Prognostic implications of DNA methylation machinery (DNMTs and TETs) expression in gliomas: correlations with tumor grading and patient survival

Purpose: DNA methylation is a crucial epigenetic modification that regulates gene expression and chromatin structure. Its dysregulation is linked to glioma progression and prognosis, particularly through alterations in methylation machinery. DNMTs and TETs play key roles in these processes, but their involvement in gliomagenesis remains complex, especially in the context of IDH mutations. This study examines the expression patterns of DNMT and TET family genes in gliomas to assess their prognostic significance and therapeutic potential. Materials and methods: mRNA expression levels of DNMT1, DNMT3A, DNMT3B, DNMT3L, TET1, TET2, TET3, and TDG were analyzed in 75 glioma samples and 10 normal controls using real-time quantitative PCR (qPCR). Statistical analyses and graphical representation were performed using R (v3.3.2) and RStudio (v1.4.1717), with p-values < 0.05 considered significant. Findings were validated using publicly available databases, TCGA and CGGA. Results: Compared to normal controls, DNMTs and TETs were significantly downregulated in gliomas, with expression levels inversely correlated with histological grade. Survival analysis using the log-rank test demonstrated a significant association between lower TETs and DNMTs expression and an increased risk of mortality. However, multivariate Cox regression analysis indicated that DNMTs and TETs expression were not independent prognostic markers for patient survival, suggesting their impact may be influenced by other clinical and molecular factors. Validation through online databases (TCGA and CGGA) showed that TET family expression across histological grades was consistent with our samples, whereas TDG and DNMT family expression differed. Conclusion: Our findings suggest that DNMTs and TETs may serve as therapeutic targets in glioma due to their downregulation and association with survival, with TET family members (TET1, TET2, and TET3) validated through online databases. However, their prognostic value is limited, as other clinical and molecular factors influence patient outcomes. The downregulation of DNMTs in our samples compared to online databases can be attributed to distinct epigenetic mechanisms: in IDH-mutant gliomas, DNMT suppression results from global hypermethylation (G-CIMP) due to 2-HG accumulation, which inhibits TET enzymes and disrupts DNA methylation homeostasis. In contrast, IDH-wildtype high-grade gliomas exhibit global hypomethylation, genomic instability, oncogenic signaling, and dedifferentiation, reducing the demand for active DNA methylation maintenance. These findings underscore the complex regulation of DNMTs and TETs in gliomas and their potential therapeutic implications.