MGMT, NUPR1, NDRG2, and GLI1 Gene Promoter Methylation in Glioblastoma Tissues and Association with Clinical Characteristics and Therapeutic Outcomes

Glioblastoma (GBM) is the most prevalent and devastating form of primary brain tumors in adults, with dismal survival despite advancements in treatment modalities. The current study sought to develop clinically significant prognostic models for GBM patients by comprehensively profiling MGMT, NUPR1, NDRG2, and GLI1 gene promoter methylation in GBM tissues vs. non-neurooncological disease (NND) and their association with clinical characteristics and therapeutic outcome. This was further evaluated by in silico functional enrichment analysis. NUPR1, NDRG2, and GLI1 gene promoter methylation were significant epigenetic discriminators between GBM and NND. However, NDRG2 methylation was the sole independent predictor for neoplastic lesions (OR = 1.71, 95% CI [1.25-3.57], <i>p</i> = 0.028). Multivariable Cox regression analysis revealed that NUPR1 promoter hypermethylation was significantly correlated with a lower risk of mortality (HR = 0.96, 95% CI [0.96-0.99], <i>p</i> = 0.002), while multiple tumor sites were linked to an increased risk of mortality in the univariate model (HR = 4.44, 95% CI [1.42-13.88], <i>p</i> = 0.01). A heatmap correlation matrix identified a robust positive correlation among the MGMT and NUPR1 methylation status (r = 0.93, <i>p</i> < 0.001). NUPR1 and MGMT promoter hypermethylation was associated with a favorable response to temozolomide therapy. Patients with NUPR1 and MGMT hypermethylation exhibited extended OS and PFS compared to those with hypomethylation levels, whereas GLI1 and NDRG2 hypermethylation were linked to shorter PFS. In conclusion, the multi-faceted epigenetic panel adopted in the current study captures different aspects of GBM biology and moves towards a more comprehensive model that reflects the molecular heterogeneity of GBM as insights for personalized therapy.