Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5p15.33 TERT-CLPTM1Ll Region

Rayjean J. Hung; Margaret R. Spitz; Richard S. Houlston; Ann G. Schwartz; John K. Field; Jun Ying; Yafang Li; Younghun Han; Xuemei Ji; Wei Chen; Xifeng Wu; Ivan P. Gorlov; Jie Na; Mariza de Andrade; Geoffrey Liu; Yonathan Brhane; Nancy Diao; Angela Wenzlaff; Michael P.A. Davies; Triantafillos Liloglou; Maria Timofeeva; Thomas Muley; Hedy Rennert; Walid Saliba; Bríd M. Ryan; Elise Bowman; Juan Miguel Barros-Dios; Mónica Pérez-Ríos; Hal Morgenstern; Shanbeh Zienolddiny; Vidar Skaug; Donatella Ugolini; Stefano Bonassi; Erik H.F.M. van der Heijden; Adonina Tardon; Stig E. Bojesen; Maria Teresa Landi; Mattias Johansson; Heike Bickeböller; Susanne Arnold; Loic Le Marchand; Olle Melander; Angeline Andrew; Kjell Grankvist; Neil Caporaso; M. Dawn Teare; Matthew B. Schabath; Melinda C. Aldrich; Lambertus A. Kiemeney; H. Erich Wichmann; Philip Lazarus; Jose Mayordomo; Monica Neri; Aage Haugen; Zuo Feng Zhang; Alberto Ruano-Raviña; Hermann Brenner; Curtis C. Harris; Irene Orlow; Gadi Rennert; Angela Risch; Paul Brennan; David C. Christiani; Christopher I. Amos; Ping Yang; Olga Y. Gorlova

doi:10.1016/j.jtho.2019.04.008

Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5_p15.33 TERT-CLPTM1Ll Region

Rayjean J. Hung, Margaret R. Spitz, Richard S. Houlston, Ann G. Schwartz, John K. Field, Jun Ying, Yafang Li, Younghun Han, Xuemei Ji, Wei Chen, Xifeng Wu, Ivan P. Gorlov, Jie Na, Mariza de Andrade, Geoffrey Liu, Yonathan Brhane, Nancy Diao, Angela Wenzlaff, Michael P.A. Davies, Triantafillos LiloglouMaria Timofeeva, Thomas Muley, Hedy Rennert, Walid Saliba, Bríd M. Ryan, Elise Bowman, Juan Miguel Barros-Dios, Mónica Pérez-Ríos, Hal Morgenstern, Shanbeh Zienolddiny, Vidar Skaug, Donatella Ugolini, Stefano Bonassi, Erik H.F.M. van der Heijden, Adonina Tardon, Stig E. Bojesen, Maria Teresa Landi, Mattias Johansson, Heike Bickeböller, Susanne Arnold, Loic Le Marchand, Olle Melander, Angeline Andrew, Kjell Grankvist, Neil Caporaso, M. Dawn Teare, Matthew B. Schabath, Melinda C. Aldrich, Lambertus A. Kiemeney, H. Erich Wichmann, Philip Lazarus, Jose Mayordomo, Monica Neri, Aage Haugen, Zuo Feng Zhang, Alberto Ruano-Raviña, Hermann Brenner, Curtis C. Harris, Irene Orlow, Gadi Rennert, Angela Risch, Paul Brennan, David C. Christiani, Christopher I. Amos, Ping Yang, Olga Y. Gorlova

Quantitative Health Sciences

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

8 Scopus citations

Abstract

Introduction: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. Methods: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. Results: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722–0.820; p value 5.31 × 10^-16), rs380286 (OR: 0.770, 95% CI: 0.723–0.820; p value 4.32 × 10^-16), and rs4975616 (OR: 0.778, 95% CI: 0.730–0.829; p value 1.04 × 10^-14). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. Conclusions: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease.

