Tuesday, April 21, 2015
The Tumor Biomarker Series: MGMT
MGMT stands for O6-methylguanine-DNA methyltransferase. I must admit that this is my favorite biomarker only because of its cool mechanism of action. The standard chemotherapy for gliomas is temozolomide, which acts by cross-linking DNA through alkylating multiple sites including the 06 position of guanine. Crosslinking at this site is reversed by the DNA repair enzyme MGMT. Thus, low levels of MGMT activity by GBM cells is associated with enhanced response to alkylating agents such as temozolomide. To a large degree, the activity level of MGMT is determined by the methylation status of the gene's promoter. MGMT can be epigenetically silenced by hypermethylation. About half of all GBMs are epigenetically silenced in this manner and are therefore more susceptible to the alkylating action of temozolomide. The methylation status of MGMT can be assessed by PCR-based testing. In addition to predicting better response to temozolomide, investigators have shown that epigenetic gene silencing of MGMT is a strong predictor of prolonged survival independent of treatment.