We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 × 10-8), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci-9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 × 10-9). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 × 10-6) than in HPV-negative (OR = 0.75, P = 0.16) cancers.

Cancer Registry of Norway Oslo Norway

Centre for Oral Health Research Newcastle University Newcastle UK

Clinical Translational Science Institute University of California at San Francisco San Francisco California USA

Croatian National Institute of Public Health Zagreb Croatia

Deparment of Molecular Medicine University of Padova Padova Italy

Departamento de Medicina Preventiva Faculdade de Medicina da Universidade de São Paulo São Paulo Brazil

Department for Determinants of Chronic Diseases Bilthoven the Netherlands

Department of Biomedical Data Sciences Geisel School of Medicine at Dartmouth Lebanon New Hampshire USA

Department of Cancer Epidemiology and Prevention Institute of Carcinogenesis N N Blokhin Russian Cancer Research Centre of the Russian Ministry of Health Moscow Russian Federation

Department of Environmental Epidemiology Nofer Institute of Occupational Medicine Lodz Poland

Department of Epidemiology and Biostatistics School of Public Health Imperial College London London UK

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

Department of Epidemiology Graduate School of Public Health University of Pittsburgh Pittsburgh Pennsylvania USA

Department of Gastroenterology Radboud University Nijmegen Medical Center Nijmegen the Netherlands

Department of Head and Neck Surgery Heliópolis Hospital São Paulo Brazil

Department of Hygiene Epidemiology and Medical Statistics School of Medicine National and Kapodistrian University of Athens Athens Greece

Department of Medical Sciences University of Turin Turin Italy

Department of Molecular Biology School of Medicine of São José do Rio Preto São José do Rio Preto Brazil

Department of Otolaryngology Head and Neck Surgery University of California at San Francisco San Francisco California USA

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

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

Department of Social and Preventive Medicine Faculty of Medicine University of Malaya Kuala Lumpur Malaysia

Department of Stomatology School of Dentistry University of São Paulo São Paulo Brazil

Epidemiology International Center for Research A C Camargo Cancer Center Sao Paulo Brazil

Faculdade de Saúde Pública Universidade de São Paulo São Paulo Brazil

German Institute of Human Nutrition in Potsdam Rehbruecke Nuthetal Germany

Institut Català d'Oncologia IDIBELL CIBERESP l'Hospitalet de Llobregat Barcelona Spain

Institute of Hygiene and Epidemiology 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Otorhinolaryngology Università Cattolica del Sacro Cuore Fondazione Policlinico 'Agostino Gemelli' Rome Italy

Instituto de Oncología 'Angel H Roffo' Universidad de Buenos Aires Buenos Aires Argentina

International Agency for Research on Cancer Lyon France

Leibniz Institute for Prevention Research and Epidemiology BIPS Bremen Germany

Lunenfeld Tanenbaum Research Institute Mount Sinai Hospital Toronto Ontario Canada

Maria Skłodowska Curie Memorial Cancer Centre and Institute of Oncology Warsaw Poland

National Institute for Health Research Biomedical Research Unit in Nutrition Diet and Lifestyle at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol Bristol UK

National Institute of Public Health Bucharest Romania

NHS National Services Scotland Edinburgh UK

Princess Margaret Cancer Centre Toronto Ontario Canada

Programa de Pós Graduacão em Epidemiologia Universidade Federal de Pelotas Pelotas Brazil

Regional Authority of Public Health Banská Bystrica Slovakia

School of Medicine Dentistry and Nursing University of Glasgow Glasgow UK

School of Medicine Medical Sciences and Nutrition University of Aberdeen Aberdeen UK

School of Oral and Dental Sciences University of Bristol Bristol UK

Section of Hygiene Institute of Public Health Università Cattolica del Sacro Cuore Fondazione Policlinico 'Agostino Gemelli' Rome Italy

Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York New York USA

Trinity College School of Dental Science Dublin Ireland

UNC Lineberger Comprehensive Cancer Center Chapel Hill North Carolina USA

Unit of Cancer Epidemiology CRO Aviano National Cancer Institute Aviano Italy

Unit of Nutrition and Cancer Cancer Epidemiology Research Program Institut Català d'Oncologia IDIBELL l'Hospitalet de Llobregat Barcelona Spain

University of Pittsburgh Cancer Institute Pittsburgh Pennsylvania 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

Germline determinants of humoral immune response to HPV-16 protect against oropharyngeal cancer

Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers

Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity