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Nat Genet. 2014 Jul;46(7):736-41. doi: 10.1038/ng.3002. Epub 2014 Jun 1.

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

Author information

  • 11] Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, UK. [2].
  • 21] International Agency for Research on Cancer (IARC, World Health Organization (WHO)), Lyon, France. [2] [3].
  • 3deCODE Genetics, Amgen, Reykjavik, Iceland.
  • 4Department of Health and Human Services, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.
  • 5International Agency for Research on Cancer (IARC, World Health Organization (WHO)), Lyon, France.
  • 6Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, UK.
  • 7Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
  • 8Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 9Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA.
  • 10Center for Genomic Medicine, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire, USA.
  • 11Information Management Services, Inc., Rockville, Maryland, USA.
  • 12Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.
  • 131] Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany. [2] Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
  • 14Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA.
  • 15Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • 16Institute of Carcinogenesis, Russian N.N. Blokhin Cancer Research Centre, Moscow, Russia.
  • 17Department of Epidemiology, Institute of Occupational Medicine, Lodz, Poland.
  • 18The M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
  • 19National Institute of Environmental Health, Budapest, Hungary.
  • 20Regional Authority of Public Health, Banská Bystrica, Slovak Republic.
  • 21National Institute of Public Health, Bucharest, Romania.
  • 221st Faculty of Medicine, Institute of Hygiene and Epidemiology, Charles University in Prague, Prague, Czech Republic.
  • 23Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
  • 24Palacky University, Olomouc, Czech Republic.
  • 25Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway.
  • 26Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
  • 27Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
  • 28Department of Community Medicine, University of Tromsø, Tromsø, Norway.
  • 29Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
  • 30INSERM U946, Paris, France.
  • 31Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
  • 32Department of Biomedicine, University of Bergen, Bergen, Norway.
  • 331] Estonian Genome Center, Institute of Molecular and Cell Biology, Tartu, Estonia. [2] Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
  • 34Estonian Genome Center, Institute of Molecular and Cell Biology, Tartu, Estonia.
  • 35Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
  • 361] Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, UK. [2] Unit of Molecular and Genetic Epidemiology, HuGeF Foundation, Torino, Italy.
  • 37Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology, Barcelona, Spain.
  • 381] INSERM, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health Team, Villejuif, France. [2] Université Paris Sud, UMRS 1018, Villejuif, France. [3] Institut Gustave Roussy, Villejuif, France.
  • 391] Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, UK. [2] National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. [3] Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands.
  • 401] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece. [3] Hellenic Health Foundation, Athens, Greece.
  • 41University of Cambridge School of Clinical Medicine, Clinical Gerontology Unit, Addenbrooke's Hospital, Cambridge, UK.
  • 42Department of Radiation Sciences, Umeå Universitet, Umeå, Sverige, Sweden.
  • 431] Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway. [2] Department of Research, Cancer Registry of Norway, Oslo, Norway. [3] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. [4] Samfundet Folkhälsan, Helsinki, Finland.
  • 44Danish Cancer Society Research Center, Copenhagen, Denmark.
  • 45Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, UK.
  • 46Centre d'Etude du Polymorphisme Humain (CEPH), Paris, France.
  • 47Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • 48Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
  • 491] Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany. [2] Department of Thoracic Surgery, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany.
  • 50Department of Genetic Epidemiology, University of Göttingen, Göttingen, Germany.
  • 51Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.
  • 521] Department of Oncology, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK. [2] Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, UK.
  • 531] Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany. [2] Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
  • 541] Department of Health and Human Services, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA. [2] [3].
  • 551] Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, UK. [2] [3].
  • 561] Center for Genomic Medicine, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire, USA. [2] [3].

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.

PMID:
24880342
PMCID:
PMC4074058
DOI:
10.1038/ng.3002
[PubMed - indexed for MEDLINE]
Free PMC Article

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