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 Le 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; Rayjean J. Hung

doi:10.1038/s41467-019-13855-2

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. GoodmanJennifer 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 Le 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, Rayjean J. Hung

Research output: Contribution to journal › Article › peer-review

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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: r_g = 0.098, p = 2.3 × 10⁻⁸) and the ratio of FEV₁ to forced vital capacity (FEV₁/FVC: r_g = 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.

Original language	English
Article number	27
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13855-2
State	Published - Dec 1 2020

Bibliographical note

Funding Information:
Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. This research was supported by funding from the National Institutes of Health (US NCI R25T CA112355 and R01 CA201358; PI: Witte) and the Canadian Institute for Health Research (Foundation grant FDN 167273, PI: Hung; Canada Research Chair, PI: Hung). The OncoArray project was supported by NIH U19 CA203654 (MPI: Hung, Amos, Brennan, Lin). The Boston Lung Cancer Study was funded by NIH (NCI) U01CA209414 (PI: Christiani). The lung eQTL study at Laval University was supported by the Fon-dation de l’Institut universitaire de cardiologie et de pneumologie de Québec and the Canadian Institutes of Health Research (MOP − 123369). Y.B. holds a Canada Research Chair in Genomics of Heart and Lung Diseases. The EAGLE study was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS. The Multiethnic Cohort Study is supported by National Institutes of Health (CA164973). The CARET study was supported by the National Institutes of Health/National Cancer Institute: UM1 CA167462 (PI: Goodman), U01 CA6367307 (PIs: Omen, Goodman); R01 CA111703 (PI: Chen), 5R01 CA151989-01A1 (PI: Doherty) and U01 CA167462 (PI: Chen). M.B.S. was supported in part by a Cancer Center Support Grant (P30 CA076292) and by NIH P50 CA119997. R.M.M. is supported by a CRUK programme grant, the Integrative Cancer Epidemiology Programme (C18281/A19169), and by the National Institute for Health Research (NIHR) Bristol Biomedical Research Centre based at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. Dr Haycock is supported by CRUK Population Research Postdoctoral Fellowship C52724/A20138. M.P.D. is supported by the Roy Castle Lung Cancer Foundation UK.

Publisher Copyright:
© 2020, The Author(s).

ASJC Scopus subject areas

Physics and Astronomy (all)
Chemistry (all)
Biochemistry, Genetics and Molecular Biology (all)

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10.1038/s41467-019-13855-2

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Kachuri, L., Johansson, M., Rashkin, S. R., Graff, R. E., Bossé, Y., Manem, V., Caporaso, N. E., Landi, M. T., Christiani, D. C., Vineis, P., Liu, G., Scelo, G., Zaridze, D., Shete, S. S., Albanes, D., Aldrich, M. C., Tardón, A., Rennert, G., Chen, C., ... Hung, R. J. (2020). Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility. Nature Communications, 11(1), Article 27. https://doi.org/10.1038/s41467-019-13855-2

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title = "Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility",

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.",

author = "Linda Kachuri and Mattias Johansson and Rashkin, {Sara R.} and Graff, {Rebecca E.} and Yohan Boss{\'e} and Venkata Manem and Caporaso, {Neil E.} and Landi, {Maria Teresa} and Christiani, {David C.} and Paolo Vineis and Geoffrey Liu and Ghislaine Scelo and David Zaridze and Shete, {Sanjay S.} and Demetrius Albanes and Aldrich, {Melinda C.} and Adonina Tard{\'o}n and Gad Rennert and Chu Chen and Goodman, {Gary E.} and Doherty, {Jennifer A.} and Heike Bickeb{\"o}ller and Field, {John K.} and Davies, {Michael P.} and {Dawn Teare}, M. and Kiemeney, {Lambertus A.} and Bojesen, {Stig E.} and Aage Haugen and Shanbeh Zienolddiny and Stephen Lam and {Le Marchand}, Lo{\"i}c and Iona Cheng and Schabath, {Matthew B.} and Duell, {Eric J.} and Andrew, {Angeline S.} and Jonas Manjer and Philip Lazarus and Susanne Arnold and McKay, {James D.} and Emami, {Nima C.} and Warkentin, {Matthew T.} and Yonathan Brhane and Ma{\textquoteright}en Obeidat and Martin, {Richard M.} and Caroline Relton and {Davey Smith}, George and Haycock, {Philip C.} and Amos, {Christopher I.} and Paul Brennan and Witte, {John S.} and Hung, {Rayjean J.}",

