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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 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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References

  1. 1.

    , , & GLOBOCAN 2002. IARC CancerBase No 5, version 2.0 (IARC, Lyon, 2004)

  2. 2.

    Nicotine exposure and bronchial epithelial cell nicotinic acetylcholine receptor expression in the pathogenesis of lung cancer. J. Clin. Invest. 111, 31–33 (2003)

  3. 3.

    et al. Human bronchial epithelial and endothelial cells express α7 nicotinic acetylcholine receptors. Mol. Pharmacol. 60, 1201–1209 (2001)

  4. 4.

    Nitrosamines as nicotinic receptor ligands. Life Sci. 80, 2274–2280 (2007)

  5. 5.

    , , & Development of novel therapeutic strategies for lung cancer: targeting the cholinergic system. Curr. Med. Chem. 13, 3493–3512 (2006)

  6. 6.

    International Agency for Research on Cancer. Reversal of risk after quitting smoking. IARC Handbooks of Cancer Prevention Vol. 11 15–27 (IARC, Lyon, 2007)

  7. 7.

    International Agency for Research on Cancer. Tobacco smoke and involuntary smoking. IARC Monographs Vol. 83 33–47 (IARC, Lyon, 2004)

  8. 8.

    et al. EUROCARE Working Group. EUROCARE-3 summary: cancer survival in Europe at the end of the 20th century. Ann. Oncol. 14 (suppl. 5). v128–v149 (2003)

  9. 9.

    , & Systematic review of the relationship between family history and lung cancer risk. Br. J. Cancer 93, 825–833 (2005)

  10. 10.

    & Evaluating coverage of genome-wide association studies. Nature Genet. 38, 659–662 (2006)

  11. 11.

    et al. Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum. Mol. Genet. 16, 36–49 (2007)

  12. 12.

    International HapMap Consortium. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007)

  13. 13.

    et al. α-5/α-3 nicotinic receptor subunit alleles increase risk for heavy smoking. Mol. Psychiatry advance online publication 10.1038/sj.mp.4002154 (29 January 2008)

  14. 14.

    , , , & Variability in response to nicotine in the LSxSS RI strains: potential role of polymorphisms in α4 and α6 nicotinic receptor genes. Pharmacogenetics 12, 197–208 (2002)

  15. 15.

    & Measuring nicotine dependence: a review of the Fagerstrom Tolerance Questionnaire. J. Behav. Med. 12, 159–182 (1989)

  16. 16.

    , , & A Fagerstrom test for nicotine dependence: a revision of the Fagerstrom tolerance questionnaire. Br. J. Addict. 86, 1119–1127 (1991)

  17. 17.

    et al. Comparison of the Heavy Smoking Index and of the Fagerstrom test for nicotine dependence in a sample of 749 cigarette smokers. Addict. Behav. 30, 1474–1477 (2005)

  18. 18.

    et al. Expression of nicotinic acetylcholine receptor subunit genes in non-small-cell lung cancer reveals differences between smokers and nonsmokers. Cancer Res. 67, 4638–4647 (2007)

  19. 19.

    et al. Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells. J. Clin. Invest. 111, 81–90 (2003)

  20. 20.

    & Nicotine-mediated cell proliferation and angiogenesis: new twists to an old story. Cell Cycle 5, 2324–2328 (2006)

  21. 21.

    et al. A high resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nature Genet. 38, 1166–1172 (2006)

  22. 22.

    , & Inference of population structure using multilocus genotype data: linked loci and correlated allele frequencies. Genetics 164, 1567–1587 (2003)

  23. 23.

    et al. Principal components analysis corrects for stratification in genome-wide association studies. Nature Genet. 38, 904–909 (2006)

Download references

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

    • Rayjean J. Hung
    •  & James D. McKay

    These authors contributed equally to this work.

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. 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

    • 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, University of Athens School of Medicine, Athens 11527, Greece, and Department of Epidemiology, 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

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Correspondence to Paul Brennan.

Supplementary information

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    Supplementary Information

    The file contains Supplementary Methods, Supplementary Discussion with additional references, Supplementary Figures 1-6 with Legends and Supplementary Tables 1-5.

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DOI

https://doi.org/10.1038/nature06885

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