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在胶质瘤进展过程中,DNMT1、MGMT 和 EGFR 基因的同时甲基化。

Concurrent hypermethylation of DNMT1, MGMT and EGFR genes in progression of gliomas.

机构信息

Department of Pathology, Faculty of Medicine, Pécs University, Hungary.

出版信息

Diagn Pathol. 2012 Jan 20;7:8. doi: 10.1186/1746-1596-7-8.

Abstract

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSION

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.

VIRTUAL SLIDES

The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1935054011612460.

摘要

背景

神经胶质瘤是最常见的脑肿瘤。高级别神经胶质瘤即使经过积极的手术切除和辅助放疗及化疗,也常常难以治疗。尽管采用了联合治疗,它们仍经常以相同或更高级别组织学复发。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致癌基因的激活有关,这种激活是由于启动子超甲基化的改变所致,但神经胶质瘤的组织学和临床进展的分子机制仍知之甚少。

方法

本研究通过对原发性和复发性神经胶质瘤的纵向分析样本,通过基于 PCR 的限制性酶分析来确定低级别和高级别神经胶质瘤的进展是否与 DNMT1、MGMT 和 EGFR 基因的启动子甲基化有关。在 18 例肿瘤复发患者的配对活检样本中分析了这三个重要的神经胶质瘤相关基因的表观遗传失活。

结果

在复发性神经胶质瘤中,DNA 甲基转移酶(DNMT1)启动子的 CpG 位点的甲基化分析总共显示出 6 个高甲基化(6/18),甲基鸟嘌呤-DNA 甲基转移酶(MGMT)启动子总共显示出 10 个高甲基化(10/18),表皮生长因子受体(EGFR)启动子总共显示出 12 个高甲基化(12/18)。结果表明,DNMT1 启动子的高甲基化不会发生在低级别神经胶质瘤中,主要发生在继发性胶质母细胞瘤中。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 GL 中均发生高甲基化。

结论

本研究进一步证明了神经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 启动子的高甲基化是神经胶质瘤克隆进化的早期事件,这种基因失活即使在肿瘤复发时也是稳定的。然而,DNMT 高甲基化是神经胶质瘤进展的晚期部分。

虚拟幻灯片

本文的虚拟幻灯片可在此处找到:http://www.diagnosticpathology.diagnomx.eu/vs/1935054011612460。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c431/3292961/58d1d9831af7/1746-1596-7-8-1.jpg

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