MGMT Promoter Methylation as a Prognostic Factor in Primary Glioblastoma: A Single-Institution Observational Study (original) (raw)
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Bali Medical Journal, 2021
Background: O 6-methylguanine-DNA methyltransferase (MGMT) is a DNA-repair enzyme that correlates with tumor resistance mechanism to chemotherapy. Methylation of the MGMT promoter inhibits the cells from producing MGMT and is useful to predict chemotherapy's effectiveness with alkylating agents. This study aims to evaluate the MGMT promoter methylation of low-grade and high-grade glioma in the Neurosurgery Department of Cipto Mangunkusumo National General Hospital. Methods: We evaluated MGMT promoter methylation status using methylation-specific polymerase chain reaction in low and high-grade glioma patients who underwent surgical resection in the Neurosurgery Department of Cipto Mangunkusomo Hospital Jakarta. The result then correlated with age, sex, Karnofsky Performance Scale (KPS), and glioma grading. Data were analyzed using SPSS version 20 for Windows. Results: MGMT promoter methylation was observed more often in patients diagnosed with age more than 40 years old than in patients less than 40 years old (85.7% vs. 50.0%), also more in men than women (77.7% vs. 50.0%). In patients with KPS more than 70 and KPS 70 or less, methylation of MGMT promoter was observed in 70.0% and 57.1%, respectively. Based on tumor grading, MGMT promoter methylation was observed more often in low-grade gliomas (WHO grade II) than highgrade gliomas (WHO grade II and IV) (85.7% vs. 50.0%). There was no significant relationship between gender, age, KPS, malignancy degree, and Overall Survival (OS) to the MGMT promoter methylation (p>0.05). Conclusion: MGMT promoter methylation was observed less in the higher grade of tumors (grade IV), lower KPS, younger age at the time of diagnosis, and female patients, although the differences were not statistically significant. MGMT promoter methylation was observed more often in gliomas with oligodendroglioma components.
Prognostic significance of MGMT promoter methylation in diffuse glioma patients
Biotechnology & Biotechnological Equipment, 2019
Current treatment options for diffuse glioma patients include maximum safe resection followed by a combination of radiation therapy and chemotherapy with alkylating agents. The DNA-repair enzyme O 6-methylguanine-DNA methyltransferase (MGMT) counteracts the cytotoxic effect of alkylating agents and mediates chemoresistance. Disruption of the DNA methylation mechanism in diffuse glioma cells results in epigenetic silencing of MGMT through methylation of cytidinephosphate-guanosine dinucleotides (CpG) in the promoter region. The methylation status of MGMT is widely accepted to be a strong prognostic factor in diffuse glioma patients. This study was designed to screen Serbian diffuse glioma patients for hypermethylation of the MGMT promoter and to estimate its impact on overall survival. The results obtained in our study on 33 samples of diffuse glioma detected a positive methylation status in 17 patients (51.5%) by methylation-specific polymerase chain reaction. The positive methylation status of the MGMT promoter did not correlate with overall survival. In this study group, the patients older than 50 years had significantly lower overall survival in comparison with younger patients (7 months-19 months median survival). Extent of tumour resection also had influence on overall survival of patients. The relevance of the MGMT promoter methylation status should be further evaluated in a larger study and in association with other markers.
MGMT promoter methylation in malignant gliomas: ready for personalized medicine?
Nature Reviews Neurology, 2009
The DNA repair enzyme O 6-methylguanine-DNA methyltransferase (MGMT) antagonizes the genotoxic effects of alkylating agents. MGMT promoter methylation is the key mechanism of MGMT gene silencing and predicts a favorable outcome in patients with glioblastoma who are exposed to alkylating agent chemotherapy. This biomarker is on the verge of entering clinical decision-making and is currently used to stratify or even select glioblastoma patients for clinical trials. In other subtypes of glioma, such as anaplastic gliomas, the relevance of MGMT promoter methylation might extend beyond the prediction of chemosensitivity, and could reflect a distinct molecular profile. Here, we review the most commonly used assays for evaluation of MGMT status, outline the prerequisites for standardized tests, and evaluate reasons for difficulties in reproducibility. We critically discuss the prognostic and predictive value of MGMT silencing, reviewing trials in which patients with different types of glioma were treated with various chemotherapy schedules, either upfront or at recurrence. Standardization of MGMT testing requires comparison of different technologies across laboratories, and prospectively validated cutoff values for prognostic or predictive effects. Moreover, future clinical trials will need to determine, for each subtype of glioma, the degree to which MGMT promoter methylation is predictive or prognostic, and whether testing should become routine clinical practice.
