Positive Prognostic Overall Survival Impacts of Methylated TGFB2 and MGMT in Adult Glioblastoma Patients

(1) Background: Glioblastoma (GBM) is the most aggressive and common primary malignant brain tumor in adults, constituting 45.6% of tumors. We explored the impact of gene methylation of the O-6-Methylguanine-DNA Methyltransferase (<i>MGMT</i>) and the Transforming Growth Factor Beta (<i>TGFB)</i> gene complex using the TCGA dataset for GBM patients. (2) Methods: We implemented a multivariate Cox proportional hazards model to directly compare hazard ratios for <i>TGFB1/2/3</i> and <i>MGMT</i> methylation in relation to OS, considering male versus female, age at diagnosis, and age interactions with <i>TGFB2</i> gene methylation and sex variables. Reactome analysis was performed to identify enriched pathways negatively correlated with <i>TGFB2</i> methylation. (3) Results: The GBM patients had high levels of <i>TGFB2</i> gene methylation; this primarily benefited the young adult male patients, and multivariate analysis exhibited a significantly improved OS prognosis HR (95% CI range) = 0.04 (0.006-0.274); <i>p</i> = 0.001) relative to the <i>TGFB1^highMe</i> (HR (95% CI range) = 0.657 (0.454-0.951); <i>p</i> = 0.026) and <i>MGMT^highMe</i> (HR (95% CI range) = 0.667 (0.475-0.936); <i>p</i> = 0.019) groups of GBM patients. The Reactome pathways collectively represented T-cell activation, differentiation, effector functions, antigen presentation, and Toll-like receptor pathways. Gene level mRNA expression highlighted four positive prognostic genes upregulated in tumor tissues, and their expression was validated in independent single-cell RNA-seq experiments. These genes were highly expressed in macrophages (HIF1A, TRIM22, IRAK4, PARP9). In contrast, MALT1 mRNA expression was the only gene product with a negative prognostic impact on OS in GBM patients (HR (95% CI range) = 1.997 (1.1-3.625); <i>p</i> = 0.023). (4) Conclusions: Increased levels <i>of TGFB2</i> gene methylation predict improved OS, especially in young adult male GBM patients, above that of <i>MGMT</i> gene methylation, and should be considered during the administration of mRNA-based TGFB2 therapies.