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

HEADSpAcE Consortium; 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; Miranda Pring; Nicholas Timpson; Tom Dudding

doi:10.1101/2024.11.18.24317473

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

HEADSpAcE Consortium, 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 GormleyMaryam Hadji, Sarah Hargreaves, Claire M Healy, Ivana Holcatova, Rayjean J Hung, Luis P Kowalski, Pagona Lagiou, Areti Lagiou, Miranda Pring, Nicholas Timpson, Tom Dudding^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

2 Citations (Scopus)

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.

Original language	English
Article number	8787
Pages (from-to)	8787
Number of pages	18
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1101/2024.11.18.24317473 https://doi.org/10.1038/s41467-025-63842-z
Publication status	Published - 2 Oct 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2025.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Humans
Genome-Wide Association Study
Head and Neck Neoplasms/genetics
Genetic Predisposition to Disease
Squamous Cell Carcinoma of Head and Neck/genetics
Polymorphism, Single Nucleotide
Papillomavirus Infections/genetics
Female
Gene-Environment Interaction
BRCA2 Protein/genetics
Male
Alcohol Dehydrogenase/genetics
Alcohol Drinking
Tumor Suppressor Protein p53/genetics
Smoking/adverse effects
Risk Factors
Middle Aged
Case-Control Studies
HLA Antigens/genetics
Carcinoma, Squamous Cell/genetics

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8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival
Martin, R. M. (Principal Investigator)
1/10/20 → 30/09/25
Project: Research

Cite this

HEADSpAcE Consortium, Ebrahimi, E., Sangphukieo, A., Park, H. A., Gaborieau, V., Ferreiro-Iglesias, A., Diergaarde, B., Ahrens, W., Alemany, L., Arantes, L. M., Betka, J., Bratman, S. V., Canova, C., Conlon, M. S., Conway, D. I., Cuello, M., Curado, M. P., de Carvalho, A. C., de Oliviera, J. C., ... Dudding, T. (2025). Cross-ancestral GWAS identifies 29 variants across head and neck cancer subsites. Nature Communications, 16(1), 8787. Article 8787. https://doi.org/10.1101/2024.11.18.24317473, https://doi.org/10.1038/s41467-025-63842-z

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title = "Cross-ancestral GWAS identifies 29 variants across head and neck cancer subsites",

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.",

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author = "\{HEADSpAcE Consortium\} and Elmira Ebrahimi and Apiwat Sangphukieo and Park, \{Hanla A\} and Valerie Gaborieau and Aida Ferreiro-Iglesias and Brenda Diergaarde and Wolfgang Ahrens and Laia Alemany and Arantes, \{Lidia Mrb\} and Jaroslav Betka and Bratman, \{Scott V\} and Cristina Canova and Conlon, \{Michael Sc\} and Conway, \{David I\} and Mauricio Cuello and Curado, \{Maria Paula\} and \{de Carvalho\}, \{Ana Carolina\} and \{de Oliviera\}, \{Jose Carlos\} and Mark Gormley and Maryam Hadji and Sarah Hargreaves and Healy, \{Claire M\} and Ivana Holcatova and Hung, \{Rayjean J\} and Kowalski, \{Luis P\} and Pagona Lagiou and Areti Lagiou and Miranda Pring and Nicholas Timpson and Tom Dudding",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = oct,

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doi = "10.1101/2024.11.18.24317473",

language = "English",

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HEADSpAcE Consortium, Ebrahimi, E, Sangphukieo, A, Park, HA, Gaborieau, V, Ferreiro-Iglesias, A, Diergaarde, B, Ahrens, W, Alemany, L, Arantes, LM, Betka, J, Bratman, SV, Canova, C, Conlon, MS, Conway, DI, Cuello, M, Curado, MP, de Carvalho, AC, de Oliviera, JC, Gormley, M, Hadji, M, Hargreaves, S, Healy, CM, Holcatova, I, Hung, RJ, Kowalski, LP, Lagiou, P, Lagiou, A, Pring, M , Timpson, N & Dudding, T 2025, 'Cross-ancestral GWAS identifies 29 variants across head and neck cancer subsites', Nature Communications, vol. 16, no. 1, 8787, pp. 8787. https://doi.org/10.1101/2024.11.18.24317473, https://doi.org/10.1038/s41467-025-63842-z

TY - JOUR

T1 - Cross-ancestral GWAS identifies 29 variants across head and neck cancer subsites

AU - HEADSpAcE Consortium

AU - Ebrahimi, Elmira

AU - Sangphukieo, Apiwat

AU - Park, Hanla A

AU - Gaborieau, Valerie

AU - Ferreiro-Iglesias, Aida

AU - Diergaarde, Brenda

AU - Ahrens, Wolfgang

AU - Alemany, Laia

AU - Arantes, Lidia Mrb

AU - Betka, Jaroslav

AU - Bratman, Scott V

AU - Canova, Cristina

AU - Conlon, Michael Sc

AU - Conway, David I

AU - Cuello, Mauricio

AU - Curado, Maria Paula

AU - de Carvalho, Ana Carolina

AU - de Oliviera, Jose Carlos

AU - Gormley, Mark

AU - Hadji, Maryam

AU - Hargreaves, Sarah

AU - Healy, Claire M

AU - Holcatova, Ivana

AU - Hung, Rayjean J

AU - Kowalski, Luis P

AU - Lagiou, Pagona

AU - Lagiou, Areti

AU - Pring, Miranda

AU - Timpson, Nicholas

AU - Dudding, Tom

N1 - Publisher Copyright: © The Author(s) 2025.

PY - 2025/10/2

Y1 - 2025/10/2

N2 - 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.

AB - 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.

KW - Humans

KW - Genome-Wide Association Study

KW - Head and Neck Neoplasms/genetics

KW - Genetic Predisposition to Disease

KW - Squamous Cell Carcinoma of Head and Neck/genetics

KW - Polymorphism, Single Nucleotide

KW - Papillomavirus Infections/genetics

KW - Female

KW - Gene-Environment Interaction

KW - BRCA2 Protein/genetics

KW - Male

KW - Alcohol Dehydrogenase/genetics

KW - Alcohol Drinking

KW - Tumor Suppressor Protein p53/genetics

KW - Smoking/adverse effects

KW - Risk Factors

KW - Middle Aged

KW - Case-Control Studies

KW - HLA Antigens/genetics

KW - Carcinoma, Squamous Cell/genetics

U2 - 10.1101/2024.11.18.24317473

DO - 10.1101/2024.11.18.24317473

M3 - Article (Academic Journal)

C2 - 39606392

SN - 2041-1723

VL - 16

SP - 8787

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 8787

ER -

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

Abstract

Bibliographical note

UN SDGs

Keywords

Access to Document

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Projects

8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival

Cite this