OBJECTIVE: Glioblastoma multiforme (GBM) is characterized by substantial heterogeneity and limited therapeutic options. As molecular approaches to central nervous system tumors have gained prominence, this study examined the roles of three genes, TWIST2, GATA3, and HES5, known to be involved in oncogenesis, developmental processes, and maintenance of cancer stem cell properties, which have not yet been extensively studied in GBM. This study is the first to present gene expression data for TWIST2, GATA3, and HES5 specifically within the context of GBM patient survival. METHODS: Gene expression data for TWIST2, GATA3, and HES5 were collected from GBM and normal brain tissues using datasets from The Cancer Genome Atlas via the Genomic Data Commons portal and the Genotype-Tissue Expression database. These data were rigorously analyzed using in silico methods. RESULTS: All three genes were significantly more expressed in GBM tissues than in normal tissues. TWIST2 and GATA3 were linked to lower survival rates in GBM patients. Interestingly, higher HES5 levels were associated with better survival rates, suggesting a complex role that needs more investigation. CONCLUSION: This study shows that TWIST2, GATA3, and HES5 could help predict outcomes in GBM patients. Our multigene model offers a better understanding of GBM and points to new treatment options, bringing hope for improved therapies and patient outcomes. This research advances our knowledge of GBM and highlights the potential of molecular diagnostics in oncology.