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

Rayjean J. Hung 1, 2 James D. Mckay 2 Valerie Gaborieau 2 Paolo Boffetta 2 Mia Hashibe 2 David Zaridze 3 Anush Mukeria 4 Neonilia Szeszenia-Dabrowska 5 Jolanta Lissowska 6 Peter Rudnai 7 Eleonora Fabianova 8 Dana Mates 9 Vladimir Bencko 10 Lenka Foretova 11 Vladimir Janout 12 Chu Chen 13 Gary Goodman 13 John K. Field 14 Triantafillos Liloglou 14 George Xinarianos 14 Adrian Cassidy 15 John Mclaughlin 16 Geoffrey Liu 17 Steven Narod 18 Hans E. Krokan 19 Frank Skorpen 19 Maiken Bratt Elvestad 19 Kristian Hveem 19 Lars Vatten 19 Jakob Linseisen 20 Françoise Clavel-Chapelon 21 Paolo Vineis 22 H. Bas Bueno-De-Mesquita 23 Eiliv Lund 24 Carmen Martinez 25 Sheila Bingham 26 Torgny Rasmuson 27 Pierre Hainaut 2 Elio Riboli 22 Wolfgang Ahrens 28 Simone Benhamou 29, 30 Pagona Lagiou 31, 32 Dimitrios Trichopoulos 31, 32 Ivana Holcátová 10 Franco Merletti 33 Kristina Kjaerheim 34 Antonio Agudo 35 Gary Macfarlane 36 Renato Talamini 37 Lorenzo Simonato 38 Ray Lowry 39 David I. Conway 40 Ariana Znaor 41 Claire Healy 42 Diana Zelenika 43 Anne Boland 43 Marc Délépine 43 Mario Foglio 43 Doris Lechner 43 Fumihiko Matsuda 43 Helene Blanche 44 Ivo Gut 43 Simon Heath 44 Mark Lathrop 43, 44 Paul Brennan 2, * 
* Corresponding author
Abstract : 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 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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Submitted on : Monday, February 1, 2021 - 3:01:25 PM
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Rayjean J. Hung, James D. Mckay, Valerie Gaborieau, Paolo Boffetta, Mia Hashibe, et al.. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature, 2008, 452 (7187), pp.633-637. ⟨10.1038/nature06885⟩. ⟨cea-00944415⟩



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