Lung cancer risk in never-smokers of European descent is associated with genetic variation in the 5p15.33 TERT-CLPTM1Ll region Journal Article


Authors: 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.; Liloglou, T.; Timofeeva, M.; Muley, T.; Rennert, H.; Saliba, W.; Ryan, B. M.; Bowman, E.; Barros-Dios, J. M.; Pérez-Ríos, M.; Morgenstern, H.; Zienolddiny, S.; Skaug, V.; Ugolini, D.; Bonassi, S.; van der Heijden, E. H. F. M.; Tardon, A.; Bojesen, S. E.; Landi, M. T.; Johansson, M.; Bickeböller, H.; Arnold, S.; Le Marchand, L.; Melander, O.; Andrew, A.; Grankvist, K.; Caporaso, N.; Teare, M. D.; Schabath, M. B.; Aldrich, M. C.; Kiemeney, L. A.; Wichmann, H. E.; Lazarus, P.; Mayordomo, J.; Neri, M.; Haugen, A.; Zhang, Z. F.; Ruano-Raviña, A.; Brenner, H.; Harris, C. C.; Orlow, I.; Rennert, G.; Risch, A.; Brennan, P.; Christiani, D. C.; Amos, C. I.; Yang, P.; Gorlova, O. Y.
Article 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. © 2019 International Association for the Study of Lung Cancer
Keywords: adult; controlled study; middle aged; major clinical study; single nucleotide polymorphism; cigarette smoking; cancer risk; colorectal cancer; ovary cancer; breast cancer; genetic association; genetic variability; genetic variation; genome-wide association study; odds ratio; lung cancer; smoking; risk assessment; prostate cancer; oncogene; genetic susceptibility; telomerase reverse transcriptase; lung carcinogenesis; chromosome 5p; asian; genotype environment interaction; never smokers; european; tert gene; human; male; female; priority journal; article; clptm1li gene; nonsmoker
Journal Title: Journal of Thoracic Oncology
Volume: 14
Issue: 8
ISSN: 1556-0864
Publisher: Elsevier Inc.  
Date Published: 2019-08-01
Start Page: 1360
End Page: 1369
Language: English
DOI: 10.1016/j.jtho.2019.04.008
PUBMED: 31009812
PROVIDER: scopus
DOI/URL:
Notes: Source: Scopus
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MSK Authors
  1. Irene Orlow
    201 Orlow