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

See more in PubMed

Sung, H. et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. PubMed

Johnson, D. E. et al. Head and neck squamous cell carcinoma. PubMed PMC

Lubin, J. H. et al. An examination of male and female odds ratios by BMI, cigarette smoking, and alcohol consumption for cancers of the oral cavity, pharynx, and larynx in pooled data from 15 case-control studies. PubMed PMC

Thomas, S. J., Penfold, C. M., Waylen, A. & Ness, A. R. The changing aetiology of head and neck squamous cell cancer: a tale of three cancers?. PubMed

Hobbs, C. G. L. et al. Human papillomavirus and head and neck cancer: a systematic review and meta-analysis. PubMed

Gillison, M. L., Chaturvedi, A. K., Anderson, W. F. & Fakhry, C. Epidemiology of human papillomavirus-positive head and neck squamous cell carcinoma. PubMed PMC

Chaturvedi, A. K. et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. PubMed PMC

Jamieson, L. M. et al. Cohort profile: indigenous human papillomavirus and oropharyngeal squamous cell carcinoma study - a prospective longitudinal cohort. PubMed PMC

WHO Classification of Tumours Editorial Board.

Ferreiro-Iglesias, A. et al. Germline determinants of humoral immune response to HPV-16 protect against oropharyngeal cancer. PubMed PMC

Lesseur, C. et al. Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer. PubMed PMC

Lesseur, C. et al. Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers. PubMed PMC

Shete, S. et al. A genome-wide association study identifies two novel susceptible regions for squamous cell carcinoma of the head and neck. PubMed PMC

McKay, J. D. et al. A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium. PubMed PMC

Elmusrati, A., Wang, J. & Wang, C. Y. Tumor microenvironment and immune evasion in head and neck squamous cell carcinoma. PubMed PMC

Zhang, Z. et al. Polymorphisms in the PVT1 gene and susceptibility to the lung cancer in a chinese northeast population: a case-control study. PubMed PMC

Song, N. et al. Evaluation of gene-environment interactions for colorectal cancer susceptibility loci using case-only and case-control designs. PubMed PMC

Lesseur, C. et al. A case-control study of polymorphisms in xenobiotic and arsenic metabolism genes and arsenic-related bladder cancer in New Hampshire. PubMed PMC

Garcia-Closas, M. et al. Genome-wide association studies identify four ER-negative-specific breast cancer risk loci. PubMed PMC

Eeles, R. A. et al. Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array. PubMed PMC

Stacey, S. N. et al. A germline variant in the TP53 polyadenylation signal confers cancer susceptibility. PubMed PMC

Zaidi, A. A., Verma, A., Morse, C., Ritchie, M. D. & Mathieson, I. The genetic and phenotypic correlates of mtDNA copy number in a multi-ancestry cohort. PubMed PMC

Hägg, S., Jylhävä, J., Wang, Y., Czene, K. & Grassmann, F. Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance. PubMed PMC

Guo, H., Cao, W., Zhu, Y., Li, T. & Hu, B. A genome-wide cross-cancer meta-analysis highlights the shared genetic links of five solid cancers. PubMed PMC

Drobni, P., Näslund, J. & Evander, M. Lactoferrin inhibits human papillomavirus binding and uptake in vitro. PubMed

Bukowska-Ośko, I. et al. Lactoferrin as a human genome “Guardian”—an overall point of view. PubMed PMC

Delahaye-Sourdeix, M. et al. A rare truncating BRCA2 variant and genetic susceptibility to upper aerodigestive tract cancer. PubMed PMC

Chen, D. et al. Genome-wide association study of susceptibility loci for cervical cancer. PubMed

Guan, X., Wang, L. E., Liu, Z., Sturgis, E. M. & Wei, Q. Association between a rare novel TP53 variant (rs78378222) and melanoma, squamous cell carcinoma of head and neck and lung cancer susceptibility in non-Hispanic Whites. PubMed PMC

Zhang, H. et al. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses. PubMed PMC

Zhou, L., Yuan, Q. & Yang, M. A functional germline variant in the P53 polyadenylation signal and risk of esophageal squamous cell carcinoma. PubMed

