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Nat Genet. 2017 Jul;49(7):1126-1132. doi: 10.1038/ng.3892. Epub 2017 Jun 12.

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

McKay JD1, Hung RJ2, Han Y3, Zong X2, Carreras-Torres R1, Christiani DC4, Caporaso NE5, Johansson M1, Xiao X3, Li Y3, Byun J3, Dunning A6, Pooley KA6, Qian DC3, Ji X3, Liu G2, Timofeeva MN1, Bojesen SE7,8,9, Wu X10, Le Marchand L11, Albanes D5, Bickeböller H12, Aldrich MC13, Bush WS14, Tardon A15, Rennert G16, Teare MD17, Field JK18, Kiemeney LA19, Lazarus P20, Haugen A21, Lam S22, Schabath MB23, Andrew AS24, Shen H25, Hong YC26, Yuan JM27, Bertazzi PA28,29, Pesatori AC29, Ye Y10, Diao N4, Su L4, Zhang R4, Brhane Y2, Leighl N30, Johansen JS31, Mellemgaard A31, Saliba W16, Haiman CA32, Wilkens LR11, Fernandez-Somoano A15, Fernandez-Tardon G15, van der Heijden HFM19, Kim JH33, Dai J25, Hu Z25, Davies MPA18, Marcus MW18, Brunnström H34, Manjer J35, Melander O35, Muller DC36, Overvad K37, Trichopoulou A38, Tumino R39, Doherty JA24,40,41,42, Barnett MP40, Chen C40, Goodman GE43, Cox A44, Taylor F44, Woll P44, Brüske I45, Wichmann HE45,46,47, Manz J48, Muley TR49,50, Risch A48,49,50,51,52, Rosenberger A12, Grankvist K53, Johansson M54, Shepherd FA30, Tsao MS30, Arnold SM55, Haura EB56, Bolca C57, Holcatova I58, Janout V59, Kontic M60,61, Lissowska J62, Mukeria A63, Ognjanovic S64, Orlowski TM65, Scelo G1, Swiatkowska B66, Zaridze D63, Bakke P67, Skaug V21, Zienolddiny S21, Duell EJ68, Butler LM27, Koh WP69, Gao YT70, Houlston RS71, McLaughlin J72, Stevens VL73, Joubert P74, Lamontagne M74, Nickle DC75, Obeidat M76, Timens W77, Zhu B5, Song L5, Kachuri L2, Artigas MS78,79, Tobin MD78,79, Wain LV78,79; SpiroMeta Consortium, Rafnar T80, Thorgeirsson TE80, Reginsson GW80, Stefansson K80, Hancock DB81, Bierut LJ82, Spitz MR83, Gaddis NC84, Lutz SM85, Gu F5, Johnson EO86, Kamal A3, Pikielny C3, Zhu D3, Lindströem S87, Jiang X88, Tyndale RF89,90, Chenevix-Trench G91, Beesley J91, Bossé Y74,92, Chanock S5, Brennan P1, Landi MT5, Amos CI3.

