Cross-ancestral GWAS identifies 29 variants across head and neck cancer subsites
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.
Authors
- Erick Cantor (ORCID: https://orcid.org/0000-0002-0920-219X)
- José Antonio Hakim
- Luís Fernando Batista Pinto (ORCID: https://orcid.org/0000-0002-0831-3293)
- Hanla A. Park (ORCID: https://orcid.org/0000-0001-8055-3729)
- Jeferson Lenzi (ORCID: https://orcid.org/0000-0002-9407-0784)
- Lucas Avondet
- Laís Corsino Durant (ORCID: https://orcid.org/0000-0002-2525-6729)
- Oscar Tórres
- Shachi Jenny Sharma (ORCID: https://orcid.org/0000-0002-2768-7936)
- Alberto Escallón
- Sandra Ventorin von Zeidler (ORCID: https://orcid.org/0000-0002-8897-5747)
- James McCaul (ORCID: https://orcid.org/0000-0001-7732-145X)
- Ricardo Rocha (ORCID: https://orcid.org/0000-0001-5283-6860)
- Béatrice Fervers
- Gisele Aparecida Fernandes (ORCID: https://orcid.org/0000-0002-5978-3279)
- Álvaro Muñoz (ORCID: https://orcid.org/0000-0002-4037-0490)
- André Lopes Carvalho (ORCID: https://orcid.org/0000-0001-7214-6402)
- Marco Botta (ORCID: https://orcid.org/0000-0003-2747-8517)
- Ricardo Ribeiro Gama (ORCID: https://orcid.org/0000-0003-4406-8958)
- Agenor Sena (ORCID: https://orcid.org/0009-0009-3811-551X)
- Carol Brentisci
- Nilton Barnabé Rodrigues (ORCID: https://orcid.org/0000-0002-5290-3063)
- Miranda Pring (ORCID: https://orcid.org/0000-0003-4658-5772)
- Alex D. McMahon (ORCID: https://orcid.org/0000-0002-9425-7792)
- Katrina Hurley (ORCID: https://orcid.org/0000-0002-8079-5258)
- Andy Ness (ORCID: https://orcid.org/0000-0003-3548-9523)
- Luís Pinto (ORCID: https://orcid.org/0000-0002-4813-5225)
- Jannik Johannsen (ORCID: https://orcid.org/0000-0002-0947-198X)
- Marco Antônio Oliva (ORCID: https://orcid.org/0000-0003-0525-3114)
- Shahid Pervez (ORCID: https://orcid.org/0000-0003-3556-1687)
- R. Giglio
- Lorenzo Richiardi (ORCID: https://orcid.org/0000-0003-0316-9402)
- Mark Gormley (ORCID: https://orcid.org/0000-0001-5733-6304)
- Ricardo Serrano
- Marta Vilensky (ORCID: https://orcid.org/0000-0003-0990-4092)
- Antonio Agudo (ORCID: https://orcid.org/0000-0001-9900-5677)
- Stacey A. Santi
- Cecilia Cuffini
- Paula Andrea Rodríguez-Urrego (ORCID: https://orcid.org/0000-0003-3693-7690)
- A.M. Baldión-Elorza
- Patricia Bernal (ORCID: https://orcid.org/0000-0001-7885-5007)
- Wolfgang Ahrens (ORCID: https://orcid.org/0000-0003-3777-570X)
- Nicole Brenner (ORCID: https://orcid.org/0000-0002-7690-4925)
- Mariél de Aquino Goulart (ORCID: https://orcid.org/0000-0001-5263-6746)
- Adriana Valenzuela (ORCID: https://orcid.org/0000-0002-0785-8371)
- Ivana Holcátová (ORCID: https://orcid.org/0000-0002-1366-0337)
- Oliver Siefer
- Valentina Fiano (ORCID: https://orcid.org/0000-0001-7978-372X)
- Jaroslav Betka (ORCID: https://orcid.org/0000-0002-2704-0972)
- S. Alibhai
- Rui Manuel Reis (ORCID: https://orcid.org/0000-0002-9639-7940)
- Juliana S Oliveira (ORCID: https://orcid.org/0000-0002-8044-8520)
- Maryam Marzban (ORCID: https://orcid.org/0000-0001-6703-2224)
- Javier Segovia (ORCID: https://orcid.org/0000-0001-8971-0911)
- Anna Clara Gregório Có (ORCID: https://orcid.org/0000-0002-7737-0371)
- Sandra Pérdomo (ORCID: https://orcid.org/0000-0001-7740-8141)
- Simon M. Smart (ORCID: https://orcid.org/0000-0003-2750-7832)
- Geoffrey Liu
- Martin Kaňa (ORCID: https://orcid.org/0000-0002-5530-6803)
