Tobacco smoking and methylation of genes related to lung cancer development.
Tobacco smoking and methylation of genes related to lung cancer development.
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DOI：
10.18632/oncotarget.10007
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发表时间：
2016-09-13
期刊：
影响因子：
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通讯作者：
Brenner H
中科院分区：
文献类型：
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作者：
Gao X;Zhang Y;Breitling LP;Brenner H
肺癌是全球癌症相关死亡的主要原因，吸烟是其发病的主要环境危险因素。本研究旨在探讨吸烟是否会改变全基因组关联研究（GWAS）所确定的肺癌风险位点基因的甲基化。通过系统的文献综述，我们基于120个单核苷酸多态性（SNP）选择了75个基因组候选区域。在ESTHER研究的两个独立子样本中，使用Illumina Infinium Human Methylation450 Beadchip芯片阵列测量了全血样本中2854个相应的胞嘧啶 - 磷酸 - 鸟嘌呤（CpG）候选位点的DNA甲基化水平。经过多重检验校正后，我们成功证实了KLF6基因内一个先前确定的CpG位点与吸烟的关联，并确定了位于7个基因（STK32A、TERT、MSH5、ACTA2、GATA3、VTI1A和CHRNA5）中的12个新位点（错误发现率<0.05）。与从不吸烟者相比，当前吸烟者在11个位点的DNA甲基化降低了0.74% - 2.4%，并且除一个位点外，所有位点都与终生累积吸烟量（包 - 年）显示出显著关联（错误发现率<0.05）。总之，我们的研究证明了吸烟对肺癌相关基因DNA甲基化的影响，这可能表明肺癌易感基因可能通过甲基化变化来响应吸烟而受到调节。然而，这一机制在未来的表观遗传学和生物标志物研究中值得进一步探索。
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.