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: 5.29). 02/2010; 12(2):116-21. DOI: 10.1093/neuonc/nop020
Source: PubMed

ABSTRACT 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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    • "Furthermore, Hegi et al. (2005) reported that patients treated with radiotherapy and temozolomide, and whose tumors had a methylated MGMT promoter (which is seen in approximately 40% of primary glioblastomas), survived significantly longer than did patients whose tumors lacked MGMT promoter methylation. Rivera et al. (2010) recently reported that MGMT promoter methylation in anaplastic gliomas (WHO grade III) is also predictive of the response to radiotherapy and linked to longer survival in the absence of adjuvant chemotherapy. The use of temozolomide based on MGMT methylation status highlights the importance of understanding epigenetic changes in glioblastomas for the discovery of novel therapies and prognostic factors for the treatment of this deadly cancer (Komine et al., 2003; Nakagawachi et al., 2003) "
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