MGMT Status as a Clinical Biomarker in Glioblastoma

Abstract

Glioblastoma is the most common primary malignant brain tumor. Although current standard therapy extends median survival to ~15 months, most patients do not have a sustained response to treatment. While O⁶-methylguanine (O⁶-MeG)-DNA methyltransferase (MGMT) promoter methylation status is accepted as a prognostic and promising predictive biomarker in glioblastoma, its value in informing treatment decisions for glioblastoma patients remains debatable. Discrepancies between MGMT promoter methylation status and treatment response in some patients may stem from inconsistencies between MGMT methylation and expression levels in glioblastoma. Here, we discuss MGMT as a biomarker and elucidate the discordance between MGMT methylation, expression, and patient outcome, which currently challenges the implementation of this biomarker in clinical practice.

Keywords: MGMT; biomarker; glioblastoma; neuro-oncology; precision medicine.

Figure I.

Function of MGMT as determinant of response to TMZ A) Mechanism of MGMT-mediated repair of TMZ-induced DNA damage. Methylation of the O⁶ position of guanine by TMZ is removed by MGMT, and prevents cell killing by MMR. B) Proposed role of MGMT promoter methylation and expression as determinant of response to TMZ. When the MGMT promoter is methylated (top), silencing of transcription results in low MGMT protein expression. This promotes sensitivity to temozolomide in MMR-proficient cells due to lack of MGMT-mediated DNA damage repair. MMR-deficient cells do not respond to TMZ due to evasion of MMR-dependent DNA double-stranded breaks. When the MGMT promoter is unmethylated (middle), transcription of the MGMT gene results in high expression of MGMT protein, which is able to remove the alkylation adducts, promoting resistance to temozolomide. In some glioblastomas (bottom), MGMT is not expressed in spite of lack of promoter methylation. This promotes sensitivity to TMZ in MMR-proficient cells and resistance in MMR-deficient cells. Created with BioRender.com

Figure 1.

Association of MGMT mRNA expression with DNA methylation. A) Plot of MGMT gene expression levels and promoter methylation levels in glioblastoma cell lines using Genomics of Drug Sensitivity in Cancer Project (GDSC) data from CellMinerCDB (http://discover.nci.nih.gov/cellminercdb) [52]. Six cell lines were selected based on expression and promoter methylation for further visualization: 1) high expression and low promoter methylation (red), 2) low expression and low promoter methylation (green) and 3) low expression and high promoter methylation (blue). B) Promoter and C) gene body probe level methylation (beta values) of MGMT gene for the six selected cell lines.