A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25 by Hung Rayjean J, McKay James D, Gaborieau Valerie, Boffetta Paolo, Hashibe Mia, Zaridze David, Mukeria Anush, Szeszenia-Dabrowska Neonilia, Lissowska Jolanta, Rudnai Peter, Fabianova Eleonora, Mates Dana, Bencko Vladimir, Foretova Lenka, Janout Vladimir, Chen Chu, Goodman Gary, Field John K, Liloglou Triantafillos, Xinarianos George, Cassidy Adrian, McLaughlin John, Liu Geoffrey, Narod Steven, Krokan Hans E, Skorpen Frank, Elvestad Maiken Bratt, Hveem Kristian, Vatten Lars, Linseisen Jakob, Clavel-Chapelon Françoise, Vineis Paolo, Bueno-de-Mesquita H Bas, Lund Eiliv, Martinez Carmen, Bingham Sheila, Rasmuson Torgny, Hainaut Pierre, Riboli Elio, Ahrens Wolfgang, Benhamou Simone, Lagiou Pagona, Trichopoulos Dimitrios, Holcátová Ivana, Merletti Franco, Kjaerheim Kristina, Agudo Antonio, Macfarlane Gary, Talamini Renato, Simonato Lorenzo, Lowry Ray, Conway David I, Znaor Ariana, Healy Claire, Zelenika Diana, Boland Anne, Delepine Marc, Foglio Mario, Lechner Doris, Matsuda Fumihiko, Blanche Helene, Gut Ivo, Heath Simon, Lathrop Mark, Brennan Paul in Nature (2008). PubMed

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 x 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 x 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.

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