Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.,Nature Genetics

当前位置： X-MOL 学术 › Nat. Genet. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.
Nature Genetics ( IF 31.7 ) Pub Date : 2017-06-12 , DOI: 10.1038/ng.3892
James D McKay ₁ , Rayjean J Hung ₂ , Younghun Han ₃ , Xuchen Zong ₂ , Robert Carreras-Torres ₁ , David C Christiani ₄ , Neil E Caporaso ₅ , Mattias Johansson ₁ , Xiangjun Xiao ₃ , Yafang Li ₃ , Jinyoung Byun ₃ , Alison Dunning ₆ , Karen A Pooley ₆ , David C Qian ₃ , Xuemei Ji ₃ , Geoffrey Liu ₂ , Maria N Timofeeva ₁ , Stig E Bojesen _{7,

8,

9} , Xifeng Wu ₁₀ , Loic Le Marchand ₁₁ , Demetrios Albanes ₅ , Heike Bickeböller ₁₂ , Melinda C Aldrich ₁₃ , William S Bush ₁₄ , Adonina Tardon ₁₅ , Gad Rennert ₁₆ , M Dawn Teare ₁₇ , John K Field ₁₈ , Lambertus A Kiemeney ₁₉ , Philip Lazarus ₂₀ , Aage Haugen ₂₁ , Stephen Lam ₂₂ , Matthew B Schabath ₂₃ , Angeline S Andrew ₂₄ , Hongbing Shen ₂₅ , Yun-Chul Hong ₂₆ , Jian-Min Yuan ₂₇ , Pier Alberto Bertazzi _{28,

29} , Angela C Pesatori ₂₉ , Yuanqing Ye ₁₀ , Nancy Diao ₄ , Li Su ₄ , Ruyang Zhang ₄ , Yonathan Brhane ₂ , Natasha Leighl ₃₀ , Jakob S Johansen ₃₁ , Anders Mellemgaard ₃₁ , Walid Saliba ₁₆ , Christopher A Haiman ₃₂ , Lynne R Wilkens ₁₁ , Ana Fernandez-Somoano ₁₅ , Guillermo Fernandez-Tardon ₁₅ , Henricus F M van der Heijden ₁₉ , Jin Hee Kim ₃₃ , Juncheng Dai ₂₅ , Zhibin Hu ₂₅ , Michael P A Davies ₁₈ , Michael W Marcus ₁₈ , Hans Brunnström ₃₄ , Jonas Manjer ₃₅ , Olle Melander ₃₅ , David C Muller ₃₆ , Kim Overvad ₃₇ , Antonia Trichopoulou ₃₈ , Rosario Tumino ₃₉ , Jennifer A Doherty _{24,

40,

41,

42} , Matt P Barnett ₄₀ , Chu Chen ₄₀ , Gary E Goodman ₄₃ , Angela Cox ₄₄ , Fiona Taylor ₄₄ , Penella Woll ₄₄ , Irene Brüske ₄₅ , H-Erich Wichmann _{45,

46,

47} , Judith Manz ₄₈ , Thomas R Muley _{49,

50} , Angela Risch _{48,

49,

50,

51,

52} , Albert Rosenberger ₁₂ , Kjell Grankvist ₅₃ , Mikael Johansson ₅₄ , Frances A Shepherd ₃₀ , Ming-Sound Tsao ₃₀ , Susanne M Arnold ₅₅ , Eric B Haura ₅₆ , Ciprian Bolca ₅₇ , Ivana Holcatova ₅₈ , Vladimir Janout ₅₉ , Milica Kontic _{60,

61} , Jolanta Lissowska ₆₂ , Anush Mukeria ₆₃ , Simona Ognjanovic ₆₄ , Tadeusz M Orlowski ₆₅ , Ghislaine Scelo ₁ , Beata Swiatkowska ₆₆ , David Zaridze ₆₃ , Per Bakke ₆₇ , Vidar Skaug ₂₁ , Shanbeh Zienolddiny ₂₁ , Eric J Duell ₆₈ , Lesley M Butler ₂₇ , Woon-Puay Koh ₆₉ , Yu-Tang Gao ₇₀ , Richard S Houlston ₇₁ , John McLaughlin ₇₂ , Victoria L Stevens ₇₃ , Philippe Joubert ₇₄ , Maxime Lamontagne ₇₄ , David C Nickle ₇₅ , Ma'en Obeidat ₇₆ , Wim Timens ₇₇ , Bin Zhu ₅ , Lei Song ₅ , Linda Kachuri ₂ , María Soler Artigas _{78,

79} , Martin D Tobin _{78,

79} , Louise V Wain _{78,

79} , , Thorunn Rafnar ₈₀ , Thorgeir E Thorgeirsson ₈₀ , Gunnar W Reginsson ₈₀ , Kari Stefansson ₈₀ , Dana B Hancock ₈₁ , Laura J Bierut ₈₂ , Margaret R Spitz ₈₃ , Nathan C Gaddis ₈₄ , Sharon M Lutz ₈₅ , Fangyi Gu ₅ , Eric O Johnson ₈₆ , Ahsan Kamal ₃ , Claudio Pikielny ₃ , Dakai Zhu ₃ , Sara Lindströem ₈₇ , Xia Jiang ₈₈ , Rachel F Tyndale _{89,

90} , Georgia Chenevix-Trench ₉₁ , Jonathan Beesley ₉₁ , Yohan Bossé _{74,

92} , Stephen Chanock ₅ , Paul Brennan ₁ , Maria Teresa Landi ₅ , Christopher I Amos ₃

