Methylation-Expression Discordance Reveals Immune Pathway-Specific Epigenetic Dysregulation in IDH-Wildtype Glioblastoma

Background Glioblastoma (GBM) is the most common malignant primary brain tumor with poor prognosis despite multimodal therapy. Epigenetic dysregulation and immune microenvironment are key drivers of GBM aggressiveness. Methods A total of 111 IDH-wildtype GBM tumors were analyzed using integrated methylation and expression data. Regulatory state discordance was quantified by comparing methylation status with expression levels. Immune cell abundance was estimated via mean Z-score of curated marker genes. Associations with survival, copy number alterations (CNAs), and molecular subtypes were evaluated and validated in CPTAC proteomics data. Results Genome-wide methylation-expression coupling was subtle; however, gene-specific discordance enriched in immune pathways. Discordant Escape genes (methylated-high expression) were elevated in immune-hot tumors (14.9% vs. 12.2%, p < 0.001) and associated with PTEN loss (p = 0.018). Age emerged as independent prognosticator in multivariate Cox regression (HR = 1.38, p = 0.028), though proportional hazards assumption was violated. CPTAC proteomics analysis in 92 samples revealed subtype-specific immune protein patterns, though cross-platform validation of immune discordance scores was limited (r = − 0.003, p = 0.986). Conclusions Gene-specific methylation-expression discordance in immune regulation contributes to immune phenotype heterogeneity in GBM. Targeting epigenetically dysregulated immune genes may enhance immunotherapy response and improve outcomes.