Cis-regulatory element (cRE) mutations underlie hereditary cancers and may contribute significantly to sporadic cancer, but cancer genetics research to date has primarily focused on the protein coding exome. Non-coding mutations can contribute to tumorigenesis by altering transcription factor (TF) binding and the expression level of their target gene(s). Determining which cRE mutations are functional and act as drivers of a malignant phenotype in part depends on the cell type-specific chromatin state and the presence of relevant transcription factors. Only a fraction of cREs in the genome are active in a given cell type, and many show little conservation between species, making their identification difficult using comparative genomics alone. Recent advances in mapping histone modifications using ChIP-seq allows for the rapid identification of active cREs in any accessible tissue type. We generated these “chromatin state” maps from primary Glioblastoma (GBM) and adult normal brain tissues, and intersected publicly available GBM whole genome and transcriptome sequencing data to identify novel mutations in cREs. We identified the TERT promoter to be the most commonly mutated cRE in GBM patients. TERT gene expression is critical for the modulation of telomerase activity, the enzyme responsible for telomere maintenance, and TERT promoter mutations are among the most common genetic alterations observed across multiple cancer types. We identify the functional consequence of these mutations in GBM to be recruitment of the multimeric GABP transcription factor specifically to the mutant promoter. Allelic recruitment of GABP is consistently observed across four cancer types, highlighting a shared mechanism underlying TERT reactivation. This study provides an experimental and computational framework to identify driver cRE mutations that is widely applicable to most other tumor types.