Multi-omic Data Analysis for Identification of Novel Biomarkers and Therapeutic Targets in Pediatric Brain Tumours

Abstract

This study provides comprehensive insights into the molecular characterization of medulloblastoma (MB) and pediatric high-grade gliomas (HGG), along with the similarities of genetically engineered mouse models of HGG MYCN-amplified and Group3 MB to human counterparts, aiding in the identification of potential therapeutic targets and personalized treatment strategies. Firslty, we focused on multi-omic profiling of MB, aiming to identify clinically relevant subtypes and alternative treatment targets. Through large-scale proteome analysis of FFPE MB tumours, harmonized with publicly available data revealed six stable proteomic clusters, each associated with distinct DNA methylome and transcriptome subtypes. Survival analysis highlighted pG3myc MB with least overall survival, while pWNT patients exhibited the best survival rate. Moreover, group-specific correlation analysis of DNA methylome and proteome data unveiled subtype-specific correlations, with PALMD as a potential biomarker identified for high-risk pG3myc subtype and TNC as a biomarker for the pWNT MB subtype with a good sruvival. Additionally, N-glycan profiling suggested differential immune therapy targets across high-risk MB subtypes. Then we investigated MYC/SMARCA4-driven MB formation in mice, characterizing these tumours on a molecular level and elucidating their similarity to human Group 3 MB. RNA sequencing highlighted upregulation of Myc and downregulation of genes associated with neuronal development. Integration with human MB datasets revealed molecular resemblance to Group 3 MB based on gene expression and DNA methylation patterns. Finally, we investigated mouse models of HGG with MYCN amplification, emphasizing their resemblance to human counterparts. DNA methylation and transcriptomic profiles of murine tumours demonstrated high similarity to human HGG-MYCN tumours. Comparison of SHH mouse models with its human counterpart confirmed expected similarities, indicating the utility of mouse models in studying human brain tumours and developing therapeutic strategies Overall, the study provides a comprehensive understanding of MB and HGG MYCN amplified tumours, emphasizing molecular subtypes, potential biomarkers, and therapeutic targets. These findings pave the way for personalized treatment strategies and improved patient outcomes in these devastating pediatric brain tumours.