Original language	English (US)
Pages (from-to)	1360-1369
Number of pages	10
Journal	Journal of Thoracic Oncology
Volume	14
Issue number	8
DOIs	https://doi.org/10.1016/j.jtho.2019.04.008
State	Published - Aug 2019

Keywords

Genetic susceptibility
Genome-wide association study
Lung cancer
Never smokers

ASJC Scopus subject areas

Oncology
Pulmonary and Respiratory Medicine

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10.1016/j.jtho.2019.04.008

Cite this

Hung, R. J., Spitz, M. R., Houlston, R. S., Schwartz, A. G., Field, J. K., Ying, J., Li, Y., Han, Y., Ji, X., Chen, W., Wu, X., Gorlov, I. P., Na, J., de Andrade, M., Liu, G., Brhane, Y., Diao, N., Wenzlaff, A., Davies, M. P. A., ... Gorlova, O. Y. (2019). Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5_p15.33 TERT-CLPTM1Ll Region. Journal of Thoracic Oncology, 14(8), 1360-1369. https://doi.org/10.1016/j.jtho.2019.04.008

Hung, RJ, Spitz, MR, Houlston, RS, Schwartz, AG, Field, JK, Ying, J, Li, Y, Han, Y, Ji, X, Chen, W, Wu, X, Gorlov, IP, Na, J, de Andrade, M, Liu, G, Brhane, Y, Diao, N, Wenzlaff, A, Davies, MPA, Liloglou, T, Timofeeva, M, Muley, T, Rennert, H, Saliba, W, Ryan, BM, Bowman, E, Barros-Dios, JM, Pérez-Ríos, M, Morgenstern, H, Zienolddiny, S, Skaug, V, Ugolini, D, Bonassi, S, van der Heijden, EHFM, Tardon, A, Bojesen, SE, Landi, MT, Johansson, M, Bickeböller, H, Arnold, S, Le Marchand, L, Melander, O, Andrew, A, Grankvist, K, Caporaso, N, Teare, MD, Schabath, MB, Aldrich, MC, Kiemeney, LA, Wichmann, HE, Lazarus, P, Mayordomo, J, Neri, M, Haugen, A, Zhang, ZF, Ruano-Raviña, A, Brenner, H, Harris, CC, Orlow, I, Rennert, G, Risch, A, Brennan, P, Christiani, DC, Amos, CI, Yang, P & Gorlova, OY 2019, 'Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5_p15.33 TERT-CLPTM1Ll Region', Journal of Thoracic Oncology, vol. 14, no. 8, pp. 1360-1369. https://doi.org/10.1016/j.jtho.2019.04.008

@article{61867e8864cc4a13b430ef0711d25825,

title = "Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5p15.33 TERT-CLPTM1Ll Region",

abstract = "Introduction: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. Methods: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. Results: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722–0.820; p value 5.31 × 10-16), rs380286 (OR: 0.770, 95% CI: 0.723–0.820; p value 4.32 × 10-16), and rs4975616 (OR: 0.778, 95% CI: 0.730–0.829; p value 1.04 × 10-14). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. Conclusions: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease.",

keywords = "Genetic susceptibility, Genome-wide association study, Lung cancer, Never smokers",

author = "Hung, {Rayjean J.} and Spitz, {Margaret R.} and Houlston, {Richard S.} and Schwartz, {Ann G.} and Field, {John K.} and Jun Ying and Yafang Li and Younghun Han and Xuemei Ji and Wei Chen and Xifeng Wu and Gorlov, {Ivan P.} and Jie Na and {de Andrade}, Mariza and Geoffrey Liu and Yonathan Brhane and Nancy Diao and Angela Wenzlaff and Davies, {Michael P.A.} and Triantafillos Liloglou and Maria Timofeeva and Thomas Muley and Hedy Rennert and Walid Saliba and Ryan, {Br{\'i}d M.} and Elise Bowman and Barros-Dios, {Juan Miguel} and M{\'o}nica P{\'e}rez-R{\'i}os and Hal Morgenstern and Shanbeh Zienolddiny and Vidar Skaug and Donatella Ugolini and Stefano Bonassi and {van der Heijden}, {Erik H.F.M.} and Adonina Tardon and Bojesen, {Stig E.} and Landi, {Maria Teresa} and Mattias Johansson and Heike Bickeb{\"o}ller and Susanne Arnold and {Le Marchand}, Loic and Olle Melander and Angeline Andrew and Kjell Grankvist and Neil Caporaso and Teare, {M. Dawn} and Schabath, {Matthew B.} and Aldrich, {Melinda C.} and Kiemeney, {Lambertus A.} and Wichmann, {H. Erich} and Philip Lazarus and Jose Mayordomo and Monica Neri and Aage Haugen and Zhang, {Zuo Feng} and Alberto Ruano-Ravi{\~n}a and Hermann Brenner and Harris, {Curtis C.} and Irene Orlow and Gadi Rennert and Angela Risch and Paul Brennan and Christiani, {David C.} and Amos, {Christopher I.} and Ping Yang and Gorlova, {Olga Y.}",

