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

E Elmira Ebrahimi A Apiwat Sangphukieo H Hanla A. Park V Valerie Gaborieau A Aida Ferreiro-Iglesias B Brenda Diergaarde W Wolfgang Ahrens L Laia Alemany L Lidia MRB Arantes J Jaroslav Betka S Scott V. Bratman C Cristina Canova M Michael SC Conlon D David I. Conway (School of Medicine, Dentistry, and Nursing University of Glasgow Glasgow UK) M Mauricio Cuello M Maria Paula Curado M Mark Gormley M Maryam Hadji S Sarah Hargreaves C Claire M. Healy I Ivana Holcatova R Rayjean J. Hung L Luis P. Kowalski P Pagona Lagiou A Areti Lagiou G Geoffrey Liu G Gary J. Macfarlane A Andrew F. Olshan S Sandra Perdomo L Luis Felipe Ribiero Pinto J Jose Roberto V. Podesta J Jerry Polesel M Miranda Pring H Hamideh Rashidian R Ricardo R. Gama L Lorenzo Richiardi M Max Robinson P Paula A. Rodriguez-Urrego S Stacey A. Santi D Deborah P. Saunders S Sheila C. Soares-Lima N Nicholas Timpson M Marta Vilensky T Tim Waterboer K Kazem Zendehdel A Ariana Znaor P Paul Brennan A Ana Carolina de Carvalho J Jose Carlos de Oliviera L Luis F. Pinto N Nic Timpson S Sandra V. von Zeidler R Roque Adam A Antonio Agudo S Salima Alibhai S Shaymaa F. AlWaheidi M Miquel Angel Pavon N Namrah Anwar P Paola Engelmann Arantes L Lisa Arguello Y Yubelly Avello L Lucas Avondet A Ana M. Baldión-Elorza C Camila Batista Daniel B Bianca Beraldi B Barbara Berenstein P Patricia Bernal N Natália Bernardino Rodrigues J Josipa Bilic Zimmermann M Marianna G. Botta L Lourine Bouvard J Jesús Brenes N Nicole Brenner C Carol Brentisci C Catalina Burtica M María L. Cabañas E Erick Cantor R Raiany S. Carvalho A Andre L. Carvalho (Early Detection, Prevention, and Infections Branch International Agency for Research on Cancer Lyon France) L Luigi Chiusa P Priscilia Chopard Q Qurratulain Chundriger O Omar Clavero I Isabela Costa G Grant Creaney C Cecilia Cuffini T Tauana C. Dias E Evandro Duccini de Souza L Lais C. Durant A Alberto Escallón G Gisele Aparecida Fernandes B Béatrice Fervers V Valentina Fiano F Frederico Firme Figueira R Regina Furbino Villefort M Manuela Gangemi P Paolo Garzino-Demo M Mahin Gholipour R Raul Giglio M Mariel A. Goulart J Jéssica Graça Sant’Anna M Marek Grega A Anna Clara Gregório Có A Arnau Guasch J Jose A. Hakim D David N. Hayes M Marco Homero de Sá Santos K Katrina Hurley M Magalí Insfran G Giuseppe C. Iorio M Moghira Iqbaluddin Siddiqui J Jannik Johannsen M Martin Kaňa J Jens Peter Klussmann E Evelio Legal J Jeferson Lenzi F Fernando Luiz Dias I Iván Lyra González W Willene Machado Zorzaneli R Ricardo Mai Rocha M Manel Mañós P Priscila Marinho de Abreu M Maryam Marzban J James McCaul A Alex D. McMahon C Carlos Mena E Elismauro F. Mendonça L Laura Mendoza L Lorena Meza B Birgitta Michels M Matinair S. Mineiro C Chiara Moccia P Pamela Mongelos A Ana L. Montealegre-Páez F Francisca Morey Cortes A Alvaro Muñoz A Andy Ness A Aline B. Neves M Marco Oliva J José Carlos de Oliveira H Hernán Ortiz J José Ortiz M Marta Osorio V Vanessa Ospina O Oliviero Ostellino M Mauricio Palau C Claire Paterson S Sonia Paytubi Casabona G Giancarlo Pecorari D David M. Pereira O Olivia Pérol S Shahid Pervez A Alicia Pomata M Maja Popovic A Alisson Poveda C Carol P. Prado K Kristina M. Prager G Guglielmo Ramieri S Saida Rasul J Juliana NI Rego R Rui M. Reis H Helene Renard U Umberto Ricardi G Giuseppe Riva F Frederic Rodilla I Ingrid Rodriguez M María I. Rodríguez A Alastair Ross P Pierre-Eric Roux T Tazeen Saeed Ali P Pierre Saintigny J Juan J. Santivañez C Cristóvam Scapultampo-Neto J Javier Segovia A Agenor Sena R Ricardo Serrano S Shachi J. Sharma O Oliver Siefer S Stephanie Smart B Bruna P. Sorroche C Cinthia Sosa J Juliana Souza de Oliveira A Antonella Stura S Steven Thomas (Department of Biological Sciences, University of Alabama) O Oscar Torres S Sara Tous G Gonzálo Ucross A Adriana Valenzuela J José Roberto Vasconcelos de Podestá A Alex Whitmarsh S Sylvia Wright J James McKay S Shama Virani (Genetic Epidemiology Branch International Agency for Research on Cancer Lyon France) T Tom Dudding

