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 von Zeidler, Tim Waterboer, Kazem Zendehdel, Ariana Znaor, Paul Brennan, James McKay, Shama Virani, Tom Dudding
{"title":"Cross-ancestral GWAS identifies 29 variants across head and neck cancer subsites.","authors":"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 von Zeidler, Tim Waterboer, Kazem Zendehdel, Ariana Znaor, Paul Brennan, James McKay, Shama Virani, Tom Dudding","doi":"10.1038/s41467-025-63842-z","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"16 1","pages":"8787"},"PeriodicalIF":15.7000,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Communications","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1038/s41467-025-63842-z","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍：
Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.
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