note = "Funding Information: Disclosure: Dr. Field has received grants from HTA funding for the UKLS trial and Liverpool CCG; and has received personal fees from Epigenomics, Vision Gate, Astra Zeneca, and Janssen. Dr. Liu has received personal fees from Pfizer, Novartis, Astra Zeneca, Roche, Bayer, Abbvie, Takeda, Merck, and Bristol-Myers Squibb. Dr. Muley has received grants and personal fees from Roche Diagnostics. Dr. van der Heijden has received grants from AstraZeneca Oncology, Pentax Medical, and Philips Medical Systems; personal fees from Pentax Medical and Medtronic; and has received nonfinancial support from Pentax Medical, Philips Medical Systems, and Medtronic. Dr. Aldrich has received grants from the National Institutes of Health/National Cancer Institute. Dr. Risch has received grants from the National Institutes of Health/National Cancer Institute and Deutsche Krebshilfe. Dr. Gorlova has received grants from the National Institutes of Health/National Cancer Institute. The remaining authors declare no conflict of interest.This work was supported in part by National Institutes of Health (NIH) grants CA149462, CA209414, CA092824, ES00002, U01CA209414, U19CA203654, 1K07CA172294, P50CA119997, R01CA060691, R01CA87895, P30CA22453, P30CA008748, P30CA076292, and U01CA164973; Department of Health and Human Services grant HHSN261201300011; James & Esther King Biomedical Research Program Grant 09KN-15; Helmholtz-DAAD fellowship A/07/97379; the Society of Memorial Sloan Kettering Cancer Center through their annual appeal and Steps for Breath; Italian Ministry of Health grant for Institutional Research 2017-2018 and Associazione Italiana per la Ricerca sul Cancro grant IG2015/17564IO; and Instituto de Salud Carlos III. PI15/01211 grant and Xunta de Galicia grant 10CSA208057PR. The Toronto study was supported by The Canadian Cancer Society Research Institute (020214), and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. The LUCY study was funded in part by the Germany National Genome Research Network (NGFN), the DFG (BI576/2-1; BI 576/2–2, Bi 576/4-1; Bi 576/4-2; Wi 621/10-1; Wi 621/10-2), the Helmholtzgemeinschaft (HGF) and the Federal office for Radiation Protection (BfS:STSch4454). KORA Surveys were funded by the Helmholtz-Zentrum M{\"u}nchen (HMGU), which is funded by the German Federal Ministry of Education, Science, Research and Technology and the State of Bavaria. The Liverpool Lung Project is funded by the Roy Castle Lung Cancer Foundation. The Resource for the Study of Lung Cancer Epidemiology in North Trent (ReSoLuCENT) study was funded by the Sheffield Hospitals Charity, Sheffield Experimental Cancer Medicine Centre and Weston Park Hospital Cancer Charity. ILCCO data harmonization was supported by Canada Research Chair to Dr. Hung. Partial support for this research was provided by Cancer Prevention Research Institute of Texas grant RR170048 which supports Dr. Christopher Amos, a CPRIT Scholar in Cancer Research. Funding Information: This work was supported in part by National Institutes of Health (NIH) grants CA149462 , CA209414 , CA092824 , ES00002 , U01CA209414 , U19CA203654 , 1K07CA172294 , P50CA119997 , R01CA060691 , R01CA87895 , P30CA22453 , P30CA008748 , P30CA076292 , and U01CA164973 ; Department of Health and Human Services grant HHSN261201300011 ; James & Esther King Biomedical Research Program Grant 09KN-15 ; Helmholtz-DAAD fellowship A/07/97379; the Society of Memorial Sloan Kettering Cancer Center through their annual appeal and Steps for Breath; Italian Ministry of Health grant for Institutional Research 2017-2018 and Associazione Italiana per la Ricerca sul Cancro grant IG2015/17564IO ; and Instituto de Salud Carlos III . PI15/01211 grant and Xunta de Galicia grant 10CSA208057PR . The Toronto study was supported by The Canadian Cancer Society Research Institute ( 020214 ), and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. The LUCY study was funded in part by the Germany National Genome Research Network (NGFN), the DFG ( BI576/2-1 ; BI 576/2–2 , Bi 576/4-1 ; Bi 576/4-2 ; Wi 621/10-1 ; Wi 621/10-2 ), the Helmholtzgemeinschaft (HGF) and the Federal office for Radiation Protection (BfS:STSch4454). KORA Surveys were funded by the Helmholtz-Zentrum M{\"u}nchen (HMGU), which is funded by the German Federal Ministry of Education , Science, Research and