Tobacco smoking and methylation of genes related to lung cancer development

// Xu Gao 1 , Yan Zhang 1 , Lutz Philipp Breitling 1, 4 , Hermann Brenner 1, 2, 3 1 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany 2 Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), D-69120 Heidelberg, Germany 3 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany 4 Pneumology and Respiratory Critical Care Medicine, Thoraxklinik, University of Heidelberg, D-69126 Heidelberg, Germany Correspondence to: Hermann Brenner, email: h.brenner@dkfz-heidelberg.de Keywords: DNA methylation, tobacco smoking, lung cancer, whole blood sample Received: March 3, 2016     Accepted: May 23, 2016     Published: June 14, 2016 ABSTRACT Lung cancer is a leading cause of cancer-related mortality worldwide, and cigarette smoking is the major environmental hazard for its development. This study intended to examine whether smoking could alter methylation of genes at lung cancer risk loci identified by genome-wide association studies (GWASs). By systematic literature review, we selected 75 genomic candidate regions based on 120 single-nucleotide polymorphisms (SNPs). DNA methylation levels of 2854 corresponding cytosine-phosphate-guanine (CpG) candidates in whole blood samples were measured by the Illumina Infinium Human Methylation450 Beadchip array in two independent subsamples of the ESTHER study. After correction for multiple testing, we successfully confirmed associations with smoking for one previously identified CpG site within the KLF6 gene and identified 12 novel sites located in 7 genes: STK32A , TERT , MSH5 , ACTA2 , GATA3 , VTI1A and CHRNA5 (FDR <0.05). Current smoking was linked to a 0.74% to 2.4% decrease of DNA methylation compared to never smoking in 11 loci, and all but one showed significant associations (FDR <0.05) with life-time cumulative smoking (pack-years). In conclusion, our study demonstrates the impact of tobacco smoking on DNA methylation of lung cancer related genes, which may indicate that lung cancer susceptibility genes might be regulated by methylation changes in response to smoking. Nevertheless, this mechanism warrants further exploration in future epigenetic and biomarker studies.