title: Fine mapping of chromosome 5p15.33 based on a targeted deep sequencing and high density genotyping identifies novel lung cancer susceptibility loci.
abstract: Chromosome 5p15.33 has been identified as a lung cancer susceptibility locus, however the underlying causal mechanisms were not fully elucidated. Previous fine-mapping studies of this locus have relied on imputation or investigated a small number of known, common variants. This study represents a significant advance over previous research by investigating a large number of novel, rare variants, as well as their underlying mechanisms through telomere length. Variants for this fine-mapping study were identified through a targeted deep sequencing (average depth of coverage greater than 4000×) of 576 individuals. Subsequently, 4652 SNPs, including 1108 novel SNPs, were genotyped in 5164 cases and 5716 controls of European ancestry. After adjusting for known risk loci, rs2736100 and rs401681, we identified a new, independent lung cancer susceptibility variant in LPCAT1: rs139852726 (OR = 0.46, P = 4.73×10(-9)), and three new adenocarcinoma risk variants in TERT: rs61748181 (OR = 0.53, P = 2.64×10(-6)), rs112290073 (OR = 1.85, P = 1.27×10(-5)), rs138895564 (OR = 2.16, P = 2.06×10(-5); among young cases, OR = 3.77, P = 8.41×10(-4)). In addition, we found that rs139852726 (P = 1.44×10(-3)) was associated with telomere length in a sample of 922 healthy individuals. The gene-based SKAT-O analysis implicated TERT as the most relevant gene in the 5p15.33 region for adenocarcinoma (P = 7.84×10(-7)) and lung cancer (P = 2.37×10(-5)) risk. In this largest fine-mapping study to investigate a large number of rare and novel variants within 5p15.33, we identified novel lung and adenocarcinoma susceptibility loci with large effects and provided support for the role of telomere length as the potential underlying mechanism.
authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5T 3L9, Canada.|Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario M5T 3M7, Canada.
authors.forename: Linda
authors.initials: L
authors.lastname: Kachuri
authors.affiliation: Department of Community and Family Medicine , Center for Genomic Medicine , Geisel School of Medicine , Dartmouth College , Lebanon , NH 03766 , USA.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.affiliation: International Agency for Research on Cancer , Lyon, CEDEX 08, 69372 , France.
authors.forename: James D
authors.initials: JD
authors.lastname: McKay
authors.affiliation: International Agency for Research on Cancer , Lyon, CEDEX 08, 69372 , France.
authors.forename: Mattias
authors.initials: M
authors.lastname: Johansson
authors.affiliation: Human Genetics Foundation (HuGeF), 10126 Torino, Italy.|Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, Norfolk Place, London W2 1PG, UK.
authors.forename: Paolo
authors.initials: P
authors.lastname: Vineis
authors.affiliation: Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), 3721 MA Bilthoven, The Netherlands.|Department of Gastroenterology and Hepatology, University Medical Centre, 3584 CX Utrecht, The Netherlands.|Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London SW7 2AZ, UK.|Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia.
authors.forename: H Bas
authors.initials: HB
authors.lastname: Bueno-de-Mesquita
authors.affiliation: INSERM, Centre for Research in Epidemiology and Population Health (CESP), U1018, Lifestyle, Genes and Health: Integrative Trans-Generational Epidemiology, 94805 Villejuif, France.|Université Paris Sud, UMRS 1018 94805, Villejuif, France.|Institut Gustave Roussy F-94805, Villejuif, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Boutron-Ruault
authors.affiliation: Department of Radiation Sciences , Umeå University , Umeå SE-901 87 , Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Johansson
authors.affiliation: Public Health Directorate Asturias , CP 33006 Oviedo , Spain.
authors.forename: J Ramón
authors.initials: JR
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authors.affiliation: Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori , 20133 Milano , Italy.
authors.forename: Sabina
authors.initials: S
authors.lastname: Sieri
authors.affiliation: Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford , Oxford OX3 7LF , UK.
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Travis
authors.affiliation: Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, 9037 Tromsø, Norway.|Department of Research, Cancer Registry of Norway, 0379 Oslo, Norway.|Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden.|Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki FI-00014, Finland.
authors.forename: Elisabete
authors.initials: E
authors.lastname: Weiderpass
authors.affiliation: University of Hawaii Cancer Center , Honolulu, HI 96813 , USA.
authors.forename: Loic
authors.initials: L
authors.lastname: Le Marchand
authors.affiliation: University of Hawaii Cancer Center , Honolulu, HI 96813 , USA.
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authors.initials: BE
authors.lastname: Henderson
authors.affiliation: University of Hawaii Cancer Center , Honolulu, HI 96813 , USA.
