Elmira Ebrahimi, Apiwat Sangphukieo, Hanla A. Park, Valérie Gaborieau, Aida Ferreiro-Iglesias, Brenda Diergaarde, Wolfgang Ahrens, Laia Alemany, Lidia MRB Arantes, Jaroslav Betka, Scott V. Bratman, Cristina Canova, Michael Conlon, David I. Conway, Mauricio Cuello, María Paula Curado, Ana Carolina de Carvalho, Jose Carlos de Oliviera, Mark Gormley, Maryam Hadji, Sarah Hargreaves, Claire M. Healy, Ivana Holcátová, Rayjean J. Hung, Luis P. Kowalski, Παγώνα Λάγιου, Areti Lagiou, Geoffrey Liu, Gary J. Macfarlane, Andrew F. Olshan, Sandra Pérdomo, Luís Pinto, Jose Roberto V. Podesta, Jerry Polesel, Miranda Pring, Hamideh Rashidian, Ricardo Ribeiro Gama, Lorenzo Richiardi, Max Robinson, Paula A. Rodríguez‐Urrego, Stacey A. Santi, Deborah Saunders, Sheila Coelho Soares‐Lima, Nicholas J. Timpson, Marta Vilensky, Sandra Ventorin von Zeidler, Tim Waterboer, Kazem Zendehdel, Ariana Znaor, Paul Brennan, Ana Carolina de Carvalho, Jose Carlos de Oliviera, Luís Fernando Batista Pinto, Nicholas J. Timpson, Sandra Ventorin von Zeidler, Roque Adam, Antonio Agudo, S. Alibhai, Shaymaa AlWaheidi, Miquel Angel Pavon, Namrah Anwar, Paola Engelmann Arantes, Lisa Arguello, Yubelly Avello, Lucas Avondet, A.M. Baldión-Elorza, Camila Batista Daniel, Bianca Beraldi, Barbara Berenstein, Patricia Bernal, Natália Bernardino Rodrigues, Josipa Bilic Zimmermann, Marianna G. Botta, Lourine Bouvard, Jesús Brenes, Nicole Brenner, Carol Brentisci, Catalina Burtica, María Lavín Cabanas, Erick Cantor, Raiany Santos Carvalho, André Lopes Carvalho, Luigi Chiusa, Priscilia Chopard, Qurratulain Chundriger, Omar Clavero, Isabela Costa, Grant Creaney, Cecilia Cuffini, Tauana Christina Dias, Evandro Duccini Souza, Laís Corsino Durant, Alberto Escallón, Gisele Aparecida Fernandes, Béatrice Fervers, Valentina Fiano, Frederico Firme Figueira, Regina Furbino Villefort, Manuela Gangemi, Paolo Garzino‐Demo
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.