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

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, Ghislaine Scelo, David Zaridze, Sanjay S. Shete, Demetrius Albanes, Melinda C. Aldrich, Adonina Tardón, Gad Rennert, Chu Chen, Gary E. Goodman, Jennifer A. Doherty, Heike Bickeböller, John K. Field, Michael P. Davies, M. Dawn Teare, Lambertus A. Kiemeney, Stig E. Bojesen, Aage Haugen, Shanbeh Zienolddiny, Stephen Lam, Loïc Marchand, Iona Cheng, Matthew B. Schabath, Eric J. Duell, Angeline S. Andrew, Jonas Manjer, Philip Lazarus, Susanne Arnold, James D. McKay, Nima C. Emami, Matthew T. Warkentin, Yonathan Brhane, Ma’en Obeidat, Richard M. Martin, Caroline Relton, George Davey Smith, Philip C. Haycock, Christopher I. Amos, Paul Brennan, John S. Witte () and Rayjean J. Hung ()
Additional contact information
Linda Kachuri: University of California San Francisco
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
Yonathan Brhane: Lunenfeld-Tanenbaum Research Institute, Sinai Health System
Ma’en Obeidat: Centre for Heart Lung Innovation
Richard M. Martin: University of Bristol
Caroline Relton: University of Bristol
George Davey Smith: University of Bristol
Philip C. Haycock: 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

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-13855-2

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