Glioblastoma (GBM) and low-grade glioma (LGG) are brain tumors with distinct molecular features. GBM represents the most aggressive primary brain tumor (median survival = 15 months, 5-year overall survival rate <10%) whose heterogeneity is reflected in distinct gene expression profiles.1 Non-coding alterations compromise nearly 98% of the genome and remain largely underexplored.2 In this scenario, the Pan-Cancer Analysis of Whole Genomes project detected numerous somatic single-nucleotide variations (SNVs) in gene regulatory elements, suggesting a functional impact on gene regulation. These mutations disrupt transcription factor binding sites, leading to dysregulated transcriptional programs.3 Enhancer elements (EEs), a class of gene regulatory elements, regulate proximal and distal gene expression and can become aberrantly activated in cancer, contributing to tumor progression.3 This study identified GBM-specific EEs affected by non-coding somatic SNVs in two independent and demographically diverse GBM patient cohorts (Spain and Sweden). Computational modeling demonstrated that these SNVs disrupted transcription factor (TF) binding motifs, altering the affinity of key TFs, such as transcriptional enhancer-associated domain (TEAD), early 2 factor 1 (E2F1), and signal transducer and activator of transcription 3 (STAT3), which are known to drive GBM malignancy. Our findings emphasize the role of non-coding SNVs in reprogramming the GBM epigenetic landscape and driving tumor progression through aberrant TF activity.