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

Naturevolume 452, pages633–637 (2008)Cite this article

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 andCHRNB4). 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 toN′-nitrosonornicotine and potential lung carcinogens4. A non-synonymous variant ofCHRNA5 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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Figure 1:Genome-wide association results in the central Europe study.
Figure 2:Lung cancer area of interest across 15q25.

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Acknowledgements

The authors thank all of the participants who took part in this research and the funders and support staff who made this study possible. We also thank R. Peto for his comments on the manuscript. Funding for the initial genome-wide study was provided by INCa, France. Additional funding for replication studies was provided by the US NCI (R01 CA092039) and the Ontario Institute for Cancer Research (OICR).

Author Contributions P.B. and M.L. designed the study. R.J.H., J.D.M., A.B. and H.B. coordinated the preparation and inclusion of all biological samples. R.J.H., J.D.M., V.G. and S.H. undertook the statistical analysis. Bioinformatics analysis was undertaken by F.M., M.F. and S.H., D.Z. and M.D. coordinated the genotyping of the central Europe samples, and J.D.M, R.J.H. and V.G. coordinated the genotyping of the other studies. All other co-authors coordinated the initial recruitment and management of the studies. M.L. obtained financial support for genotyping of the central Europe study, and P.B. and R.J.H. obtained financial support for genotyping of the other studies. P.B. and M.L. drafted the manuscript with substantial contributions from R.J.H. and J.D.M. All authors contributed to the final paper.

Author information

Author notes

  1. Rayjean J. Hung and James D. McKay: These authors contributed equally to this work.

Authors and Affiliations

  1. International Agency for Research on Cancer (IARC), Lyon 69008, France

    Rayjean J. Hung, James D. McKay, Valerie Gaborieau, Paolo Boffetta, Mia Hashibe, Pierre Hainaut & Paul Brennan

  2. School of Public Health, University of California at Berkeley, Berkeley, California 94720, USA ,

    Rayjean J. Hung

  3. Institute of Carcinogenesis, Cancer Research Centre, Moscow 115478, Russia ,

    David Zaridze & Anush Mukeria

  4. Department of Epidemiology, Institute of Occupational Medicine, Lodz 90950, Poland

    Neonilia Szeszenia-Dabrowska

  5. M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw 02781, Poland

    Jolanta Lissowska

  6. National Institute of Environmental Health, Budapest 1097, Hungary

    Peter Rudnai

  7. Specialized Institute of Hygiene and Epidemiology, Banska Bystrica 97556, Slovakia

    Eleonora Fabianova

  8. Institute of Public Health, Bucharest 050463, Romania

    Dana Mates

  9. Charles University in Prague, First Faculty of Medicine, Institute of Hygiene and Epidemiology, Prague 2 12800, Czech Republic

    Vladimir Bencko

  10. Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno 65653, Czech Republic

    Lenka Foretova

  11. Palacky University, Olomouc 77515, Czech Republic

    Vladimir Janout

  12. Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA ,

    Chu Chen & Gary Goodman

  13. Roy Castle Lung Cancer Research Programme, University of Liverpool Cancer Research Centre, Liverpool L3 9TA, UK

    John K. Field, Triantafillos Liloglou, George Xinarianos & Adrian Cassidy

  14. Cancer Care Ontario, and the Samuel Lunenfeld Research Institute, Toronto M5G 2L7, Canada

    John McLaughlin

  15. Princess Margaret Hospital, Ontario Cancer Institute, Toronto M5G 2M9, Canada

    Geoffrey Liu

  16. Women’s College Research Institute, Toronto M5G 1N8, Canada

    Steven Narod

  17. Norwegian University of Science and Technology, Trondheim 7489, Norway

    Hans E. Krokan, Frank Skorpen, Maiken Bratt Elvestad, Kristian Hveem & Lars Vatten

  18. Division of Cancer Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg 69120, Germany,

    Jakob Linseisen

  19. INSERM ERI20, Institut Gustave Roussy, Villejuif 94805, France

    Françoise Clavel-Chapelon

  20. Department of Epidemiology and Public Health, Imperial College, London W2 1PG, UK

    Paolo Vineis & Elio Riboli

  21. Institute for Scientific Interchange (ISI), Torino 10133, Italy

    Paolo Vineis

  22. Centre for Nutrition and Health, National Institute of Public Health and the Environment, Bilthoven 3710 BA, The Netherlands

    H. Bas Bueno-de-Mesquita

  23. Institute of Community Medicine, University of Tromsö, Tromsö 9037, Norway

    Eiliv Lund

  24. Andalusian school of Public Health and Ciber Epidemiology y Salud Publica, Granada 18011, Spain

    Carmen Martinez

  25. Department of Public Health and Primary Care and MRC Dunn Human Nutrition Unit, MRC Centre for Nutrition and Cancer, University of Cambridge, Cambridge CB2 0XY, UK