2016
Background: Temozolomide (TMZ) plays an important role in the treatment of glioblastoma multiforme (GBM). O6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation has been described as a prognostic factor in patients with GBM treated by TMZ. However, the prognostic value of MGMT gene promoter methylation in GBM, as investigated by gel-based methylation-specific polymerase chain reaction (MS-PCR), remains unclear. Thus, this systematic review provides an overview of the prognostic value of methylated MGMT promoter in the patients with GBMs treated by TMZ as detected by gel-based MS-PCR. Method: The relevant literatures were conducted on PubMed, Medline and Cochrane databases. The outcomes including the median survival, median progression-free survival (PFS), survival rate, and PFS rate were extracted and analyzed. Results: Five studies were reviewed. The methylated MGMT promoter was described in 35% to 67.9% of patients. Median survival ranged from 16 to 43.6 months (m...
…, 2010
Glioblastoma is the most frequent and malignant brain tumor with most patients dying within 1 year after diagnosis. O 6 -Methylguanine DNA methyltransferase (MGMT) is implicated as a major predictive factor for treatment response to alkylating agents including temozolomide (TMZ). In general, epigenetic silencing of the MGMT gene by promoter methylation is associated with loss of MGMT protein expression. We investigated the correlation between MGMT protein expression and MGMT methylation status and the prognostic relevance of TP53 and Ki-67 in a series of glioblastomas. A total of twenty-eight patients between 2008 and 2011 were included in this study. Nineteen patients (68%) showed nuclear TP53 immunopositivity, and mean Ki-67 index was 27%. Immunohistochemistry for MGMT protein revealed high expression (¤30% positive cells) in 11 tumors, and low expression (‹30% positive cells) in 17 tumors. There was a good correlation between immunoreactivity for MGMT protein, Ki-67 index and tumor extent. MGMT promoter methylation as well as MGMT protein expression was completely uncorrelated to survival prediction; neither TP53 nor Ki-67 were correlated to survival. Our study confirms the role of the Ki-67 index and the extent of tumor as two important factors associated with prognosis of glioblastoma. In contrast, MGMT protein expression as well as the MGMT promoter methylation status does not provide prognostically relevant information.
Journal of Neuro-Oncology, 2008
Methylation of the promoter region of the O 6 -methylguanine-DNA methyltransferase (MGMT) gene is known to be predictive of response to temozolomide treatment in patients with glioblastoma. Contrastingly, little is known about variation in the methylation status of the MGMT promoter after treatment or across different regions of the same tumor. About 22 samples from 10 patients who had undergone multiple resections of a glioblastoma were examined with promoter sequencing. Of these, 20 were also analyzed using Methylation Specific PCR (MSP). The methylation status of the MGMT promoter was altered in the specimens obtained pre and post treatment in 2 of 9 samples as assessed by MSP and 7 out of 10 patients as assessed by promoter sequencing. In four patients, the MGMT promoter was unmethylated at primary surgery, but displayed some methylation (32, 44, 12, and 4%) on posttreatment sampling. Alteration in MSP status from unmethylated to methylated was also observed in 2 of these 4 patients. In another patient, methylation increased from 40% on initial sampling to 68% on the second sample. The remaining two patients initially demonstrated some degree of methylation (72% and 12%); subsequent sampling showed no methylation of the MGMT promoter. To ensure variable methylation status was not due to intra-tumoral variability, three to four specimens were sampled from different regions of large glioblastomas (n = 7). Promoter sequencing revealed minimal variation in methylation in all but two sites examined. Immunohistochemistry also demonstrated minimal change in MGMT expression across the tumors. This suggests that variation in MGMT promoter methylation can occur within the same tumor after treatment, necessitating caution in clinical decision-making based on this analysis.
