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

Abstract

(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 (MGMT) and the Transforming Growth Factor Beta (TGFB) 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 TGFB1/2/3 and MGMT methylation in relation to OS, considering male versus female, age at diagnosis, and age interactions with TGFB2 gene methylation and sex variables. Reactome analysis was performed to identify enriched pathways negatively correlated with TGFB2 methylation. (3) Results: The GBM patients had high levels of TGFB2 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); p = 0.001) relative to the TGFB1highMe (HR (95% CI range) = 0.657 (0.454–0.951); p = 0.026) and MGMThighMe (HR (95% CI range) = 0.667 (0.475–0.936); p = 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); p = 0.023). (4) Conclusions: Increased levels of TGFB2 gene methylation predict improved OS, especially in young adult male GBM patients, above that of MGMT gene methylation, and should be considered during the administration of mRNA-based TGFB2 therapies.