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.

Bristol Dental School University of Bristol Bristol UK

Cancer Registry of Norway Oslo Norway

Cancer Surveillance Section International Agency for Research on Cancer World Health Organization Lyon France

Catalan Institute of Oncology IDIBELL Barcelona Spain

Centre for Oral Health Research Newcastle University Newcastle UK

Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública CIBERESP Madrid Spain

CeRMS and University of Turin Turin Italy

Department of Environmental Medicine and Public Health Icahn School of Medicine at Mount Sinai New York NY USA

Department of Epidemiology Gillings School of Global Public Health University of North Carolina at Chapel Hill Chapel Hill NC USA

Department of Head and Neck Surgery Institute of Clinical Otorhinolaryngology Università Cattolica del Sacro Cuore Roma Italy

Department of Human Genetics Graduate School of Public Health University of Pittsburgh Pittsburgh PA USA

Department of Medicine Baylor College of Medicine Houston TX USA

Department of Otolaryngology Head and Neck Surgery University of North Carolina at Chapel Hill Chapel Hill Chapel Hill NC USA

Department of Otorhinolaryngology Head and Neck Surgery Maastricht University Medical Center Maastricht The Netherlands

Department of Research Cancer Registry of Norway Oslo Norway

Department of Woman and Child Health and Public Health Public Health Area Fondazione Policlinico Universitario A Gemelli IRCCS Roma Italy

Division of Medical Oncology and Center for Cancer Research University of Tennessee Health Science Center Memphis TN USA

Infections and Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Institute of Hygiene and Epidemiology Prague Czech Republic

Istituto di Clinica Otorinolaringoiatrica Fondazione Policlinico Universitario A Gemelli IRCCS Roma Italy

Lunenfeld Tanenbaum Research Institute of Sinai Health System University of Toronto Toronto ON Canada

National Cancer Institute IRCCS Aviano Italy

National Institute for Health Research Bristol Biomedical Research Centre University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol Bristol UK

Oncology Data Analytics Program Catalan Institute of Oncology Barcelona Spain

Prosserman Centre for Population Health Research Lunenfeld Tanenbaum Research Institute Sinai Health System Toronto ON Canada

Queen Elizabeth University Hospital NHS Greater Glasgow and Clyde Glasgow UK

School of Medicine Dentistry and Nursing University of Glasgow Glasgow UK

School of Medicine National and Kapodistrian University of Athens Athens Greece

School of Public Health University of West Attica Athens Greece

Section of Early Detection and Prevention Prevention and Implementation Group International Agency for Research on Cancer World Health Organization Lyon France

Section of Genetics Genetic Cancer Susceptibility Group International Agency for Research on Cancer World Health Organization Lyon France

Section of Genetics Genetic Epidemiology Group International Agency for Research on Cancer World Health Organization Lyon France

Section of Hygiene University Department of Life Sciences and Public Health Università Cattolica del Sacro Cuore Roma Italy

Trinity College School of Dental Science Dublin Ireland

University Bremen Bremen Germany

University of Aberdeen Aberdeen UK

University of Padova Padova Italy

UPMC Hillman Cancer Center Pittsburgh PA USA

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VOYAGER: an international consortium investigating the role of human papilloma virus and genetics in oral and oropharyngeal cancer risk and survival

Smoking and alcohol by HPV status in head and neck cancer: a Mendelian randomization study

A risk prediction model for head and neck cancers incorporating lifestyle factors, HPV serology and genetic markers