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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
1 School of Public Health
2 CIRC - IARC - Centre International de Recherche contre le Cancer - International Agency for Research on Cancer
3 Institute of Carcinogenesis
4 Institute of Carcinogenesis
5 Department of Epidemiology
6 The M Sklodowska-Curie Cancer Center
7 National Institute of Environment Health
8 Specialized Institute of Hygiene and Epidemiology
9 Institute of Public Health
10 Institute of Hygiene and Epidemiology
11 Masaryk Memorial Cancer Institute
12 Department of Preventive Medicine [Univ Palacký]
13 FHCRC - Fred Hutchinson Cancer Research Center [Seattle]
14 Roy Castle Lung Cancer Research Programme
15 Roy Castle Lung Cancer Research Programme
16 Cancer Care Ontario
17 Princess Margaret Hospital
18 Women's College Research Institute
19 NTNU - Norwegian University of Science and Technology [Trondheim]
20 Division of Cancer Epidemiology
21 E3N - Nutrition, hormones et cancer: épidémiologie et prévention
22 Department of Epidemiology and Public Health
23 Centre for Nutrition and Health (CVG)
24 Institute of Community Medicine
25 Andalusian School of Public Health [Granada]
26 MRC Centrer for Nutritional Epidemiology and Cancer Prevention and Survival
27 Department of Radiation Sciences, Oncology
28 Bremen Institute for Prevention Research and Social Medicine
29 INSERM U794
30 GC (FRE2939) - Génomes et cancer
31 Department of Hygiene, Epidemiology and Medical Statistics
32 Department of Epidemiology
33 Cancer Epidemiology Unit
34 Cancer registry of Norway
35 Institut Català d'Oncologia
36 University of Aberdeen
37 Aviano cancer center
38 Department of Environmental Medicine and Public Health
39 University of Newcastle Dental School
40 University of Glasgow Dental School
41 Croatian National Cancer Registry
42 Trinity College School of Dental Science
43 CNG - Centre National de Génotypage
44 CEPH - Centre d'Etude du Polymorphisme Humain
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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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, Nature Publishing Group, 2008, 452 (7187), pp.633-637. ⟨10.1038/nature06885⟩. ⟨cea-00944415⟩

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