Diskin, S. J. et al. Rare variants in TP53 and susceptibility to neuroblastoma. PubMed PMC

Lobo, S. et al. Cancer predisposition and germline CTNNA1 variants. PubMed

Rafnar, T. et al. Association of brca2 k3326∗ with small cell lung cancer and squamous cell cancer of the skin. PubMed PMC

Ware, J. J., Van den bree, M. B. M. & Munafò, M. R. Association of the CHRNA5-A3-B4 gene cluster with heaviness of smoking: a meta-analysis. PubMed PMC

Pugliese, A. et al. HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype protects autoantibody-positive relatives from type 1 diabetes throughout the stages of disease progression. PubMed PMC

Ramos-Garcia, P., Roca-Rodriguez, M., del, M., Aguilar-Diosdado, M. & Gonzalez-Moles, M. A. Diabetes mellitus and oral cancer/oral potentially malignant disorders: a systematic review and meta-analysis. PubMed

Tseng, K. S., Lin, C., Lin, Y. S. & Weng, S. F. Risk of head and neck cancer in patients with diabetes mellitus: a retrospective cohort study in Taiwan. PubMed

Zhou, X. H. et al. Diabetes, prediabetes and cancer mortality. PubMed

Lo, S. F. et al. Modest increase in risk of specific types of cancer types in type 2 diabetes mellitus patients. PubMed

Stott-Miller, M. et al. History of diabetes and risk of head and neck cancer: a pooled analysis from the international head and neck cancer epidemiology consortium. PubMed PMC

Kachuri, L. et al. The landscape of host genetic factors involved in immune response to common viral infections. PubMed PMC

Orlandi, E. et al. Potential role of microbiome in oncogenesis, outcome prediction and therapeutic targeting for head and neck cancer. PubMed

Kwak, S. et al. Oral microbiome and subsequent risk of head and neck squamous cell cancer. PubMed PMC

Hibbert, J., Halec, G., Baaken, D., Waterboer, T. & Brenner, N. Sensitivity and specificity of human papillomavirus (Hpv) 16 early antigen serology for HPV-driven oropharyngeal cancer: a systematic literature review and meta-analysis. PubMed PMC

Meyer H. V. plinkQC: Genotype quality control in genetic association studies.

Chang, C. C. et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. PubMed PMC

Taliun, D. et al. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. PubMed PMC

Das, S. et al. Next-generation genotype imputation service and methods. PubMed PMC

Fraser, A. et al. Cohort profile: The Avon longitudinal study of parents and children: ALSPAC mothers cohort. PubMed PMC

Jones, R. W. et al. A new human genetic resource: a DNA bank established as part of the Avon longitudinal study of pregnancy and childhood (ALSPAC). PubMed

Manichaikul, A. et al. Robust relationship inference in genome-wide association studies. PubMed PMC

Alexander, D. H., Novembre, J. & Lange, K. Fast model-based estimation of ancestry in unrelated individuals. PubMed PMC

1000 Genomes Project Consortium et al. A global reference for human genetic variation. PubMed PMC

Willer, C. J., Li, Y. & Abecasis, G. R. METAL: fast and efficient meta-analysis of genomewide association scans. PubMed PMC

Han, B. & Eskin, E. Interpreting meta-analyses of genome-wide association studies. PubMed PMC

Luo, Y. et al. A high-resolution HLA reference panel capturing global population diversity enables multi-ancestry fine-mapping in HIV host response. PubMed PMC

Okada, Y. et al. Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes. PubMed PMC

Bulik-Sullivan, B. K. et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. PubMed PMC

Cuéllar-Partida, G. et al. Complex-traits genetics virtual lab: a community-driven web platform for post-GWAS analyses. Preprint at

Giambartolomei, C. et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PubMed PMC

Võsa, U. et al. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression. PubMed PMC

Aguet, F. et al. The GTEx Consortium atlas of genetic regulatory effects across human tissues. PubMed PMC

Liu, M. et al. Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. PubMed PMC

Oliva, M. et al. DNA methylation QTL mapping across diverse human tissues provides molecular links between genetic variation and complex traits. PubMed PMC

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