MGMT Promoter Methylation as a Prognostic Factor in Primary Glioblastoma: A Single-Institution Observational Study

Abstract

Glioblastoma is the most malignant central nervous system tumor, which represents 50% of all glial tumors. The understanding of glioma genesis, prognostic evaluation, and treatment planning has been significantly enhanced by the discovery of molecular genetic biomarkers. This study aimed to evaluate survival in patients with primary glioblastoma concerning O6-methylguanine–DNA methyltransferase (MGMT) promoter methylation and other clinical factors. The study included 41 newly diagnosed glioblastoma patients treated from 2011 to 2014 in the 10th Military Research Hospital and Polyclinic, Poland. All patients underwent surgical resection followed by radiation and chemotherapy with alkylating agents. The MGMT promoter methylation was evaluated in all patients, and 43% were found to be methylated. In 26 and 15 cases, gross total resection and subtotal resection were conducted, respectively. Patients with a methylated MGMT promoter had a median survival of 504 days, while those without methylation had a median survival of 329 days. The group that was examined had a median age of 53. In a patient group younger than 53 years, those with methylation had significantly longer overall survival (639 days), compared to 433.5 days for patients without methylation. The most prolonged survival (551 days) was in patients with MGMT promoter methylation after gross total resection. The value of MGMT promoter methylation as a predictive biomarker is widely acknowledged. However, its prognostic significance remains unclear. Our findings proved that MGMT promoter methylation is also an essential positive prognostic biomarker.

Standardizing analysis of intra‐tumoral heterogeneity with computational pathology

“…31 This event is found in 50% of patients and its ability to signal differential response to a specific therapy makes it a critical predictive biomarker in glioma care. 28,32 Lastly, IDH-wildtype glioblastoma were also shown to exhibit inter-patient transcriptional variation. Comparison of RNA profiles from large cohorts of glioblastomas revealed three well-accepted transcriptional subgroups coined proneural, classical, and mesenchymal.…”

“…Interestingly, a subset of patients show a repressive hypermethylation pattern in the MGMT promoter region resulting in an improved response to chemotherapy of ~3 months 31 . This event is found in ~50% of patients and its ability to signal differential response to a specific therapy makes it a critical predictive biomarker in glioma care 28,32 …”

“…23 Another clinically relevant form of inter-patient heterogeneity in glioblastoma is the epigenetic methylation status of the O 6 -methylguanine-DNA methyl-transferase (MGMT) gene promoter. [27][28][29] MGMT is a DNA repair enzyme that antagonizes alkylating agents and inhibits their function, including temozolomide (TMZ), the primary chemotherapy used in the treatment of glioblastoma. [27][28][29][30] Interestingly, a subset of patients show a repressive hypermethylation pattern in the MGMT promoter region resulting in an improved response to chemotherapy of 3 months.…”

“…[27][28][29] MGMT is a DNA repair enzyme that antagonizes alkylating agents and inhibits their function, including temozolomide (TMZ), the primary chemotherapy used in the treatment of glioblastoma. [27][28][29][30] Interestingly, a subset of patients show a repressive hypermethylation pattern in the MGMT promoter region resulting in an improved response to chemotherapy of 3 months. 31 This event is found in 50% of patients and its ability to signal differential response to a specific therapy makes it a critical predictive biomarker in glioma care.…”

MRI radiomics and potential applications to glioblastoma

“…Production of this enzyme is inhibited by methylation of its promoter region; therefore, methylation status can predict a patient's response to temozolomide therapy (33). Indeed, MGMT methylation status is the dominant predictor of increased survival in patients with glioblastoma, even showing significant value in patients with unresectable disease (34). Consequently, utilizing MRI to assess this gene's methylation status would have prognostic and treatment value.…”