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

Lookup NU author(s): Professor Dawn Teare, Dr Paul Brennan

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Abstract

© 2019 International Association for the Study of Lung CancerIntroduction: 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.


Publication metadata

Author(s): 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 J-M, Perez-Rios M, Morgenstern H, Zienolddiny S, Skaug V, Ugolini D, Bonassi S, van der Heijden EHFM, Tardon A, Bojesen SE, Landi MT, Johansson M, Bickeboller H, Arnold S, Le Marchand L, Melander O, Andrew A, Grankvist K, Caporaso N, Teare MD, Schabath MB, Aldrich MC, Kiemeney LA, Wichmann H-E, Lazarus P, Mayordomo J, Neri M, Haugen A, Zhang Z-F, Ruano-Ravina A, Brenner H, Harris CC, Orlow I, Rennert G, Risch A, Brennan P, Christiani DC, Amos CI, Yang P, Gorlova OY

Publication type: Article

Publication status: Published

Journal: Journal of Thoracic Oncology

Year: 2019

Volume: 14

Issue: 8

Pages: 1360-1369

Print publication date: 01/08/2019

Online publication date: 19/04/2019

Acceptance date: 11/04/2019

Date deposited: 11/11/2019

ISSN (print): 1556-0864

ISSN (electronic): 1556-1380

Publisher: Elsevier

URL: https://doi.org/10.1016/j.jtho.2019.04.008

DOI: 10.1016/j.jtho.2019.04.008

PubMed id: 31009812


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Funding

Funder referenceFunder name
020214
09KN-15
10CS208057PR
1K07CA172294
A/07/97379
BfS:STSch4454
Bi 576/4-1
Bi 576/4-2
BI576/2-1
BI576/2-2
CA149462
CA092824
CA209414
ES00002
Germany National Genome Research Network (NGFN)
IG2015/17564IO
Helmholtz-Zentrum Munchen
HHSN261201300011
Italian Ministry of Health grant for Institutional Research 2017-2018
R01CA87895
Roy Castle Lung Cancer Foundation
RR170048
Sheffield Hospital Charity
Society of Memorial Sloan Kettering Cancer Center
U01CA209414
P30CA008748
P30CA076292
P30CA22453
P50CA119997
Wi 621/10-1
PI15/01211
R01CA060691
U01CA164973
U19CA203654
Wi 621/10-2

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