Changes of O6-Methylguanine DNA Methyltransferase (MGMT) Promoter Methylation in Glioblastoma Relapse-A Meta-Analysis Type Literature Review

Abstract

Methylation of the O⁶-methylguanine DNA methyltransferase (MGMT) promoter has emerged as strong prognostic factor in the therapy of glioblastoma multiforme. It is associated with an improved response to chemotherapy with temozolomide and longer overall survival. MGMT promoter methylation has implications for the clinical course of patients. In recent years, there have been observations of patients changing their MGMT promoter methylation from primary tumor to relapse. Still, data on this topic are scarce. Studies often consist of only few patients and provide rather contrasting results, making it hard to draw a clear conclusion on clinical implications. Here, we summarize the previous publications on this topic, add new cases of changing MGMT status in relapse and finally combine all reports of more than ten patients in a statistical analysis based on the Wilson score interval. MGMT promoter methylation changes are seen in 115 of 476 analyzed patients (24%; CI: 0.21-0.28). We discuss potential reasons like technical issues, intratumoral heterogeneity and selective pressure of therapy. The clinical implications are still ambiguous and do not yet support a change in clinical practice. However, retesting MGMT methylation might be useful for future treatment decisions and we encourage clinical studies to address this topic.

Keywords: MGMT promoter methylation; glioblastoma multiforme (GBM); glioma; recurrence; relapse; resistance; temozolomide; therapy.

Figure A1

PRISMA guidelines for methodological review of literature related to MGMT promoter methylation changes in glioblastoma relapse.

Figure 1

Example of two patients (patient 3 and 7) with a change in O⁶-methylguanine-DNA methyltransferase (MGMT) methylation status as determined by high-resolution melting PCR (HRM). Shown are the melting curves. The methodology has been described in detail elsewhere [37] and is highly accurate compared to methylation-specific PCR (MSP) [55]. (a) Patient 3 had a glioblastoma multiforme (GBM) which was methylated between 25% and 50%, while his two relapses were unmethylated. (b) Patient 7’s GBM had MGMT promoter methylation between 10% and 25%. His relapse was unmethylated. Patients’ details are summarized in Table 1.

Figure 2

Combined analysis of selected data from publications reporting changes in MGMT promoter methylation in GBM relapse using IBM SPSS Statistics 25 (IBM, New York, NY, USA). For this analysis only studies investigating at least 10 patients were included. In addition, changes were analyzed based on the cut-off value of the respective study and not based on the degree of methylation. In case MGMT promoter methylation was reported to be analyzed by two or more different methods, we focused on the method with the larger number of patients. Only patients with a reported MGMT status in the primary tumor and matching relapse were included. Therefore, these data often have been extracted from tables or supplementary material published with the respective paper. (a) Changes of MGMT promoter methylation in both directions. (b) Loss and (c) gain of MGMT promoter methylation. Black squares: percentage of patients with change, loss or gain of MGMT promoter methylation; arrows: 95% confidence interval (CI, calculated based on the Wilson score interval, [57]); vertical dashed line: overall percentage of MGMT promoter methylation changes from the combined analysis of the listed publications.