Prognostic Impact of MGMT Promoter Methylation in Glioblastoma - A Systematic Review
Journal of Cancer Science & Therapy, 2014
MGMT promoter methylation is currently considered the main prognostic biomarker in glioblastoma, yet some concerns remain about its actual impact on outcome. The aim of the present study was to analyze literature data on this topic. Therefore, a systematic review and analysis of recently published glioblastoma cohorts examining the relationship between MGMT methylation and prognosis was performed. We found that only 19/28 studies (68%) confirmed the prognostic value of MGMT methylation and/or its role in predicting response to temozolomide. In these studies, however, the population showed significantly lower rates of unfavorable prognosticators as compared with studies where MGMT methylation was not prognostic/predictive. Moreover, studies demonstrating a better prognosis for MGMT methylated cases had significantly lower rates of deaths at 3 and 6 months. Multivariate analysis showed that the 3-month and 6-month deaths are significantly associated with the prognostic/predictive value of MGMT methylation, and that the percent of MGMT methylated tumors and of patients treated with alkylating drugs trend towards statistical significance if modeled with the 6-month but not with the 3-month mortality rate.
Neurology India, 2011
Assessment of promoter methylation of the O 6-methylguanine DNA methyltransferase (MGMT) gene has recently gained importance in molecular profiling of high-grade gliomas. It has emerged not only as an important prognostic marker but also as a predictive marker for response to temozolomide in patients with newly diagnosed glioblastoma. Further, recent studies indicate that MGMT promoter methylation has strong prognostic relevance even in anaplastic (grade III) gliomas, irrespective of therapy (chemotherapy or radiotherapy). This article provides an overview of its use as a predictive and prognostic biomarker, as well as the methods employed for its assessment and use in therapeutic decision making.
Journal of Neuro-Oncology, 2011
O 6 -methylguanine-DNA methyltransferase (MGMT) is known as a DNA repair protein, and loss of function in MGMT is related to an increase in survival in patients with malignant gliomas treated with alkylating agents. In the present study, we determined the status of MGMT using methylation-specific polymerase chain reaction (PCR) and immunohistochemistry on paraffin-embedded specimens in 12 human gliosarcomas, and these results were then related to overall survival (OS) and response to alkylating agents. The MGMT promoter was methylated in six patients. Immunostaining of MGMT was positive in 58.3% of patients. MGMT methylation status was correlated with immunostaining results in five patients (41.7%). The median OS and progression-free survival (PFS) of the whole population were 13.4 months [95% confidence interval (CI), 12.3-14.5 months] and 8.3 months (95% CI, 7.4-9.2 months), respectively. In patients with methylated MGMT promoter, median OS was 15.0 months, compared with 11.3 months in the unmethylated group. Median PFS of gliosarcoma patients was 10.3 months for the methylated group, whereas it was 7.3 months for the unmethylated group. On multivariate analysis, patients with methylated MGMT promoter had better prognosis than patients with unmethylated MGMT promoter with respect to OS and PFS (P = 0.045 and 0.034, respectively). However, there was no statistical significance between MGMT protein expression and survival. The results show that a significant fraction of gliosarcomas have MGMT promoter methylation and protein expression, and suggest that patient survival is associated with MGMT methylation status.
BBA clinical, 2015
CpG methylation in the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter is associated with better outcome following alkylating agent chemotherapy in glioblastoma (GBM) and anaplastic glioma (AG). To what extent improved response reflects low or absent MGMT activity in glioma tissue has not been unequivocally assessed. This information is central to developing anti-resistance therapies. We examined the relationship of MGMT activity in 91 GBMs and 84 AGs with progression-free survival (PFS) following alkylator therapy and with promoter methylation status determined by methylation-specific PCR (MSP). Cox regression analysis revealed that GBMs with high activity had a significantly greater risk for progression in dichotomous (P ≤ 0.001) and continuous (P ≤ 0.003) models, an association observed for different alkylator regimens, including concurrent chemo-radiation with temozolomide. Analysis of MGMT promoter methylation status in 47 of the GBMs revealed that methylated tumors ha...