Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts

Francesca Fasanelli, Laura Baglietto, Erica Ponzi, Florence Guida, Gianluca Campanella, Mattias Johansson, Kjell Grankvist, Mikael Johansson, Manuela Bianca Assumma, Alessio Naccarati, Marc Chadeau-Hyam, Ugo Ala, Christian Faltus, Rudolf Kaaks, Angela Risch, Bianca De Stavola, Allison Hodge, Graham G. Giles, Melissa C. Southey, Caroline L. Relton, Philip C. Haycock, Eiliv Lund, Silvia Polidoro, Torkjel M. Sandanger, Gianluca Severi and Paolo Vineis ()
Additional contact information
Francesca Fasanelli: Molecular end Epidemiology Unit, HuGeF, Human Genetics Foundation
Laura Baglietto: Inserm (Institut National de la Santé et de la Recherche Médicale), Centre for Research in Epidemiology and Population Health
Erica Ponzi: Molecular end Epidemiology Unit, HuGeF, Human Genetics Foundation
Florence Guida: MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, Norfolk Place
Gianluca Campanella: MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, Norfolk Place
Mattias Johansson: International Agency for Research on Cancer
Kjell Grankvist: Umeå University
Mikael Johansson: Umeå University
Manuela Bianca Assumma: Molecular end Epidemiology Unit, HuGeF, Human Genetics Foundation
Alessio Naccarati: Molecular end Epidemiology Unit, HuGeF, Human Genetics Foundation
Marc Chadeau-Hyam: MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, Norfolk Place
Ugo Ala: Università di Torino
Christian Faltus: DKFZ—German Cancer Research Center
Rudolf Kaaks: DKFZ—German Cancer Research Center
Angela Risch: DKFZ—German Cancer Research Center
Bianca De Stavola: London School of Hygiene and Tropical Medicine
Allison Hodge: Cancer Epidemiology Centre, Cancer Council of Victoria
Graham G. Giles: Cancer Epidemiology Centre, Cancer Council of Victoria
Melissa C. Southey: Genetic Epidemiology Laboratory, University of Melbourne
Caroline L. Relton: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol
Philip C. Haycock: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol
Eiliv Lund: Department of Community Medicine UiT–The Arctic University of Norway
Silvia Polidoro: Molecular end Epidemiology Unit, HuGeF, Human Genetics Foundation
Torkjel M. Sandanger: Department of Community Medicine UiT–The Arctic University of Norway
Gianluca Severi: Molecular end Epidemiology Unit, HuGeF, Human Genetics Foundation
Paolo Vineis: Molecular end Epidemiology Unit, HuGeF, Human Genetics Foundation

Nature Communications, 2015, vol. 6, issue 1, 1-9

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms10192

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