Technology and the State of Bavaria. The Liverpool Lung Project is funded by the Roy Castle Lung Cancer Foundation . The Resource for the Study of Lung Cancer Epidemiology in North Trent (ReSoLuCENT) study was funded by the Sheffield Hospitals Charity , Sheffield Experimental Cancer Medicine Centre and Weston Park Hospital Cancer Charity. ILCCO data harmonization was supported by Canada Research Chair to Dr. Hung. Funding Information: Disclosure: Dr. Field has received grants from HTA funding for the UKLS trial and Liverpool CCG; and has received personal fees from Epigenomics, Vision Gate, Astra Zeneca, and Janssen. Dr. Liu has received personal fees from Pfizer, Novartis, Astra Zeneca, Roche, Bayer, Abbvie, Takeda, Merck, and Bristol-Myers Squibb. Dr. Muley has received grants and personal fees from Roche Diagnostics. Dr. van der Heijden has received grants from AstraZeneca Oncology, Pentax Medical, and Philips Medical Systems; personal fees from Pentax Medical and Medtronic; and has received nonfinancial support from Pentax Medical, Philips Medical Systems, and Medtronic. Dr. Aldrich has received grants from the National Institutes of Health/National Cancer Institute. Dr. Risch has received grants from the National Institutes of Health/National Cancer Institute and Deutsche Krebshilfe. Dr. Gorlova has received grants from the National Institutes of Health/National Cancer Institute. The remaining authors declare no conflict of interest.This work was supported in part by National Institutes of Health (NIH) grants CA149462, CA209414, CA092824, ES00002, U01CA209414, U19CA203654, 1K07CA172294, P50CA119997, R01CA060691, R01CA87895, P30CA22453, P30CA008748, P30CA076292, and U01CA164973; Department of Health and Human Services grant HHSN261201300011; James & Esther King Biomedical Research Program Grant 09KN-15; Helmholtz-DAAD fellowship A/07/97379; the Society of Memorial Sloan Kettering Cancer Center through their annual appeal and Steps for Breath; Italian Ministry of Health grant for Institutional Research 2017-2018 and Associazione Italiana per la Ricerca sul Cancro grant IG2015/17564IO; and Instituto de Salud Carlos III. PI15/01211 grant and Xunta de Galicia grant 10CSA208057PR. The Toronto study was supported by The Canadian Cancer Society Research Institute (020214), and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. The LUCY study was funded in part by the Germany National Genome Research Network (NGFN), the DFG (BI576/2-1; BI 576/2–2, Bi 576/4-1; Bi 576/4-2; Wi 621/10-1; Wi 621/10-2), the Helmholtzgemeinschaft (HGF) and the Federal office for Radiation Protection (BfS:STSch4454). KORA Surveys were funded by the Helmholtz-Zentrum M{\"u}nchen (HMGU), which is funded by the German Federal Ministry of Education, Science, Research and Technology and the State of Bavaria. The Liverpool Lung Project is funded by the Roy Castle Lung Cancer Foundation. The Resource for the Study of Lung Cancer Epidemiology in North Trent (ReSoLuCENT) study was funded by the Sheffield Hospitals Charity, Sheffield Experimental Cancer Medicine Centre and Weston Park Hospital Cancer Charity. ILCCO data harmonization was supported by Canada Research Chair to Dr. Hung. Funding Information: Disclosure: Dr. Field has received grants from HTA funding for the UKLS trial and Liverpool CCG; and has received personal fees from Epigenomics, Vision Gate, Astra Zeneca, and Janssen. Dr. Liu has received personal fees from Pfizer, Novartis, Astra Zeneca, Roche, Bayer, Abbvie, Takeda, Merck, and Bristol-Myers Squibb. Dr. Muley has received grants and personal fees from Roche Diagnostics. Dr. van der Heijden has received grants from AstraZeneca Oncology , Pentax Medical , and Philips Medical Systems; personal fees from Pentax Medical and Medtronic; and has received nonfinancial support from Pentax Medical , Philips Medical Systems, and Medtronic . Dr. Aldrich has received grants from the National Institutes of Health / National Cancer Institute . Dr. Risch has received grants from the National Institutes of Health / National Cancer Institute and Deutsche Krebshilfe . Dr. Gorlova has received grants from the National Institutes of Health / National Cancer Institute . The remaining authors declare no conflict of interest. Publisher Copyright: {\textcopyright} 2019 International Association for the Study of Lung Cancer",