- Guglielmo Amedeo Ramieri (ORCID: https://orcid.org/0000-0002-3131-9669)
- Shama Virani (ORCID: https://orcid.org/0000-0002-1163-432X)
- Marek Grega
- Aline Borburema Neves (ORCID: https://orcid.org/0000-0002-0879-9035)
- Priscilia Chopard
- Antonella Stura
- Ana Lorena Montealegre-Páez
- Laura Mendoza (ORCID: https://orcid.org/0000-0001-6124-1244)
- Juan José Santivañez (ORCID: https://orcid.org/0000-0001-9701-6575)
- Grant Creaney (ORCID: https://orcid.org/0000-0001-9972-7629)
- David I. Conway (ORCID: https://orcid.org/0000-0001-7762-4063)
- Arnau Guasch
- Max Robinson (ORCID: https://orcid.org/0000-0003-4491-6865)
- José Roberto Vasconcelos de Podestá (ORCID: https://orcid.org/0000-0001-6995-955X)
- Marta Osorio
- Paolo Garzino‐Demo (ORCID: https://orcid.org/0000-0003-0462-2299)
- Rayjean J. Hung (ORCID: https://orcid.org/0000-0002-4486-7496)
- Jörg Zimmermann (ORCID: https://orcid.org/0000-0002-7667-5616)
- Gary J. Macfarlane (ORCID: https://orcid.org/0000-0003-2322-3314)
- Giuseppe Carlo Iorio (ORCID: https://orcid.org/0000-0003-1390-4191)
- Claire Paterson (ORCID: https://orcid.org/0000-0002-1691-5016)
- Luigi Chiusa (ORCID: https://orcid.org/0000-0002-7968-493X)
- Valérie Gaborieau (ORCID: https://orcid.org/0000-0002-0210-5215)
- Tom Dudding (ORCID: https://orcid.org/0000-0003-3756-040X)
- Shaymaa AlWaheidi (ORCID: https://orcid.org/0000-0002-1485-7078)
- Mahin Gholipour (ORCID: https://orcid.org/0000-0003-1551-9254)
- Cristina Canova (ORCID: https://orcid.org/0000-0001-7027-7935)
- Iván Gónzalez (ORCID: https://orcid.org/0000-0001-5302-1831)
- Francisca Morey (ORCID: https://orcid.org/0000-0001-5329-9649)
- Jens Peter Klußmann (ORCID: https://orcid.org/0000-0002-8223-7954)
- Evandro Duccini Souza (ORCID: https://orcid.org/0000-0002-4272-6091)
- Umberto Ricardi (ORCID: https://orcid.org/0000-0003-4406-7621)
- Chiara Moccia (ORCID: https://orcid.org/0000-0002-7970-8727)
- Miguel Ángel Pavón (ORCID: https://orcid.org/0000-0003-3677-5329)
- Bruna Pereira Sorroche (ORCID: https://orcid.org/0000-0001-9802-8236)
- Tauana Christina Dias (ORCID: https://orcid.org/0000-0002-7293-2937)
- Jesús Brenes (ORCID: https://orcid.org/0000-0003-0238-3319)
- Scott V. Bratman (ORCID: https://orcid.org/0000-0001-8610-4908)
- Alex Whitmarsh (ORCID: https://orcid.org/0000-0002-1198-8427)
- Nicholas J. Timpson (ORCID: https://orcid.org/0000-0002-7141-9189)
- Ana Carolina de Carvalho (ORCID: https://orcid.org/0000-0002-0114-7659)
- Mauricio Cuello (ORCID: https://orcid.org/0000-0003-1273-8080)
- Alastair Ross (ORCID: https://orcid.org/0000-0003-2952-3182)
- Ariana Znaor (ORCID: https://orcid.org/0000-0002-5849-4782)
- Aida Ferreiro-Iglesias (ORCID: https://orcid.org/0000-0002-1458-7936)
- Elismauro Francisco Mendonça (ORCID: https://orcid.org/0000-0002-6751-3279)
- Matinair Siqueira Mineiro
- A. Poveda
- Regina Furbino Villefort (ORCID: https://orcid.org/0000-0002-9196-5400)
- Hamideh Rashidian (ORCID: https://orcid.org/0000-0002-2155-1683)
- D. Neil Hayes (ORCID: https://orcid.org/0000-0001-6203-7771)
- Yubelly Avello
- Olivia Pérol (ORCID: https://orcid.org/0000-0002-7543-7050)
- Rodney D. Adam (ORCID: https://orcid.org/0000-0002-6665-4280)
- Priscila Marinho de Abreu (ORCID: https://orcid.org/0000-0001-6453-7171)
- Claire M. Healy (ORCID: https://orcid.org/0000-0003-0583-6360)
- Namrah Anwar (ORCID: https://orcid.org/0000-0002-9409-7928)
- Qurratulain Chundriger
