Copy Number Variation and p53 Mutations in Sonic Hedgehog Medulloblastoma: Therapeutic Implications

The Sonic hedgehog subgroup of medulloblastoma (SHH-MB) originates from the cerebellar granule neuron progenitor (CGNP) population that relies on SHH pathway signaling for its perinatal expansion. Copy number variation (CNV) is a genomic structural variation that causes abnormal gene copy numbers including gene amplifications, gains, and losses. It is a vital factor regulating the expression of both protein-coding and non-coding genes, affecting various signaling pathways. Based on p53 mutations, the WHO has classified SHH-MB into two distinct prognostic categories. Here, we decipher the genomic patterns of SHH-MB tumors and evaluate the use of PI3K and HDAC inhibitors as therapeutic options. We utilized SHH-MB tumors (IRB-approved) from the Brazilian population to evaluate the genomic abnormalities using OncoScan CNV Plus-Assay and ChAS 4.2 software. Presence of isochromosome 17q [i(17q)] was determined by FISH. Effects of small molecule inhibitors targeting PI3K (Buparlisib; BKM-120) and HDAC (LBH-589) in SHH-MB cells (Daoy), were assessed via functional assays, such as cell proliferation, migration, cell cycle, and drug resistance. Results demonstrated: 1. Approximately 30% of patients exhibited i(17q) with multiple p53 mutations in the hotspot zone of the gene; 2. Other frequent genetic aberrations in IDH2:p.R140Q:c.419G>A (40%); PTEN:p.P248fs*5:c.741_742insA (60%); and KRAS:p.Q61H:c.183A>C (60%); 3. Some patients display aberrant chromosome 9; 4. Treatments with BKM-120 or LBH-589 or combined treatments inhibited cell proliferation, migration, cell cycle entry, and tumor formation of SHH-MB cells; 5. SHH-MB cells displayed resistance to BKM-120 treatments; 6. Western blotting analysis revealed that BKM-120 suppressed the activation of Akt and downstream target of mTOR, S6K, as evident by reduced levels of phosphorylation. In conclusion, we observed discrete genetic alterations in SHH-MB in a specialized population. The presence of i(17q) may define a poor prognosis and aberrant p53 is possibly an essential criterion for disease progression leading to therapy resistance. Furthermore, small molecule PI3K and HDAC inhibitors suppressed PI3K/AKT/mTOR pathways inhibiting cell proliferation, migration, and tumor formation. These studies provide evidence of genomic anomalies as well as treatment options for SHH-MB. Citation Format: Austin Carpenter, Mohan Das, Raphael Salles S Medeiros, Sidnei Epelman, Nelci Epelman, Zanon, Chirag D. Gandhi, Meena Jhanwar-Uniyal. Copy number variation in Sonic hedgehog-medulloblastoma with unique p53 mutations: Inhibition of PI3K/AKT/mTOR pathways with HDAC inhibitors can serve as therapeutic options [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1171.