Cross-ancestral GWAS identifies 29 variants across head and neck cancer subsites
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.
Article Details
Authors (194)
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
School of Medicine, Dentistry, and Nursing University of Glasgow Glasgow UK
Mauricio Cuello
Maria Paula Curado
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
Tim Waterboer
Kazem Zendehdel
Ariana Znaor
Paul Brennan
Ana Carolina de Carvalho
Jose Carlos de Oliviera
Luis F. Pinto
Nic Timpson
Sandra V. von Zeidler
Roque Adam
Antonio Agudo
Salima Alibhai
Shaymaa F. AlWaheidi
Miquel Angel Pavon
Namrah Anwar
Paola Engelmann Arantes
Lisa Arguello
Yubelly Avello
Lucas Avondet
Ana 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 L. Cabañas
Erick Cantor
Raiany S. Carvalho
Andre L. Carvalho
Early Detection, Prevention, and Infections Branch International Agency for Research on Cancer Lyon France
Luigi Chiusa
Priscilia Chopard
Qurratulain Chundriger
Omar Clavero
Isabela Costa
Grant Creaney
Cecilia Cuffini
Tauana C. Dias
Evandro Duccini de Souza
Lais C. Durant
Alberto Escallón
Gisele Aparecida Fernandes
Béatrice Fervers
Valentina Fiano
Frederico Firme Figueira
Regina Furbino Villefort
Manuela Gangemi
Paolo Garzino-Demo
Mahin Gholipour
Raul Giglio
Mariel A. Goulart
Jéssica Graça Sant’Anna
Marek Grega
Anna Clara Gregório Có
Arnau Guasch
Jose A. Hakim
David N. Hayes
Marco Homero de Sá Santos
Katrina Hurley
Magalí Insfran
Giuseppe C. Iorio
Moghira Iqbaluddin Siddiqui
Jannik Johannsen
Martin Kaňa
Jens Peter Klussmann
Evelio Legal
Jeferson Lenzi
Fernando Luiz Dias
Iván Lyra González
Willene Machado Zorzaneli
Ricardo Mai Rocha
Manel Mañós
Priscila Marinho de Abreu
Maryam Marzban
James McCaul
Alex D. McMahon
Carlos Mena
Elismauro F. Mendonça
Laura Mendoza
Lorena Meza
Birgitta Michels
Matinair S. Mineiro
Chiara Moccia
Pamela Mongelos
Ana L. Montealegre-Páez
Francisca Morey Cortes
Alvaro Muñoz
Andy Ness
Aline B. Neves
Marco Oliva
José Carlos de Oliveira
Hernán Ortiz
José Ortiz
Marta Osorio
Vanessa Ospina
Oliviero Ostellino
Mauricio Palau
Claire Paterson
Sonia Paytubi Casabona
Giancarlo Pecorari
David M. Pereira
Olivia Pérol
Shahid Pervez
Alicia Pomata
Maja Popovic
Alisson Poveda
Carol P. Prado
Kristina M. Prager
Guglielmo Ramieri
Saida Rasul
Juliana NI Rego
Rui M. Reis
Helene Renard
Umberto Ricardi
Giuseppe Riva
Frederic Rodilla
Ingrid Rodriguez
María I. Rodríguez
Alastair Ross
Pierre-Eric Roux
Tazeen Saeed Ali
Pierre Saintigny
Juan J. Santivañez
Cristóvam Scapultampo-Neto
Javier Segovia
Agenor Sena
Ricardo Serrano
Shachi J. Sharma
Oliver Siefer
Stephanie Smart
Bruna P. Sorroche
Cinthia Sosa
Juliana Souza de Oliveira
Antonella Stura
Steven Thomas
Department of Biological Sciences, University of Alabama
Oscar Torres
Sara Tous
Gonzálo Ucross
Adriana Valenzuela
José Roberto Vasconcelos de Podestá
Alex Whitmarsh
Sylvia Wright
James McKay
Shama Virani
Genetic Epidemiology Branch International Agency for Research on Cancer Lyon France
Tom Dudding