MDB-19. MULTIOMIC PROFILING OF MEDULLOBLASTOMA REVEALS SUBTYPE-SPECIFIC TARGETABLE ALTERATIONS AT THE PROTEOME AND N-GLYCAN LEVEL

Abstract

Abstract Medulloblastomas (MBs) are malignant pediatric brain tumors which are clinically and histologically very heterogeneous. Epigenomic and transcriptomic analyses have advanced the understanding of these tumors and four main molecular subgroups – which themselves comprise several subtypes- have been defined: WNT-activated MB, Sonic hedgehog (SHH)-activated MB, Group3 and Group4 MB. Despite tremendous advances in classification and stratification, the pathogenesis of subtypes is still poorly understood and there is still a lack of targeted therapies. In contrast to nucleic acids, proteins more directly account for the phenotype and hold the potential to discover clinically relevant phenotypes, new biomarkers and therapy targets. In this study, we put together a harmonized cohort of 167 MB samples and integrated proteome data with DNA methylome and N-glycan data. At proteome level, we found six stable subtypes which could be assigned to two main molecular signatures namely-transcriptional/translational processes (pWNT, pG3myc and pSHHt) and synaptic/immunological processes (pG3, pG4 and pSHHs). pG3myc MB showed poor survival and accumulated high risk features such as anaplastic histology, epigenetic subtype II and MYC amplification. They showed an overlap of proteome patterns with favorable pWNT MBs but displayed significantly different protein abundancies of the vincristine resistance associated TriC/CCT complex and N-glycan turnover associated factors. Of note. N-glycan profiles distinguished MB subtypes and pG3myc MBs were enriched by complex bisecting N-glycans. We further identified Tenascin C (TNC) and Palmdelphin (PALMD) as suitable biomarkers for the pWNT and pG3myc MBs, respectively. Integration of proteome and DNA methylome data revealed that pWNT MBs showed the highest correlation of data modalities among MB subtypes, indicating a higher conservation of biological processes compared to other proteome subtypes. Our results shed light on new targetable alterations in MB and set a foundation for potential immunotherapies targeting glycan structures.