year = "2019",

month = aug,

doi = "10.1016/j.jtho.2019.04.008",

language = "English (US)",

volume = "14",

pages = "1360--1369",

journal = "Journal of Thoracic Oncology",

issn = "1556-0864",

publisher = "International Association for the Study of Lung Cancer",

number = "8",

}

TY - JOUR

T1 - Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5p15.33 TERT-CLPTM1Ll Region

AU - Hung, Rayjean J.

AU - Spitz, Margaret R.

AU - Houlston, Richard S.

AU - Schwartz, Ann G.

AU - Field, John K.

AU - Ying, Jun

AU - Li, Yafang

AU - Han, Younghun

AU - Ji, Xuemei

AU - Chen, Wei

AU - Wu, Xifeng

AU - Gorlov, Ivan P.

AU - Na, Jie

AU - de Andrade, Mariza

AU - Liu, Geoffrey

AU - Brhane, Yonathan

AU - Diao, Nancy

AU - Wenzlaff, Angela

AU - Davies, Michael P.A.

AU - Liloglou, Triantafillos

AU - Timofeeva, Maria

AU - Muley, Thomas

AU - Rennert, Hedy

AU - Saliba, Walid

AU - Ryan, Bríd M.

AU - Bowman, Elise

AU - Barros-Dios, Juan Miguel

AU - Pérez-Ríos, Mónica

AU - Morgenstern, Hal

AU - Zienolddiny, Shanbeh

AU - Skaug, Vidar

AU - Ugolini, Donatella

AU - Bonassi, Stefano

AU - van der Heijden, Erik H.F.M.

AU - Tardon, Adonina

AU - Bojesen, Stig E.

AU - Landi, Maria Teresa

AU - Johansson, Mattias

AU - Bickeböller, Heike

AU - Arnold, Susanne

AU - Le Marchand, Loic

AU - Melander, Olle

AU - Andrew, Angeline

AU - Grankvist, Kjell

AU - Caporaso, Neil

AU - Teare, M. Dawn

AU - Schabath, Matthew B.

AU - Aldrich, Melinda C.

AU - Kiemeney, Lambertus A.

AU - Wichmann, H. Erich

AU - Lazarus, Philip

AU - Mayordomo, Jose

AU - Neri, Monica

AU - Haugen, Aage

AU - Zhang, Zuo Feng

AU - Ruano-Raviña, Alberto

AU - Brenner, Hermann

AU - Harris, Curtis C.

AU - Orlow, Irene

AU - Rennert, Gadi

AU - Risch, Angela

AU - Brennan, Paul

AU - Christiani, David C.

AU - Amos, Christopher I.

AU - Yang, Ping

AU - Gorlova, Olga Y.

