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mgmt_promoter_methylation

MGMT promoter methylation

Methylation of the gene's promoter may play a significant role in carcinogenesis.

Although O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation status is an important marker for glioblastoma multiforme (GBM), there is considerable variability in the clinical outcome of patients with similar methylation profles.

In patients with glioblastoma multiforme, the methylation state of the MGMT gene determined whether tumor cells would be responsive to temozolomide; if the promoter was methylated, temozolomide was more effective.

On a clinical level, this translates into a prolonged survival of glioblastoma patients with a methylated MGMT promoter. In addition, MGMT methylation can be used to predict patient survival in clinical prediction models.

For testing of the MGMT promoter methylation status in the clinical setting, DNA-based methods such as methylation-specific polymerase chain reaction (MS-PCR) or pyrosequencing are preferred over immunohistochemical or RNA- based essays.

The O6-methylguanine-DNAmethyltransferase (MGMT) promoter methylation and 1p19q codeletion status can predict sensitivity to chemotherapy and radiation in low- and intermediate-grade gliomas. Thus, these recent advances, which have led to a better understanding of how molecular, genetic, and epigenetic alterations influence the pathogenicity of the different histological grades of gliomas, can lead to better prognostication and may lead to specific targeted surgical interventions and medical therapies 1).

To what extent improved response reflects low or absent MGMT activity in glioma tissue has not been unequivocally assessed.

Results provide strong support for the hypotheses that MGMT activity promotes alkylator resistance and reflects promoter methylation status in malignant gliomas 2).


Temozolomide rechallenge is a treatment option for MGMT promoter-methylated recurrent glioblastoma. Alternative strategies need to be considered for patients with progressive glioblastoma without MGMT promoter methylation 3).


MGMT promoter methylation and IDH1 mutation were associated with pseudoprogression disease (psPD) and predicted a longer median survival in GBM patients after TMZ-based chemoradiotherapy. Genetic analyses of the MGMT promoter and IDH1 may allow us to effectively treat GBM patients 4).

Analysis

Several methods have been applied to its analysis, with methylation-specific polymerase chain reaction (MSP) the most commonly used for promoter methylation study, while immunohistochemistry (IHC) has become the most frequently used for the detection of MGMT protein expression. Agreement on the best and most reliable technique for evaluating MGMT status remains unsettled.

Protein expression assessed by IHC alone fails to reflect the promoter methylation status of MGMT. Thus, in attempts at clinical diagnosis the two methods seem to select different groups of patients and should not be used interchangeably 5).


Hypermethylation of the O6 methylguanine DNA methyltransferase (MGMT) gene has been shown to be associated with improved outcome in glioblastoma (GBM) and may be a predictive marker of sensitivity to alkylating agents. However, the predictive utility of this marker has not been rigorously tested with regard to sensitivity to other therapies, namely radiation.

To address this issue, Rivera et al. assessed MGMT methylation status in a cohort of patients with GBM who underwent radiation treatment but did not receive chemotherapy as a component of adjuvant treatment. Formalin-fixed, paraffin-embedded tumor samples from 225 patients with newly diagnosed GBM were analyzed via methylation-specific, quantitative real-time polymerase chain reaction following bisulfite treatment on isolated DNA to assess MGMT promoter methylation status. In patients who received radiotherapy alone following resection, methylation of the MGMT promoter correlated with an improved response to radiotherapy. Unmethylated tumors were twice as likely to progress during radiation treatment. The median time interval between resection and tumor progression of unmethylated tumors was also nearly half that of methylated tumors. Promoter methylation was also found to confer improved overall survival in patients who did not receive adjuvant alkylating chemotherapy. Multivariable analysis demonstrated that methylation status was independent of age, Karnofsky performance score, and extent of resection as a predictor of time to progression and overall survival. Our data suggest that MGMT promoter methylation appears to be a predictive biomarker of radiation response. Since this biomarker has also been shown to predict response to alkylating agents, perhaps MGMT promoter methylation represents a general, favorable prognostic factor in GBM 6).

1)
Chen R, Ravindra VM, Cohen AL, Jensen RL, Salzman KL, Prescot AP, Colman H. Molecular features assisting in diagnosis, surgery, and treatment decision making in low-grade gliomas. Neurosurg Focus. 2015 Mar;38(3):E2. doi: 10.3171/2015.1.FOCUS14745. PubMed PMID: 25727224.
2)
Bobola MS, Alnoor M, Chen JY, Kolstoe DD, Silbergeld DL, Rostomily RC, Blank A, Chamberlain MC, Silber JR. O(6)-methylguanine-DNA methyltransferase activity is associated with response to alkylating agent therapy and with MGMT promoter methylation in glioblastoma and anaplastic glioma. BBA Clin. 2015 Jun 1;3:1-10. PubMed PMID: 25558448; PubMed Central PMCID: PMC4280839.
3)
Weller M, Tabatabai G, Kästner B, Felsberg J, Steinbach JP, Wick A, Schnell O, Hau P, Herrlinger U, Sabel MC, Wirsching HG, Ketter R, Bähr O, Platten M, Tonn JC, Schlegel U, Marosi C, Goldbrunner R, Stupp R, Homicsko K, Pichler J, Nikkhah G, Meixensberger J, Vajkoczy P, Kollias S, Hüsing J, Reifenberger G, Wick W; DIRECTOR Study Group. MGMT Promoter Methylation Is a Strong Prognostic Biomarker for Benefit from Dose-Intensified Temozolomide Rechallenge in Progressive Glioblastoma: The DIRECTOR Trial. Clin Cancer Res. 2015 May 1;21(9):2057-64. doi: 10.1158/1078-0432.CCR-14-2737. Epub 2015 Feb 5. PubMed PMID: 25655102.
4)
Li H, Li J, Cheng G, Zhang J, Li X. IDH mutation and MGMT promoter methylation are associated with the pseudoprogression and improved prognosis of glioblastoma multiforme patients who have undergone concurrent and adjuvant temozolomide-based chemoradiotherapy. Clin Neurol Neurosurg. 2016 Oct 12;151:31-36. doi: 10.1016/j.clineuro.2016.10.004. PubMed PMID: 27764705.
5)
Brell M, Ibáñez J, Tortosa A. O6-Methylguanine-DNA methyltransferase protein expression by immunohistochemistry in brain and non-brain systemic tumours: systematic review and meta-analysis of correlation with methylation-specific polymerase chain reaction. BMC Cancer. 2011 Jan 26;11:35. doi: 10.1186/1471-2407-11-35. Review. PubMed PMID: 21269507; PubMed Central PMCID: PMC3039628.
6)
Rivera AL, Pelloski CE, Gilbert MR, Colman H, De La Cruz C, Sulman EP, Bekele BN, Aldape KD. MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma. Neuro Oncol. 2010 Feb;12(2):116-21. doi: 10.1093/neuonc/nop020. Epub 2009 Dec 14. Erratum in: Neuro Oncol. 2010 Jun;12(6):617. PubMed PMID: 20150378; PubMed Central PMCID: PMC2940581.
mgmt_promoter_methylation.txt · Last modified: 2017/09/05 17:27 by administrador