Quantitative Analysis of the MGMT Methylation Status of Glioblastomas in Light of the 2021 WHO Classification

SIMPLE SUMMARY: The status of a DNA repair protein called MGMT is a prognostic marker in patients with glioblastomas, the most frequent malignant brain tumor. Epigenetic silencing of this gene predicts increased sensitivity to chemotherapy. Silencing is assessed by analyzing modifications, so-called methylation, of a certain gene region. Whereas most studies report such information only in a qualitative manner, quantitative testing might provide additional information. The aim of our study was to determine a quantitative threshold for better survival among patients with glioblastomas. Among 321 patients suffering from glioblastoma, we found better survival in patients with glioblastomas that have ≥16% methylation of a particular region of the MGMT gene. Above 16% methylation, we found no additional benefit with increasing degree of methylation. We suggest using this threshold for selection in clinical trials and for patient counseling. ABSTRACT: Background: Glioblastomas with methylation of the promoter region of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene exhibit increased sensitivity to alkylating chemotherapy. Quantitative assessment of the MGMT promoter methylation status might provide additional prognostic information. The aim of our study was to determine a quantitative methylation threshold for better survival among patients with glioblastomas. Methods: We included consecutive patients ≥18 years treated at our department between 11/2010 and 08/2018 for a glioblastoma, IDH wildtype, undergoing quantitative MGMT promoter methylation analysis. The primary endpoint was overall survival. Results: A total of 321 patients were included. Median overall survival was 12.6 months. Kaplan–Meier and adjusted Cox regression analysis showed better survival for the groups with 16–30%, 31–60%, and 61–100% methylation. In contrast, survival in the group with 1–15% methylation was similar to those with unmethylated promoter regions. A secondary analysis confirmed this threshold. Conclusions: Better survival is observed in patients with glioblastomas with ≥16% methylation of the MGMT promoter region than with <16% methylation. Survival with tumors with 1–15% methylation is similar to with unmethylated tumors. Above 16% methylation, we found no additional benefit with increasing methylation.