Dataset Information

Tobacco smoking and methylation of genes related to lung cancer development.

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.

SUBMITTER: Gao X

PROVIDER: S-EPMC5312292 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Tobacco smoking and methylation of genes related to lung cancer development.

Gao Xu X Zhang Yan Y Breitling Lutz Philipp LP Brenner Hermann H

Oncotarget 20160901 37

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-gu ...[more]

PMID: 27323854

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Project description:Aims/hypothesisTobacco smoking, a risk factor for diabetes, is an established modifier of DNA methylation. We hypothesised that tobacco smoking modifies DNA methylation of genes previously identified for diabetes.MethodsWe annotated CpG sites available on the Illumina Human Methylation 450K array to diabetes genes previously identified by genome-wide association studies (GWAS), and investigated them for an association with smoking by comparing current to never smokers. The discovery study consisted of 630 individuals (Bonferroni-corrected p = 1.4 × 10(-5)), and we sought replication in an independent sample of 674 individuals. The replicated sites were tested for association with nearby genetic variants and gene expression and fasting glucose and insulin levels.ResultsWe annotated 3,620 CpG sites to the genes identified in the GWAS on type 2 diabetes. Comparing current smokers to never smokers, we found 12 differentially methylated CpG sites, of which five replicated: cg23161492 within ANPEP (p = 1.3 × 10(-12)); cg26963277 (p = 1.2 × 10(-9)), cg01744331 (p = 8.0 × 10(-6)) and cg16556677 (p = 1.2 × 10(-5)) within KCNQ1 and cg03450842 (p = 3.1 × 10(-8)) within ZMIZ1. The effect of smoking on DNA methylation at the replicated CpG sites attenuated after smoking cessation. Increased DNA methylation at cg23161492 was associated with decreased gene expression levels of ANPEP (p = 8.9 × 10(-5)). rs231356-T, which was associated with hypomethylation of cg26963277 (KCNQ1), was associated with a higher odds of diabetes (OR 1.06, p = 1.3 × 10(-5)). Additionally, hypomethylation of cg26963277 was associated with lower fasting insulin levels (p = 0.04).Conclusions/interpretationTobacco smoking is associated with differential DNA methylation of the diabetes risk genes ANPEP, KCNQ1 and ZMIZ1. Our study highlights potential biological mechanisms connecting tobacco smoking to excess risk of type 2 diabetes.

Project description:IntroductionLung cancer survivors are at high risk of developing a second primary lung cancer (SPLC). However, SPLC risk factors have not been established and the impact of tobacco smoking remains controversial. We examined the risk factors for SPLC across multiple epidemiologic cohorts and evaluated the impact of smoking cessation on reducing SPLC risk.MethodsWe analyzed data from 7059 participants in the Multiethnic Cohort (MEC) diagnosed with an initial primary lung cancer (IPLC) between 1993 and 2017. Cause-specific proportional hazards models estimated SPLC risk. We conducted validation studies using the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (N = 3423 IPLC cases) and European Prospective Investigation into Cancer and Nutrition (N = 4731 IPLC cases) cohorts and pooled the SPLC risk estimates using random effects meta-analysis.ResultsOverall, 163 MEC cases (2.3%) developed SPLC. Smoking pack-years (hazard ratio [HR] = 1.18 per 10 pack-years, p < 0.001) and smoking intensity (HR = 1.30 per 10 cigarettes per day, p < 0.001) were significantly associated with increased SPLC risk. Individuals who met the 2013 U.S. Preventive Services Task Force's screening criteria at IPLC diagnosis also had an increased SPLC risk (HR = 1.92; p < 0.001). Validation studies with the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and European Prospective Investigation into Cancer and Nutrition revealed consistent results. Meta-analysis yielded pooled HRs of 1.16 per 10 pack-years (pmeta < 0.001), 1.25 per 10 cigarettes per day (pmeta < 0.001), and 1.99 (pmeta < 0.001) for meeting the U.S. Preventive Services Task Force's criteria. In MEC, smoking cessation after IPLC diagnosis was associated with an 83% reduction in SPLC risk (HR = 0.17; p < 0.001).ConclusionsTobacco smoking is a risk factor for SPLC. Smoking cessation may reduce the risk of SPLC. Additional strategies for SPLC surveillance and screening are warranted.

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Tobacco smoking and methylation of genes related to lung cancer development.

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Tobacco smoking and methylation of genes related to lung cancer development.

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