Stueve Theresa Ryan, Li Wen-Qing, Shi Jianxin, Marconett Crystal N, Zhang Tongwu, Yang Chenchen, Mullen Daniel, Yan Chunli, Wheeler William, Hua Xing, Zhou Beiyun, Borok Zea, Caporaso Neil E, Pesatori Angela C, Duan Jubao, Laird-Offringa Ite A, Landi Maria Teresa
Department of Preventive Medicine.
USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
Hum Mol Genet. 2017 Aug 1;26(15):3014-3027. doi: 10.1093/hmg/ddx188.
Smoking-associated DNA hypomethylation has been observed in blood cells and linked to lung cancer risk. However, its cause and mechanistic relationship to lung cancer remain unclear. We studied the association between tobacco smoking and epigenome-wide methylation in non-tumor lung (NTL) tissue from 237 lung cancer cases in the Environment And Genetics in Lung cancer Etiology study, using the Infinium HumanMethylation450 BeadChip. We identified seven smoking-associated hypomethylated CpGs (P < 1.0 × 10-7), which were replicated in NTL data from The Cancer Genome Atlas. Five of these loci were previously reported as hypomethylated in smokers' blood, suggesting that blood-based biomarkers can reflect changes in the target tissue for these loci. Four CpGs border sequences carrying aryl hydrocarbon receptor binding sites and enhancer-specific histone modifications in primary alveolar epithelium and A549 lung adenocarcinoma cells. A549 cell exposure to cigarette smoke condensate increased these enhancer marks significantly and stimulated expression of predicted target xenobiotic response-related genes AHRR (P = 1.13 × 10-62) and CYP1B1 (P < 2.49 × 10-61). Expression of both genes was linked to smoking-related transversion mutations in lung tumors. Thus, smoking-associated hypomethylation may be a consequence of enhancer activation, revealing environmentally-induced regulatory elements implicated in lung carcinogenesis.
在血细胞中已观察到与吸烟相关的DNA低甲基化，且其与肺癌风险相关。然而，其成因及其与肺癌的机制关系仍不清楚。在肺癌病因环境与遗传学研究中，我们使用Infinium HumanMethylation450 BeadChip研究了237例肺癌病例的非肿瘤肺（NTL）组织中吸烟与全基因组甲基化之间的关联。我们鉴定出7个与吸烟相关的低甲基化CpG（P < 1.0×10-7），这些在来自癌症基因组图谱的NTL数据中得到了重复验证。其中5个位点先前报道在吸烟者血液中呈低甲基化，这表明基于血液的生物标志物可以反映这些位点在靶组织中的变化。4个CpG边界序列在原代肺泡上皮细胞和A549肺腺癌细胞中携带芳烃受体结合位点和增强子特异性组蛋白修饰。A549细胞暴露于香烟烟雾冷凝物中可显著增加这些增强子标记，并刺激预测的靶标外源生物反应相关基因AHRR（P = 1.13×10-62）和CYP1B1（P < 2.49×10-61）的表达。这两个基因的表达均与肺肿瘤中与吸烟相关的颠换突变有关。因此，与吸烟相关的低甲基化可能是增强子激活的结果，揭示了与肺癌发生有关的环境诱导调控元件。
