Concurrent hypermethylation of DNMT1, MGMT and EGFR genes in progression of gliomas.
Concurrent hypermethylation of DNMT1, MGMT and EGFR genes in progression of gliomas.
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DOI：
10.1186/1746-1596-7-8
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发表时间：
2012-01-20
影响因子：
2.6
通讯作者：
Dóczi T
中科院分区：
文献类型：
--
作者：
Gömöri E;Pál J;Kovács B;Dóczi T
神经胶质瘤是最常见的脑肿瘤。高级别胶质瘤即使采用积极的手术切除和辅助放疗和化疗也常常抵抗治疗。尽管联合治疗，他们经常复发相同或更高级别的组织学。遗传不稳定性通常与正常DNA修复功能和肿瘤抑制基因的失活以及启动子高甲基化改变导致的癌基因激活有关，但对胶质瘤组织学和临床进展的分子机制仍知之甚少。本研究涉及原发性和复发性胶质瘤的纵向分析样本，以确定低级别和高级别胶质瘤的进展是否与DNMT 1，MGMT和EGFR基因的启动子甲基化相关，通过基于PCR的限制性内切酶分析。这三个重要的神经胶质瘤相关基因的表观遗传失活进行了分析，在配对活检样本18例肿瘤复发。DNA甲基转移酶1（DNMT 1）启动子区CpG位点甲基化分析显示6例（6/18）高甲基化，甲基鸟嘌呤DNA甲基转移酶（MGMT）启动子区10例（10/18）高甲基化，表皮生长因子受体（EGFR）启动子区12例（12/18）高甲基化。结果表明，DNMT 1启动子高甲基化不发生在低级别胶质瘤，它主要是在继发性胶质母细胞瘤中观察到。此外，MGMT和EGFR启动子在低级别和高级别GL及其相应的组织学转化的GL中均高度甲基化。本研究进一步证明了胶质瘤的组织学转化和进展可能与EGFR和MGMT基因的失活有关。似乎EGFR和MGMT启动子高甲基化是胶质瘤克隆进化的早期事件，并且这种基因失活已被证明即使在肿瘤复发中也是稳定的。然而，DNMT高甲基化是胶质瘤进展的晚期部分。本文的虚拟幻灯片可以在这里找到：http://www.diagnosticpathology.diagnomx.eu/vs/1935054011612460
Gliomas are the most common neoplasm of the brain. High-grade gliomas often resist treatment even with aggressive surgical resection and adjuvant radiation and chemotherapy. Despite the combined treatment, they frequently recur with the same or higher-grade histology. Genetic instability is commonly associated with inactivation of the normal DNA repair function and tumour suppressor genes as well as activation of oncogenes resulting from alterations of promoter hypermethylation, but the molecular mechanisms of the histological and clinical progression of gliomas are still poorly understood. This study involved longitudinal analysis samples of primary and recurrent gliomas to determine whether the progression of low- and high-grade gliomas is associated with the promoter methylation of the DNMT1, MGMT and EGFR genes by PCR-based restriction enzyme assay. Epigenetic inactivation of these three important glioma-associated genes was analyzed in paired biopsy samples from 18 patients with tumour recurrence. The methylation analysis of the CpG sites in the DNA methyltransferase (DNMT1) promoter revealed a total of 6 hypermethylations (6/18), the methylguanine-DNA methyltransferase (MGMT) promoter revealed a total of 10 hypermethylations (10/18) and the epithelial grow factor receptor (EGFR) promoter revealed a total of 12 (12/18) hypermethylations respectively in recurrent gliomas. The results demonstrated that DNMT1 promoter hypermethylation does not occur in low-grade gliomas, it was mainly observed in secondary glioblastomas. Additionally, the MGMT and EGFR promoter was hypermethylated in both low-and high-grade GLs and their corresponding histological transformed GLs. This study has provided further evidence that the histological transformation and progression of gliomas may be associated with the inactivation of the EGFR and MGMT genes. It seems that EGFR and MGMT promoter hypermethylations are early events in the clonal evolution of gliomas and this gene inactivation has proved to be stable even in tumour recurrence. However, the DNMT hypermethylation is a late part of glioma progression. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1935054011612460
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DOI：
10.1073/pnas.93.18.9821
发表时间：
1996-09-03
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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