Molecular Signature of the TP53 Pathway in Glioblastoma Genomics: Clinical Profiling and Integrated Analysis

Introduction: Glioblastoma multiforme (GBM) is the most fatal malignant astrocytic neoplasm, distinguished by molecular heterogeneity and unfavorable outcomes. Despite progress in molecular oncology, treatment alternatives remain limited. The TP53 signaling system is crucial for genomic integrity; however, its modification patterns in GBM are not fully elucidated. We conducted a comprehensive data analysis. Method: Genomic and clinical data from GBM patients were obtained via cBioPortal. Mutations, amplifications, and deletions in TP53, CDKN2A, MDM2, and MDM4 were analyzed using OncoPrint and Mutual Exclusivity. Clinical indicators, cancer categorization, and therapy status were evaluated. Statistical analyses included Fisher’s exact and Chi-square tests (P<0.05). Results: Data from 2,745 GBM cases (mean age=55 years) were analyzed. Of these, 91.4% were GBM and 8.6% glioma. Most tumors remained untreated (12.1%). OncoPrint indicated CDKN2A had the highest alteration frequency (54.7%), mainly deep deletions. TP53 mutations were mostly missense (18%). MDM2 (9%) and MDM4 (8%) were chiefly amplified. Mutual exclusivity showed significant associations as follows: CDKN2A–TP53, CDKN2A–MDM2, MDM2–TP53, and MDM4–TP53 (all P<0.001). Alterations related to DNA replication stress were found in ATM (1.8%), affecting CHEK2 and RPS6KA3 (<1%). Conclusion: This comprehensive bioinformatics study highlights that disruption of the TP53 pathway is critical in GBM etiology. Deletions of CDKN2A and amplifications of MDM2/ MDM4 represent key routes for TP53 inactivation. Rare alterations in ATM, CHEK2, and RPS6KA3 indicate new low-frequency genomic events. The findings suggest multidimensional bioinformatics profiling may provide novel diagnostic and therapeutic targets for GBM.