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Nat Commun. 2018 Aug 13;9(1):3221. doi: 10.1038/s41467-018-05074-y.

Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk.

Ji X1, Bossé Y2,3, Landi MT4, Gui J1, Xiao X1, Qian D1, Joubert P3, Lamontagne M3, Li Y1, Gorlov I1, de Biasi M5,6, Han Y1, Gorlova O1, Hung RJ7, Wu X8, McKay J9, Zong X7, Carreras-Torres R9, Christiani DC10,11, Caporaso N4, Johansson M9, Liu G7, Bojesen SE12,13,14, Le Marchand L15, Albanes D4, Bickeböller H16, Aldrich MC17, Bush WS17,18, Tardon A19,20, Rennert G21,22, Chen C23, Teare MD24, Field JK25, Kiemeney LA26, Lazarus P27, Haugen A28, Lam S29, Schabath MB30, Andrew AS31, Shen H32, Hong YC33, Yuan JM34, Bertazzi PA35,36, Pesatori AC35,36, Ye Y8, Diao N10, Su L10, Zhang R10,32, Brhane Y7, Leighl N37, Johansen JS38, Mellemgaard A38, Saliba W21,22, Haiman C39, Wilkens L15, Fernandez-Somoano A19,20, Fernandez-Tardon G19,20, van der Heijden EHFM26, Kim JH40, Dai J32, Hu Z32, Davies MPA25, Marcus MW25, Brunnström H41, Manjer J42, Melander O42, Muller DC43, Overvad K42, Trichopoulou A44, Tumino R45, Doherty J31,46, Goodman GE46,47, Cox A48, Taylor F48, Woll P48, Brüske I49, Manz J49, Muley T50,51, Risch A52, Rosenberger A16, Grankvist K53, Johansson M54, Shepherd F55, Tsao MS55, Arnold SM56, Haura EB57, Bolca C58, Holcatova I59, Janout V59, Kontic M60, Lissowska J61, Mukeria A62, Ognjanovic S63, Orlowski TM64, Scelo G9, Swiatkowska B65, Zaridze D62, Bakke P66, Skaug V28, Zienolddiny S28, Duell EJ67, Butler LM34, Koh WP68,69, Gao YT70, Houlston R71, McLaughlin J72, Stevens V73, Nickle DC74, Obeidat M75, Timens W76, Zhu B4, Song L4, Artigas MS77,78, Tobin MD77,78, Wain LV77,78, Gu F4, Byun J1, Kamal A1, Zhu D1, Tyndale RF79,80,81, Wei WQ82, Chanock S4, Brennan P9, Amos CI83,84.

