Clinical Information

Glioblastoma is the most frequent malignant primary central nervous system (CNS) tumor in adults as originally defined based on morphology. Based on the 2021 World Health Organization (WHO) classification of CNS tumors, the original glioblastoma is now divided in "glioblastoma, IDH-wildtype, CNS WHO grade 4" (most cases) and "astrocytoma, IDH-mutant, CNS WHO grade 4." Current standard of care in both tumor types consists of surgical resection followed by radiotherapy in addition to alkylating chemotherapy with temozolomide.

MGMT (O[6]-methylguanine-DNA methyltransferase) encodes a DNA repair enzyme. This enzyme rescues tumor cells from alkylating agent-induced damage and confers tumor resistance to chemotherapy with alkylating agents. Epigenetic silencing of MGMT by promoter methylation of upstream and downstream CpG sites within differentially methylated regions results in decreased MGMT expression and presumably reduces MGMT-mediated DNA repair of alkylating agent-induced DNA damage in tumor cells.

In newly diagnosed original glioblastoma patients, MGMT promoter methylation has been shown to be a favorable prognostic biomarker and a strong predictor of responsiveness to alkylating chemotherapy. This is particularly relevant for older patients (>60-65 years), who may have decreased tolerance for combined chemoradiation. For this group of patients, MGMT promoter methylation status guides therapy decision making, as MGMT promoter methylation identifies patients who would benefit from monotherapy with the alkylating agent temozolomide instead of radiotherapy alone.

In IDH-mutant diffuse gliomas, MGMT promoter methylation is very frequent and occurs as part of the IDH mutation-induced glioma CpG island methylation phenotype; in infratentorial IDH-mutant astrocytomas, however, MGMT promoter methylation is less common. The prognostic and predictive significance of MGMT promoter methylation status in the context of IDH-mutant tumors is unclear. MGMT promoter methylation is also frequent in "diffuse hemispheric glioma, H3 G34-mutant" and limited data suggest that it is also a favorable prognostic marker in this tumor context.

MGMT promoter methylation status may be evaluated by multiple methods, and the testing platform with most prospective clinical trial validation is methylation-specific polymerase chain reaction evaluating downstream CpG sites.