Concurrent hypermethylation of DNMT1, MGMT and EGFR genes in progression of gliomas
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Updated: May 25, 2026

Quantitative Immunohistochemistry of the Cellular Microenvironment in Patient Glioblastoma Resections
Published on: July 31, 2017
Eva Gömöri1, József Pál, Bernadett Kovács
1Department of Pathology, Faculty of Medicine, Pécs University, Hungary. eva.gomori@kk.pte.hu
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.
Insights
Glioma progression involves promoter hypermethylation of MGMT and EGFR genes, which are early events. DNMT1 promoter hypermethylation is a later event in glioma development and recurrence.
Area of Science:
- Neuro-oncology
- Epigenetics
- Molecular Pathology
Background:
- Gliomas are primary brain tumors with poor prognosis.
- High-grade gliomas often resist treatment and recur.
- Molecular mechanisms of glioma progression are not fully understood.
Purpose of the Study:
- To investigate the association between glioma progression and promoter methylation of DNMT1, MGMT, and EGFR genes.
- To analyze epigenetic inactivation of these genes in paired primary and recurrent glioma samples.
Main Methods:
- Longitudinal analysis of primary and recurrent glioma samples.
- PCR-based restriction enzyme assay to detect promoter methylation.
- Analysis of DNA methyltransferase 1 (DNMT1), methylguanine-DNA methyltransferase (MGMT), and epithelial growth factor receptor (EGFR) gene promoters.
Main Results:
- MGMT and EGFR promoter hypermethylation occurred in both low- and high-grade gliomas and their transformed counterparts.
- DNMT1 promoter hypermethylation was primarily observed in secondary glioblastomas, not low-grade gliomas.
- Hypermethylation of MGMT and EGFR promoters was found in 10/18 and 12/18 recurrent gliomas, respectively.
Conclusions:
- EGFR and MGMT gene inactivation through promoter hypermethylation are associated with glioma histological transformation and progression.
- EGFR and MGMT promoter hypermethylation are early events in glioma evolution, remaining stable upon recurrence.
- DNMT1 promoter hypermethylation appears to be a late event in glioma progression.
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