Author information

1
Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, 03750, NH, USA.
2
Department of Molecular Medicine, Laval University, Québec, G1V 4G5, Canada.
3
Institut universitaire de cardiologie et de pneumologie de Québec, Québec, G1V 4G5, Canada.
4
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, 20892, MD, USA.
5
Annenberg School of Communication, University of Pennsylvania, Philadelphia, 19104, PA, USA.
6
Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, PA, USA.
7
Lunenfeld-Tanenbaum Research Institute, Sinai Health System and University of Toronto, Toronto, M5T 3L9, Canada.
8
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA.
9
International Agency for Research on Cancer, World Health Organization, Lyon, 69372 CEDEX 08, France.
10
Department of Environmental Health, Harvard School of Public Health, Boston, 02115, MA, USA.
11
Department of Medicine, Massachusetts General Hospital, Boston, 02115, MA, USA.
12
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Herlev 2730, Denmark.
13
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200 København N, Denmark.
14
Copenhagen General Population Study, Herlev and Gentofte Hospital, Ringvej 75, Copenhagen, Herlev 2730, Denmark.
15
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, 96813, HI, USA.
16
Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, Göttingen, 37073, Germany.
17
Department of Thoracic Surgery, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, 37203, TN, USA.
18
Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, 44106, OH, USA.
19
Faculty of Medicine, University of Oviedo, Oviedo, 33006, Spain.
20
Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública, Campus del Cristo s/n, Oviedo, 33006, Spain.
21
Clalit National Cancer Control Center, Carmel Medical Center, Haifa, 34361, Israel.
22
Faculty of Medicine, Technion, Haifa, 34361, Israel.
23
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, 98109, WA, USA.
24
School of Health and Related Research, University of Sheffield, Sheffield, S1 4DA, UK.
25
Roy Castle Lung Cancer Research Programme, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3BX, UK.
26
Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, 6525 EZ, The Netherlands.
27
Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, 99210-1495, WA, USA.
28
National Institute of Occupational Health, 0033, Gydas vei 8, 0033, Oslo, Norway.
29
British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, V5Z1L3, Canada.
30
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, 33612, FL, USA.
31
Department of Epidemiology, Geisel School of Medicine, 1 Medical Center Drive, Hanover, 03755, NH, USA.
32
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, 101 Longmian Ave, Nanjing, 211166, PR China.
33
Department of Preventive Medicine, Seoul National University College of Medicine, 1 Gwanak-ro, Gwanak-gu, Seoul, 151 742, Republic of Korea.
34
University of Pittsburgh Cancer Institute, Pittsburgh, 15232, PA, USA.
35
Department of Preventive Medicine, IRCCS Foundation Ca'Granda Ospedale Maggiore Policlinico, Milan, 20133, Italy.
36
Department of Clinical Sciences and Community Health, University of Milan, Milan, 20133, Italy.
37
University Health Network-The Princess Margaret Cancer Centre, 600 University Avenue, Toronto, M5G 2C4, Canada.
38
Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, 2730, Denmark.
39
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, 90033, CA, USA.
40
Department of Integrative Bioscience & Biotechnology, Sejong University, Gwangjin-gu, Seoul, 05029, Republic of Korea.
41
Department of Pathology, Lund University, Lund, 222 41, Sweden.
42
Faculty of Medicine, Lund University, Lund, 22100, Sweden.
43
School of Public Health, St Mary's Campus, Imperial College London, London, W2 1PG, UK.
44
Hellenic Health Foundation, Athens, GR-115 27, Greece.
45
Cancer Registry and Histopathology Department, "Civic-M.P. Arezzo" Hospital, ASP, Ragusa, 97100, Italy.
46
Fred Hutchinson Cancer Research Center, Seattle, 98109-1024, WA, USA.
47
Swedish Medical Group, Arnold Pavilion, Suite 200, Seattle, 98104, WA, USA.
48
Department of Oncology and Metabolism, University of Sheffield, Sheffield, S10 2RX, UK.
49
Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, D-85764, Germany.
50
Thoraxklinik at University Hospital Heidelberg, Heidelberg, 69126, Germany.
51
Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, 69120, Germany.
52
Cancer Cluster Salzburg, University of Salzburg, Salzburg, 5020, Austria.
53
Department of Medical Biosciences, Umeå University, Umeå, 901 85, Sweden.
54
Department of Radiation Sciences, Umeå University, Umeå, 901 85, Sweden.
55
Princess Margaret Cancer Centre, Toronto, M5G2M9, Canada.
56
Markey Cancer Center, University of Kentucky, First Floor, 800 Rose Street, Lexington, 40508, KY, USA.
57
Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, 33612, KY, USA.
58
Institute of Pneumology "Marius Nasta", Bucharest, RO-050159, Romania.
59
1st Faculty of Medicine, Charles University, Kateřinská 32, Prague, 121 08 Praha 2, Czech Republic.
60
Clinical Center of Serbia, Clinic for Pulmonology, School of Medicine, University of Belgrade, Belgrade, 11000, Serbia.
61
Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Institute-Oncology Center, Warsaw, 02-781, Poland.
62
Department of Epidemiology and Prevention, Russian N.N. Blokhin Cancer Research Centre, Moscow, 115478, Russian Federation.
63
International Organization for Cancer Prevention and Research, Belgrade, 11070, Serbia.
64
Department of Surgery, National Tuberculosis and Lung Diseases Research Institute, Warsaw, PL-01-138, Poland.
65
Department of Environmental Epidemiology, Nofer Institute of Occupational Medicine, Lodz, 91-348, Poland.
66
Department of Clinical Science, University of Bergen, Bergen, 5021, Norway.
67
Unit of Nutrition and Cancer, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, 08908, Spain.
68
Duke-NUS Medical School, Singapore, 119077, Singapore.
69
Saw Swee Hock School of Public Health, National University of Singapore, Singapore, 117549, Singapore.
70
Department of Epidemiology, Shanghai Cancer Institute, Shanghai, 2200, China.
71
The Institute of Cancer Research, London, SW7 3RP, England, UK.
72
Public Health Ontario, Windsor, Ontario, N8W 5K5, Canada.
73
American Cancer Society, Inc., Atlanta, 30303, GA, USA.
74
Department of Genetics and Pharmacogenomics, Merck Research Laboratories, Boston, 02115-5727, MA, USA.
75
Centre for Heart Lung Innovation, St Paul's Hospital, The University of British Columbia, Vancouver, V6Z 1Y6, BC, Canada.
76
Department of Pathology and Medical Biology, GRIAC, University of Groningen, University Medical Center Groningen, Groningen, NL - 9713 GZ, The Netherlands.
77
Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, LE1 7RH, UK.
78
Leicester Respiratory Biomedical Research Unit, National Institute for Health Research (NIHR), Glenfield Hospital, Leicester, LE3 9QP, UK.
79
Department of Pharmacology and Toxicology, University of Toronto, Toronto, M5S 1A8, ON, Canada.
80
Department of Psychiatry, University of Toronto, Toronto, M5T 1R8, ON, Canada.
81
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, M6J 1H4, ON, Canada.
82
Department of Biomedical Informatics, School of Medicine, Vanderbilt University, Nashville, TN, 37235, USA.
83
Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, 03750, NH, USA. chrisa@bcm.edu.
84
The Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, 77030, TX, USA. chrisa@bcm.edu.

Abstract

Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.

PMID:
30104567
PMCID:
PMC6089967
DOI:
10.1038/s41467-018-05074-y
[Indexed for MEDLINE]
Free PMC Article

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