Cross-ancestral GWAS identifies 29 variants across head and neck cancer subsites

Elmira Ebrahimi, Apiwat Sangphukieo, Hanla A. Park, Valerie Gaborieau, Aida Ferreiro-Iglesias, Brenda Diergaarde, Wolfgang Ahrens, Laia Alemany, Lidia MRB Arantes, Jaroslav Betka, Scott V. Bratman, Cristina Canova, Michael SC Conlon, David I. Conway, Mauricio Cuello, Maria Paula Curado, Ana Carolina de Carvalho, Jose Carlos de Oliviera, Mark Gormley, Maryam Hadji, Sarah Hargreaves, Claire M. Healy, Ivana Holcatova, Rayjean J. Hung, Luis P. Kowalski, Pagona Lagiou, Areti Lagiou, Geoffrey Liu, Gary J. Macfarlane, Andrew F. Olshan, Sandra Perdomo, Luis Felipe Ribiero Pinto, Jose Roberto V. Podesta, Jerry Polesel, Miranda Pring, Hamideh Rashidian, Ricardo R. Gama, Lorenzo Richiardi, Max Robinson, Paula A. Rodriguez-Urrego, Stacey A. Santi, Deborah P. Saunders, Sheila C. Soares-Lima, Nicholas Timpson, Marta Vilensky, Sandra V. Zeidler, Tim Waterboer, Kazem Zendehdel, Ariana Znaor, Paul Brennan, James McKay, Shama Virani () and Tom Dudding ()
Additional contact information
Elmira Ebrahimi: International Agency for Research on Cancer (IARC/WHO)
Apiwat Sangphukieo: International Agency for Research on Cancer (IARC/WHO)
Hanla A. Park: International Agency for Research on Cancer (IARC/WHO)
Valerie Gaborieau: International Agency for Research on Cancer (IARC/WHO)
Aida Ferreiro-Iglesias: International Agency for Research on Cancer (IARC/WHO)
Brenda Diergaarde: University of Pittsburgh
Wolfgang Ahrens: Leibniz Institute for Prevention Research and Epidemiology-BIPS
Laia Alemany: L’Hospitalet
Lidia MRB Arantes: Barretos Cancer Hospital
Jaroslav Betka: Faculty Hospital Motol
Scott V. Bratman: University of Toronto
Cristina Canova: University of Padova
Michael SC Conlon: Health Sciences North Research Institute
David I. Conway: University of Glasgow
Mauricio Cuello: Hospital de Clinicas Dr. Manuel Quintela
Maria Paula Curado: A.C Camargo Cancer Center
Ana Carolina de Carvalho: International Agency for Research on Cancer (IARC/WHO)
Jose Carlos de Oliviera: Associação de Combate ao Câncer em Goiás
Mark Gormley: Bristol University
Maryam Hadji: Tehran University of Medical Sciences
Sarah Hargreaves: University Hospitals Bristol and Weston NHS Foundation Trust
Claire M. Healy: Trinity College Dublin
Ivana Holcatova: Charles University
Rayjean J. Hung: Sinai Health System
Luis P. Kowalski: University of São Paulo Medical School
Pagona Lagiou: National and Kapodistrian University of Athens
Areti Lagiou: University of West Attica
Geoffrey Liu: University of Toronto
Gary J. Macfarlane: University of Aberdeen
Andrew F. Olshan: University of North Carolina
Sandra Perdomo: International Agency for Research on Cancer (IARC/WHO)
Luis Felipe Ribiero Pinto: Instituto Nacional de Câncer - INCA
Jose Roberto V. Podesta: Women’s Association for Education and Fight Against Cancer/AFECC
Jerry Polesel: Centro di Riferimento Oncologico di Aviano (CRO) IRCCS
Miranda Pring: Bristol University
Hamideh Rashidian: Tehran University of Medical Sciences
Ricardo R. Gama: Barretos Cancer Hospital
Lorenzo Richiardi: University of Turin
Max Robinson: The Newcastle upon Tyne Hospitals NHS Foundation Trust
Paula A. Rodriguez-Urrego: University Hospital Fundacion Santa Fe de Bogota
Stacey A. Santi: Health Sciences North Research Institute
Deborah P. Saunders: Northern Ontario School of Medicine University
Sheila C. Soares-Lima: Brazilian National Cancer Institute
Nicholas Timpson: Bristol University
Marta Vilensky: Universidad de Buenos Aires
Sandra V. Zeidler: Federal University of Espírito Santo
Tim Waterboer: DKFZ)
Kazem Zendehdel: Tehran University of Medical Sciences
Ariana Znaor: International Agency for Research on Cancer (IARC/WHO)
Paul Brennan: International Agency for Research on Cancer (IARC/WHO)
James McKay: International Agency for Research on Cancer (IARC/WHO)
Shama Virani: International Agency for Research on Cancer (IARC/WHO)
Tom Dudding: Bristol University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-63842-z

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