title: Characterization of HPV and host genome interactions in primary head and neck cancers.
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.
authors.affiliation: Departments of Genetics and.
authors.forename: Michael
authors.initials: M
authors.lastname: Parfenov
authors.affiliation: Department of Medical Oncology and The Eli and Edythe L. Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142;
authors.forename: Chandra Sekhar
authors.initials: CS
authors.lastname: Pedamallu
authors.affiliation: 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;
authors.forename: Nils
authors.initials: N
authors.lastname: Gehlenborg
authors.affiliation: The Eli and Edythe L. Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142;
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Freeman
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287;
authors.forename: Ludmila
authors.initials: L
authors.lastname: Danilova
authors.affiliation: Institute for Applied Cancer Science, Department of Genomic Medicine and.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Bristow
authors.affiliation: Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115;
authors.forename: Semin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Departments of Genetics and.
authors.forename: Angela G
authors.initials: AG
authors.lastname: Hadjipanayis
authors.affiliation: Department of Medical Oncology and Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02115;
authors.forename: Elena V
authors.initials: EV
authors.lastname: Ivanova
authors.affiliation: Lineberger Comprehensive Cancer Center and Department of Genetics and.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Wilkerson
authors.affiliation: Institute for Applied Cancer Science, Department of Genomic Medicine and.
authors.forename: Alexei
authors.initials: A
authors.lastname: Protopopov
authors.affiliation: Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115;
authors.forename: Lixing
authors.initials: L
authors.lastname: Yang
authors.affiliation: Institute for Applied Cancer Science, Department of Genomic Medicine and.
authors.forename: Sahil
authors.initials: S
authors.lastname: Seth
authors.affiliation: Institute for Applied Cancer Science, Department of Genomic Medicine and.
authors.forename: Xingzhi
authors.initials: X
authors.lastname: Song
authors.affiliation: Institute for Applied Cancer Science, Department of Genomic Medicine and.
authors.forename: Jiabin
authors.initials: J
authors.lastname: Tang
authors.affiliation: Departments of Genetics and.
authors.forename: Xiaojia
authors.initials: X
authors.lastname: Ren
authors.affiliation: Institute for Applied Cancer Science, Department of Genomic Medicine and.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Departments of Genetics and.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Pantazi
authors.affiliation: Departments of Genetics and.
authors.forename: Netty
authors.initials: N
authors.lastname: Santoso
authors.affiliation: Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115;
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Xu
authors.affiliation: Institute for Applied Cancer Science, Department of Genomic Medicine and.
authors.forename: Harshad
authors.initials: H
authors.lastname: Mahadeshwar
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030;
authors.forename: David A
authors.initials: DA
authors.lastname: Wheeler
authors.affiliation: Department of Medical Oncology, Head and Neck Oncology Program, Dana-Farber Cancer Institute, Boston, MA 02215;
authors.forename: Robert I
authors.initials: RI
authors.lastname: Haddad
authors.affiliation: The Eli and Edythe L. Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142;
authors.forename: Joonil
authors.initials: J
authors.lastname: Jung
authors.affiliation: Department of Medical Oncology and The Eli and Edythe L. Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142;
authors.forename: Akinyemi I
authors.initials: AI
authors.lastname: Ojesina
authors.affiliation: Department of Surgery, Division of Otolaryngology, Yale School of Medicine, New Haven, CT 06520-8041;
authors.forename: Natalia
authors.initials: N
authors.lastname: Issaeva
authors.affiliation: Department of Surgery, Division of Otolaryngology, Yale School of Medicine, New Haven, CT 06520-8041;
authors.forename: Wendell G
authors.initials: WG
authors.lastname: Yarbrough
authors.affiliation: Lineberger Comprehensive Cancer Center and Department of Internal Medicine, Division of Medical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
authors.forename: D Neil
authors.initials: DN
authors.lastname: Hayes
authors.affiliation: Departments of Otolaryngology and Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
authors.affiliation: Departments of Pathology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Adel K
authors.initials: AK
authors.lastname: El-Naggar
authors.affiliation: Department of Medical Oncology and The Eli and Edythe L. Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142; Pathology and.
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.affiliation: Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115;
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Park
authors.affiliation: 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.
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.affiliation: Departments of Genetics and seidman@genetics.med.harvard.edu peterh@broadinstitute.org rkucherlapati@partners.org.
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
authors.affiliation: 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.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hammerman
authors.affiliation: Harvard Medical School, Partners HealthCare Center for Genetics and Genomics, Boston, MA 02115 seidman@genetics.med.harvard.edu peterh@broadinstitute.org rkucherlapati@partners.org.
authors.forename: Raju
authors.initials: R
authors.lastname: Kucherlapati
mesh_terms: D001483:Base Sequence; D019175:DNA Methylation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D015894:Genome, Human / Q000235:genetics*; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000821:virology*; D054884:Host-Pathogen Interactions / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D027383:Papillomaviridae / Q000502:physiology*; D016662:Virus Integration / Q000235:genetics
keywords: cancer; genome rearrangement; head and neck; integration sites; papilloma virus