A cut-off value of 0.242% for was found to have strong diagnostic performance in glioblastoma patients.
High methylation levels (≥ 0.242%) are associated with significantly longer median overall survival (24 months vs. 12 months; p = 0.006).
The prognostic relevance of MGMT methylation status holds true across various surgical and anatomical subgroups.
High qMSP methylation (HR ≈ 0.45, p < 0.001) and an extent of resection ≥ 90% (HR ≈ 0.30, p = 0.002) are identified as independent predictors of improved survival.
TERT promoter mutation (HR ≈ 1.9, p = 0.017) is linked to worse survival outcomes.
Neocortical tumor involvement and excisional surgery are associated with significantly better survival (p = 0.0010 and p = 0.0218, respectively).
Simplified
BACKGROUND: Glioblastoma (GBM) is the most common and aggressive primary brain tumor, with limited survival despite multimodal treatment strategies. O6-Methylguanine-DNA Methyltransferase (MGMT) promoter methylation is a well-established predictive biomarker for response to temozolomide (TMZ) therapy. However, determining an optimal quantitative methylation-specific PCR () cut-off value remains a challenge in clinical practice.
OBJECTIVE: This study aimed to establish an optimal qMSP cut-off value for and validate its prognostic significance in GBM patients. The impact of MGMT methylation status on survival outcomes was analyzed concerning surgical extent, tumor localization, and white matter tract involvement.
METHODS: A retrospective analysis of 101 GBM patients (IDH-wildtype) diagnosed between 2008 and 2022 was performed. All patients underwent surgical resection (total/partial excision or stereotactic biopsy) followed by standard chemoradiotherapy. MGMT promoter methylation status was assessed using real-time qMSP. The optimal cut-off value was determined via receiver operating characteristic curve analysis. Kaplan-Meier survival analysis and Cox regression models evaluated the association between MGMT methylation levels, clinical characteristics, and overall survival (OS).
RESULTS: Among 101 patients with IDH-wildtype glioblastoma, a qMSP cut-off value of 0.242% demonstrated strong diagnostic performance for MGMT methylation status (AUC = 0.875), with 78% sensitivity and 86% specificity. Patients with high methylation levels (≥ 0.242%) showed significantly longer median overall survival compared to those with low methylation (24 vs. 12 months; p = 0.006). This prognostic relevance persisted across surgical and anatomical subgroups. Multivariable Cox regression identified high qMSP methylation (HR ≈ 0.45, p < 0.001) and extent of resection ≥ 90% (HR ≈ 0.30, p = 0.002) as independent predictors of improved survival, whereas TERT promoter mutation (HR ≈ 1.9, p = 0.017) was associated with worse survival. Stratified analysis revealed that TERTp-mutant tumors with low methylation had the worst outcomes. Additionally, excisional surgery and neocortical tumor involvement were associated with significantly better survival (p = 0.0010 and p = 0.0218, respectively). These findings validate within our institutional setting the clinical utility of the 0.242% qMSP threshold for prognostic stratification in glioblastoma, although external multicenter validation is warranted before generalization to routine clinical practice.
CONCLUSION: The identified qMSP cut-off value (0.242) based on the procedure described in this study provides a robust prognostic stratification tool for GBM patients. High MGMT methylation correlates with improved survival, supporting its integration into clinical decision-making. Further multi-center validation studies are warranted to establish standardized MGMT assessment methodologies.
Key numbers
0.875
Diagnostic Performance AUC
AUC from ROC analysis for cut-off determination.
24 months
Median Overall Survival
Median OS for patients with ≥ 0.242% vs. < 0.242%.
HR ≈ 0.45
Overall Survival Hazard Ratio
Hazard ratio from multivariable Cox regression analysis.
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Declarations. Ethics approval and consent to participate: The study was conducted in accordance with the Declaration of Helsinki, and the study was approved by the Medical Research Ethics Committee of Acıbadem University Institutions (No: ATADEK-2022-04/109). Informed consent was obtained from all participants. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
