MDB-59. INTEGRATIVE PROTEO-GENOMICS TO DECIPHER MOLECULAR MECHANISMS UNDERLYING SUBGROUP-SPECIFIC HETEROGENEITY IN MEDULLOBLASTOMA

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Abstract BACKGROUND Medulloblastoma (MB), an aggressive pediatric brain cancer, poses significant treatment challenges due to its complex disease biology, comprising a collection of discrete molecular subtypes that require different treatment. Although the genomics, transcriptomics, and epigenetic landscapes of biologically distinct MB subgroups are well-annotated and have contributed to enhanced diagnostics and risk stratification, the intersection of these molecular layers with the MB proteome remains poorly defined METHODS To overcome this knowledge gap, we sought to create a deep proteomics and phospho-proteomics cohort from a large MB clinical trial cohort (SJMB12), comprising 166 primary patient tumors, complemented with matched DNA methylation, whole-exome sequencing (WES), and RNA sequencing (RNA-seq) datasets. Proteomics data were interrogated using unsupervised computational techniques and evaluated for pathway enrichment and kinase activity. To complement these bulk tumor datasets, we investigated the tumor microenvironment focusing on immune and glial cell populations, using single-nuclei RNA and ATAC sequencing (snRNA-seq and snATAC-seq) for validation RESULTS Distinct proteomics subgroups were identified, correlating with established MB clinical subgroups and unveiling previously unrecognized proteomics subgroups. The integration of proteomics with mutational data revealed downstream effects of genetic alterations not evident in the transcriptome, implicating novel molecular mechanisms contributing to disease pathogenesis. Protein-protein interaction networks discovered novel signaling hubs and pathways, highlighting the power of proteomics to detect subgroup-specific drivers of disease that may represent attractive therapeutic vulnerabilities CONCLUSIONS Our multi-omics approach applied to a large series of primary MB patient tumors revealed novel mechanisms underlying MB subgroup biology that were previously hidden at the genetic, epigenetic, and transcriptional level. These findings offer a comprehensive, systems biology view of MB pathogenesis, fostering provocative insights that serve as a foundation for future discovery and the development of more effective personalized treatment strategies.

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