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Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility

Author

Listed:
  • Linda Kachuri

    (University of California San Francisco
    Lunenfeld-Tanenbaum Research Institute, Sinai Health System)

  • Mattias Johansson

    (International Agency for Research on Cancer)

  • Sara R. Rashkin

    (University of California San Francisco)

  • Rebecca E. Graff

    (University of California San Francisco)

  • Yohan Bossé

    (Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval)

  • Venkata Manem

    (Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval)

  • Neil E. Caporaso

    (Division of Cancer Epidemiology & Genetics, US NCI)

  • Maria Teresa Landi

    (Division of Cancer Epidemiology & Genetics, US NCI)

  • David C. Christiani

    (Harvard TH Chan School of Public Health)

  • Paolo Vineis

    (School of Public Health, Imperial College London)

  • Geoffrey Liu

    (University Health Network)

  • Ghislaine Scelo

    (International Agency for Research on Cancer)

  • David Zaridze

    (Russian N.N. Blokhin Cancer Research Centre)

  • Sanjay S. Shete

    (Division of Basic Sciences, MD Anderson Cancer Center)

  • Demetrius Albanes

    (Division of Cancer Epidemiology & Genetics, US NCI)

  • Melinda C. Aldrich

    (Vanderbilt University Medical Center)

  • Adonina Tardón

    (University of Oviedo and ISPA and CIBERESP, Campus del Cristo)

  • Gad Rennert

    (Technion Faculty of Medicine)

  • Chu Chen

    (Fred Hutchinson Cancer Research Center)

  • Gary E. Goodman

    (Fred Hutchinson Cancer Research Center)

  • Jennifer A. Doherty

    (Huntsman Cancer Institute)

  • Heike Bickeböller

    (University Medical Center, Georg-August-Universität Göttingen)

  • John K. Field

    (The University of Liverpool)

  • Michael P. Davies

    (The University of Liverpool)

  • M. Dawn Teare

    (Newcastle University)

  • Lambertus A. Kiemeney

    (Radboud University Medical Centre)

  • Stig E. Bojesen

    (Copenhagen University Hospital)

  • Aage Haugen

    (The National Institute of Occupational Health)

  • Shanbeh Zienolddiny

    (The National Institute of Occupational Health)

  • Stephen Lam

    (BC Cancer Agency)

  • Loïc Marchand

    (University of Hawaii Cancer Center)

  • Iona Cheng

    (University of California San Francisco)

  • Matthew B. Schabath

    (H. Lee Moffitt Cancer Center & Research Institute)

  • Eric J. Duell

    (Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL))

  • Angeline S. Andrew

    (Geisel School of Medicine, Dartmouth College)

  • Jonas Manjer

    (Skåne University Hospital, Lund University)

  • Philip Lazarus

    (College of Pharmacy and Pharmaceutical Sciences, Washington State University)

  • Susanne Arnold

    (University of Kentucky)

  • James D. McKay

    (International Agency for Research on Cancer)

  • Nima C. Emami

    (University of California San Francisco)

  • Matthew T. Warkentin

    (Lunenfeld-Tanenbaum Research Institute, Sinai Health System
    University of Toronto)

  • Yonathan Brhane

    (Lunenfeld-Tanenbaum Research Institute, Sinai Health System)

  • Ma’en Obeidat

    (Centre for Heart Lung Innovation)

  • Richard M. Martin

    (University of Bristol
    University of Bristol
    University Hospitals Bristol NHS Foundation Trust and the University of Bristol)

  • Caroline Relton

    (University of Bristol
    University of Bristol)

  • George Davey Smith

    (University of Bristol
    University of Bristol)

  • Philip C. Haycock

    (University of Bristol
    University of Bristol)

  • Christopher I. Amos

    (Baylor College of Medicine)

  • Paul Brennan

    (International Agency for Research on Cancer)

  • John S. Witte

    (University of California San Francisco)

  • Rayjean J. Hung

    (Lunenfeld-Tanenbaum Research Institute, Sinai Health System
    University of Toronto)

Abstract

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: rg = 0.098, p = 2.3 × 10−8) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: rg = 0.137, p = 2.0 × 10−12). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21–1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01–1.35) and lung cancer in never smokers (OR = 1.56, 1.05–2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.

Suggested Citation

  • Linda Kachuri & Mattias Johansson & Sara R. Rashkin & Rebecca E. Graff & Yohan Bossé & Venkata Manem & Neil E. Caporaso & Maria Teresa Landi & David C. Christiani & Paolo Vineis & Geoffrey Liu & Ghisl, 2020. "Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-13855-2
    DOI: 10.1038/s41467-019-13855-2
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