Head and neck squamous cell carcinoma (HNSCC) includes diverse cancers arising in the oral cavity, oropharynx, and larynx, with the main risk factors being environmental exposures such as tobacco, alcohol, and human papillomavirus (HPV) infection. The genetic factors contributing to susceptibility across different populations and tumour subsites remain incompletely understood. Here we show, through a genome-wide association and fine mapping study of over 19,000 HNSCC cases and 38,000 controls from multiple ancestries, 18 genetic risk variants and 11 signals from fine mapping of the human leukocyte antigen (HLA) region, all previously unreported. rs78378222, a regulatory variant for TP53 is associated with a 40% reduction in overall HNSCC risk. We also identify gene-environment interactions, with BRCA2 and ADH1B variants showing effects modified by smoking and alcohol use. Subsite-specific analysis of the HLA region reveals distinct immune-related associations across HPV-positive and HPV-negative tumours. These findings refine the genetic architecture of HNSCC and highlight mechanisms linking inherited variation, immunity, and environmental exposures.

A 1 Virtanen Institute for Molecular Sciences University of Eastern Finland Kuopio Finland

Araújo Jorge Cancer Hospital Associação de Combate ao Câncer em Goiás Goiania Brazil

Barretos Cancer Hospital Barretos Brazil

Bellvitge Biomedical Research Institute L'Hospitalet Barcelona Spain

Brazilian National Cancer Institute Rio de Janeiro Brazil

Bristol Dental School Bristol University Bristol UK

Cancer Epidemiology Unit University of Turin Turin Italy

Cancer Research Center Cancer Institute Tehran University of Medical Sciences Tehran Iran

Cancer Surveillance Branch International Agency for Research on Cancer Lyon France

Catalan Institute of Oncology ICO L'Hospitalet Barcelona Spain

Cellular Pathology The Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle upon Tyne UK

Center of Multidisciplinary Technology for Advanced Medicine Faculty of Medicine Chiang Mai University Chiang Mai Thailand

CIBER en Epidemiología y Salud Pública Madrid Spain

Clinical Oncology Research Health Sciences North Research Institute Sudbury Canada

Department of Dental Oncology Health Sciences North Northern Ontario School of Medicine University Sudbury Canada

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

Department of Head and Neck Surgery and Otorhinolaryngology A C Camargo Cancer Center São Paulo Brazil

Department of Head and Neck Surgery Barretos Cancer Hospital São Paulo Brazil

Department of Head and Neck Surgery University of São Paulo Medical School São Paulo Brazil

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

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

Department of Otorhinolarygology and Head And Neck Surgery 1 st Medical Faculty Charles University Faculty Hospital Motol Prague Czech Republic

Department of Public and Community Health School of Public Health University of West Attica Athens Greece

Depts of Radiation Oncology Princess Margaret Cancer Centre University of Toronto Toronto Canada

Division of Epidemiology Dalla Lana School of Public Health University of Toronto Toronto Canada

Epidemiology and Statistics Group Research Center A C Camargo Cancer Center São Paulo Brazil

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

Epidemiology Outcomes and Evaluation Research Health Sciences North Research Institute Sudbury Canada

Genomic Epidemiology Branch International Agency for Research on Cancer Lyon France

Head and Neck Surgery Division Women's Association for Education and Fight Against Cancer AFECC Vitória Brazil

Infections and Cancer Epidemiology German Cancer Research Center Heidelberg Germany

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

Instituto de Oncologia Angel H Roffo Universidad de Buenos Aires Buenos Aires Argentina

Leibniz Institute for Prevention Research and Epidemiology BIPS Bremen Germany

Medicine Epidemiology Medical Oncology Princess Margaret Cancer Centre University of Toronto Toronto Canada

MRC Integrative Epidemiology Unit Bristol University Bristol UK

Oncology Hospital de Clinicas Dr Manuel Quintela Montevideo Uruguay

Pathology and Laboratories Pathology University Hospital Fundacion Santa Fe de Bogota Bogota Colombia

Pathology Department Federal University of Espírito Santo Vitória Brazil

Programa de Carcinogênese Molecular Instituto Nacional de Câncer INCA Rio de Janeiro Brazil

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

School of Dental Science Dublin Dental University Hospital Trinity College Dublin Dublin Ireland

School of Medicine Dentistry and Nursing University of Glasgow Glasgow UK

Unit of Biostatistics Epidemiology and Public Health Department of Cardio Thoraco Vascular Sciences and Public Health University of Padova Padova Italy

Unit of Cancer Epidemiology Centro di Riferimento Oncologico di Aviano IRCCS Aviano Italy

University Hospitals Bristol and Weston NHS Foundation Trust Bristol UK

UPMC Hillman Cancer Center Pittsburgh USA

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medRxiv. 2024 Nov 18:2024.11.18.24317473. doi: 10.1101/2024.11.18.24317473. PubMed

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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