    Sheila Bingham

  26. Department of Radiation Sciences, Oncology, Umea University, Umea 90187, Sweden

    Torgny Rasmuson

  27. Epidemiological Methods and Etiologic Research, Bremen Institute for Prevention Research and Social Medicine, Bremen 28359, Germany

    Wolfgang Ahrens

  28. INSERM U794, Fondation Jean Dausset-CEPH, Paris 75010, France ,

    Simone Benhamou

  29. CNRS FRE2939, Institute Gustave Roussy, Villejuif 94805, France

    Simone Benhamou

  30. Department of Hygiene and Epidemiology, and Department of Epidemiology, University of Athens School of Medicine, Athens 11527, Greece, Harvard School of Public Health, Boston, Massachusetts 02115, USA,

    Pagona Lagiou & Dimitrios Trichopoulos

  31. Institute of Hygiene and Epidemiology, Prague 2 12800, Czech Republic

    Ivana Holcátová

  32. University of Turin, Turin 10126, Italy

    Franco Merletti

  33. Cancer registry of Norway, Oslo 0310, Norway

    Kristina Kjaerheim

  34. Institut Català d’Oncologia, Barcelona 08907, Spain

    Antonio Agudo

  35. University of Aberdeen School of Medicine, Aberdeen AB25 2ZD, UK

    Gary Macfarlane

  36. Aviano cancer center, Aviano 33081, Italy

    Renato Talamini

  37. Department of Environmental Medicine and Public Health, University of Padua, Padua 35131, Italy

    Lorenzo Simonato

  38. University of Newcastle Dental School, Newcastle NE2 4BW, UK

    Ray Lowry

  39. University of Glasgow Dental School, Glasgow G2 3JZ, UK

    David I. Conway

  40. Croatian National Cancer Registry, National Institute of Public Health, Zagreb 10000, Croatia

    Ariana Znaor

  41. Trinity College School of Dental Science, Dublin 2, Ireland

    Claire Healy

  42. Centre National de Genotypage, Institut Genomique, Commissariat à l’énergie Atomique, Evry 91000, France ,

    Diana Zelenika, Anne Boland, Marc Delepine, Mario Foglio, Doris Lechner, Fumihiko Matsuda, Ivo Gut & Mark Lathrop

  43. Fondation Jean Dausset-CEPH, Paris 75010, France

    Helene Blanche, Simon Heath & Mark Lathrop

Authors
  1. Rayjean J. Hung

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  2. James D. McKay

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  3. Valerie Gaborieau

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  4. Paolo Boffetta

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  5. Mia Hashibe

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  6. David Zaridze

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  7. Anush Mukeria

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  8. Neonilia Szeszenia-Dabrowska

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  9. Jolanta Lissowska

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  10. Peter Rudnai

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  11. Eleonora Fabianova

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  12. Dana Mates

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  13. Vladimir Bencko

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  14. Lenka Foretova

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  15. Vladimir Janout

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  16. Chu Chen

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  17. Gary Goodman

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  18. John K. Field

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  19. Triantafillos Liloglou

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  20. George Xinarianos

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  21. Adrian Cassidy

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  22. John McLaughlin

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  23. Geoffrey Liu

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  25. Hans E. Krokan

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  26. Frank Skorpen

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  27. Maiken Bratt Elvestad

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  28. Kristian Hveem

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  30. Jakob Linseisen

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  31. Françoise Clavel-Chapelon

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  32. Paolo Vineis

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  33. H. Bas Bueno-de-Mesquita

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  34. Eiliv Lund

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  35. Carmen Martinez

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  42. Pagona Lagiou

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  65. Paul Brennan

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Corresponding author

Correspondence toPaul Brennan.

Supplementary information

Supplementary Information

The file contains Supplementary Methods, Supplementary Discussion with additional references, Supplementary Figures 1-6 with Legends and Supplementary Tables 1-5. (PDF 2062 kb)

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Hung, R., McKay, J., Gaborieau, V.et al. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25.Nature452, 633–637 (2008). https://doi.org/10.1038/nature06885

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Editorial Summary

Where there's smoke...

With the advent of large genomic data sets, geneticists can examine at a new level the influence of genes on behaviour. Two groups have conducted genome-wide association studies involving lung cancer, and both find that sequences in the nicotinic acetylcholine receptor subunit gene cluster contribute susceptibility, although the groups took different paths to this result. Hunget al. suggest that this susceptibility is not related to smoking status or frequency, and show association with a specific amino acid change. Thorgeirssonet al. find that alleles present in a cluster of nicotinic acid receptor genes do not influence whether or not a person smokes, but do affect the number of cigarettes smoked per day, and are therefore also associated with risk of lung cancer and peripheral arterial disease. Either way, the possible potential of nicotinic acetylcholine receptors as drug targets is underlined.

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