Differential DNA hypermethylation of critical genes mediates the stage-specific tobacco smoke-induced neoplastic progression of lung cancer
Differential DNA hypermethylation of critical genes mediates the stage-specific tobacco smoke-induced neoplastic progression of lung cancer
复制标题
DOI：
10.1158/1078-0432.ccr-04-1962
复制
发表时间：
2005-04-01
影响因子：
11.5
通讯作者：
Thiagalingam, S
中科院分区：
文献类型：
--
作者：
Russo, AL;Thiagalingam, A;Thiagalingam, S
使用甲基化特异性PCR（MSP）测定来自27个支气管上皮细胞的样品和来自22个前/当前吸烟者和5个非吸烟者的匹配血液样品以及49个原发性非小细胞肺癌样品和相应血液对照的6个基因的启动子DNA甲基化状态。肺肿瘤组织中p16、MGMT和DAPK基因启动子DNA甲基化的频率显著增高（P < 0.05; Fisher精确检验）。与所有其他分析样本相比，肿瘤中p16启动子DNA甲基化水平始终较高（P = 0.001; Fisher精确检验）。ECAD和DAPK在吸烟者肿瘤和支气管上皮细胞中的DNA甲基化水平显示统计学上无显著差异。有趣的是，在支气管上皮细胞和来自吸烟者的相应血液中观察到所有四个基因（ECAD、p16、MGMT和DAPK）的相似甲基化水平，这些基因显示吸烟/肺癌相关的甲基化变化。总之，我们的数据表明，ECAD和DAPK的靶向DNA甲基化沉默发生在肺癌进展的早期阶段，而p16和MGMT的靶向DNA甲基化沉默发生在肺癌进展的晚期阶段。我们还提供了初步证据，外周淋巴细胞可能被用作替代支气管上皮细胞检测吸烟者的DNA甲基化改变。
Promoter DNA methylation status of six genes in samples derived from 27 bronchial epithelial cells and matching blood samples from 22 former/current smokers and five nonsmokers as well as 49 primary non - small cell lung cancer samples with corresponding blood controls was determined using methylation-specific PCR (MSP). Lung tumor tissues showed a significantly higher frequency of promoter DNA methylation in p16, MGMT, and DAPK (P < 0.05; Fisher's exact test). p16 promoter DNA methylation in tumors was observed at consistently higher levels when compared with all the other samples analyzed (P = 0.001; Fisher's exact test). ECAD and DAPK exhibited statistically insignificant differences in their levels of DNA methylation among the tumors and bronchial epithelial cells from the smokers. Interestingly, similar levels of methylation were observed in bronchial epithelial cells and corresponding blood from smokers for all four genes (ECAD, p16, MGMT, and DAPK) that showed smoking/lung cancer -associated methylation changes. In summary, our data suggest that targeted DNA methylation silencing of ECAD and DAPK occurs in the early stages and that of p16 and MGMT in the later stages of lung cancer progression. We also provide preliminary evidence that peripheral lymphocytes could potentially be used as a surrogate for bronchial epithelial cells to detect altered DNA methylation in smokers.