CpG island promoter hypermethylation of the pro-apoptotic gene caspase-8 is a common hallmark of relapsed glioblastoma multiforme
CpG island promoter hypermethylation of the pro-apoptotic gene caspase-8 is a common hallmark of relapsed glioblastoma multiforme
复制标题
DOI：
10.1093/carcin/bgm014
复制
发表时间：
2007-06-01
期刊：
影响因子：
4.7
通讯作者：
Esteller, Manel
中科院分区：
文献类型：
--
作者：
Martinez, Ramon;Setien, Fernando;Esteller, Manel
多形性胶质母细胞瘤（GBM）是一种无法治愈的恶性肿瘤，具有固有的复发倾向。在这项研究中，我们比较分析了32对复发性GBM及其相应的原发性肿瘤的肿瘤样本的表观遗传学特征，特别注意参与非依赖于细胞凋亡途径的基因。通过甲基化特异性聚合酶链反应评估CpG岛启动子超甲基化状态，并通过亚硫酸氢盐基因组测序对所选样本进行双重检查。分析了13个基因的DNA甲基化：促凋亡CASP 8，CASP 3，CASP 9，DcR 1，DR 4，DR 5和TMS 1;细胞粘附CDH 1和CDH 13;候选肿瘤抑制因子RASSF 1A和BLU;细胞周期调节因子CHFR和DNA修复MGMT。复发GBM的CpG岛启动子高甲基化模式与其相应的原发性肿瘤相比，在37.5%的病例中是相同的，而在62.5%的患者中，观察到13个基因的DNA甲基化模式的差异。最显著的区别是GBM复发中存在先前未检测到的CASP 8超甲基化（P = 0.031）。这一发现也与以下观察结果有关：原发性GBM中未甲基化的CASP 8 CpG岛与甲基化的BLU启动子与肿瘤进展时间延长相关（P = 0.0035）。我们的数据有力地表明，促凋亡CASP 8的高甲基化是GBM复发的一个差异特征。这些显著的发现可能促进使用DNA去甲基化药物和外源性凋亡途径激活剂的治疗方法的发展，以改善GBM的不良预后。
Glioblastoma multiforme (GBM) is an incurable malignancy with inherent tendency to recur. In this study, we have comparatively analyzed the epigenetic profile of 32 paired tumor samples of relapsed GBM and their corresponding primary neoplasms with special attention to genes involved in the mitochondria-independent apoptotic pathway. The CpG island promoter hypermethylation status was assessed by methylation-specific polymerase chain reaction and selected samples were double checked by bisulfite genomic sequencing. Thirteen genes were analyzed for DNA methylation: the pro-apoptotic CASP8, CASP3, CASP9, DcR1, DR4, DR5 and TMS1; the cell adherence CDH1 and CDH13; the candidate tumor suppressor RASSF1A and BLU; the cell cycle regulator CHFR and the DNA repair MGMT. The CpG island promoter hypermethylation profile of relapsed GBM in comparison with their corresponding primary tumors was identical in 37.5% of the cases, whereas in 62.5% of patients, differences in the DNA methylation patterns of the 13 genes were observed. The most prominent distinction was the presence of previously undetected CASP8 hypermethylation in the GBM relapses (P = 0.031). This finding was also linked to the observation that an unmethylated CASP8 CpG island together with methylated BLU promoter in the primary GBM was associated with prolonged time to tumor progression (P = 0.0035). Our data strongly suggest that hypermethylation of the pro-apoptotic CASP8 is a differential feature of GBM relapses. These remarkable findings may foster the development of therapeutic approaches using DNA demethylating drugs and activators of the extrinsic apoptotic pathway to improve the dismal prognosis of GBM.