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Simone Kreth LMU Munich, Germany |
Abstract
O6-Methylguanine-DNA-methyltransferase (MGMT) is a unique protein, which repairs DNA damage caused by alkylating agents. It has recently been linked to the therapeutic success of alkylating agent chemotherapy, such as temozolomide treatment: The relative expression of MGMT in the tumor may determine response to therapy. Epigenetic silencing of the MGMT gene by promoter methylation plays an important role in regulating MGMT expression. In human malignant gliomas – tumors with an extremely poor prognosis and rapid progression rates- it was shown that MGMT promoter methylation is correlated with improved progression-free and overall survival after temozolomide treatment. Thus, MGMT promoter methylation status is used as predictive factor for survival benefit of glioma patients from temozolomide therapy, based on the assumption that epigenetic silencing of the MGMT promoter leads to a decreased MGMT protein expression with a diminished ability of the tumour to repair chemotherapy-induced lesions. The real clinical impact of this assumption still is controversial as in 20 – 30 % of all cases MGMT CGI methylation status does not correlate with the clinical response to chemotherapy. In particular the rather high number of patients with response to treatment despite a non-methylated MGMT promoter indicates that the MGMT methylation status cannot yet be used to exclude patients from chemotherapy. In the current prospective study, we tested the predictive impact of MGMT mRNA expression in malignant glioma (65 patients) after radiotherapy and/or chemotherapy with temozolomide and its correlation with MGMT promoter methylation status. As a prerequisite, we first evaluated adequate reference genes that are stably expressed in malignant glioma using the RealTime ready Human Reference Gene Panel (Roche). MGMT mRNA expression was discordant to MGMT promoter methylation status in 30% of the evaluated tumors. In particular, 15% of the unmethylated tumors expressed unexpected low levels of MGMT mRNA; Low MGMT mRNA expression turned out to be an independent and strong prognostic factor for time to progression and length of survival in univariate and multivariale models (p<0.0001); patients with an unmethyleted tumor and low MGMT mRNA expression did significantly better than those with high mRNA expression. The determination of MGMT mRNA expression is a powerful method for predictive evaluation of malignant glioma patients undergoing chemotherapy with temozolomide. In particular, it allows to further stratify those patients with an unmethylated MGMT promoter.
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