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 M.R.B.
AU - Betka, Jaroslav
AU - Bratman, Scott V.
AU - Canova, Cristina
AU - Conlon, Michael S.C.
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 - Liu, Geoffrey
AU - Macfarlane, Gary J.
AU - Olshan, Andrew F.
AU - Perdomo, Sandra
AU - Pinto, Luis Felipe Ribiero
AU - Podesta, Jose Roberto V.
AU - Polesel, Jerry
AU - Pring, Miranda
AU - Rashidian, Hamideh
AU - Gama, Ricardo R.
AU - Richiardi, Lorenzo
AU - Robinson, Max
AU - Rodriguez-Urrego, Paula A.
AU - Santi, Stacey A.
AU - Saunders, Deborah P.
AU - Soares-Lima, Sheila C.
AU - Timpson, Nicholas
AU - Vilensky, Marta
AU - von Zeidler, Sandra V.
AU - Waterboer, Tim
AU - Ali, Tazeen Saeed
AU - Pervez, Shahid
AU - Siddiqui, Moghira Iqbaluddin
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12
Y1 - 2025/12
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.
UR - https://www.scopus.com/pages/publications/105017709035
U2 - 10.1038/s41467-025-63842-z
DO - 10.1038/s41467-025-63842-z
M3 - Article
C2 - 41038832
AN - SCOPUS:105017709035
SN - 2041-1723
VL - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 8787
ER -
