ABSTRACT
Adjuvant temozolomide-based chemotherapy has become the standard of care for most postoperative glioma patients. However, a large proportion of these patients do not respond to temozolomide. DNA repair enzyme O6-methylguanine-DNA methyl-transferase (MGMT) promoter methylation has emerged as an important molecular marker in patients with gliomas. It is associated with prognosis and resistance to alkylated drugs such as temozolomide. MGMT promoter methylation is the key mechanism of MGMT gene silencing, thereby inhibiting DNA repair and increasing the sensitivity of chemotherapy. We reviewed current data on the prog-nostic and predictive relevance of MGMT testing and clinical trials, summarized the clinical application of MGMT promoter methyla-tion, in order to provide reference for the individualized treatment of glioma patients.
ABSTRACT
OBJECTIVES: 1) To correlate the methylation status of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter to its gene and protein expression levels in glioblastoma and 2) to determine the most reliable method for using MGMT to predict the response to adjuvant therapy in patients with glioblastoma. BACKGROUND: The MGMT gene is epigenetically silenced by promoter hypermethylation in gliomas, and this modification has emerged as a relevant predictor of therapeutic response. METHODS: Fifty-one cases of glioblastoma were analyzed for MGMT promoter methylation by methylation-specific PCR and pyrosequencing, gene expression by real time polymerase chain reaction, and protein expression by immunohistochemistry. RESULTS: MGMT promoter methylation was found in 43.1 percent of glioblastoma by methylation-specific PCR and 38.8 percent by pyrosequencing. A low level of MGMT gene expression was correlated with positive MGMT promoter methylation (p = 0.001). However, no correlation was found between promoter methylation and MGMT protein expression (p = 0.297). The mean survival time of glioblastoma patients submitted to adjuvant therapy was significantly higher among patients with MGMT promoter methylation (log rank = 0.025 by methylation-specific PCR and 0.004 by pyrosequencing), and methylation was an independent predictive factor that was associated with improved prognosis by multivariate analysis. DISCUSSION AND CONCLUSION: MGMT promoter methylation status was a more reliable predictor of susceptibility to adjuvant therapy and prognosis of glioblastoma than were MGMT protein or gene expression levels. Methylation-specific polymerase chain reaction and pyrosequencing methods were both sensitive methods for determining MGMT promoter methylation status using DNA extracted from frozen tissue.