen MA, Kahn AB, Pihl TD, Pot DA, Srinivasan D, Walton JS, Wan Y, Burton R, Davidsen T, Demchok JA, Eley G, Ferguson ML, Mills Shaw KR, Ozenberger BA, Sheth M, Sofia HJ, Tarnuzzer R, Wang Z, Yang L, Zenklusen JC, Saller C, Tarvin K, Chen C, Bollag R, Weinberger P, Golusiński W, Golusiński P, Ibbs M, Korski K, Mackiewicz A, Suchorska W, Szybiak B, Wiznerowicz M, Burnett K, Curley E, Gardner J, Mallery D, Penny R, Shelton T, Yena P, Beard C, Mitchell C, Sandusky G, Agrawal N, Ahn J, Bishop J, Califano J, Khan Z, Bruce JP, Hui AB, Irish J, Liu FF, Perez-Ordonez B, Waldron J, Boutros PC, Waggott DM, Myers J, Lippman SM, Egea S, Gomez-Fernandez C, Herbert L, Bradford CR, Carey TE, Chepeha DB, Haddad AS, Jones TR, Komarck CM, Malakh M, McHugh JB, Moyer JS, Nguyen A, Peterson LA, Prince ME, Rozek LS, Sartor MA, Taylor EG, Walline HM, Wolf GT, Boice L, Chera BS, Funkhouser WK, Gulley ML, Hackman TG, Hayes DN, Hayward MC, Huang M, Rathmell WK, Salazar AH, Shockley WW, Shores CG, Thorne L, Weissler MC, Wrenn S, Zanation AM, Chiosea SI, Diergaarde B, Egloff AM, Ferris RL, Romkes M, Seethala R, Brown BT, Guo Y, Pham M, Yarbrough WG.

Author information

1
Departments of Genetics and.
2
Department of Medical Oncology and The Eli and Edythe L. Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142;
3
The Eli and Edythe L. Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142; Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115;
4
The Eli and Edythe L. Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142;
5
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287;
6
Institute for Applied Cancer Science, Department of Genomic Medicine and.
7
Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115;
8
Department of Medical Oncology and Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02115;
9
Lineberger Comprehensive Cancer Center and Department of Genetics and.
10
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030;
11
Department of Medical Oncology, Head and Neck Oncology Program, Dana-Farber Cancer Institute, Boston, MA 02215;
12
Department of Surgery, Division of Otolaryngology, Yale School of Medicine, New Haven, CT 06520-8041;
13
Lineberger Comprehensive Cancer Center and Department of Internal Medicine, Division of Medical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
14
Departments of Otolaryngology and Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and.
15
Departments of Pathology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
16
Department of Medical Oncology and The Eli and Edythe L. Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142; Pathology and.
17
The Eli and Edythe L. Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142; Institute for Applied Cancer Science, Department of Genomic Medicine and.
18
Departments of Genetics and seidman@genetics.med.harvard.edu peterh@broadinstitute.org rkucherlapati@partners.org.
19
Department of Medical Oncology and The Eli and Edythe L. Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142; seidman@genetics.med.harvard.edu peterh@broadinstitute.org rkucherlapati@partners.org.
20
Harvard Medical School, Partners HealthCare Center for Genetics and Genomics, Boston, MA 02115 seidman@genetics.med.harvard.edu peterh@broadinstitute.org rkucherlapati@partners.org.

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.

KEYWORDS:

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

PMID:
25313082
PMCID:
PMC4217452
DOI:
10.1073/pnas.1416074111
[Indexed for MEDLINE]
Free PMC Article

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