Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5p15.33 TERT-CLPTM1Ll Region |
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| Affiliation: | 1. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada;2. Baylor College of Medicine, Houston, Texas;3. Institute of Cancer Research, London, United Kingdom;4. Wayne State University, Detroit, Michigan;5. University of Liverpool, Liverpool, United Kingdom;6. University of Texas McGovern Medical School, Houston, Texas;7. Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire;8. The University of Texas, MD Anderson Cancer Center, Houston, Texas;9. Mayo Clinic, Rochester, Minnesota;10. Princess Margaret Cancer Center, Toronto, Ontario, Canada;11. Harvard T.H. Chan School of Public Health, Boston, Massachusetts;12. German Cancer Research Center (DKFZ), Heidelberg, Germany;13. University of Edinburgh, Edinburgh, United Kingdom;14. German Center for Lung Research, Heidelberg, Germany;15. University Hospital Heidelberg, Heidelberg, Germany;p. Technion-Israel Institute of Technology, Haifa, Israel;q. Center for Cancer Research, National Cancer Institute, Bethesda, Maryland;r. University of Santiago de Compostela, Praza do Obradoiro, Coruña, Spain;s. Medical School, University of Michigan, Ann Arbor, Michigan;t. National Institute of Occupational Health (STAMI), Oslo, Norway;u. University of Genoa, Genoa, Italy;v. San Raffaele University, Rome, Italy;w. San Raffaele Pisana - Scientific Hospitalization and Care Insitution, Rome, Italy;x. Radboud University Medical Center, Nijmegen, Netherlands;y. University of Oviedo and CIBERESP, Oviedo, Spain;z. Copenhagen University Hospital, Copenhagen, Denmark;11. National Cancer Institute, Bethesda, Maryland;22. International Agency for Research on Cancer, Lyon, France;33. University Medical Center Goettingen, Goettingen, Germany;44. University of Kentucky, Lexington, Kentucky;55. University of Hawaii Cancer Center, Honolulu, Hawaii;66. Lund University, Lund, Sweden;77. Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire;88. Umeå University, Umeå, Sweden;99. University of Sheffield, Sheffield, United Kingdom;1010. H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida;1111. Vanderbilt University Medical Center, Nashville, Tennessee;1212. Helmholtz Zentrum Munchen, German Research Center for Environmental Health (GmbH), Bavaria, Germany;1313. Washington State University, Spokane, Washington;1414. University of Colorado, Aurora, Colorado;1515. University of California – Los Angeles, Los Angeles, California;pp. Memorial Sloan Kettering Cancer Center, New York, New York;qq. University of Salzburg, Salzburg, Austria;rr. Cancer Cluster Salzburg, Salzburg, Austria;ss. Mayo Clinic, Scottsdale, Arizona |
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| Abstract: | IntroductionInherited 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.MethodsWe 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.ResultsWe 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.ConclusionsWe 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. |
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| Keywords: | Lung cancer Never smokers Genome-wide association study Genetic susceptibility |
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