title: Biomarkers of HPV in head and neck squamous cell carcinoma.
abstract: Human papillomavirus (HPV) is an accepted cause of head and neck squamous cell carcinoma (HNSCC), and patients with HPV-associated HNSCC have a favorable prognosis. Currently, there is no general guidance on the most appropriate biomarkers for clinical assessment of HPV in these malignancies. We compared PCR-based and serologic HPV assays, as well as p16 immunohistochemistry, individually and in combination in a single population-based study to assess their associations with overall survival among patients with HNSCC, and thus their potential value as biomarkers. HPV16 serology was determined for 488 patients; immunohistochemical detection of p16 expression in tumors was conducted in a subset of 233 cases, and PCR-based methods to assess the presence of HPV16 DNA in a subset of 179 cases of tumors. Considering each biomarker individually in the subset of patients studied for all endpoints, seropositivity for the E6 and E7 proteins was significantly associated with enhanced all-cause survival in oropharyngeal disease [HR(E6/E7+) = 0.1, 95% confidence interval (CI) = 0.02-0.3]. Neither the presence of HPV16 DNA nor p16 immunostaining was associated with significant enhanced overall survival in oropharyngeal disease (HR(DNA) = 0.9, 95% CI = 0.3-2.9; HR(p16) = 0.3, 95% CI = 0.1-1.1). However, the combination of HPV-positive DNA and E6 or E7 serology was associated with enhanced overall survival in oropharyngeal disease (HR(DNA+/E6/E7+) = 0.1, 95% CI = 0.02-1.0), whereas E6/E7 seronegative patients with evidence of HPV in tumor DNA did not show any evidence of favorable survival (HR(DNA+/E6-/E7-) = 3.4, 95% CI = 0.6-18.1). Furthermore, patients with p16 staining and E6 or E7 seropositivity had favorable survival from oropharyngeal disease (HR(p16+/E6/E7+) = 0.1, 95% CI = 0.02-0.4), whereas patients who were p16 positive and E6/E7 seronegative had significantly increased hazard of all causes of death (HR(p16+/E6-/E7-) = 3.1, 95% CI = 1.2-7.7). A stronger association of HPV presence with prognosis (assessed by all-cause survival) is observed when "HPV-associated" HNSCC is defined using tumor status (HPV DNA status or P16) and HPV E6/E7 serology in combination rather using tumor HPV status alone.
authors.affiliation: Department of Epidemiology, Division of Biology and Medicine, Brown University, Providence, Rhode Island, USA.
authors.forename: Caihua
authors.initials: C
authors.lastname: Liang
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Marsit
authors.forename: Michael D
authors.initials: MD
authors.lastname: McClean
authors.forename: Heather H
authors.initials: HH
authors.lastname: Nelson
authors.forename: Brock C
authors.initials: BC
authors.lastname: Christensen
authors.forename: Robert I
authors.initials: RI
authors.lastname: Haddad
authors.forename: John R
authors.initials: JR
authors.lastname: Clark
authors.forename: Richard O
authors.initials: RO
authors.lastname: Wein
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Grillone
authors.forename: E Andres
authors.initials: EA
authors.lastname: Houseman
authors.forename: Gordana
authors.initials: G
authors.lastname: Halec
authors.forename: Tim
authors.initials: T
authors.lastname: Waterboer
authors.forename: Michael
authors.initials: M
authors.lastname: Pawlita
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Krane
authors.forename: Karl T
authors.initials: KT
authors.lastname: Kelsey
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000097:blood; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000821:virology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000821:virology*; D054884:Host-Pathogen Interactions; D052162:Human papillomavirus 16 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009856:Oncogene Proteins, Viral / Q000097:blood / Q000235:genetics; D009959:Oropharyngeal Neoplasms / Q000378:metabolism / Q000821:virology; D050725:Papillomavirus E7 Proteins / Q000097:blood / Q000235:genetics; D030361:Papillomavirus Infections / Q000378:metabolism / Q000821:virology*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012097:Repressor Proteins / Q000097:blood / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; 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