Nature 452, 633-637 (3 April 2008) | doi:10.1038/nature06885; Received 30 November 2007; Accepted 7 March 2008

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

Rayjean J. Hung1,2,44, James D. McKay1,44, Valerie Gaborieau1, Paolo Boffetta1, Mia Hashibe1, David Zaridze3, Anush Mukeria3, Neonilia Szeszenia-Dabrowska4, Jolanta Lissowska5, Peter Rudnai6, Eleonora Fabianova7, Dana Mates8, Vladimir Bencko9, Lenka Foretova10, Vladimir Janout11, Chu Chen12, Gary Goodman12, John K. Field13, Triantafillos Liloglou13, George Xinarianos13, Adrian Cassidy13, John McLaughlin14, Geoffrey Liu15, Steven Narod16, Hans E. Krokan17, Frank Skorpen17, Maiken Bratt Elvestad17, Kristian Hveem17, Lars Vatten17, Jakob Linseisen18, Françoise Clavel-Chapelon19, Paolo Vineis20,21, H. Bas Bueno-de-Mesquita22, Eiliv Lund23, Carmen Martinez24, Sheila Bingham25, Torgny Rasmuson26, Pierre Hainaut1, Elio Riboli20, Wolfgang Ahrens27, Simone Benhamou28,29, Pagona Lagiou30, Dimitrios Trichopoulos30, Ivana Holcátová31, Franco Merletti32, Kristina Kjaerheim33, Antonio Agudo34, Gary Macfarlane35, Renato Talamini36, Lorenzo Simonato37, Ray Lowry38, David I. Conway39, Ariana Znaor40, Claire Healy41, Diana Zelenika42, Anne Boland42, Marc Delepine42, Mario Foglio42, Doris Lechner42, Fumihiko Matsuda42, Helene Blanche43, Ivo Gut42, Simon Heath43, Mark Lathrop42,43 & Paul Brennan1

  1. International Agency for Research on Cancer (IARC), Lyon 69008, France
  2. School of Public Health, University of California at Berkeley, Berkeley, California 94720, USA
  3. Institute of Carcinogenesis, Cancer Research Centre, Moscow 115478, Russia
  4. Department of Epidemiology, Institute of Occupational Medicine, Lodz 90950, Poland
  5. M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw 02781, Poland
  6. National Institute of Environmental Health, Budapest 1097, Hungary
  7. Specialized Institute of Hygiene and Epidemiology, Banska Bystrica 97556, Slovakia
  8. Institute of Public Health, Bucharest 050463, Romania
  9. Charles University in Prague, First Faculty of Medicine, Institute of Hygiene and Epidemiology, Prague 2 12800, Czech Republic
  10. Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno 65653, Czech Republic
  11. Palacky University, Olomouc 77515, Czech Republic
  12. Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
  13. Roy Castle Lung Cancer Research Programme, University of Liverpool Cancer Research Centre, Liverpool L3 9TA, UK
  14. Cancer Care Ontario, and the Samuel Lunenfeld Research Institute, Toronto M5G 2L7, Canada
  15. Princess Margaret Hospital, Ontario Cancer Institute, Toronto M5G 2M9, Canada
  16. Women's College Research Institute, Toronto M5G 1N8, Canada
  17. Norwegian University of Science and Technology, Trondheim 7489, Norway
  18. Division of Cancer Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg 69120, Germany
  19. INSERM ERI20, Institut Gustave Roussy, Villejuif 94805, France
  20. Department of Epidemiology and Public Health, Imperial College, London W2 1PG, UK
  21. Institute for Scientific Interchange (ISI), Torino 10133, Italy
  22. Centre for Nutrition and Health, National Institute of Public Health and the Environment, Bilthoven 3710 BA, The Netherlands
  23. Institute of Community Medicine, University of Tromsö, Tromsö 9037, Norway
  24. Andalusian school of Public Health and Ciber Epidemiology y Salud Publica, Granada 18011, Spain
  25. MRC Centre for Nutrition and Cancer, University of Cambridge, Department of Public Health and Primary Care and MRC Dunn Human Nutrition Unit, Cambridge CB2 0XY, UK
  26. Department of Radiation Sciences, Oncology, Umea University, Umea 90187, Sweden
  27. Epidemiological Methods and Etiologic Research, Bremen Institute for Prevention Research and Social Medicine, Bremen 28359, Germany
  28. INSERM U794, Fondation Jean Dausset-CEPH, Paris 75010, France
  29. CNRS FRE2939, Institute Gustave Roussy, Villejuif 94805, France
  30. Department of Hygiene and Epidemiology, University of Athens School of Medicine, Athens 11527, Greece, and Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA
  31. Institute of Hygiene and Epidemiology, Prague 2 12800, Czech Republic
  32. University of Turin, Turin 10126, Italy
  33. Cancer registry of Norway, Oslo 0310, Norway
  34. Institut Català d'Oncologia, Barcelona 08907, Spain
  35. University of Aberdeen School of Medicine, Aberdeen AB25 2ZD, UK
  36. Aviano cancer center, Aviano 33081, Italy
  37. Department of Environmental Medicine and Public Health, University of Padua, Padua 35131, Italy
  38. University of Newcastle Dental School, Newcastle NE2 4BW, UK
  39. University of Glasgow Dental School, Glasgow G2 3JZ, UK
  40. Croatian National Cancer Registry, National Institute of Public Health, Zagreb 10000, Croatia
  41. Trinity College School of Dental Science, Dublin 2, Ireland
  42. Centre National de Genotypage, Institut Genomique, Commissariat à l'énergie Atomique, Evry 91000, France
  43. Fondation Jean Dausset-CEPH, Paris 75010, France
  44. These authors contributed equally to this work.

Correspondence to: Paul Brennan1 Correspondence and requests for materials should be addressed to P.B. (Email: brennan@iarc.fr).

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 times 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 times 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 lines2, 3, and they bind to N'-nitrosonornicotine and potential lung carcinogens4. 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 targets5.


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