- Raiany Santos Carvalho (ORCID: https://orcid.org/0000-0003-4409-5403)
- Frederico Firme Figueira (ORCID: https://orcid.org/0000-0003-1366-0035)
- Kirsty Prager
- Areti Lagiou (ORCID: https://orcid.org/0000-0002-6687-358X)
- Alicia Pomata (ORCID: https://orcid.org/0000-0001-6085-3783)
- Pamela Mongelós (ORCID: https://orcid.org/0000-0002-7771-3688)
- L Argüello (ORCID: https://orcid.org/0000-0001-7959-1904)
- Carlos Mena Canata (ORCID: https://orcid.org/0000-0003-4429-4840)
- Maja Beck Popovic (ORCID: https://orcid.org/0000-0003-4500-6572)
- Marco Homero de Sá Santos (ORCID: https://orcid.org/0000-0001-6097-0971)
- Birgitta E. Michels (ORCID: https://orcid.org/0000-0001-9948-4567)
- Tim Waterboer (ORCID: https://orcid.org/0000-0002-0616-6963)
- Lorena Meza
- Paola Engelmann Arantes (ORCID: https://orcid.org/0000-0003-3813-3178)
- Jéssica Graça Sant’Anna (ORCID: https://orcid.org/0000-0001-9759-2978)
- Kazem Zendehdel (ORCID: https://orcid.org/0000-0002-0269-4945)
- Sheila Coelho Soares‐Lima (ORCID: https://orcid.org/0000-0002-6742-3708)
- Hélène Renard
- Tazeen Saeed Ali (ORCID: https://orcid.org/0000-0002-8896-8766)
- Fernando Luiz Dias (ORCID: https://orcid.org/0000-0003-1000-7436)
- Manuela Gangemi
- Oliviero Ostellino
- Παγώνα Λάγιου (ORCID: https://orcid.org/0000-0001-7877-6253)
- Brenda Diergaarde (ORCID: https://orcid.org/0000-0002-3578-6547)
- Barbara Berenstein (ORCID: https://orcid.org/0009-0000-0503-104X)
- Deborah Saunders (ORCID: https://orcid.org/0000-0001-9499-4488)
- James McKay (ORCID: https://orcid.org/0000-0002-1787-3874)
- Apiwat Sangphukieo (ORCID: https://orcid.org/0000-0001-5210-5398)
- Chrystian C Sosa (ORCID: https://orcid.org/0000-0002-3734-3248)
- Jerry Polesel (ORCID: https://orcid.org/0000-0001-9381-1520)
- María Paula Curado (ORCID: https://orcid.org/0000-0001-8172-2483)
- Sylvia Wright (ORCID: https://orcid.org/0000-0002-0810-3915)
- Sara Tous (ORCID: https://orcid.org/0000-0002-5423-7092)
- José Carlos de Oliveira (ORCID: https://orcid.org/0000-0002-7078-7334)
- Ingrid Rodrı́guez (ORCID: https://orcid.org/0000-0002-2623-4441)
- David M. Pereira (ORCID: https://orcid.org/0000-0003-0384-7592)
- José Ortíz (ORCID: https://orcid.org/0000-0001-9650-1341)
- Omar Clavero (ORCID: https://orcid.org/0000-0001-9721-6382)
- Michael Conlon (ORCID: https://orcid.org/0000-0003-4815-8125)
- Elmira Ebrahimi (ORCID: https://orcid.org/0000-0003-0910-3447)
- María Inés Rodriguez (ORCID: https://orcid.org/0000-0001-9278-7928)
- Giuseppe Riva (ORCID: https://orcid.org/0000-0002-1825-7635)
- Steven J. Thomas
- Moghira Iqbaluddin Siddiqui
- Lidia MRB Arantes
- Andrew F. Olshan
- María Lavín Cabanas
- Laia Alemany
- Maryam Hadji
- Juliana F. Rego
- M. Mañós
- Hernán Ortiz
- Pierre Saintigny
- Camila Batista Daniel (ORCID: https://orcid.org/0000-0003-3992-5986)
- Shahid Rasul
- Pierre-Eric Roux
- Paul Brennan
- Vanessa Ospina
- Caroline Costa Prado (ORCID: https://orcid.org/0009-0006-0192-707X)
- Giancarlo Pecorari
- Mauricio Palau
- Isabela Costa
- Sarah Hargreaves (ORCID: https://orcid.org/0000-0002-8272-5915)
- Magalí Insfran
- Evelio Legal
- Willene Machado Zorzaneli
- Sonia Paytubi Casabona
- Frederic Rodilla
- Cristóvam Scapultampo-Neto
- Gonzálo Ucross
- Jose Carlos de Oliviera
- Bianca Beraldi
- Lourine Bouvard
- Catalina Burtica
Institutions
- University of North Carolina at Chapel Hill (US)