Affiliation

International Agency for Research on Cancer, World Health Organization, Lyon, France.
Lunenfeld-Tanenbaum Research Institute, Sinai Health System, University of Toronto, Toronto, Ontario, Canada.
Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
Department of Environmental Health, Harvard T.H. Chan School of Public Health and Massachusetts General Hospital/ Harvard Medical School, Boston, Massachusetts, USA.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen, Denmark.
Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
Department of Genetic Epidemiology, University Medical Center, Georg August University Göttingen, Göttingen, Germany.
Department of Thoracic Surgery, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
University of Oviedo and CIBERESP, Faculty of Medicine, Oviedo, Spain.
Clalit National Cancer Control Center at Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
School of Health and Related Research, University of Sheffield, Sheffield, UK.
Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
Departments of Health Evidence and Urology, Radboud University Medical Center, Nijmegen, the Netherlands.
Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, Washington, USA.
National Institute of Occupational Health, Oslo, Norway.
British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
Department of Epidemiology, Geisel School of Medicine, Hanover, New Hampshire, USA.
Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China.
Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
Department of Preventive Medicine, IRCCS Foundation Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
Department of Clinical Sciences and Community Health-DISCCO, University of Milan, Milan, Italy.
University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA.
Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, Republic of Korea.
Department of Pathology, Lund University, Lund, Sweden.
Faculty of Medicine, Lund University, Lund, Sweden.
School of Public Health, St Mary's Campus, Imperial College London, London, UK.
Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark.
Hellenic Health Foundation, Athens, Greece.
Molecular and Nutritional Epidemiology Unit, CSPO (Cancer Research and Prevention Centre), Scientific Institute of Tuscany, Florence, Italy.
Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Huntsman Cancer Institute, Salt Lake City, Utah, USA.
Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA.
Swedish Medical Group, Seattle, Washington, USA.
Department of Oncology, University of Sheffield, Sheffield, UK.
Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
Institute of Medical Informatics, Biometry and Epidemiology, Ludwig Maximilians University, Munich, Germany.
Institute of Medical Statistics and Epidemiology, Technical University of Munich, Munich, Germany.
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany.
Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Germany.
German Center for Lung Research (DZL), Heidelberg, Germany.
University of Salzburg and Cancer Cluster Salzburg, Salzburg, Austria.
Department of Medical Biosciences, Umeå University, Umeå, Sweden.
Department of Radiation Sciences, Umeå University, Umeå, Sweden.
Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.
Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
Institute of Pneumology 'Marius Nasta', Bucharest, Romania.
2nd Faculty of Medicine, Charles University, Prague, Czech Republic.
Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.
Clinical Center of Serbia, Belgrade, Serbia.
School of Medicine, University of Belgrade, Belgrade, Serbia.
M. Sklodowska-Curie Cancer Center, Institute of Oncology, Warsaw, Poland.
Department of Epidemiology and Prevention, Russian N.N.Blokhin Cancer Research Centre, Moscow, Russian Federation.
International Organization for Cancer Prevention and Research, Belgrade, Serbia.
Department of Surgery, National Tuberculosis and Lung Diseases Research Institute, Warsaw, Poland.
Nofer Institute of Occupational Medicine, Department of Environmental Epidemiology, Lodz, Poland.
Department of Clinical Science, University of Bergen, Bergen, Norway.
Unit of Nutrition and Cancer, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain.
Duke-National University of Singapore Medical School, Singapore.
Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.
The Institute of Cancer Research, London, UK.
Public Health Ontario, Toronto, Ontario, Canada.
American Cancer Society, Atlanta, Georgia, USA.
Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada.
Merck Research Laboratories, Genetics and Pharmacogenomics, Boston, Massachusetts, USA.
University of British Columbia Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, British Columbia, Canada.
University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, the Netherlands.
Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK.
National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
deCODE Genetics, Amgen, Inc., Reykjavik, Iceland.
Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, North Carolina, USA.
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.
Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
Research Computing Division, RTI International, Research Triangle Park, North Carolina, USA.
Department of Biostatistics and Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Fellow Program and Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, North Carolina, USA.
Department of Epidemiology, University of Washington, Seattle, Washington, USA.
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
Departments of Pharmacology and Toxicology &Psychiatry, University of Toronto, Toronto, Ontario, Canada.
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Department of Molecular Medicine, Laval University, Québec, Québec, Canada.

Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

中文翻译：

大规模关联分析确定了新的肺癌易感性位点和组织学亚型遗传易感性的异质性。

尽管已经确定了几个肺癌易感位点，但肺癌的大部分遗传性仍然无法解释。这里，在 OncoArray 上对欧洲血统的 14,803 个病例和 12,262 个对照进行了基因分型，并结合现有数据对 29,266 个病例和 56,450 个对照进行了肺癌全基因组关联研究 (GWAS) 分析。我们鉴定了 18 个具有全基因组意义的易感位点，其中包括 10 个新位点。新的基因座突显了肺癌组织学亚型之间遗传易感性的显着异质性，其中四个基因座总体上与肺癌相关，六个基因座与肺腺癌相关。对 1,425 个正常肺组织样本的基因表达数量性状位点 (eQTL) 分析突出显示 RNASET2、SECISBP2L 和 NRG1 作为候选基因。其他基因座包括胆碱能烟碱受体 CHRNA2 以及端粒相关基因 OFBC1 和 RTEL1 等基因。对靶基因的进一步探索将继续为肺癌的病因学提供新的见解。

更新日期：2017-06-29

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11