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

Volume / Issue Vol. 16, Issue 1
Published October 02, 2025
ISSN 2041-1723
Publisher Nature Portfolio

Journal Info

Nature Communications

Nature Portfolio

ISSN: 2041-1723 Open Access Life Sciences

Authors (194)

E

Elmira Ebrahimi

A

Apiwat Sangphukieo

H

Hanla A. Park

V

Valerie Gaborieau

A

Aida Ferreiro-Iglesias

B

Brenda Diergaarde

W

Wolfgang Ahrens

L

Laia Alemany

L

Lidia MRB Arantes

J

Jaroslav Betka

S

Scott V. Bratman

C

Cristina Canova

M

Michael SC Conlon

D

David I. Conway

School of Medicine, Dentistry, and Nursing University of Glasgow Glasgow UK

M

Mauricio Cuello

M

Maria Paula Curado

M

Mark Gormley

M

Maryam Hadji

S

Sarah Hargreaves

C

Claire M. Healy

I

Ivana Holcatova

R

Rayjean J. Hung

L

Luis P. Kowalski

P

Pagona Lagiou

A

Areti Lagiou

G

Geoffrey Liu

G

Gary J. Macfarlane

A

Andrew F. Olshan

S

Sandra Perdomo

L

Luis Felipe Ribiero Pinto

J

Jose Roberto V. Podesta

J

Jerry Polesel

M

Miranda Pring

H

Hamideh Rashidian

R

Ricardo R. Gama

L

Lorenzo Richiardi

M

Max Robinson

P

Paula A. Rodriguez-Urrego

S

Stacey A. Santi

D

Deborah P. Saunders

S

Sheila C. Soares-Lima

N

Nicholas Timpson

M

Marta Vilensky

T

Tim Waterboer

K

Kazem Zendehdel

A

Ariana Znaor

P

Paul Brennan

A

Ana Carolina de Carvalho

J

Jose Carlos de Oliviera

L

Luis F. Pinto

N

Nic Timpson

S

Sandra V. von Zeidler

R

Roque Adam

A

Antonio Agudo

S

Salima Alibhai

S

Shaymaa F. AlWaheidi

M

Miquel Angel Pavon

N

Namrah Anwar

P

Paola Engelmann Arantes

L

Lisa Arguello

Y

Yubelly Avello

L

Lucas Avondet

A

Ana M. Baldión-Elorza

C

Camila Batista Daniel

B

Bianca Beraldi

B

Barbara Berenstein

P

Patricia Bernal

N

Natália Bernardino Rodrigues

J

Josipa Bilic Zimmermann

M

Marianna G. Botta

L

Lourine Bouvard

J

Jesús Brenes

N

Nicole Brenner

C

Carol Brentisci

C

Catalina Burtica

M

María L. Cabañas

E

Erick Cantor

R

Raiany S. Carvalho

A

Andre L. Carvalho

Early Detection, Prevention, and Infections Branch International Agency for Research on Cancer Lyon France

