Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls

Human Molecular Genetics, Nov 2012

Recent genome-wide association studies (GWASs) have identified common genetic variants at 5p15.33, 6p21–6p22 and 15q25.1 associated with lung cancer risk. Several other genetic regions including variants of CHEK2 (22q12), TP53BP1 (15q15) and RAD52 (12p13) have been demonstrated to influence lung cancer risk in candidate- or pathway-based analyses. To identify novel risk variants for lung cancer, we performed a meta-analysis of 16 GWASs, totaling 14 900 cases and 29 485 controls of European descent. Our data provided increased support for previously identified risk loci at 5p15 (P = 7.2 × 10−16), 6p21 (P = 2.3 × 10−14) and 15q25 (P = 2.2 × 10−63). Furthermore, we demonstrated histology-specific effects for 5p15, 6p21 and 12p13 loci but not for the 15q25 region. Subgroup analysis also identified a novel disease locus for squamous cell carcinoma at 9p21 (CDKN2A/p16INK4A/p14ARF/CDKN2B/p15INK4B/ANRIL; rs1333040, P = 3.0 × 10−7) which was replicated in a series of 5415 Han Chinese (P = 0.03; combined analysis, P = 2.3 × 10−8). This large analysis provides additional evidence for the role of inherited genetic susceptibility to lung cancer and insight into biological differences in the development of the different histological types of lung cancer.

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Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls

Human Molecular Genetics Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls Maria N. Timofeeva 11 Rayjean J. Hung 10 Thorunn Rafnar 9 David C. Christiani 16 John K. Field 15 Heike Bickebo¨ ller 14 Angela Risch 13 James D. McKay 11 Yufei Wang 18 Juncheng Dai 17 Valerie Gaborieau 11 John McLaughlin 10 Darren Brenner 10 Steven A. Narod 12 Neil E. Caporaso 7 Demetrius Albanes 7 Michael Thun 8 Timothy Eisen 5 H.-Erich Wichmann 3 6 Albert Rosenberger 14 Younghun Han 4 Wei Chen 4 Dakai Zhu 4 Margaret Spitz 2 Xifeng Wu 1 Mala Pande 1 Yang Zhao 16 David Zaridze 0 Neonilia Szeszenia-Dabrowska Jolanta Lissowska Peter Rudnai Eleonora Fabianova Dana Mates Vladimir Bencko Lenka Foretova Vladimir Janout Hans E. Krokan Maiken Elvestad Gabrielsen Frank Skorpen Lars Vatten Inger Njølstad Chu Chen Gary Goodman Mark Lathrop Simone Benhamou To˜ nu Vooder Kristjan Va¨ lk Mari Nelis Andres Metspalu Olaide Raji 15 Ying Chen 15 John Gosney 15 Triantafillos Liloglou 15 Thomas Muley Hendrik Dienemann Gudmar Thorleifsson 9 Hongbing Shen 17 Kari Stefansson 9 Paul Brennan 11 Christopher I. Amos 4 Richard Houlston 18 Maria Teresa Landi 7 TRICL Research Team 0 Institute of Carcinogenesis 1 Department of Epidemiology, The University of Texas MD Anderson Cancer Center , Houston, TX 77030 , USA 2 Baylor College of Medicine , Houston, TX 77030 , USA 3 Chair of Epidemiology, Institute of Medical Informatics , Biometry and Epidemiology , Ludwig-Maximilians-Universita ̈ t Munich , 81377 Munich , Germany 4 Department of Genetics 5 Department of Oncology, Cambridge University Hospitals NHS Foundation Trust , Cambridge , UK 6 Helmholtz Center Munich, Institute of Epidemiology I , 85764 Neuherberg , Germany 7 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, U.S. Public Health Service , Bethesda, MD 20892 , USA 8 American Cancer Society, Epidemiology and Surveillance Research , Atlanta, GA 30301 , USA 9 DeCODE Genetics , Reykjavik , Iceland 10 Samuel Lunenfeld Research Institute of Mount Sinai Hospital , Toronto, ON , Canada M5G 1X5 11 International Agency for Research on Cancer , Lyon 69008 , France 12 Women's College Research Institute , Toronto, Ontario , Canada 13 DKFZ - German Cancer Research Center, Translational Lung Research Centre Heidelberg (TLRC-H), Member of the German Center for Lung Research , 69120 Heidelberg , Germany 14 Department of Genetic Epidemiology, University Medical Center, Georg-August-University Go ̈ ttingen , 37073 Go ̈ ttingen , Germany 15 Roy Castle Lung Cancer Research Programme, Department of Molecular and Clinical Cancer Medicine, The University of Liverpool Cancer Research Centre, Institute of Translational Medicine, The University of Liverpool , Liverpool , UK 16 Harvard University School of Public Health , Boston, MA 02115 , USA 17 Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University , Nanjing , China 18 Division of Genetics and Epidemiology, Institute of Cancer Research , Sutton, Surrey SM2 5NG , UK - Russian N.N. Blokhin Cancer Research Centre, 115478 Moscow, Russia, 20Department of Epidemiology, Institute of Occupational Medicine, 91348 Lodz, Poland, 21The M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw 02781, Poland, 22National Institute of Environmental Health, Budapest 1097, Hungary, 23Regional Authority of Public Health, Banska´ Bystrica 97556, Slovak Republic, 24National Institute of Public Health, Bucharest 050463, Romania, 251st Faculty of Medicine, Institute of Hygiene and Epidemiology, Charles University in Prague, 128 00 Prague 2, Czech Republic, 26Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno 65653, Czech Republic, 27Palacky University, Olomouc 77515, Czech Republic, 28Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim 7489, Norway, 29Department of Laboratory Medicine, Children’s and Women’s Health, Faculty of Medicine and 30Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim 7489, Norway, 31Department of Community Medicine, University of Tromso, Tromso 9037, Norway, 32Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, 33Centre d’Etude du Polymorphisme Humain (CEPH), Paris 75010, France, 34INSERM U946, Paris 75010, France, 35Institute of Molecular and Cell Biology, University of Tartu, Tartu 51010, Estonia, 36Competence Centre on Reproductive Medicine and Biology, 50410 Tartu, Estonia, 37Estonian Genome Center, Institute of Molecular and Cell Biology, Tartu 51010, Estonia, 38Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland, 39Translational Research Unit and 40Department of Thoracic Surgery, Thoraxklinik am Universita¨ tsklinikum Heidelberg, Germany, (...truncated)


