Human papillomavirus infections and upper aero-digestive tract cancers: the ARCAGE study

Devasena Anantharaman, Tarik Gheit, Tim Waterboer, Behnoush Abedi-Ardekani, Christine Carreira, Sandrine McKay-Chopin, Valerie Gaborieau, Manuela Marron, Pagona Lagiou, Wolfgang Ahrens, Ivana Holcátová, Franco Merletti, Kristina Kjaerheim, Renato Talamini, Lorenzo Simonato, Xavier Castellsague, Tatiana MacFarlane, Anne-Marie Biggs, Nalin Thakker, Ariana ZnaorPeter Thomson, Cristina Canova, David I Conway, Claire M Healy, Massimo Tommasino, Michael Pawlita, Paul Brennan

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BACKGROUND: Human papillomavirus (HPV) is causally implicated in a subset of cancers of the upper aero-digestive tract (UADT).

METHODS: Associations between type-specific HPV antibodies were examined among 1496 UADT cancer case subjects and 1425 control subjects by estimating odds ratios (ORs) in logistic regression analyses adjusted for potential confounders. The agreement between serology and tumor markers of HPV infection, including presence of HPV DNA and p16 expression, were examined in a subset of tumors.

RESULTS: HPV16 L1 seropositivity was associated with increased risk of oral cavity and oropharyngeal cancer (OR = 1.94, 95% confidence interval [CI] = 1.03 to 3.65; OR = 8.60, 95% CI = 5.21 to 14.20, respectively). HPV16 E6 antibodies were present in 30.2% of oropharyngeal case subjects and only 0.8% of control subjects (OR = 132.0, 95% CI = 65.29 to 266.86). Combined seropositivity to HPV16 E6 and E7 was rare (n = 1 of 1425 control subjects). An agreement of 67% was observed between HPV16 E6 serology and the corresponding presence of an HPV-related cancer: four of six HPV DNA-positive/p16-overexpressing tumors were HPV16 E6 antibody positive. An HPV16 independent association was observed for HPV18 and oropharyngeal cancer (OR = 8.14, 95% CI = 2.21 to 29.99 for HPV18 E6 seropositivity) and HPV6 and laryngeal cancer (OR = 3.25, 95% CI = 1.46 to 7.24 for HPV6 E7 seropositivity).

CONCLUSIONS: These results confirm an important role for HPV16 infection in oropharyngeal cancer. HPV16 E6 antibodies are strongly associated with HPV16-related oropharyngeal cancers. Continuing efforts are needed to consider both HPV serology and p16 staining as biomarkers relevant to the etiology and natural history of HPV16-related oropharyngeal tumors. These results also support a marginal role for HPV18 in oropharyngeal cancer and HPV6 in laryngeal cancer.

Original languageEnglish
Pages (from-to)536-545
Number of pages10
JournalJournal of the National Cancer Institute
Issue number8
Publication statusPublished - 17 Apr 2013


  • Aged
  • Antibodies, Viral
  • Case-Control Studies
  • DNA, Viral
  • Female
  • Fluorescent Antibody Technique
  • Human papillomavirus 16
  • Humans
  • Laryngeal Neoplasms
  • Logistic Models
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Odds Ratio
  • Oncogene Proteins, Viral
  • Oropharyngeal Neoplasms
  • Papillomavirus E7 Proteins
  • Papillomavirus Infections
  • Polymerase Chain Reaction
  • Repressor Proteins
  • Tumor Markers, Biological
  • Up-Regulation


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