L

Luigi Chiusa

P

Priscilia Chopard

Q

Qurratulain Chundriger

O

Omar Clavero

I

Isabela Costa

G

Grant Creaney

C

Cecilia Cuffini

T

Tauana C. Dias

E

Evandro Duccini de Souza

L

Lais C. Durant

A

Alberto Escallón

G

Gisele Aparecida Fernandes

B

Béatrice Fervers

V

Valentina Fiano

F

Frederico Firme Figueira

R

Regina Furbino Villefort

M

Manuela Gangemi

P

Paolo Garzino-Demo

M

Mahin Gholipour

R

Raul Giglio

M

Mariel A. Goulart

J

Jéssica Graça Sant’Anna

M

Marek Grega

A

Anna Clara Gregório Có

A

Arnau Guasch

J

Jose A. Hakim

D

David N. Hayes

M

Marco Homero de Sá Santos

K

Katrina Hurley

M

Magalí Insfran

G

Giuseppe C. Iorio

M

Moghira Iqbaluddin Siddiqui

J

Jannik Johannsen

M

Martin Kaňa

J

Jens Peter Klussmann

E

Evelio Legal

J

Jeferson Lenzi

F

Fernando Luiz Dias

I

Iván Lyra González

W

Willene Machado Zorzaneli

R

Ricardo Mai Rocha

M

Manel Mañós

P

Priscila Marinho de Abreu

M

Maryam Marzban

J

James McCaul

A

Alex D. McMahon

C

Carlos Mena

E

Elismauro F. Mendonça

L

Laura Mendoza

L

Lorena Meza

B

Birgitta Michels

M

Matinair S. Mineiro

C

Chiara Moccia

P

Pamela Mongelos

A

Ana L. Montealegre-Páez

F

Francisca Morey Cortes

A

Alvaro Muñoz

A

Andy Ness

A

Aline B. Neves

M

Marco Oliva

J

José Carlos de Oliveira

H

Hernán Ortiz

J

José Ortiz

M

Marta Osorio

V

Vanessa Ospina

O

Oliviero Ostellino

M

Mauricio Palau

C

Claire Paterson

S

Sonia Paytubi Casabona

G

Giancarlo Pecorari

D

David M. Pereira

O

Olivia Pérol

S

Shahid Pervez

A

Alicia Pomata

M

Maja Popovic

A

Alisson Poveda

C

Carol P. Prado

K

Kristina M. Prager

G

Guglielmo Ramieri

S

Saida Rasul

J

Juliana NI Rego

R

Rui M. Reis

H

Helene Renard

U

Umberto Ricardi

G

Giuseppe Riva

F

Frederic Rodilla

I

Ingrid Rodriguez

M

María I. Rodríguez

A

Alastair Ross

P

Pierre-Eric Roux

T

Tazeen Saeed Ali

P

Pierre Saintigny

J

Juan J. Santivañez

C

Cristóvam Scapultampo-Neto

J

Javier Segovia

A

Agenor Sena

R

Ricardo Serrano

S

Shachi J. Sharma

O

Oliver Siefer

S

Stephanie Smart

B

Bruna P. Sorroche

C

Cinthia Sosa

J

Juliana Souza de Oliveira

A

Antonella Stura

S

Steven Thomas

Department of Biological Sciences, University of Alabama

O

Oscar Torres

S

Sara Tous

G

Gonzálo Ucross

A

Adriana Valenzuela

J

José Roberto Vasconcelos de Podestá

A

Alex Whitmarsh

S

Sylvia Wright

J

James McKay

S

Shama Virani

Genetic Epidemiology Branch International Agency for Research on Cancer Lyon France

T

Tom Dudding