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Maria N. Timofeeva, Rayjean J. Hung, Thorunn Rafnar, David C. Christiani, John K. Field, Heike Bickeböller, Angela Risch, James D. McKay, Yufei Wang, Juncheng Dai, Valerie Gaborieau, John McLaughlin, Darren Brenner, Steven A. Narod, Neil E. Caporaso, Demetrius Albanes, Michael Thun, Timothy Eisen, H.-Erich Wichmann, Albert Rosenberger, Younghun Han, Wei Chen, Dakai Zhu, Margaret Spitz, Xifeng Wu, Mala Pande, Yang Zhao, David Zaridze, Neonilia Szeszenia-Dabrowska, Jolanta Lissowska, Peter Rudnai, Eleonora Fabianova, Dana Mates, Vladimir Bencko, Lenka Foretova, Vladimir Janout, Hans E. Krokan, Maiken Elvestad Gabrielsen, Frank Skorpen, Lars Vatten, Inger Njølstad, Chu Chen, Gary Goodman, Mark Lathrop, Simone Benhamou, Tõnu Vooder, Kristjan Välk, Mari Nelis, Andres Metspalu, Olaide Raji, Ying Chen, John Gosney, Triantafillos Liloglou, Thomas Muley, Hendrik Dienemann, Gudmar Thorleifsson, Hongbing Shen, Kari Stefansson, Paul Brennan, Christopher I. Amos, Richard Houlston, Maria Teresa Landi, for TRICL Research Team. Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls, Human Molecular Genetics, 2012, pp. 4980-4995, 21/22, DOI: 10.1093/hmg/dds334