title: Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts.
abstract: DNA hypomethylation in certain genes is associated with tobacco exposure but it is unknown whether these methylation changes translate into increased lung cancer risk. In an epigenome-wide study of DNA from pre-diagnostic blood samples from 132 case-control pairs in the NOWAC cohort, we observe that the most significant associations with lung cancer risk are for cg05575921 in AHRR (OR for 1 s.d.=0.37, 95% CI: 0.31-0.54, P-value=3.3 × 10(-11)) and cg03636183 in F2RL3 (OR for 1 s.d.=0.40, 95% CI: 0.31-0.56, P-value=3.9 × 10(-10)), previously shown to be strongly hypomethylated in smokers. These associations remain significant after adjustment for smoking and are confirmed in additional 664 case-control pairs tightly matched for smoking from the MCCS, NSHDS and EPIC HD cohorts. The replication and mediation analyses suggest that residual confounding is unlikely to explain the observed associations and that hypomethylation of these CpG sites may mediate the effect of tobacco on lung cancer risk.
authors.affiliation: Molecular end Epidemiology Unit, HuGeF, Human Genetics Foundation, Torino 10126, Italy.|Unit of Cancer Epidemiology, Citta' della Salute e della Scienza Hospital-University of Turin, Center for Cancer Prevention, Via Santena 7, Torino 10126, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fasanelli
authors.affiliation: Inserm (Institut National de la Santé et de la Recherche Médicale), Centre for Research in Epidemiology and Population Health, U1018, Team 9, 114 rue Edouard Vaillant, Villejuif 94805, France.|Paris-South University, Villejuif 91450, France.|Department of Genetic Epidemiology, Cancer Epidemiology Centre, Cancer Council of Victoria, Melbourne, Victoria 3004, Australia.|School of Population and Global Health, Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Baglietto
authors.affiliation: Molecular end Epidemiology Unit, HuGeF, Human Genetics Foundation, Torino 10126, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Ponzi
authors.affiliation: MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London W2 1PG, UK.
authors.forename: Florence
authors.initials: F
authors.lastname: Guida
authors.affiliation: MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London W2 1PG, UK.
authors.forename: Gianluca
authors.identifier: http://orcid.org/0000-0002-5411-6338
authors.initials: G
authors.lastname: Campanella
authors.affiliation: Genetic Epidemiology Division, International Agency for Research on Cancer, Lyon 69008, France.|Department of Biobank Research, Umeå University, Umeå SE-90187, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Johansson
authors.affiliation: Department of Biobank Research, Umeå University, Umeå SE-90187, Sweden.
authors.forename: Kjell
authors.initials: K
authors.lastname: Grankvist
authors.affiliation: Department of Radiation Sciences, Umeå University, Umeå SE-90187, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Johansson
authors.affiliation: Molecular end Epidemiology Unit, HuGeF, Human Genetics Foundation, Torino 10126, Italy.
authors.forename: Manuela Bianca
authors.initials: MB
authors.lastname: Assumma
authors.affiliation: Molecular end Epidemiology Unit, HuGeF, Human Genetics Foundation, Torino 10126, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Naccarati
authors.affiliation: MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London W2 1PG, UK.
authors.forename: Marc
authors.initials: M
authors.lastname: Chadeau-Hyam
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Università di Torino, Torino 10126, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Ala
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, DKFZ-German Cancer Research Center, Heidelberg 69121, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Faltus
authors.affiliation: Division of Cancer Epidemiology, DKFZ-German Cancer Research Center, Heidelberg 69121, Germany.|Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research (DZL), Heidelberg 69120, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kaaks
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, DKFZ-German Cancer Research Center, Heidelberg 69121, Germany.|Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research (DZL), Heidelberg 69120, Germany.|Division of Cancer Research and Epigenetics, Department of Molecular Biology, University of Salzburg, Salzburg 5020, Austria.
authors.forename: Angela
authors.identifier: http://orcid.org/0000-0002-8026-5505
authors.initials: A
authors.lastname: Risch
authors.affiliation: Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
authors.forename: Bianca
authors.initials: B
authors.lastname: De Stavola
authors.affiliation: Department of Genetic Epidemiology, Cancer Epidemiology Centre, Cancer Council of Victoria, Melbourne, Victoria 3004, Australia.
authors.forename: Allison
authors.initials: A
authors.lastname: Hodge
authors.affiliation: Department of Genetic Epidemiology, Cancer Epidemiology Centre, Cancer Council of Victoria, Melbourne, Victoria 3004, Australia.|School of Population and Global Health, Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.affiliation: Genetic Epidemiology Laboratory, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK.
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Relton
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Haycock
authors.affiliation: Department of Community Medicine UiT-The Arctic University of Norway, Tromso 9019, Norway.
authors.forename: Eiliv
authors.initials: E
authors.lastname: Lund
authors.affiliation: Molecular end Epidemiology Unit, HuGeF, Human Genetics Foundation, Torino 10126, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Polidoro
authors.affiliation: Department of Community Medicine UiT-The Arctic University of Norway, Tromso 9019, Norway.
authors.forename: Torkjel M
authors.initials: TM
authors.lastname: Sandanger
authors.affiliation: Molecular end Epidemiology Unit, HuGeF, Human Genetics Foundation, Torino 10126, Italy.|Inserm (Institut National de la Santé et de la Recherche Médicale), Centre for Research in Epidemiology and Population Health, U1018, Team 9, 114 rue Edouard Vaillant, Villejuif 94805, France.|Paris-South University, Villejuif 91450, France.|Department of Genetic Epidemiology, Cancer Epidemiology Centre, Cancer Council of Victoria, Melbourne, Victoria 3004, Australia.|School of Population and Global Health, Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Severi
authors.affiliation: Molecular end Epidemiology Unit, HuGeF, Human Genetics Foundation, Torino 10126, Italy.|MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London W2 1PG, UK.
authors.forename: Paolo
authors.initials: P
authors.lastname: Vineis
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D018899:CpG Islands; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D012907:Smoking / Q000235:genetics*