Abstract 544: Dissecting the functional impairment of wild-type Tp53 in human glioblastoma

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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) has identified the tumor suppressor gene TP53 as one of the GBM drivers. However, in contrast to several cancers, only ~ 35% of GBM cases carry mutations in the TP53 gene. Furthermore, recent work from our lab showed that TP53 mutations emerge as ‘late’ events during GBM growth. This led us to hypothesize that wild-type (wt) Tp53 function is impaired in GBM. To test our hypothesis, we used clinical and molecular data of 591 GBM patients from TCGA and compared survival, age, gender, race, TP53 levels, and MGMT methylation status between wt and mutant patients. We also compiled a list of key players regulating Tp53 activity and used expression data to (i) compare the correlation of TP53 levels with the expression of each player and (ii) identify differentially expressed genes between our two groups. Our preliminary data suggest that wt TP53 patients live less in comparison to mutant patients and that both groups respond similarly to treatment, suggesting impairment of wt Tp53 function. We did not observe differences in age, sex, race, TP53 levels, or MGMT methylation status between the two groups. However, correlation analysis revealed that, among Tp53 activators, MAPK8 shows a strong negative correlation with TP53 expression in the wt group, raising the possibility that Tp53 function may be impaired. Furthermore, gene expression analysis of key Tp53 players showed that approximately 21% are differentially expressed between wt and mutant patients. Altogether, our results suggest that Tp53 function is impaired in wt patients and provide insights into the possible players affecting its activity. Our future work will focus on validating these results using GBM patient-derived cells and mouse models. Citation Format: Leopoldo A. García-Montaño, Yamhilette Licón Muñoz, Frank Martinez, Kandee Gallegos, Huining Kang, Sara G. Piccirillo. Dissecting the functional impairment of wild-type Tp53 in human glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 544.