Letter | Published:

Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer

Nature Genetics volume 46, pages 736741 (2014) | Download Citation

  • A Corrigendum to this article was published on 01 April 2017

This article has been updated

Abstract

We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants BRCA2 p.Lys3326X (rs11571833, odds ratio (OR) = 2.47, P = 4.74 × 10−20) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 × 10−13). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 × 10−10) and lung adenocarcinoma that had been previously reported only in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants with substantive effects on cancer risk from preexisting genome-wide association study data.

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Change history

  • 23 January 2017

    In the version of this article initially published, the name of author Florence Le Calvez-Kelm appeared incorrectly as Florence LeCalvez-Kelm. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank all individuals who participated in this study. We are also grateful to the patients, clinicians and allied health care professions. We thank Z. Chen and K. Boyle for sample handling and data management of the Toronto study, and L. Admas and L.R. Zhang for field recruitment. We thank L. Su, Y. Zhao, G. Liu, J. Wain, R. Heist and K. Asomaning for providing computing support at MDACC. We thank G. Thomas and Synergy Lyon Cancer (Lyon France) for high performance computing support and J. Olivier and A. Chabrier for IARC's PGM ion torrent sequencing optimization and TaqMan genotyping, respectively. We thank D. Goldgar for sharing information from The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) on sequence variation in BRCA2 from familial breast cancer analysis. We acknowledge the Icelandic Cancer Registry (http://www.krabbameinsskra.is/indexen.jsp?id=summary) for assistance in the ascertainment of the Icelandic patients with lung cancer. The ICR study made use of genotyping data from the Wellcome Trust Case-Control Consortium 2 (WTCCC2); a full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk. We acknowledge The Cancer Genome Atlas (TCGA) for their contribution of lung cancer genomic data to this study (TCGA Project Number 3230). We also acknowledge support from the National Institute for Health Research Biomedical Research Centre at the Royal Marsden Hospital. This study was supported by the NIH (U19CA148127, R01CA055769, 5R01CA127219, 5R01CA133996 and 5R01CA121197). The work performed at ICR was supported by Cancer Research UK (C1298/A8780 and C1298/A8362), National Cancer Research Network (NCRN), HEAL, Sanofi-Aventis and National Health Service funding to the Royal Marsden Hospital and Institute of Cancer Research, as well as the National Institute for Health Research Biomedical Research Centre. B.K. was the recipient of a Sir John Fisher Foundation PhD studentship. Work at ICR was also supported by NIH GM103534 and the Institute for Quantitative Biomedical Sciences at Dartmouth to C.I.A. The work performed in Toronto was supported by The Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.J.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. The work performed at Heidelberg was supported by Deutsche Krebshilfe (70-2387 and 70-2919) and the German Federal Ministry of Education and Research (EPIC-Heidelberg). The work performed at IARC was supported by the Institut National du Cancer, France, the European Community (LSHG-CT-2005-512113), the Norwegian Cancer Association, the Functional Genomics Programme of Research Council of Norway, the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101), the NIH (R01-CA111703 and UO1-CA63673), the Fred Hutchinson Cancer Research Center, the US NCI (R01 CA092039), an FP7 grant (REGPOT 245536), the Estonian Government (SF0180142s08), the EU European Regional Development Fund in the frame of Centre of Excellence in Genomics and Estonian Research Infrastructure's Roadmap and the University of Tartu (SP1GVARENG) and an IARC Postdoctoral Fellowship (M.N.T.). Work at the NCI was supported by the Intramural Research Program of the NIH, the NCI, US Public Health Service contracts NCI (N01-CN-45165, N01-RC-45035, N01-RC-37004, NO1-CN-25514, NO1-CN-25515, NO1-CN-25512, NO1-CN-25513, NO1-CN-25516, NO1-CN-25511, NO1-CN-25524, NO1-CN-25518, NO1-CN-75022, NO1-CN-25476 and NO1-CN-25404), the American Cancer Society, the NIH Genes, Environment and Health Initiative in part by HG-06-033-NCI-01 and RO1HL091172-01, genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C) and study coordination at the GENEVA Coordination Center (U01 HG004446). Work was also supported by NIH grants (P50 CA70907, R01CA121197, RO1 CA127219, U19 CA148127 and RO1 CA55769) and a Cancer Prevention Research Institute of Texas grant (RP100443). Genotyping was provided by the Center for Inherited Disease Research (CIDR). Work performed at Harvard was supported by the NIH (CA074386, CA092824 and CA090578). The Icelandic study was supported in part by NIH DA17932.

Author information

Author notes

    • Yufei Wang
    • , James D McKay
    • , Maria Teresa Landi
    • , Richard S Houlston
    •  & Christopher I Amos

    These authors contributed equally to this work.

