A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25

Rayjean J. Hung, James D. McKay, Valerie Gaborieau, Paolo Boffetta, Mia Hashibe, David Zaridze, Anush Mukeria, Neonilia Szeszenia-Dabrowska, Jolanta Lissowska, Peter Rudnai, Eleonora Fabianova, Dana Mates, Vladimir Bencko, Lenka Foretova, Vladimir Janout, Chu Chen, Gary Goodman, John K. Field, Triantafillos Liloglou, George XinarianosAdrian Cassidy, John McLaughlin, Geoffrey Liu, Steven Narod, Hans E. Krokan, Frank Skorpen, Maiken Bratt Elvestad, Kristian Hveem, Lars Vatten, Jakob Linseisen, Françoise Clavel-Chapelon, Paolo Vineis, H. Bas Bueno-De-Mesquita, Eiliv Lund, Carmen Martinez, Sheila Bingham, Torgny Rasmuson, Pierre Hainaut, Elio Riboli, Wolfgang Ahrens, Simone Benhamou, Pagona Lagiou, Dimitrios Trichopoulos, Ivana Holcátová, Franco Merletti, Kristina Kjaerheim, Antonio Agudo, Gary MacFarlane, Renato Talamini, Lorenzo Simonato, Ray Lowry, David I. Conway, Ariana Znaor, Claire Healy, Diana Zelenika, Anne Boland, Marc Delepine, Mario Foglio, Doris Lechner, Fumihiko Matsuda, Helene Blanche, Ivo Gut, Simon Heath, Mark Lathrop, Paul Brennan

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Abstract

Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. 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 lines, and they bind to N′-nitrosonornicotine and potential lung carcinogens. 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 targets.

Original languageEnglish
Pages (from-to)633-637
Number of pages5
JournalNature
Volume452
Issue number7187
DOIs
Publication statusPublished - Apr 3 2008

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Hung, R. J., McKay, J. D., Gaborieau, V., Boffetta, P., Hashibe, M., Zaridze, D., Mukeria, A., Szeszenia-Dabrowska, N., Lissowska, J., Rudnai, P., Fabianova, E., Mates, D., Bencko, V., Foretova, L., Janout, V., Chen, C., Goodman, G., Field, J. K., Liloglou, T., ... Brennan, P. (2008). A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature, 452(7187), 633-637. https://doi.org/10.1038/nature06885