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Principal Investigator
Aimee Kreimer
Position Title
About this CDAS Project
PLCO (Learn more about this study)
Project ID
Initial CDAS Request Approval
Jan 16, 2014
Expanded evaluation of markers of human papillomavirus (HPV) infection and cancer at multiple anatomic sites - using PLCO data to bolster the cohort consortium effort
HPV is a necessary cause of cancer of the cervix, and also causes a subset of cancers of the anus, penis, vagina, vulva, oropharynx, and to a lesser degree, oral cavity and larynx. We prospectively evaluated the risk conferred by HPV infection as indicated by seropositivity against HPV antibodies for multiple anatomic sites in the European Prospective Investigation into Cancer (EPIC) cohort. We found that seropositivity against HPV16 E6, one of the two HPV oncogenes that are preferentially retained and expressed in cancers, was present in prediagnostic plasma of 35% (N=47 of 135) of cases with oropharyngeal cancer and 0.6% (N=9 of 1599) of controls (adjusted OR=274, 95% CI 110 to 681). We further evaluated HPV16 E6 seropositivity and oropharyngeal cancer in strata defined by lead-time between blood collection and cancer diagnosis (less than 5 years, 5-10 years, and 10+ years), and noted that the proportion of seropositive cases was nearly identical in all lead-time categories, the maximum lead-time in EPIC being 13.7 years. We sought to validate this discovery using PLCO data and found similar results- preliminary analysis suggests an even higher proportion of oropharynx cases were HPV16 E6 seropositive (48%); again, seropositivity in controls was extremely rare (less than 1.0%). In addition, we have new data from EPIC that suggests that HPV16 E6 positivity is also present in prediagnostic samples from individuals with anogenital cancers (approximately 20% of anal cancers and a lesser proportion of the genital cancers), although given the rarity of these cancers, these preliminary findings need confirmation. The aims of this proposal are two-fold: 1) to evaluate the stability (or velocity) of the HPV16 E6 antibody titer among the individuals identified as HPV16 E6 seropositive in the previous round of testing using all available serial samples, and 2) to confirm our anogenital findings from EPIC using anogenital cancer cases and matched controls from PLCO and other cohorts using the cohort consortium infrastructure.

There are two aims in this proposal, which build on our existing research on HPV16 E6 as a promising biomarker for HPV16-driven oropharynx cancer. First, we aim to expand upon the PLCO finding that 48% of 46 incident oropharynx cancers had evidence of HPV16 E6 antibody positivity prior to diagnosis by testing all serial samples from all oropharynx cases (and any other HPV16 E6 seropositive individuals). This aim will address the hypothesis that HPV16 E6 seropositivity is present years before diagnosis of oropharyngeal cancer and assess how the titer levels vary prior to diagnosis in seropositive cases.

To better understand this potential marker, I aim to evaluate its utility in the prediction of other cancers known to be caused, at least in part, by HPV16 infection. Specifically, I will evaluate the risk conferred by serologic evidence HPV infection on anogenital cancer, including cancers of the anus, penis, vagina, vulva and cervix, by conducting a case-control study nested within PLCO and multiple cohorts. This study will address the hypothesis that HPV16 E6 antibodies are a specific marker of HPV infection within the oropharynx (compared to HPV infection at other anatomic sites) given the proximity of oral HPV infection to the highly-immunogenic lymphoid tissue of the tonsils, and that the HPV16 E6 seroprevalence will be higher among cases with oropharyngeal cancer compared to those with anogenital cancer.


Mattias Johannson (IARC)
Michael Pawlita (DKFZ)
Paul Brennan (IARC)
Allan Hildesheim (NCI, DCEG, IIB)
Aimee Kreimer (NCI, DCEG, IIB)

Approved Addenda This project has one or more approved addenda.
  • Update of nested case control study and expansion to unknown primary of the head and neck and lymph nodes
  • Retesting of PLCO serum samples at higher dilution volume
  • Validation of an ELISA assay to measure the HPV16 E6 antibody
Related Publications
  • Timing of HPV16-E6 antibody seroconversion before OPSCC: findings from the HPVC3 consortium.
    Kreimer AR, Ferreiro-Iglesias A, Nygard M, Bender N, Schroeder L, Hildesheim A, Robbins HA, Pawlita M, Langseth H, Schlecht NF, Tinker LF, Agalliu I, Smoller SW, Ness-Jensen E, Hveem K, D'Souza G, Visvanathan K, May B, Ursin G, Weiderpass E, Giles GG, Milne RL, Cai Q, Blot WJ, Zheng W, Weinstein SJ, Albanes D, Brenner N, Hoffman-Bolton J, Kaaks R, Barricarte A, Tjønneland A, Sacerdote C, Trichopoulou A, Vermeulen RCH, Huang WY, Freedman ND, Brennan P, Waterboer T, Johansson M
    Ann. Oncol. 2019 Aug 1; Volume 30 (Issue 8): Pages 1335-1343 PUBMED
  • Kinetics of the Human Papillomavirus Type 16 E6 Antibody Response Prior to Oropharyngeal Cancer.
    Kreimer AR, Johansson M, Yanik EL, Katki HA, Check DP, Lang Kuhs KA, Willhauck-Fleckenstein M, Holzinger D, Hildesheim A, Pfeiffer R, Williams C, Freedman ND, Huang WY, Purdue MP, Michel A, Pawlita M, Brennan P, Waterboer T
    J. Natl. Cancer Inst. 2017; Volume 109 (Issue 8) PUBMED