O6-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that is important in predicting the effects of alkylating chemotherapeutic agents (e.g. temozolomide) in the treatment of high-grade gliomas (astrocytomas and glioblastomas).
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Mechanism of action
MGMT is an enzyme that removes the methyl group added to DNA by temozolomide in a one-step reaction that transfers the alkyl group from DNA to itself. It, therefore, undoes the damage done by temozolomide to DNA which would have led to eventual cell death 4.
Importantly, this reaction can occur only once per MGMT molecule, and therefore, the ability of MGMT to repair the damage done by temozolomide relies on the cell's ability to regenerate new MGMT molecules 4.
MGMT promoter methylation, which reduces MGMT expression, is very common in low-grade gliomas (80%) 2,5 and is almost invariably present in low-grade tumors with IDH mutations 3. In contrast, MGMT promoter methylation is far less common in higher grade gliomas (WHO grade 3 and 4), found in only 35-45% of such tumors 2.
Assessment
MGMT promoter methylation can be assessed with numerous techniques and no uniform consensus has been reached in regards to which technique is the most appropriate in clinical practice. Immunohistochemistry, nonquantitative methylation-specific polymerase chain reaction (MSP) and sequencing have all been used.
Viable (non-necrotic) tissue must be sampled to avoid false-negative results 2.
Prognostic impact
High activity of MGMT (i.e. unmethylated) results in reduced efficacy of alkylating agents, and thus is a poor prognostic factor 1,2.
On the other hand, when the MGMT promoter is methylated, there is decreased activity of MGMT and thus alkylating agents are more effective. In other words, the identification of methylated-MGMT is a positive prognostic factor 1. It is also predictive of pseudoprogression following Stupp protocol 2.
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