Although several oropharyngeal cancer (OPC) susceptibility loci have been identified, most previous studies lacked detailed information on human papillomavirus (HPV) status. We conduct a genome-wide analysis by HPV16 serology status in 4,002 oral cancer cases (OPC and oral cavity cancer (OCC)) and 5,256 controls. We detect four susceptibility loci pointing to a distinct genetic predisposition by HPV status. Our most notable finding in the HLA region, that is now confirmed to be specific of HPV(+)OPC risk, reveal two independent loci with strong protective effects, one refining the previously reported HLA class II haplotype association. Antibody levels against HPV16 viral proteins strongly implicate the protective HLA variants as major determinants of humoral response against L1 capsid protein or E6 oncoprotein suggesting a natural immune response against HPV(+)OPC promoted by HLA variants. This indicates that therapeutic vaccines that target E6 and attenuate viral response after established HPV infections might protect against HPV(+)OPC.
Bibliographical noteFunding Information:
This study is part of an NIDCR funded project called VOYAGER (R01DE025712) with co-PIs Paul Brennan (IARC, Lyon), Brenda Diergaarde (University of Pittsburgh) and Neil Hayes (University of Tennessee Health Science Centre). Genotyping of cases and controls was performed at the Center for Inherited Disease Research (CIDR) and funded by the US National Institute of Dental and Craniofacial Research (NIDCR; 1X01HG007780-0). The work performed in MSH-PMH study was supported by The Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer, Canada Research Chair Award to R.J.H. and the Alan Brown Chair to G.L. and Lusi Wong Programs at the Princess Margaret Hospital Foundation. Coordination of the EPIC study is financially supported by the European Commission (DG SANCO) and the International Agency for Research on Cancer. The University of Pittsburgh head and neck cancer case–control study is supported by US National Institutes of Health grants P50CA097190 and P30CA047904. The Alcohol-Related Cancers and Genetic Susceptibility Study in Europe (ARCAGE) was funded by the European Commission’s fifth framework program (QLK1-2001-00182), the Italian Association for Cancer Research, Compagnia di San Paolo/FIRMS, Region Piemonte and Padova University (CPDA057222). The Carolina Head and Neck Cancer Study (CHANCE) was supported by the National Cancer Institute (R01CA90731). This publication presents data from the Head and Neck 5000 study. The study was a component of independent research funded by the National Institute for Health Research (NIHR) under its Program Grants for Applied Research scheme (RP-PG-0707-10034). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Core funding was also provided through awards from Above and Beyond, University Hospitals Bristol Research Capability Funding and the NIHR Senior Investigator award to Professor Andy Ness. Human papillomavirus (HPV) serology was supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant number: C18281/A19169). This study is supported by the US National Institute of Dental and Craniofacial Research (R01DE025712 to P.B., B.D., and N.H.). The IARC Oral Cancer Multicenter study was funded by grant S06 96 202489 05F02 from Europe against Cancer; grants FIS 97/0024, FIS 97/0662 and BAE 01/5013 from Fondo de Investigaciones Sanitarias, Spain; the UICC Yamagiwa-Yoshida Memorial International Cancer Study; the National Cancer Institute of Canada; Associazione Italiana per la Ricerca sul Cancro; and the Pan-American Health Organization. The IARC Central Europe study was supported by the European Commission’s INCO-COPERNICUS Program (IC15-CT98-0332), US NIH/National Cancer Institute grant CA92039 and World Cancer Research Foundation grant WCRF 99A28. The Rome Study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) awards IG 2011 10491 and IG 2013 14220 to S.B. and by Fondazione Veronesi to S.B. This publication presents data that contributes to the HEADSpAcE study supported by the European Union Horizon 2020 (grant no 825771).