N1 - Funding Information: Disclosure: Dr. Field has received grants from HTA funding for the UKLS trial and Liverpool CCG; and has received personal fees from Epigenomics, Vision Gate, Astra Zeneca, and Janssen. Dr. Liu has received personal fees from Pfizer, Novartis, Astra Zeneca, Roche, Bayer, Abbvie, Takeda, Merck, and Bristol-Myers Squibb. Dr. Muley has received grants and personal fees from Roche Diagnostics. Dr. van der Heijden has received grants from AstraZeneca Oncology, Pentax Medical, and Philips Medical Systems; personal fees from Pentax Medical and Medtronic; and has received nonfinancial support from Pentax Medical, Philips Medical Systems, and Medtronic. Dr. Aldrich has received grants from the National Institutes of Health/National Cancer Institute. Dr. Risch has received grants from the National Institutes of Health/National Cancer Institute and Deutsche Krebshilfe. Dr. Gorlova has received grants from the National Institutes of Health/National Cancer Institute. The remaining authors declare no conflict of interest.This work was supported in part by National Institutes of Health (NIH) grants CA149462, CA209414, CA092824, ES00002, U01CA209414, U19CA203654, 1K07CA172294, P50CA119997, R01CA060691, R01CA87895, P30CA22453, P30CA008748, P30CA076292, and U01CA164973; Department of Health and Human Services grant HHSN261201300011; James & Esther King Biomedical Research Program Grant 09KN-15; Helmholtz-DAAD fellowship A/07/97379; the Society of Memorial Sloan Kettering Cancer Center through their annual appeal and Steps for Breath; Italian Ministry of Health grant for Institutional Research 2017-2018 and Associazione Italiana per la Ricerca sul Cancro grant IG2015/17564IO; and Instituto de Salud Carlos III. PI15/01211 grant and Xunta de Galicia grant 10CSA208057PR. The Toronto study was supported by The Canadian Cancer Society Research Institute (020214), and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. The LUCY study was funded in part by the Germany National Genome Research Network (NGFN), the DFG (BI576/2-1; BI 576/2–2, Bi 576/4-1; Bi 576/4-2; Wi 621/10-1; Wi 621/10-2), the Helmholtzgemeinschaft (HGF) and the Federal office for Radiation Protection (BfS:STSch4454). KORA Surveys were funded by the Helmholtz-Zentrum München (HMGU), which is funded by the German Federal Ministry of Education, Science, Research and Technology and the State of Bavaria. The Liverpool Lung Project is funded by the Roy Castle Lung Cancer Foundation. The Resource for the Study of Lung Cancer Epidemiology in North Trent (ReSoLuCENT) study was funded by the Sheffield Hospitals Charity, Sheffield Experimental Cancer Medicine Centre and Weston Park Hospital Cancer Charity. ILCCO data harmonization was supported by Canada Research Chair to Dr. Hung. Partial support for this research was provided by Cancer Prevention Research Institute of Texas grant RR170048 which supports Dr. Christopher Amos, a CPRIT Scholar in Cancer Research. Funding Information: This work was supported in part by National Institutes of Health (NIH) grants CA149462 , CA209414 , CA092824 , ES00002 , U01CA209414 , U19CA203654 , 1K07CA172294 , P50CA119997 , R01CA060691 , R01CA87895 , P30CA22453 , P30CA008748 , P30CA076292 , and U01CA164973 ; Department of Health and Human Services grant HHSN261201300011 ; James & Esther King Biomedical Research Program Grant 09KN-15 ; Helmholtz-DAAD fellowship A/07/97379; the Society of Memorial Sloan Kettering Cancer Center through their annual appeal and Steps for Breath; Italian Ministry of Health grant for Institutional Research 2017-2018 and Associazione Italiana per la Ricerca sul Cancro grant IG2015/17564IO ; and Instituto de Salud Carlos III . PI15/01211 grant and Xunta de Galicia grant 10CSA208057PR . The Toronto study was supported by The Canadian Cancer Society Research Institute ( 020214 ), and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. The LUCY study was funded in part by the Germany National Genome Research Network (NGFN), the DFG ( BI576/2-1 ; BI 576/2–2 , Bi 576/4-1 ; Bi 576/4-2 ; Wi 621/10-1 ; Wi 621/10-2 ), the Helmholtzgemeinschaft (HGF) and the Federal office for Radiation Protection (BfS:STSch4454). KORA Surveys were funded by the Helmholtz-Zentrum München (HMGU), which is funded by the German Federal Ministry of Education , Science, Research and Technology and the State of Bavaria. The Liverpool Lung Project is funded by the Roy Castle Lung Cancer Foundation . The Resource for the Study of Lung Cancer Epidemiology in North Trent (ReSoLuCENT) study was funded by the Sheffield Hospitals Charity , Sheffield Experimental Cancer Medicine Centre and Weston Park Hospital Cancer Charity. ILCCO data harmonization was supported by Canada Research Chair to Dr. Hung. Funding Information: Disclosure: Dr. Field has received grants from HTA funding for the UKLS trial and Liverpool CCG; and has received personal fees from Epigenomics, Vision Gate, Astra Zeneca, and Janssen. Dr. Liu has received personal fees from Pfizer, Novartis, Astra Zeneca, Roche, Bayer, Abbvie, Takeda, Merck, and Bristol-Myers Squibb. Dr. Muley has received grants and personal fees from Roche Diagnostics. Dr. van der Heijden has received grants from AstraZeneca Oncology, Pentax Medical, and Philips Medical Systems; personal fees from Pentax Medical and Medtronic; and has received nonfinancial support from Pentax Medical, Philips Medical Systems, and Medtronic. Dr. Aldrich has received grants from the National Institutes of Health/National Cancer Institute. Dr. Risch has received grants from the National Institutes of Health/National Cancer Institute and Deutsche Krebshilfe. Dr. Gorlova has received grants from the National Institutes of Health/National Cancer Institute. The remaining authors declare no conflict of interest.This work was supported in part by National Institutes of Health (NIH) grants CA149462, CA209414, CA092824, ES00002, U01CA209414, U19CA203654, 1K07CA172294, P50CA119997, R01CA060691, R01CA87895, P30CA22453, P30CA008748, P30CA076292, and U01CA164973; Department of Health and Human Services grant HHSN261201300011; James & Esther King Biomedical Research Program Grant 09KN-15; Helmholtz-DAAD fellowship A/07/97379; the Society of Memorial Sloan Kettering Cancer Center through their annual appeal and Steps for Breath; Italian Ministry of Health grant for Institutional Research 2017-2018 and Associazione Italiana per la Ricerca sul Cancro grant IG2015/17564IO; and Instituto de Salud Carlos III. PI15/01211 grant and Xunta de Galicia grant 10CSA208057PR. The Toronto study was supported by The Canadian Cancer Society Research Institute (020214), and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. The LUCY study was funded in part by the Germany National Genome Research Network (NGFN), the DFG (BI576/2-1; BI 576/2–2, Bi 576/4-1; Bi 576/4-2; Wi 621/10-1; Wi 621/10-2), the Helmholtzgemeinschaft (HGF) and the Federal office for Radiation Protection (BfS:STSch4454). KORA Surveys were funded by the Helmholtz-Zentrum München (HMGU), which is funded by the German Federal Ministry of Education, Science, Research and Technology and the State of Bavaria. The Liverpool Lung Project is funded by the Roy Castle Lung Cancer Foundation. The Resource for the Study of Lung Cancer Epidemiology in North Trent (ReSoLuCENT) study was funded by the Sheffield Hospitals Charity, Sheffield Experimental Cancer Medicine Centre and Weston Park Hospital Cancer Charity. ILCCO data harmonization was supported by Canada Research Chair to Dr. Hung. Funding Information: Disclosure: Dr. Field has received grants from HTA funding for the UKLS trial and Liverpool CCG; and has received personal fees from Epigenomics, Vision Gate, Astra Zeneca, and Janssen. Dr. Liu has received personal fees from Pfizer, Novartis, Astra Zeneca, Roche, Bayer, Abbvie, Takeda, Merck, and Bristol-Myers Squibb. Dr. Muley has received grants and personal fees from Roche Diagnostics. Dr. van der Heijden has received grants from AstraZeneca Oncology , Pentax Medical , and Philips Medical Systems; personal fees from Pentax Medical and Medtronic; and has received nonfinancial support from Pentax Medical , Philips Medical Systems, and Medtronic . Dr. Aldrich has received grants from the National Institutes of Health / National Cancer Institute . Dr. Risch has received grants from the National Institutes of Health / National Cancer Institute and Deutsche Krebshilfe . Dr. Gorlova has received grants from the National Institutes of Health / National Cancer Institute . The remaining authors declare no conflict of interest. Publisher Copyright: © 2019 International Association for the Study of Lung Cancer

