Background: Brain cancers are the most common solid tumors and the leading cause of cancer-related death in children. The causes of pediatric brain tumors are largely unknown. Epigenetic deregulation may likely play a pivotal role in their development, especially considering that the origin of these cancers may trace back to the in-utero period, which is largely driven by epigenetic mechanisms. Objectives: this project aims to define, as a proof-of-concept, whether epigenetic alterations associated with the development of brain tumors are present since birth, if they are detectable in tumor tissues and associate with patient prognosis, and whether they interplay with other omics layers (ie genomics and transcriptomics) to constitute multi-omic driver genes in pediatric brain cancers. We have recently demonstrated the feasibility of this approach in pediatric leukemia. Methods: Paediatric pilocytic astrocytomas and medulloblastoma cases will be recruited from King Abdulaziz Medical City, MNGHA hospitals, Riyadh. 30 Paediatric Brain tumour patients will be recruited from MNGHA hospital, Riyadh. Three types of samples will be collected from each patient: 1) resected brain tissue sample at diagnosis (pre-treatment); 2) blood sample at diagnosis (pre-treatment); and 3) blood sample at remission and relapse. Multi-omics investigation will include Whole Genome Sequencing, RNA-Sequencing and DNA Methylation array Sequencing. Expected Results: Such an innovative approach, spanning critical time points in pediatric brain cancer development, including birth, diagnosis, remission and relapse, cannot be implemented in single populations without international collaboration. Resources from several countries are needed to tackle this challenge and provide data and biospecimen spanning the various time points, especially given the rarity of pediatric cancers overall. Moreover, the availability of omics data on pediatric brain tumors is limited, especially multiple omic types profiled on the same brain tumor (eg. epigenomics, genomics and transcriptomics). In collaboration with IARC, KAIMRC can contribute with unique biospecimen and clinical and multi-omics data spanning diagnosis, remission and relapse from an understudied population, being Saudi Arabia. Implications: This project can lead to the discovery of molecular precursors and drivers that could be at the origins of pediatric brain cancers, with strong translational impact.