title: DNA methylation changes measured in pre-diagnostic peripheral blood samples are associated with smoking and lung cancer risk.
abstract: DNA methylation changes are associated with cigarette smoking. We used the Illumina Infinium HumanMethylation450 array to determine whether methylation in DNA from pre-diagnostic, peripheral blood samples is associated with lung cancer risk. We used a case-control study nested within the EPIC-Italy cohort and a study within the MCCS cohort as discovery sets (a total of 552 case-control pairs). We validated the top signals in 429 case-control pairs from another 3 studies. We identified six CpGs for which hypomethylation was associated with lung cancer risk: cg05575921 in the AHRR gene (p-valuepooled= 4 × 10-17), cg03636183 in the F2RL3 gene (p-valuepooled= 2 × 10- 13), cg21566642 and cg05951221 in 2q37.1 (p-valuepooled= 7 × 10-16and 1 × 10-11respectively), cg06126421 in 6p21.33 (p-valuepooled= 2 × 10-15) and cg23387569 in 12q14.1 (p-valuepooled= 5 × 10-7). For cg05951221 and cg23387569 the strength of association was virtually identical in never and current smokers. For all these CpGs except for cg23387569, the methylation levels were different across smoking categories in controls (p-valuesheterogeneity≤ 1.8 x10- 7), were lowest for current smokers and increased with time since quitting for former smokers. We observed a gain in discrimination between cases and controls measured by the area under the ROC curve of at least 8% (p-values ≥ 0.003) in former smokers by adding methylation at the 6 CpGs into risk prediction models including smoking status and number of pack-years. Our findings provide convincing evidence that smoking and possibly other factors lead to DNA methylation changes measurable in peripheral blood that may improve prediction of lung cancer risk.
authors.affiliation: Université Paris-Saclay, Univ. Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France.|Gustave Roussy, Villejuif, F-94805, France.|Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population & Global Health, The University of Melbourne, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Baglietto
authors.affiliation: Department of Evolutionary Biology and Environmental Studies, University of Zurich, Switzerland.|Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Switzerland.
authors.forename: Erica
authors.initials: E
authors.lastname: Ponzi
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social & Community Medicine, University of Bristol, BS8 2BN, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Haycock
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population & Global Health, The University of Melbourne, Australia.
authors.forename: Allison
authors.initials: A
authors.lastname: Hodge
authors.affiliation: HuGeF, Human Genetics Foundation, Torino, 10126, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Bianca Assumma
authors.affiliation: Victorian Life Sciences Computation Initiative, The University of Melbourne, Victoria, 3010, Australia.
authors.forename: Chol-Hee
authors.initials: CH
authors.lastname: Jung
authors.affiliation: Victorian Life Sciences Computation Initiative, The University of Melbourne, Victoria, 3010, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Chung
authors.affiliation: HuGeF, Human Genetics Foundation, Torino, 10126, Italy.|Unit of Cancer Epidemiology, Citta' della Salute e della Scienza Hospital-University of Turin and Center for Cancer Prevention (CPO), 10126, Torino.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fasanelli
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.initials: G
authors.lastname: Campanella
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 Biobank Research, Umeå University, Sweden.
authors.forename: Kjell
authors.initials: K
authors.lastname: Grankvist
authors.affiliation: Department of Radiation Sciences, Umeå University, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Johansson
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Università di Torino, 10126, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Ala
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Università di Torino, 10126, Italy.|Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Provero
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Australia.
authors.forename: Ee Ming
authors.initials: EM
authors.lastname: Wong
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Australia.
authors.forename: Jihoon
authors.initials: J
authors.lastname: Joo
authors.affiliation: Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population & Global Health, The University of Melbourne, Australia.
authors.forename: Dallas R
authors.initials: DR
authors.lastname: English
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social & Community Medicine, University of Bristol, BS8 2BN, UK.
authors.forename: Nabila
authors.initials: N
authors.lastname: Kazmi
authors.affiliation: Department of Community Medicine, UiT- The Arctic University of Norway, Tromso, Norway.
authors.forename: Eiliv
authors.initials: E
authors.lastname: Lund
authors.affiliation: Division of Cancer Research and Epigenetics, Department of Molecular Biology, University of Salzburg, Salzburg, Austria.|Division of Epigenomics and Cancer Risk Factors, DKFZ - German Cancer Research Center, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Faltus
authors.affiliation: Division of Cancer Epidemiology, DKFZ - German Cancer Research Center, Heidelberg, Germany.|Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kaaks
authors.affiliation: Division of Cancer Research and Epigenetics, Department of Molecular Biology, University of Salzburg, Salzburg, Austria.|Division of Epigenomics and Cancer Risk Factors, DKFZ - German Cancer Research Center, Heidelberg, Germany.|Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Risch
authors.affiliation: Division of Cancer Epidemiology, DKFZ - German Cancer Research Center, Heidelberg, Germany.
authors.forename: Myrto
authors.initials: M
authors.lastname: Barrdahl
authors.affiliation: Department of Community Medicine, UiT- The Arctic University of Norway, Tromso, Norway.
authors.forename: Torkjel M
authors.initials: TM
authors.lastname: Sandanger
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Australia.
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.affiliation: Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population & Global Health, The University of Melbourne, Australia.
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: Mattias
authors.initials: M
authors.lastname: Johansson
authors.affiliation: 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
authors.affiliation: HuGeF, Human Genetics Foundation, Torino, 10126, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Polidoro
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social & Community Medicine, University of Bristol, BS8 2BN, UK.
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Relton
authors.affiliation: Université Paris-Saclay, Univ. Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France.|Gustave Roussy, Villejuif, F-94805, France.|Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population & Global Health, The University of Melbourne, Australia.|HuGeF, Human Genetics Foundation, Torino, 10126, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Severi
mesh_terms: D016022:Case-Control Studies; D004247:DNA / Q000097:blood*; D019175:DNA Methylation; D055088:Early Detection of Cancer; D044127:Epigenesis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D046228:Microarray Analysis / Q000379:methods; D012907:Smoking / Q000009:adverse effects / Q000235:genetics*
chemical_list: D004247:DNA
keywords: DNA methylation; lung cancer risk; smoking