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authors.lastname: Wilkens
authors.affiliation: Fred Hutchinson Cancer Research Center , Seattle , WA 98109 , USA.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Goodman
authors.affiliation: Fred Hutchinson Cancer Research Center , Seattle , WA 98109 , USA.
authors.forename: Chu
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Community and Family Medicine , Center for Genomic Medicine , Geisel School of Medicine , Dartmouth College , Lebanon , NH 03766 , USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Doherty
authors.affiliation: Departments of Environmental Health and Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.|Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
authors.affiliation: Departments of Environmental Health and Epidemiology, Harvard School of Public Health , Boston, MA 02115 , USA.
authors.forename: Yongyue
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Departments of Environmental Health and Epidemiology, Harvard School of Public Health , Boston, MA 02115 , USA.
authors.forename: Li
authors.initials: L
authors.lastname: Su
authors.affiliation: Departments of Environmental Health and Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.|Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Shelley
authors.initials: S
authors.lastname: Tworoger
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School , Boston , MA 02115 , USA.
authors.forename: Xuehong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Departments of Biostatistics and Epidemiology, Harvard School of Public Health , Boston , MA 02115 , USA.
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authors.affiliation: Russian Cancer Research Center , Moscow 115478 , Russia.
authors.forename: David
authors.initials: D
authors.lastname: Zaridze
authors.affiliation: Roy Castle Lung Cancer Research Programme , University of Liverpool Cancer Research Centre Institute of Translational Medicine , University of Liverpool , Liverpool L69 3BX , UK.
authors.forename: John K
authors.initials: JK
authors.lastname: Field
authors.affiliation: Roy Castle Lung Cancer Research Programme , University of Liverpool Cancer Research Centre Institute of Translational Medicine , University of Liverpool , Liverpool L69 3BX , UK.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Marcus
authors.affiliation: Roy Castle Lung Cancer Research Programme , University of Liverpool Cancer Research Centre Institute of Translational Medicine , University of Liverpool , Liverpool L69 3BX , UK.
authors.forename: Michael P A
authors.initials: MPA
authors.lastname: Davies
authors.affiliation: Roy Castle Lung Cancer Research Programme , University of Liverpool Cancer Research Centre Institute of Translational Medicine , University of Liverpool , Liverpool L69 3BX , UK.
authors.forename: Russell
authors.initials: R
authors.lastname: Hyde
authors.affiliation: Division of Cancer Epidemiology and Genetics , National Cancer Institute , National Institutes of Health , Department of Health and Human Services , Bethesda , MD 20892 , USA.
authors.forename: Neil E
authors.initials: NE
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authors.affiliation: Division of Cancer Epidemiology and Genetics , National Cancer Institute , National Institutes of Health , Department of Health and Human Services , Bethesda , MD 20892 , USA.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Landi
authors.affiliation: Human Genetics Foundation (HuGeF), 10126 Torino, Italy.|INSERM, Centre for Research in Epidemiology and Population Health (CESP), U1018, Lifestyle, Genes and Health: Integrative Trans-Generational Epidemiology, 94805 Villejuif, France.|Université Paris Sud, UMRS 1018 94805, Villejuif, France.|Institut Gustave Roussy F-94805, Villejuif, France.|Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne 3004, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne 3010, Australia.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Severi
authors.affiliation: Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne 3004, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne 3010, Australia.|Department of Epidemiology and Preventive Medicine, Monash University, Melbourne 3004, Australia.
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.affiliation: Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario M5T 3M7, Canada.|Ontario Cancer Institute, Princess Margaret Cancer Center, Toronto, Ontario M5G 0A3, Canada.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5T 3L9, Canada.|Public Health Ontario, Toronto, Ontario M5G 1V2, Canada, and.
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authors.initials: JR
authors.lastname: McLaughlin
authors.affiliation: Department of Community and Family Medicine , Center for Genomic Medicine , Geisel School of Medicine , Dartmouth College , Lebanon , NH 03766 , USA.
authors.forename: Yafang
authors.initials: Y
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authors.affiliation: Department of Community and Family Medicine , Center for Genomic Medicine , Geisel School of Medicine , Dartmouth College , Lebanon , NH 03766 , USA.
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital , Toronto , Ontario M5T 3L9 , Canada.
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authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital , Toronto , Ontario M5T 3L9 , Canada.
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authors.affiliation: Genome Technologies, Ontario Institute for Cancer Research , Toronto , Ontario M5G 0A3 , Canada.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Denroche
authors.affiliation: Genome Technologies, Ontario Institute for Cancer Research , Toronto , Ontario M5G 0A3 , Canada.
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authors.initials: PC
authors.lastname: Zuzarte
authors.affiliation: Genome Technologies, Ontario Institute for Cancer Research , Toronto , Ontario M5G 0A3 , Canada.
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authors.affiliation: International Agency for Research on Cancer , Lyon, CEDEX 08, 69372 , France.
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authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5T 3L9, Canada.|Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario M5T 3M7, Canada.
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authors.initials: RJ
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mesh_terms: D016022:Case-Control Studies; D002874:Chromosome Mapping / Q000379:methods; D002895:Chromosomes, Human, Pair 5; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques / Q000379:methods; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged