title: Integrative analysis of head and neck cancer identifies two biologically distinct HPV and three non-HPV subtypes.
abstract: OBJECTIVE
  Current classification of head and neck squamous cell carcinomas (HNSCC) based on anatomic site and stage fails to capture biologic heterogeneity or adequately inform treatment.
  
  
  METHODS
  Here, we use gene expression-based consensus clustering, copy number profiling, and human papillomavirus (HPV) status on a clinically homogenous cohort of 134 locoregionally advanced HNSCCs with 44% HPV(+) tumors together with additional cohorts, which in total comprise 938 tumors, to identify HNSCC subtypes and discover several subtype-specific, translationally relevant characteristics.
  
  
  RESULTS
  We identified five subtypes of HNSCC, including two biologically distinct HPV subtypes. One HPV(+) and one HPV(-) subtype show a prominent immune and mesenchymal phenotype. Prominent tumor infiltration with CD8(+) lymphocytes characterizes this inflamed/mesenchymal subtype, independent of HPV status. Compared with other subtypes, the two HPV subtypes show low expression and no copy number events for EGFR/HER ligands. In contrast, the basal subtype is uniquely characterized by a prominent EGFR/HER signaling phenotype, negative HPV-status, as well as strong hypoxic differentiation not seen in other subtypes.
  
  
  CONCLUSIONS
  Our five-subtype classification provides a comprehensive overview of HPV(+) as well as HPV(-) HNSCC biology with significant translational implications for biomarker development and personalized care for patients with HNSCC.
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois. Institute of Biological Chemistry and Nutrition, The University of Hohenheim, Stuttgart, Germany.
authors.forename: Michaela K
authors.initials: MK
authors.lastname: Keck
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Zuo
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Arun
authors.initials: A
authors.lastname: Khattri
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Stricker
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Brown
authors.affiliation: Medical Center, Department of Otolaryngology-Head and Neck Surgery, The University of Texas Southwestern, Dallas, Texas.
authors.forename: Matin
authors.initials: M
authors.lastname: Imanguli
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Damian
authors.initials: D
authors.lastname: Rieke
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Katharina
authors.initials: K
authors.lastname: Endhardt
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Petra
authors.initials: P
authors.lastname: Fang
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Johannes
authors.initials: J
authors.lastname: Brägelmann
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Rebecca
authors.initials: R
authors.lastname: DeBoer
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Mohamed
authors.initials: M
authors.lastname: El-Dinali
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Serdal
authors.initials: S
authors.lastname: Aktolga
authors.affiliation: Duke-NUS Graduate Medical School, Singapore.
authors.forename: Zhengdeng
authors.initials: Z
authors.lastname: Lei
authors.affiliation: Duke-NUS Graduate Medical School, Singapore. Genome Institute of Singapore, Singapore.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.affiliation: Duke-NUS Graduate Medical School, Singapore.
authors.forename: Steve G
authors.initials: SG
authors.lastname: Rozen
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois. The University of Chicago Comprehensive Cancer Center, Chicago, Illinois.
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois. The University of Chicago Comprehensive Cancer Center, Chicago, Illinois.
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois. The University of Chicago Comprehensive Cancer Center, Chicago, Illinois.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Lingen
authors.affiliation: Southwestern Medical Center, Department of Radiation Oncology, The University of Texas, Dallas, Texas.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Story
authors.affiliation: MD Anderson Cancer Center, The University of Texas, Houston, Texas.
authors.forename: K Kian
authors.initials: KK
authors.lastname: Ang
authors.affiliation: University of California San Diego, La Jolla, California.
authors.forename: Ezra E W
authors.initials: EE
authors.lastname: Cohen
authors.affiliation: The University of Chicago Comprehensive Cancer Center, Chicago, Illinois. Institute for Genomics and Systems Biology, The University of Chicago, Chicago, Illinois.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: White
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois. The University of Chicago Comprehensive Cancer Center, Chicago, Illinois.
authors.forename: Everett E
authors.initials: EE
authors.lastname: Vokes
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois. The University of Chicago Comprehensive Cancer Center, Chicago, Illinois. Institute for Genomics and Systems Biology, The University of Chicago, Chicago, Illinois. tseiwert@medicine.bsd.uchicago.edu.
authors.forename: Tanguy Y
authors.initials: TY
authors.lastname: Seiwert
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000145:classification* / Q000821:virology; D006258:Head and Neck Neoplasms / Q000145:classification* / Q000821:virology; D006801:Humans; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000150:complications; D000077195:Squamous Cell Carcinoma of Head and Neck