    • James D McKay
    • , Maria Teresa Landi
    • , Richard S Houlston
    •  & Christopher I Amos

    These authors jointly directed this work.

Affiliations

  1. Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, UK.

    • Yufei Wang
    • , Peter Broderick
    • , Amy Lloyd
    • , Daniel Chubb
    • , Marc Henrion
    • , Ben Kinnersley
    •  & Richard S Houlston
  2. International Agency for Research on Cancer (IARC, World Health Organization (WHO)), Lyon, France.

    • James D McKay
    • , Maria N Timofeeva
    • , Manon Delahaye-Sourdeix
    • , Valerie Gaborieau
    • , Maxime Vallée
    • , Florence Le Calvez-Kelm
    • , Mattias Johansson
    • , Ghislaine Scelo
    •  & Paul Brennan
  3. deCODE Genetics, Amgen, Reykjavik, Iceland.

    • Thorunn Rafnar
    • , Gudmar Thorleifsson
    • , Patrick Sulem
    •  & Kari Stefansson
  4. Department of Health and Human Services, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.

    • Zhaoming Wang
    • , Nilanjan Chatterjee
    • , Demetrius Albanes
    • , Neil E Caporaso
    • , Stephen J Chanock
    •  & Maria Teresa Landi
  5. Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.

    • Xuchen Zong
    •  & Rayjean J Hung
  6. Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Marina Laplana
    •  & Angela Risch
  7. Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Yongyue Wei
    • , Li Su
    •  & David C Christiani
  8. Center for Genomic Medicine, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire, USA.

    • Younghun Han
    •  & Christopher I Amos
  9. Information Management Services, Inc., Rockville, Maryland, USA.

    • William Wheeler
  10. Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.

    • Geoffrey Liu
  11. Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany.

    • Rudolf Kaaks
  12. Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.

    • Rudolf Kaaks
    • , Hendrik Dienemann
    •  & Angela Risch
  13. Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA.

    • Victoria L Stevens
    •  & Susan M Gapstur
  14. Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Wei V Chen
  15. Institute of Carcinogenesis, Russian N.N. Blokhin Cancer Research Centre, Moscow, Russia.

    • David Zaridze
  16. Department of Epidemiology, Institute of Occupational Medicine, Lodz, Poland.

    • Neonilia Szeszenia-Dabrowska
  17. The M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.

    • Jolanta Lissowska
  18. National Institute of Environmental Health, Budapest, Hungary.

    • Peter Rudnai
  19. Regional Authority of Public Health, Banská Bystrica, Slovak Republic.

    • Eleonora Fabianova
  20. National Institute of Public Health, Bucharest, Romania.

    • Dana Mates
  21. 1st Faculty of Medicine, Institute of Hygiene and Epidemiology, Charles University in Prague, Prague, Czech Republic.

    • Vladimir Bencko
  22. Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.

    • Lenka Foretova
  23. Palacky University, Olomouc, Czech Republic.

    • Vladimir Janout
  24. Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway.

    • Hans E Krokan
    •  & Maiken Elvestad Gabrielsen
  25. Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.

    • Frank Skorpen
  26. Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.

    • Lars Vatten
  27. Department of Community Medicine, University of Tromsø, Tromsø, Norway.

    • Inger Njølstad
  28. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • Chu Chen
    •  & Gary Goodman
  29. INSERM U946, Paris, France.

    • Simone Benhamou
  30. Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.

    • Tonu Vooder
  31. Department of Biomedicine, University of Bergen, Bergen, Norway.

    • Kristjan Välk
  32. Estonian Genome Center, Institute of Molecular and Cell Biology, Tartu, Estonia.

    • Mari Nelis
    •  & Andres Metspalu
  33. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.

    • Mari Nelis
  34. Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.

    • Marcin Lener
    •  & Jan Lubiński
  35. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, UK.

    • Paolo Vineis
    • , H Bas Bueno-de-Mesquita
    •  & Elio Riboli
  36. Unit of Molecular and Genetic Epidemiology, HuGeF Foundation, Torino, Italy.

    • Paolo Vineis
  37. Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology, Barcelona, Spain.

    • Antonio Agudo
  38. INSERM, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health Team, Villejuif, France.

    • Francoise Clavel-Chapelon
  39. Université Paris Sud, UMRS 1018, Villejuif, France.

    • Francoise Clavel-Chapelon
  40. Institut Gustave Roussy, Villejuif, France.

    • Francoise Clavel-Chapelon
  41. National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.

    • H Bas Bueno-de-Mesquita
  42. Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands.

    • H Bas Bueno-de-Mesquita
  43. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Dimitrios Trichopoulos
  44. Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece.

    • Dimitrios Trichopoulos
  45. Hellenic Health Foundation, Athens, Greece.

    • Dimitrios Trichopoulos
  46. University of Cambridge School of Clinical Medicine, Clinical Gerontology Unit, Addenbrooke's Hospital, Cambridge, UK.

