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Author (up) 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.; Xinarianos, G.; Cassidy, A.; McLaughlin, J.; Liu, G.; Narod, S.; Krokan, H.E.; Skorpen, F.; Elvestad, M.B.; Hveem, K.; Vatten, L.; Linseisen, J.; Clavel-Chapelon, F.; Vineis, P.; Bueno-de-Mesquita, H.B.; Lund, E.; Martinez, C.; Bingham, S.; Rasmuson, T.; Hainaut, P.; Riboli, E.; Ahrens, W.; Benhamou, S.; Lagiou, P.; Trichopoulos, D.; Holcatova, I.; Merletti, F.; Kjaerheim, K.; Agudo, A.; Macfarlane, G.; Talamini, R.; Simonato, L.; Lowry, R.; Conway, D.I.; Znaor, A.; Healy, C.; Zelenika, D.; Boland, A.; Delepine, M.; Foglio, M.; Lechner, D.; Matsuda, F.; Blanche, H.; Gut, I.; Heath, S.; Lathrop, M.; Brennan, P. url  doi
  Title A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25 Type Journal Article
  Year 2008 Publication Nature Abbreviated Journal Nature  
  Volume 452 Issue 7187 Pages 633-637  
  Keywords HUNT2; Chromosomes, Human, Pair 15/*genetics; Europe; Genetic Predisposition to Disease/*genetics; Genotype; Humans; Lung Neoplasms/*genetics; Odds Ratio; Polymorphism, Single Nucleotide/genetics; Protein Subunits/*genetics; Receptors, Nicotinic/*genetics  
  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.  
  Address International Agency for Research on Cancer (IARC), Lyon 69008, France  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0028-0836 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:18385738 Approved no  
  Call Number HUNT @ maria.stuifbergen @ Serial 1678  
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