MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma

Departments of Pathology and Radiation-Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit-0097, Houston, TX 77030, USA.
Neuro-Oncology (Impact Factor: 5.56). 02/2010; 12(2):116-21. DOI: 10.1093/neuonc/nop020
Source: PubMed


Hypermethylation of the O(6)-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, we 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.

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    • "Predicting tumor recurrence is a significant challenge for glioma treatment. Although it has been reported that methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter predicts patient response to radio- and chemotherapy as well as prognosis [11], [12], [13], [14], [15], it did not apply to all patients, and other studies were unable to find a correlation between MGMT methylation and prognosis [16]. This is complicated by the fact that MGMT methylation status can change between the first surgery for newly diagnosed glioblastomas, and the second surgery for a recurring tumor [17]. "
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    ABSTRACT: Objective This study explored the effects of telomerase reverse transcriptase (TERT) promoter mutations on transcriptional activity of the TERT gene under hypoxic and temozolomide (TMZ) treatment conditions, and investigated the status and prognostic value of these mutations in gliomas. Methods The effect of TERT promoter mutations on the transcriptional activity of the TERT gene under hypoxic and TMZ treatment conditions was investigated in glioma cells using the luciferase assay. TERT promoter mutations were detected in 101 glioma samples (grades I–IV) and 49 other brain tumors by sequencing. TERT mRNA expression in gliomas was examined by real-time PCR. Hazard ratios from survival analysis of glioma patients were determined relative to the presence of TERT promoter mutations. Results Mutations in the TERT promoter enhanced gene transcription even under hypoxic and TMZ treatment conditions, inducing upregulation of TERT mRNA expression. Mutations were detected in gliomas, but not in meningiomas, pituitary adenomas, cavernomas, intracranial metastases, normal brain tissues, or peripheral blood of glioma patients. Patients with TERT promoter mutations had lower survival rates, even after adjusting for other known or potential risk factors, and the incidence of mutation was correlated with patient age. Conclusion TERT promoter mutations were specific to gliomas. TERT promoter mutations maintained its ability of inducing high transcriptional activity even under hypoxic and TMZ treatment conditions, and the presence of mutations was associated with poor prognosis in glioma patients. These findings demonstrate that TERT promoter mutations are novel prognostic markers for gliomas that can inform prospective therapeutic strategies.
    Full-text · Article · Jun 2014 · PLoS ONE
    • "In study of Rivera et al., MGMT promoter hypermethylation was associated with longer progression-free survival and overall survival in glioblastoma patients who received no chemotherapy until the time of first tumor recurrence.[35] "
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    ABSTRACT: Background: High-grade astrocytoma (Grade 4) or glioblastoma multiforme (GBM) are deadly brain tumors. New therapies attempt to increase lifetime and quality of life in patients with malignant astrocytoma. O6-methylguanine-DNA methyltransferase (MGMT) enzyme expression may be effective in prognosis and response to treatment of these patients. The aim of this study was assessment of MGMT enzyme expression in patients with astrocytoma Grade 4. Materials and Methods: In this study, 48 patients with GBM that were treated with surgery, chemotherapy and radiotherapy were investigated and followed-up for 47 months for the survival rate. Pathology blocks of patients were examined for MGMT enzyme expression using immunohistochemistry method. Results: The patients were 34 males and 14 females. The ages ranged from 24 to 77 years, with a mean age of 53.52 ± 13.39 years. There was no significant difference between two groups (positive and negative MGMT enzyme expression) in overall survival (median [range] 11.5 [4-30] vs. 13 [5-22], P = 0.9). The results of our study showed that patients although who were undergone near total surgery had higher overall survival than the group of patients who had biopsy only however, it was not significant. Patients who were treated with temozolomide (TMZ) (Temodal, Merck Canada) had significant overall median survival (14.5) more than the patients who were treated with Procarbazine (Roche, Swiss)-Lomustine (Lilly, USA)-Vincristine (Lilly, USA) regimen (8.75) (P < 0.05). Conclusion: O6-methylguanine-DNA methyltransferase enzyme expression had no effect on survival of patients with Grade 4 brain astrocytoma TMZ may increase survival rate.
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    • "Loss of expression of the MGMT protein results in decreased DNA repair and retention of alkyl groups, thereby allowing alkylating agents such as carmustine (BCNU), lomustine (CCNU), and temozolomide to have greater efficacy in patients whose tumors exhibit hypermethylation of the MGMT promoter and reducing the MGMT protein concentration. [48]. This relationship between decreased expression of a DNA repair protein (MGMT) and better response to alkylating chemotherapies lead us to investigate the expression and phosphorylation status of DNA damage sensing proteins and DNA repair proteins in our dataset. "
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    ABSTRACT: LC-MS/MS phospho-proteomics is an essential technology to help unravel the complex molecular events that lead to and propagate cancer. We have developed a global phospho-proteomic workflow to determine activity of signaling pathways and drug targets in pancreatic cancer tissue for clinical application. Peptides resulting from tryptic digestion of proteins extracted from frozen tissue of pancreatic ductal adenocarcinoma and background pancreas (n = 12), were labelled with tandem mass tags (TMT 8-plex), separated by strong cation exchange chromatography, then were analysed by LC-MS/MS directly or first enriched for phosphopeptides using IMAC and TiO2, prior to analysis. In-house, commercial and freeware bioinformatic platforms were used to identify relevant biological events from the complex dataset. Of 2,101 proteins identified, 152 demonstrated significant difference in abundance between tumor and non-tumor tissue. They included proteins that are known to be up-regulated in pancreatic cancer (e.g. Mucin-1), but the majority were new candidate markers such as HIPK1 & MLCK. Of the 6,543 unique phosphopeptides identified (6,284 unique phosphorylation sites), 635 showed significant regulation, particularly those from proteins involved in cell migration (Rho guanine nucleotide exchange factors & MRCKα) and formation of focal adhesions. Activator phosphorylation sites on FYN, AKT1, ERK2, HDAC1 and other drug targets were found to be highly modulated (≥2 fold) in different cases highlighting their predictive power. Here we provided critical information enabling us to identify the common and unique molecular events likely contributing to cancer in each case. Such information may be used to help predict more bespoke therapy suitable for an individual case.
    Full-text · Article · Mar 2014 · PLoS ONE
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