Author information

1
International Agency for Research on Cancer, World Health Organization, Lyon, France.
2
Lunenfeld-Tanenbaum Research Institute, Sinai Health System, University of Toronto, Toronto, Ontario, Canada.
3
Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
4
Department of Environmental Health, Harvard T.H. Chan School of Public Health and Massachusetts General Hospital/ Harvard Medical School, Boston, Massachusetts, USA.
5
Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
6
Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
7
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
8
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
9
Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen, Denmark.
10
Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
11
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
12
Department of Genetic Epidemiology, University Medical Center, Georg August University Göttingen, Göttingen, Germany.
13
Department of Thoracic Surgery, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
14
Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
15
University of Oviedo and CIBERESP, Faculty of Medicine, Oviedo, Spain.
16
Clalit National Cancer Control Center at Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
17
School of Health and Related Research, University of Sheffield, Sheffield, UK.
18
Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
19
Departments of Health Evidence and Urology, Radboud University Medical Center, Nijmegen, the Netherlands.
20
Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, Washington, USA.
21
National Institute of Occupational Health, Oslo, Norway.
22
British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
23
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
24
Department of Epidemiology, Geisel School of Medicine, Hanover, New Hampshire, USA.
25
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.
26
Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
27
University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
28
Department of Preventive Medicine, IRCCS Foundation Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
29
Department of Clinical Sciences and Community Health-DISCCO, University of Milan, Milan, Italy.
30
University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
31
Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
32
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA.
33
Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, Republic of Korea.
34
Department of Pathology, Lund University, Lund, Sweden.
35
Faculty of Medicine, Lund University, Lund, Sweden.
36
School of Public Health, St Mary's Campus, Imperial College London, London, UK.
37
Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark.
38
Hellenic Health Foundation, Athens, Greece.
39
Molecular and Nutritional Epidemiology Unit, CSPO (Cancer Research and Prevention Centre), Scientific Institute of Tuscany, Florence, Italy.
40
Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
41
Huntsman Cancer Institute, Salt Lake City, Utah, USA.
42
Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA.
43
Swedish Medical Group, Seattle, Washington, USA.
44
Department of Oncology, University of Sheffield, Sheffield, UK.
45
Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
46
Institute of Medical Informatics, Biometry and Epidemiology, Ludwig Maximilians University, Munich, Germany.
47
Institute of Medical Statistics and Epidemiology, Technical University of Munich, Munich, Germany.
48
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
49
Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany.
50
Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Germany.
51
German Center for Lung Research (DZL), Heidelberg, Germany.
52
University of Salzburg and Cancer Cluster Salzburg, Salzburg, Austria.
53
Department of Medical Biosciences, Umeå University, Umeå, Sweden.
54
Department of Radiation Sciences, Umeå University, Umeå, Sweden.
55
Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.
56
Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
57
Institute of Pneumology 'Marius Nasta', Bucharest, Romania.
58
2nd Faculty of Medicine, Charles University, Prague, Czech Republic.
59
Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.
60
Clinical Center of Serbia, Belgrade, Serbia.
61
School of Medicine, University of Belgrade, Belgrade, Serbia.
62
M. Sklodowska-Curie Cancer Center, Institute of Oncology, Warsaw, Poland.
63
Department of Epidemiology and Prevention, Russian N.N.Blokhin Cancer Research Centre, Moscow, Russian Federation.
64
International Organization for Cancer Prevention and Research, Belgrade, Serbia.
65
Department of Surgery, National Tuberculosis and Lung Diseases Research Institute, Warsaw, Poland.
66
Nofer Institute of Occupational Medicine, Department of Environmental Epidemiology, Lodz, Poland.
67
Department of Clinical Science, University of Bergen, Bergen, Norway.
68
Unit of Nutrition and Cancer, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain.
69
Duke-National University of Singapore Medical School, Singapore.
70
Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.
71
The Institute of Cancer Research, London, UK.
72
Public Health Ontario, Toronto, Ontario, Canada.
73
American Cancer Society, Atlanta, Georgia, USA.
74
Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada.
75
Merck Research Laboratories, Genetics and Pharmacogenomics, Boston, Massachusetts, USA.
76
University of British Columbia Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, British Columbia, Canada.
77
University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, the Netherlands.
78
Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK.
79
National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
80
deCODE Genetics, Amgen, Inc., Reykjavik, Iceland.
81
Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, North Carolina, USA.
82
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.
83
Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
84
Research Computing Division, RTI International, Research Triangle Park, North Carolina, USA.
85
Department of Biostatistics and Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
86
Fellow Program and Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, North Carolina, USA.
87
Department of Epidemiology, University of Washington, Seattle, Washington, USA.
88
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
89
Departments of Pharmacology and Toxicology &Psychiatry, University of Toronto, Toronto, Ontario, Canada.
90
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
91
Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
92
Department of Molecular Medicine, Laval University, Québec, Québec, Canada.

Abstract

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.

PMID:
28604730
PMCID:
PMC5510465
DOI:
10.1038/ng.3892
[Indexed for MEDLINE]
Free PMC Article

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