Clinical Impact of MGMT Promoter Methylation in IDH ‐Mutant Gliomas: Influence of Threshold Selection and Clinical Confounding

BACKGROUND: The clinical relevance of MGMT promoter methylation in IDH-mutant gliomas remains controversial in the era of molecular classification. We aimed to systematically evaluate its clinical relevance by integrating quantitative assessment, cutoff exploration, and adjustment for clinical confounding. METHODS: A total of 558 patients with WHO grade 2-3 IDH-mutant gliomas were retrospectively analyzed. MGMT promoter methylation was quantified by pyrosequencing. Survival outcomes were assessed using Kaplan-Meier analysis and multivariable Cox regression. Multiple cutoff thresholds were examined, and PSM was applied to balance baseline characteristics. RESULTS: Quantitative methylation stratification demonstrated significantly shorter PFS and OS in unmethylated tumors compared with methylated tumors. However, no clear stepwise association between increasing methylation levels and survival was observed. Across cutoff thresholds (9%-25%), MGMT promoter methylation was consistently associated with improved PFS, whereas its association with OS varied and diminished at higher cutoffs. In the unmatched cohort, MGMT promoter methylation was significantly associated with prolonged PFS (HR = 0.53, 95% CI: 0.33-0.85, p = 0.009) and OS (HR = 0.39, 95% CI: 0.21-0.75, p = 0.005). Following PSM, the direction and magnitude of these associations remained comparable (PFS: HR = 0.47, 95% CI: 0.23-0.98, p = 0.044; OS: HR = 0.35, 95% CI: 0.12-1.05, p = 0.06), although statistical significance was less consistent. CONCLUSION: MGMT promoter methylation is associated with favorable clinical outcomes in IDH-mutant gliomas. Its prognostic significance appears to be influenced by treatment context, methodological factors, and cohort characteristics. These findings support a context-dependent interpretation of MGMT methylation and highlight the need for standardized analytical approaches in future studies.