- Ministry of Education (BR)
- Institut Català d'Ornitologia (ES)
- University of Padua (IT)
- University of Tennessee Health Science Center (US)
- Universidad Nacional de Córdoba (AR)
- University of Pittsburgh (US)
- University of Eastern Finland (FI)
- German Cancer Research Center (DE)
- Universidade de São Paulo (BR)
- University of Cologne (DE)
- University of Toronto (CA)
- Universidad El Bosque (CO)
- University of Central Punjab (PK)
- University of Aberdeen (GB)
- Golestan University (IR)
- National and Kapodistrian University of Athens (GR)
- Lunenfeld-Tanenbaum Research Institute (CA)
- Charles University (CZ)
- QIMR Berghofer Medical Research Institute (AU)
- Heidelberg University (DE)
- Universidad de Buenos Aires (AR)
- University Of Bristol Dental Hospital (GB)
- NHS Greater Glasgow and Clyde (GB)
- Beatson West of Scotland Cancer Centre (GB)
- University Hospitals Bristol NHS Foundation Trust (GB)
- Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
- Princess Margaret Cancer Centre (CA)
- Health Sciences North (CA)
- Aga Khan University Hospital (PK)
- AC Camargo Hospital (BR)
- University of Bristol (GB)
- Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Hospital de Câncer de Barretos (BR)
- University of West Attica (GR)
- University Hospital in Motol (CZ)
- Asociación Española Contra el Cáncer (ES)
- Instituto de Investigaciones en Ciencias de la Salud (AR)
- Centre Léon Bérard (FR)
- Institut Català d'Oncologia (ES)
- Hospital Araújo Jorge (BR)
- Leibniz Institute for Prevention Research and Epidemiology - BIPS (DE)
- National Cancer Registry (IE)
- Centre de Recherche en Cancérologie de Lyon (FR)
- Public Health Ontario (CA)
- Golestan University of Medical Sciences (IR)
- UPMC Hillman Cancer Center (US)
- Centro di Riferimento Oncologico (IT)
- Sinai Health System (CA)
- Fundación para la Investigación, Docencia y Prevención del Cáncer (AR)
- Fundación Santa Fe de Bogotá (CO)
- Ministerio de Salud Pública y Bienestar Social (PY)
- Dublin Dental University Hospital (IE)
- Instituto Nacional de Câncer - INCA (BR)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Instituto de Oncología de Rosario (AR)
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (ES)
- Hospital de Clínicas (UY)
- MRC Epidemiology Unit (GB)
- Instituto Cardiovascular de Buenos Aires (AR)
- Hospital São Paulo (BR)
- Centre international de recherche sur le cancer (FR)
- MRC Integrative Epidemiology Unit
- University Hospitals Bristol and Weston NHS Foundation Trust (GB)
- Chiang Mai University (TH)
- Universidade Federal do Espírito Santo (BR)
- Bushehr University of Medical Sciences (IR)
- University of Turin (IT)
- Tehran University of Medical Sciences (IR)
- University of Glasgow (GB)
- NOSM University (CA)
- Universidad Nacional de Asunción (PY)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-02
- DOI
- https://doi.org/10.1038/s41467-025-63842-z
- Citations
- 3
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- University of Pittsburgh
- Wellcome Trust
- Cancer Research UK
- National Institute for Health and Care Research
- European Commission
- Ministero della Salute
- University of Toronto
- National Institutes of Health
- Canadian Institutes of Health Research
- World Cancer Research Fund
- Programme Grants for Applied Research
- National Cancer Institute
- National Institute of Dental and Craniofacial Research