Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually1. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 × 10-10). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 × 10-20 overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines2,3, and they bind to N′-nitrosonornicotine and potential lung carcinogens4. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets5.
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The authors thank all of the participants who took part in this research and the funders and support staff who made this study possible. We also thank R. Peto for his comments on the manuscript. Funding for the initial genome-wide study was provided by INCa, France. Additional funding for replication studies was provided by the US NCI (R01 CA092039) and the Ontario Institute for Cancer Research (OICR).
Author Contributions P.B. and M.L. designed the study. R.J.H., J.D.M., A.B. and H.B. coordinated the preparation and inclusion of all biological samples. R.J.H., J.D.M., V.G. and S.H. undertook the statistical analysis. Bioinformatics analysis was undertaken by F.M., M.F. and S.H., D.Z. and M.D. coordinated the genotyping of the central Europe samples, and J.D.M, R.J.H. and V.G. coordinated the genotyping of the other studies. All other co-authors coordinated the initial recruitment and management of the studies. M.L. obtained financial support for genotyping of the central Europe study, and P.B. and R.J.H. obtained financial support for genotyping of the other studies. P.B. and M.L. drafted the manuscript with substantial contributions from R.J.H. and J.D.M. All authors contributed to the final paper.
The file contains Supplementary Methods, Supplementary Discussion with additional references, Supplementary Figures 1-6 with Legends and Supplementary Tables 1-5.
About this article
European Journal of Human Genetics (2018)