Epigenome-wide DNA methylation signature of benzo[a]pyrene exposure and their mediation roles in benzo[a]pyrene-associated lung cancer development
Epigenome-wide DNA methylation signature of benzo[a]pyrene exposure and their mediation roles in benzo[a]pyrene-associated lung cancer development
复制标题
苯并[a]芘暴露的全表观基因组DNA甲基化特征及其在苯并[a]芘相关肺癌发展中的介导作用
DOI：
10.1016/j.jhazmat.2021.125839
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发表时间：
2021-04-19
影响因子：
13.6
通讯作者：
Guo, Huan
中科院分区：
文献类型：
--
作者：
Meng, Hua;Li, Guyanan;Guo, Huan
苯并[a]芘（B[a]P）是一种与肺癌风险增加相关的典型致癌物，但其潜在机制仍不清楚。本研究旨在通过两项涉及462名受试者的肺癌病例 - 对照研究，探究与苯并[a]芘暴露相关的全表观基因组DNA甲基化及其对苯并[a]芘 - 肺癌关联的中介作用。采用酶联免疫吸附测定（ELISA）和全基因组甲基化芯片分别检测外周血中苯并[a]芘二醇环氧化物 - 白蛋白（BPDE - Alb）加合物的血浆水平和全基因组DNA甲基化情况。进行全表观基因组的荟萃分析以分析BPDE - Alb加合物与DNA甲基化之间的关联。应用中介分析评估DNA甲基化对苯并[a]芘 - 肺癌关联的影响。我们确定了15个与BPDE - Alb加合物相关的CpG位点（P - 荟萃分析<1.0×10⁻⁵），其中5个位点（分别注释为UBE2O、SAMD4A、ACBD6、DGKZ和SLFN13的cg06245338、cg24256211、cg15107887、cg02211741和cg04354393）的甲基化水平分别介导了BPDE - Alb加合物与肺癌风险之间关联的38.5%、29.2%、41.5%、47.7%、56.5%，联合介导了58.2%。与传统因素[曲线下面积（AUC）= 0.788]相比，加入这些CpG位点对肺癌的判别能力有所提高，AUC范围为0.828 - 0.861。我们的研究结果强调DNA甲基化改变是苯并[a]芘暴露诱导肺癌发生的潜在中介因素。
Benzo[a]pyrene (B[a]P) is a typical carcinogen associated with increased lung cancer risk, but the underlying mechanisms remain unclear. This study aimed to investigate epigenome-wide DNA methylation associated with B[a]P exposure and their mediation effects on B[a]P-lung cancer association in two lung cancer case-control studies of 462 subjects. Their plasma levels of benzo[a]pyrene diol epoxide-albumin (BPDE-Alb) adducts and genome-wide DNA methylations were separately detected in peripheral blood by using enzyme-linked immunosorbent assay (ELISA) and genome-wide methylation arrays. The epigenome-wide meta-analysis was performed to analyze the associations between BPDE-Alb adducts and DNA methylations. Mediation analysis was applied to assess effect of DNA methylation on the B[a]P-lung cancer association. We identified 15 CpGs associated with BPDE-Alb adducts (P-meta < 1.0 x 10-5), among which the methylation levels at five loci (cg06245338, cg24256211, cg15107887, cg02211741, and cg04354393 annotated to UBE2O, SAMD4A, ACBD6, DGKZ, and SLFN13, respectively) mediated a separate 38.5%, 29.2%, 41.5%, 47.7%, 56.5%, and a joint 58.2% of the association between BPDE-Alb adducts and lung cancer risk. Compared to the traditional factors [area under the curve (AUC) = 0.788], addition of these CpGs exerted improved discriminations for lung cancer, with AUC ranging 0.828-0.861. Our results highlight DNA methylation alterations as potential mediators in lung tumorigenesis induced by B[a]P exposure.