Smoking, blood DNA methylation sites and lung cancer risk.

Tianxiao Huan, Maria Tellez-Plaza, Daniel Levy, Dorothy A Rhoades, Shelley A Cole, Jose D Bermudez, Allan Jerolon, Chen Yao, Jiantao Ma, Chunyu Liu, Ana Navas-Acien, Lyle G Best, Jason G Umans, Miguel Herreros-Martinez, M Daniele Fallin, Karin Haack, Lies Lahousse, Zulema Rodriguez-Hernandez, Roby Joehanes, Arce Domingo-Relloso

Journal: Environmental pollution (Barking, Essex : 1987) 2023;334():122153

PMID: 37442331

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Abstract

Altered DNA methylation (DNAm) might be a biological intermediary in the pathway from smoking to lung cancer. In this study, we investigated the contribution of differential blood DNAm to explain the association between smoking and lung cancer incidence. Blood DNAm was measured in 2321 Strong Heart Study (SHS) participants. Incident lung cancer was assessed as time to event diagnoses. We conducted mediation analysis, including validation with DNAm and paired gene expression data from the Framingham Heart Study (FHS). In the SHS, current versus never smoking and pack-years single-mediator models showed, respectively, 29 and 21 differentially methylated positions (DMPs) for lung cancer with statistically significant mediated effects (14 of 20 available, and five of 14 available, positions, replicated, respectively, in FHS). In FHS, replicated DMPs showed gene expression downregulation largely in trans, and were related to biological pathways in cancer. The multimediator model identified that DMPs annotated to the genes AHRR and IER3 jointly explained a substantial proportion of lung cancer. Thus, the association of smoking with lung cancer was partly explained by differences in baseline blood DNAm at few relevant sites. Experimental studies are needed to confirm the biological role of identified eQTMs and to evaluate potential implications for early detection and control of lung cancer.

Address: Integrative Epidemiology Group, Department of Chronic Diseases Epidemiology, National Center for Epidemiology, Carlos III Health Institute, Madrid, Spain; Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY, USA; Department of Statistics and Operations Research, University of Valencia, Spain. Electronic address: [email protected].; Population Sciences Branch, National Heart, Lung, And Blood Institute, National Institutes of Health, Bethesda, MD, USA; Framingham Heart Study, Framingham, MA, USA.; Integrative Epidemiology Group, Department of Chronic Diseases Epidemiology, National Center for Epidemiology, Carlos III Health Institute, Madrid, Spain.; Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands; Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.; Population Health Program, Texas Biomedical Research Institute, San Antonio, TX, USA.; Department of Mental Health, Johns Hopkins University, Baltimore, USA; Department of Epidemiology, Johns Hopkins University, Baltimore, USA.; Bioinformatics Unit, Institute for Biomedical Research INCLIVA, Valencia, Spain.; MedStar Health Research Institute, Washington DC, USA; Georgetown-Howard Universities Center for Clinical and Translational Science, Washington DC, USA.; Missouri Breaks Industries and Research Inc., Eagle Butte, SD, USA.; Framingham Heart Study, Framingham, MA, USA; University of Massachusetts Medical School, Worcester, MA, USA.; Framingham Heart Study, Framingham, MA, USA; Boston University School of Public Health, Boston, MA, USA.; Framingham Heart Study, Framingham, MA, USA; Tufts University Friedman School of Nutrition Science and Policy, Boston, MA, USA.; Framingham Heart Study, Framingham, MA, USA; Bristol Myers Squibb, Cambridge, MA, USA.; Université Paris Cité, CNRS, MAP5, F-75006, Paris, France.; Department of Statistics and Operations Research, University of Valencia, Spain.; Stephenson Cancer Center, University of Oklahoma Health Sciences Department of Medicine, Oklahoma City, OK, USA.; Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY, USA.

DOI: 10.1016/j.envpol.2023.122153

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MeSH Terms: Humans, DNA Methylation, Smoking, Tobacco Smoking, Lung Neoplasms, Base Sequence, Epigenesis, Genetic