    • Kay-Tee Khaw
  47. Department of Radiation Sciences, Umeå Universitet, Umeå, Sverige, Sweden.

    • Mikael Johansson
  48. Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway.

    • Elisabete Weiderpass
  49. Department of Research, Cancer Registry of Norway, Oslo, Norway.

    • Elisabete Weiderpass
  50. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Elisabete Weiderpass
  51. Samfundet Folkhälsan, Helsinki, Finland.

    • Elisabete Weiderpass
  52. Danish Cancer Society Research Center, Copenhagen, Denmark.

    • Anne Tjønneland
  53. Centre d'Etude du Polymorphisme Humain (CEPH), Paris, France.

    • Mark Lathrop
  54. Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Yuanqing Ye
    • , Jian Gu
    •  & Xifeng Wu
  55. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.

    • Margaret R Spitz
  56. Department of Thoracic Surgery, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany.

    • Hendrik Dienemann
  57. Department of Genetic Epidemiology, University of Göttingen, Göttingen, Germany.

    • Albert Rosenberger
  58. Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.

    • Athena Matakidou
  59. Department of Oncology, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK.

    • Timothy Eisen
  60. Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, UK.

    • Timothy Eisen

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Contributions

R.S.H. and Y. Wang conceived the study and provided overall project management and drafted the paper. In the UK, Y. Wang performed statistics and bioinformatics of UK data and conducted all meta-analyses; additional support was provided by M.H.; P. Broderick oversaw genotyping and sequencing; A.L. and B.K. performed genotyping and Sanger sequencing; A. Matakidou, T.E. and R.S.H. were responsible for the development and operation of the Genetic Lung Cancer Predisposition Study (GELCAPS); and D.C. and P. Broderick performed next-generation sequencing. At IARC, J.D.M. and P. Brennan provided overall project management; M.N.T., M.D.-S., V.G. and M.V. performed statistics and bioinformatics of IARC data and conducted meta-analysis; J.D.M. and F.L.C.-K. oversaw genotyping and sequencing; and G.S., D.Z., N.S.-D., J. Lissowska, P.R., E.F., D.M., V.B., L.F., V.J., H.E.K., M.E.G., F.S., L.V., I.N., C.C., G.G., M. Lathrop, S.B., T.V., K.V., M.N., A. Metspalu, M. Lathrop, J. Lubiński, Mattias Johansson, P.V., A.A., F.C.-C., H.B.-d.-M., D.T., K.-T.K., Mikael Johansson, E.W., A.T., R.K. and E.R. provided samples and data. For the Dartmouth and MDACC component, C.I.A. provided overall project management, obtained support for genotyping and contributed to statistical analyses; W.V.C. performed imputation analysis; Y.H. performed statistical analyses; and M.R.S. oversaw sample collection and development of the epidemiological studies. M.R.S. was also responsible for collecting samples that are a part of this research. X.W. provided ongoing support for the research protocol and supported large laboratory management of samples. Y.Y. and J.G. performed genotyping. At the NCI, M.T.L. was responsible for the overall project and managed the Environment and Genetics in Lung Cancer Etiology (EAGLE) study; N.E.C. managed the Prostate, Lung, Colon, Ovary Screening Trial (PLCO) study; D.A. managed the α-Tocopherol, β-Carotene Cancer Prevention Study (ATBC); S.M.G. and V.L.S. managed the Cancer Prevention Study II Nutrition Cohort (CPS-II) study; N.C. and W.W. performed statistical analyses; Z.W. performed genotyping and imputation analysis; and S.J.C. oversaw genotyping and imputation analysis. At decode, T.R. and K.S. were responsible for the development and operation of deCODE's lung cancer study; and G.T. and P.S. performed the imputations and statistical analysis of the Icelandic data. At Harvard, D.C.C. was responsible for the overall conduct of the project; L.S. was responsible for sample management, genotyping and laboratory quality control; and Y. Wei performed data management and statistical analyses. For the Heidelberg-EPIC replication, M. Laplana managed DNA samples and performed genotyping; A. Rosenberger managed genotype and phenotype information; A. Risch supervised genotyping and data analysis; and R.K., A. Risch and H.D. conceived and managed studies that contributed samples. For the Toronto replication, R.J.H. and G.L. provided overall supervision of the study conduct, including study design, field recruitment, genotyping and statistical analysis; and X.Z. performed the statistical analysis.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Maria Teresa Landi or Richard S Houlston.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figure 1 and Supplementary Tables 1, 3-7

Excel files

  1. 1.

    Supplementary Table 2

    (a) Details of study participants; (b) quality control of GWAS datasets; (c) details of imputation applied to each GWAS dataset.

About this article

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DOI

https://doi.org/10.1038/ng.3002

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