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 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

Research output: Contribution to journalArticlepeer-review

16 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 languageEnglish
Pages (from-to)1360-1369
Number of pages10
JournalJournal of Thoracic Oncology
Volume14
Issue number8
DOIs
StatePublished - Aug 2019

Bibliographical 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 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

Keywords

  • Genetic susceptibility
  • Genome-wide association study
  • Lung cancer
  • Never smokers

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Fingerprint

Dive into the research topics of 'Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5p15.33 TERT-CLPTM1Ll Region'. Together they form a unique fingerprint.

Cite this