Abstract A064: Non-canonical Glioblastoma: Discovery of a prevalent TP53/PTEN co-altered subtype utilizing project GENIE

Background: The 2021 WHO classification defines IDH-wildtype glioblastoma by canonical markers (IDH-wildtype, TERT, EGFR & chromosomes 7/10 alterations). The "non-canonical" molecular drivers and clinical significance of tumors lacking these features remain undefined, representing a critical gap and potential therapeutic vulnerabilities in precision neuro-oncology. Methods: AACR project GENIE (v18.0-public) was accessed via cBioPortal, and a total of 6,048 IDH-wt Glioblastoma cases were identified. From a total of 6,048 IDH-wt Glioblastoma cases identified, canonical cases were defined and selected by the presence of concurrent TERT promoter mutation and EGFR amplification. These canonical cases were programmatically excluded, resulting in a final study cohort of 2,532 non-canonical IDH-wildtype GBM cases (42% of the total). Results: 6048 IDH-wt Glioblastoma cases were stratified from the AACR project GENIE registry. From which, a substantial non-canonical cohort of 2,532 patients (42%), representing a major, previously uncharacterized subset of IDH-wt Glioblastoma. The most frequent alterations were in TP53 (30%), PTEN (26%), and NF1(16%). Critically, TP53 and PTEN mutations exhibit highly significant co-occurance (Log2 Odds Ration: 0.544, p < 0.001), defining a predominant "TP53/PTEN co-altered" subtype. This distinct genomic architecture, driven by concurrent cell-cycle checkpoint and PI3K pathway dysregulation, indicates these tumors are biologically different from Glioblastoma. Conclusion: These findings identify a prevalent TP53/PTEN co-altered subgroup within IDH-wildtype Glioblastoma. The co-alteration pattern implies specific, therapeutic vulnerabilities: PTEN loss is a recognized predictive biomarker to AKT inhibitors in other solid tumors (OncoKB Level 3B), while concurrent TP53 mutation increases genomic instability, potentially enhancing susceptibility to DNA damage response agents like PARP inhibitors or immune checkpoint blockade. Consequently, the identified subtype is primed for biomarker-driven clinical trials evaluating these combination strategies. Our findings validate the molecular heterogeneity within IDH-wt Glioblastoma, while providing an essential molecular framework with distinct outcomes and enriched actionable targets, providing a strong rationale for stratified trial design in this overlooked patient subset. Citation Format: Ayah S. Alsmadi, Nour Ibrahim, Ayah Alzoubi, Tasneem Al Nu'eim. Non-canonical Glioblastoma: Discovery of a prevalent TP53/PTEN co-altered subtype utilizing project GENIE [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A064.