title: Molecular classification identifies a subset of human papillomavirus--associated oropharyngeal cancers with favorable prognosis.
abstract: OBJECTIVE
  We sought to determine the prevalence of biologically relevant human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OSCC). Retinoblastoma (Rb) downregulation by HPV E7 results in p16 upregulation. We hypothesized that p16 overexpression in OSCC defines HPV-induced tumors with favorable prognosis.
  
  
  METHODS
  Using real-time polymerase chain reaction for HPV16, we determined HPV16 viral load in a cohort of 79 OSCCs annotated with long-term patient follow-up. A tissue microarray including these cases was also analyzed for p53, p16, and Rb utilizing in situ quantitative protein expression analysis. Seventy-seven tumors were classified into a three-class model on the basis of p16 expression and HPV-DNA presence: class I, HPV-, p16 low; class II, HPV+, p16 low; and class III, HPV+, p16 high.
  
  
  RESULTS
  Sixty-one percent of OSCCs were HPV16+; HPV status alone was of no prognostic value for local recurrence and was barely significant for survival times. Overall survival was improved in class III (79%) compared with the other two classes (20% and 18%; P = .0095). Disease-free survival for the same class was 75% versus 15% and 13% (P = .0025). The 5-year local recurrence was 14% in class III versus 45% and 74% (P = .03). Only patients in class III had significantly lower p53 and Rb expression (P = .017 and .001, respectively). Multivariable survival analysis confirmed the prognostic value of the three-class model.
  
  
  CONCLUSIONS
  Using this system for classification, we define the molecular profile of HPV+ OSCC with favorable prognosis, namely HPV+/p16 high (class III). This study defines a novel classification scheme that may have value for patient stratification for clinical trials testing HPV-targeted therapies.
authors.affiliation: Department of Medical Oncology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Weinberger
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Yu
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Haffty
authors.forename: Diane
authors.initials: D
authors.lastname: Kowalski
authors.forename: Malini
authors.initials: M
authors.lastname: Harigopal
authors.forename: Janet
authors.initials: J
authors.lastname: Brandsma
authors.forename: Clarence
authors.initials: C
authors.lastname: Sasaki
authors.forename: John
authors.initials: J
authors.lastname: Joe
authors.forename: Robert L
authors.initials: RL
authors.lastname: Camp
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
authors.forename: Amanda
authors.initials: A
authors.lastname: Psyrri
mesh_terms: D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000145:classification / Q000453:epidemiology / Q000473:pathology* / Q000821:virology*; D015331:Cohort Studies; D004279:DNA, Viral; D005260:Female; D052162:Human papillomavirus 16 / Q000235:genetics / Q000472:pathogenicity; D006801:Humans; D008297:Male; D008875:Middle Aged; D009959:Oropharyngeal Neoplasms / Q000145:classification / Q000453:epidemiology / Q000473:pathology* / Q000821:virology*; D030361:Papillomavirus Infections / Q000150:complications*; D016133:Polymerase Chain Reaction; D015995:Prevalence; D011379:Prognosis; D016019:Survival Analysis; D019562:Viral Load
chemical_list: D004279:DNA, Viral