title: Genomic Integration of High-Risk HPV Alters Gene Expression in Oropharyngeal Squamous Cell Carcinoma.
abstract: High-risk HPV (hrHPV) is the leading etiologic factor in oropharyngeal cancer. HPV-positive oropharyngeal tumors generally respond well to therapy, with complete recovery in approximately 80% of patients. However, it remains unclear why some patients are nonresponsive to treatment, with 20% of patients recurring within 5 years. In this study, viral factors were examined for possible clues to differences in tumor behavior. Oropharynx tumors that responded well to therapy were compared with those that persisted and recurred. Viral oncogene alternate transcripts were assessed, and cellular sites of viral integration were mapped and sequenced. Effects of integration on gene expression were assessed by transcript analysis at the integration sites. All of the tumors demonstrated active viral oncogenesis, indicated by expression of HPV E6 and E7 oncogenes and alternate E6 splicing. In the responsive tumors, HPV integration occurred exclusively in intergenic chromosome regions, except for one tumor with viral integration into TP63. Each recurrent tumor exhibited complex HPV integration patterns into cancer-associated genes, including TNFRSF13B, SCN2A, SH2B1, UBE2V2, SMOC1, NFIA, and SEMA6D Disrupted cellular transcripts were identified in the region of integration in four of the seven affected genes.
  
  
  
  Integration of transcriptionally active hrHPV into cellular intergenic regions associates with tumor behavior by altering gene expression. Mol Cancer Res; 14(10); 941-52. ©2016 AACR.
authors.affiliation: Cancer Biology Program, Program in the Biomedical Sciences, Rackham Graduate School, University of Michigan, Ann Arbor, Michigan. Department of Otolaryngology/Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Walline
authors.affiliation: Department of Otolaryngology/Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Komarck
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: McHugh
authors.affiliation: Biostatistics, University of Michigan Cancer Center, Ann Arbor, Michigan.
authors.forename: Emily L
authors.initials: EL
authors.lastname: Bellile
authors.affiliation: Department of Otolaryngology/Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan.
authors.forename: J Chad
authors.initials: JC
authors.lastname: Brenner
authors.affiliation: Department of Otolaryngology/Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Prince
authors.affiliation: Department of Otolaryngology/Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan.
authors.forename: Erin L
authors.initials: EL
authors.lastname: McKean
authors.affiliation: Department of Otolaryngology/Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Chepeha
authors.affiliation: Department of Otolaryngology/Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan.
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Wolf
authors.affiliation: Department of Internal Medicine, Division of Clinical Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Francis P
authors.initials: FP
authors.lastname: Worden
authors.affiliation: Department of Otolaryngology/Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan.
authors.forename: Carol R
authors.initials: CR
authors.lastname: Bradford
authors.affiliation: Department of Otolaryngology/Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan. careyte@med.umich.edu.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Carey
mesh_terms: D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000821:virology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D052162:Human papillomavirus 16 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D009959:Oropharyngeal Neoplasms / Q000235:genetics / Q000821:virology*; D050725:Papillomavirus E7 Proteins / Q000235:genetics*; D030361:Papillomavirus Infections / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D016662:Virus Integration
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16