Age-Dependent Attenuation of the MGMT Methylation Survival Advantage in IDH-Wildtype Glioblastoma
O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation is an established prognostic and predictive biomarker in glioblastoma (GBM), yet its clinical utility may not be uniform across age groups. We analyzed 264 IDH-wildtype GBM patients from The Cancer Genome Atlas with complete data on MGMT promoter methylation status, transcriptomic subtype, and overall survival. Using Cox proportional hazards regression, we tested whether patient age modifies the prognostic effect of MGMT methylation. In a multivariable model adjusting for transcriptomic subtype, the interaction between MGMT methylation and age >=65 was statistically significant (HR = 2.14, 95% CI: 1.23-3.72, p = 0.01), indicating that the protective association of MGMT methylation diminishes substantially in elderly patients. Stratified analyses confirmed this pattern: MGMT methylation was associated with a significant survival advantage in patients aged 55-64 (HR = 0.46, 95% CI: 0.26-0.81, p = 0.007) but conferred no detectable benefit in patients >=65 (HR = 1.00, 95% CI: 0.60-1.67, p = 0.997). The age-dependent attenuation was consistent across Classical, Mesenchymal, and Proneural transcriptomic subtypes. These findings suggest that MGMT methylation status should be interpreted in the context of patient age, with implications for clinical decision-making in elderly GBM patients.