CSIG-28. DISSECTING THE FUNCTIONAL IMPAIRMENT OF WILD-TYPE P53 IN HUMAN GLIOBLASTOMA

Abstract Glioblastoma (GBM) is the most common malignant brain tumor in adults and is characterized by heterogeneous nature, invasive potential, and poor treatment response. Work from The Cancer Genome Atlas (TCGA) identified the tumor suppressor gene TP53 as a GBM driver. In contrast to several cancers, only ~35% of GBM cases carry mutations in TP53. Work from our lab showed that TP53 mutations emerge as ‘late’ events during GBM growth. Therefore, we hypothesized that wild-type (wt) p53 function is impaired in GBM. We used the TCGA data of 591 GBM patients to compare the clinical and molecular characteristics of wt and mutant TP53 patients. Gene expression data were analyzed to compare the correlation of TP53 with the expression of key p53 regulators and identify differentially expressed regulators between our groups. Furthermore, we evaluated the expression of p53 and selected regulators in patient-derived cells (PDCs) and control lines with known TP53 status. Our results show that wt TP53 patients live less than mutant patients and both groups respond similarly to treatment. No differences in age, sex, race, TP53 levels, and MGMT methylation status were observed between the groups. Gene expression analyses revealed that MAPK8, a p53 activator, negatively correlates with TP53 in the wt group. Moreover, ~21% of p53 regulators are differentially expressed between wt and mutant patients. Among these, we selected SIRT3, a p53 repressor, for experimental validation. We verified the p53 genetic status of PDCs through western blot and confirmed Sirt3 expression in wt and mutant TP53 PDCs. By CRISPR-Cas9-based genomic editing, we are currently evaluating the impact of SIRT3 knockout in GBM-PDC and patient-derived xenografts. We expect that SIRT3 knockout will restore p53 function in the wt group. In conclusion, our results suggest that p53 function is impaired in wt patients and provide insights into mechanisms affecting its activity.