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

Author

Listed:
  • Elmira Ebrahimi

    (International Agency for Research on Cancer (IARC/WHO)
    Tehran University of Medical Sciences)

  • Apiwat Sangphukieo

    (International Agency for Research on Cancer (IARC/WHO)
    Chiang Mai University)

  • Hanla A. Park

    (International Agency for Research on Cancer (IARC/WHO))

  • Valerie Gaborieau

    (International Agency for Research on Cancer (IARC/WHO))

  • Aida Ferreiro-Iglesias

    (International Agency for Research on Cancer (IARC/WHO))

  • Brenda Diergaarde

    (University of Pittsburgh
    UPMC Hillman Cancer Center)

  • Wolfgang Ahrens

    (Leibniz Institute for Prevention Research and Epidemiology-BIPS)

  • Laia Alemany

    (L’Hospitalet
    L’Hospitalet
    CIBER en Epidemiología y Salud Pública (CIBERESP))

  • Lidia MRB Arantes

    (Barretos Cancer Hospital)

  • Jaroslav Betka

    (Faculty Hospital Motol)

  • Scott V. Bratman

    (University of Toronto)

  • Cristina Canova

    (University of Padova)

  • Michael SC Conlon

    (Health Sciences North Research Institute)

  • David I. Conway

    (University of Glasgow)

  • Mauricio Cuello

    (Hospital de Clinicas Dr. Manuel Quintela)

  • Maria Paula Curado

    (A.C Camargo Cancer Center)

  • Ana Carolina de Carvalho

    (International Agency for Research on Cancer (IARC/WHO))

  • Jose Carlos de Oliviera

    (Associação de Combate ao Câncer em Goiás)

  • Mark Gormley

    (Bristol University)

  • Maryam Hadji

    (Tehran University of Medical Sciences
    University of Eastern Finland)

  • Sarah Hargreaves

    (University Hospitals Bristol and Weston NHS Foundation Trust)

  • Claire M. Healy

    (Trinity College Dublin)

  • Ivana Holcatova

    (Charles University)

  • Rayjean J. Hung

    (Sinai Health System
    University of Toronto)

  • Luis P. Kowalski

    (University of São Paulo Medical School
    A C Camargo Cancer Center)

  • Pagona Lagiou

    (National and Kapodistrian University of Athens)

  • Areti Lagiou

    (University of West Attica)

  • Geoffrey Liu

    (University of Toronto)

  • Gary J. Macfarlane

    (University of Aberdeen)

  • Andrew F. Olshan

    (University of North Carolina)

  • Sandra Perdomo

    (International Agency for Research on Cancer (IARC/WHO))

  • Luis Felipe Ribiero Pinto

    (Instituto Nacional de Câncer - INCA)

  • Jose Roberto V. Podesta

    (Women’s Association for Education and Fight Against Cancer/AFECC)

  • Jerry Polesel

    (Centro di Riferimento Oncologico di Aviano (CRO) IRCCS)

  • Miranda Pring

    (Bristol University)

  • Hamideh Rashidian

    (Tehran University of Medical Sciences)

  • Ricardo R. Gama

    (Barretos Cancer Hospital)

  • Lorenzo Richiardi

    (University of Turin)

  • Max Robinson

    (The Newcastle upon Tyne Hospitals NHS Foundation Trust)

  • Paula A. Rodriguez-Urrego

    (University Hospital Fundacion Santa Fe de Bogota)

  • Stacey A. Santi

    (Health Sciences North Research Institute)

  • Deborah P. Saunders

    (Northern Ontario School of Medicine University)

  • Sheila C. Soares-Lima

    (Brazilian National Cancer Institute)

  • Nicholas Timpson

    (Bristol University)

  • Marta Vilensky

    (Universidad de Buenos Aires)

  • Sandra V. Zeidler

    (Federal University of Espírito Santo)

  • Tim Waterboer

    (DKFZ))

  • Kazem Zendehdel

    (Tehran University of Medical Sciences)

  • Ariana Znaor

    (International Agency for Research on Cancer (IARC/WHO))

  • Paul Brennan

    (International Agency for Research on Cancer (IARC/WHO))

  • James McKay

    (International Agency for Research on Cancer (IARC/WHO))

  • Shama Virani

    (International Agency for Research on Cancer (IARC/WHO))

  • Tom Dudding

    (Bristol University)

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.

Suggested Citation

  • 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. B, 2025. "Cross-ancestral GWAS identifies 29 variants across head and neck cancer subsites," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63842-z
    DOI: 10.1038/s41467-025-63842-z
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    References listed on IDEAS

    as
    1. Aida Ferreiro-Iglesias & James D. McKay & Nicole Brenner & Shama Virani & Corina Lesseur & Valerie Gaborieau & Andy R. Ness & Rayjean J. Hung & Geoffrey Liu & Brenda Diergaarde & Andrew F. Olshan & Ne, 2021. "Germline determinants of humoral immune response to HPV-16 protect against oropharyngeal cancer," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    2. Daniel Taliun & Daniel N. Harris & Michael D. Kessler & Jedidiah Carlson & Zachary A. Szpiech & Raul Torres & Sarah A. Gagliano Taliun & André Corvelo & Stephanie M. Gogarten & Hyun Min Kang & Achille, 2021. "Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program," Nature, Nature, vol. 590(7845), pages 290-299, February.
    Full references (including those not matched with items on IDEAS)

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