MGMT Expression Contributes to Temozolomide Resistance in H3K27M-Mutant Diffuse Midline Gliomas and MGMT Silencing to Temozolomide Sensitivity in IDH-Mutant Gliomas

Abstract

Histone H3 mutations are frequently found in diffuse midline gliomas (DMGs), which include diffuse intrinsic pontine gliomas and thalamic gliomas. These tumors have dismal prognoses. Recent evidence suggests that one reason for the poor prognoses is that O⁶-methylguanine-DNA methyltransferase (MGMT) promoter frequently lacks methylation in DMGs. This review compares the epigenetic changes brought about by histone mutations to those by isocitrate dehydrogenase-mutant gliomas, which frequently have methylated MGMT promoters and are known to be sensitive to temozolomide.

Keywords: Histone H3 mutation; MGMT; diffuse midline gliomas; epigenetics; resistance.

Fig. 1.

A schematic drawing showing the relationship between MGMT promoter methylation and MGMT protein expression. When the MGMT promoter is methylated, transcription is repressed and thus MGMT protein is not produced.

Fig. 2.

The main mechanism of action of temozolomide is to add a methyl-group at the O⁶ position of guanine (G) in the DNA of glioma cells, causing a methyl-guanine (meG)-to-thymine (T) mismatch at DNA replication, instead of cytosine (C). Mismatch repair genes locate the meG-T mismatch and remove the T, only to have a T re-inserted. This insertion and removal of T, called the “futile mismatch repair”, contributes to the vulnerability of tumor DNA and ultimately leads to apoptosis. MGMT, which is expressed in normal cells but lost in a percentage of brain tumors, removes the methyl group at the O⁶ position of guanine added by temozolomide, neutralizing its effect.

Fig. 3.

A flow chart showing the relationship between epigenetic changes in DNA, MGMT promoter methylation and response to temozolomide in IDH-mutant gliomas (left side) and diffuse midline gliomas with histone H3K27 mutations (right side).