note = "Funding Information: Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. This research was supported by funding from the National Institutes of Health (US NCI R25T CA112355 and R01 CA201358; PI: Witte) and the Canadian Institute for Health Research (Foundation grant FDN 167273, PI: Hung; Canada Research Chair, PI: Hung). The OncoArray project was supported by NIH U19 CA203654 (MPI: Hung, Amos, Brennan, Lin). The Boston Lung Cancer Study was funded by NIH (NCI) U01CA209414 (PI: Christiani). The lung eQTL study at Laval University was supported by the Fon-dation de l{\textquoteright}Institut universitaire de cardiologie et de pneumologie de Qu{\'e}bec and the Canadian Institutes of Health Research (MOP − 123369). Y.B. holds a Canada Research Chair in Genomics of Heart and Lung Diseases. The EAGLE study was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS. The Multiethnic Cohort Study is supported by National Institutes of Health (CA164973). The CARET study was supported by the National Institutes of Health/National Cancer Institute: UM1 CA167462 (PI: Goodman), U01 CA6367307 (PIs: Omen, Goodman); R01 CA111703 (PI: Chen), 5R01 CA151989-01A1 (PI: Doherty) and U01 CA167462 (PI: Chen). M.B.S. was supported in part by a Cancer Center Support Grant (P30 CA076292) and by NIH P50 CA119997. R.M.M. is supported by a CRUK programme grant, the Integrative Cancer Epidemiology Programme (C18281/A19169), and by the National Institute for Health Research (NIHR) Bristol Biomedical Research Centre based at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. Dr Haycock is supported by CRUK Population Research Postdoctoral Fellowship C52724/A20138. M.P.D. is supported by the Roy Castle Lung Cancer Foundation UK. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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Kachuri, L, Johansson, M, Rashkin, SR, Graff, RE, Bossé, Y, Manem, V, Caporaso, NE, Landi, MT, Christiani, DC, Vineis, P, Liu, G, Scelo, G, Zaridze, D, Shete, SS, Albanes, D, Aldrich, MC, Tardón, A, Rennert, G, Chen, C, Goodman, GE, Doherty, JA, Bickeböller, H, Field, JK, Davies, MP, Dawn Teare, M, Kiemeney, LA, Bojesen, SE, Haugen, A, Zienolddiny, S, Lam, S, Le Marchand, L, Cheng, I, Schabath, MB, Duell, EJ, Andrew, AS, Manjer, J, Lazarus, P, Arnold, S, McKay, JD, Emami, NC, Warkentin, MT, Brhane, Y, Obeidat, M, Martin, RM, Relton, C, Davey Smith, G, Haycock, PC, Amos, CI, Brennan, P, Witte, JS & Hung, RJ 2020, 'Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility', Nature Communications, vol. 11, no. 1, 27. https://doi.org/10.1038/s41467-019-13855-2

TY - JOUR

T1 - Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility

AU - Kachuri, Linda

AU - Johansson, Mattias

AU - Rashkin, Sara R.

AU - Graff, Rebecca E.

AU - Bossé, Yohan

AU - Manem, Venkata

AU - Caporaso, Neil E.

AU - Landi, Maria Teresa

AU - Christiani, David C.

AU - Vineis, Paolo

AU - Liu, Geoffrey

AU - Scelo, Ghislaine

AU - Zaridze, David

AU - Shete, Sanjay S.

AU - Albanes, Demetrius

AU - Aldrich, Melinda C.

AU - Tardón, Adonina

AU - Rennert, Gad

AU - Chen, Chu

AU - Goodman, Gary E.

AU - Doherty, Jennifer A.

AU - Bickeböller, Heike

AU - Field, John K.

AU - Davies, Michael P.

AU - Dawn Teare, M.

AU - Kiemeney, Lambertus A.

AU - Bojesen, Stig E.

AU - Haugen, Aage

AU - Zienolddiny, Shanbeh

AU - Lam, Stephen

AU - Le Marchand, Loïc

AU - Cheng, Iona

AU - Schabath, Matthew B.

AU - Duell, Eric J.

AU - Andrew, Angeline S.

AU - Manjer, Jonas

AU - Lazarus, Philip

AU - Arnold, Susanne

AU - McKay, James D.

AU - Emami, Nima C.

AU - Warkentin, Matthew T.

AU - Brhane, Yonathan

AU - Obeidat, Ma’en

AU - Martin, Richard M.

AU - Relton, Caroline

AU - Davey Smith, George

AU - Haycock, Philip C.

AU - Amos, Christopher I.

AU - Brennan, Paul

AU - Witte, John S.

AU - Hung, Rayjean J.

N1 - Funding Information: Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. This research was supported by funding from the National Institutes of Health (US NCI R25T CA112355 and R01 CA201358; PI: Witte) and the Canadian Institute for Health Research (Foundation grant FDN 167273, PI: Hung; Canada Research Chair, PI: Hung). The OncoArray project was supported by NIH U19 CA203654 (MPI: Hung, Amos, Brennan, Lin). The Boston Lung Cancer Study was funded by NIH (NCI) U01CA209414 (PI: Christiani). The lung eQTL study at Laval University was supported by the Fon-dation de l’Institut universitaire de cardiologie et de pneumologie de Québec and the Canadian Institutes of Health Research (MOP − 123369). Y.B. holds a Canada Research Chair in Genomics of Heart and Lung Diseases. The EAGLE study was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS. The Multiethnic Cohort Study is supported by National Institutes of Health (CA164973). The CARET study was supported by the National Institutes of Health/National Cancer Institute: UM1 CA167462 (PI: Goodman), U01 CA6367307 (PIs: Omen, Goodman); R01 CA111703 (PI: Chen), 5R01 CA151989-01A1 (PI: Doherty) and U01 CA167462 (PI: Chen). M.B.S. was supported in part by a Cancer Center Support Grant (P30 CA076292) and by NIH P50 CA119997. R.M.M. is supported by a CRUK programme grant, the Integrative Cancer Epidemiology Programme (C18281/A19169), and by the National Institute for Health Research (NIHR) Bristol Biomedical Research Centre based at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. Dr Haycock is supported by CRUK Population Research Postdoctoral Fellowship C52724/A20138. M.P.D. is supported by the Roy Castle Lung Cancer Foundation UK. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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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U2 - 10.1038/s41467-019-13855-2

DO - 10.1038/s41467-019-13855-2

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JO - Nature Communications

JF - Nature Communications

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M1 - 27

ER -

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

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Bibliographical note

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UN SDGs

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