PY - 2019/8

Y1 - 2019/8

N2 - Introduction: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. Methods: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. Results: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722–0.820; p value 5.31 × 10-16), rs380286 (OR: 0.770, 95% CI: 0.723–0.820; p value 4.32 × 10-16), and rs4975616 (OR: 0.778, 95% CI: 0.730–0.829; p value 1.04 × 10-14). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. Conclusions: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease.

AB - Introduction: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. Methods: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. Results: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722–0.820; p value 5.31 × 10-16), rs380286 (OR: 0.770, 95% CI: 0.723–0.820; p value 4.32 × 10-16), and rs4975616 (OR: 0.778, 95% CI: 0.730–0.829; p value 1.04 × 10-14). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. Conclusions: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease.

KW - Genetic susceptibility

KW - Genome-wide association study

KW - Lung cancer

KW - Never smokers

UR - http://www.scopus.com/inward/record.url?scp=85066990163&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85066990163&partnerID=8YFLogxK

U2 - 10.1016/j.jtho.2019.04.008

DO - 10.1016/j.jtho.2019.04.008

M3 - Article

C2 - 31009812

AN - SCOPUS:85066990163

SN - 1556-0864

VL - 14

SP - 1360

EP - 1369

JO - Journal of Thoracic Oncology

JF - Journal of Thoracic Oncology

IS - 8

ER -