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Nat Commun. 2020 Jan 7;11(1):27. doi: 10.1038/s41467-019-13855-2.

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

Author information

1
Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, CA, USA.
2
Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.
3
International Agency for Research on Cancer, Lyon, France.
4
Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval, Quebec City, Canada.
5
Division of Cancer Epidemiology & Genetics, US NCI, Bethesda, MD, USA.
6
Departments of Environmental Health and Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA.
7
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
8
Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada.
9
Russian N.N. Blokhin Cancer Research Centre, Moscow, Russian Federation.
10
Department of Biostatistics, Division of Basic Sciences, MD Anderson Cancer Center, Houston, TX, USA.
11
Department of Thoracic Surgery and Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN, USA.
12
Faculty of Medicine, University of Oviedo and ISPA and CIBERESP, Campus del Cristo, Oviedo, Spain.
13
Clalit National Cancer Control Center, Technion Faculty of Medicine, Haifa, Israel.
14
Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
15
Department of Population Health Sciences, Huntsman Cancer Institute, Salt Lake City, UT, USA.
16
Department of Genetic Epidemiology, University Medical Center, Georg-August-Universität Göttingen, Göttingen, Germany.
17
Roy Castle Lung Cancer Research Programme, Department of Molecular and Clinical Cancer Medicine, The University of Liverpool, London, UK.
18
Biostatistics Research Group, Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK.
19
Radboud Institute for Health Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
20
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
21
The National Institute of Occupational Health, Oslo, Norway.
22
BC Cancer Agency, Vancouver, BC, Canada.
23
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
24
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
25
Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
26
Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA.
27
Skåne University Hospital, Lund University, Lund, Sweden.
28
Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA.
29
Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
30
Epidemiology Division, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
31
University of British Columbia, Centre for Heart Lung Innovation, Vancouver, BC, Canada.
32
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
33
Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK.
34
National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Bristol, UK.
35
Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA.
36
Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, CA, USA. jwitte@ucsf.edu.
37
Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada. rayjean.hung@lunenfeld.ca.
38
Epidemiology Division, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada. rayjean.hung@lunenfeld.ca.

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.

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