Pediatric brain and spinal cancer are the leading disease-related cause of death in children, thus we urgently need curative therapeutic strategies for these tumors. To accelerate such discoveries, the Children's Brain Tumor Network and Pacific Pediatric Neuro-Oncology Consortium created a systematic process for tumor biobanking, model generation, and sequencing with immediate access to harmonized data. We leverage these data to create OpenPBTA, an open collaborative project which establishes over 40 scalable analysis modules to genomically characterize 1,074 pediatric brain tumors. Transcriptomic classification reveals that TP53 loss is a significant marker for poor overall survival in ependymomas and H3 K28-altered diffuse midline gliomas and further identifies universal TP53 dysregulation in mismatch repair-deficient hypermutant high-grade gliomas. OpenPBTA is a foundational analysis platform actively being applied to other pediatric cancers and inform molecular tumor board decision-making, making it an invaluable resource to the pediatric oncology community.

Pediatric brain tumors comprise a heterogeneous molecular and histological landscape that challenges most current precision-medicine approaches. While recent large-scale efforts to molecularly characterize distinct histological entities have dramatically advanced the field’s capacity to classify and further define molecular subtypes, developing therapeutic and less toxic molecularly-defined clinical approaches remains a challenge. To define new approaches to meet these challenges and advance scalable, shared biospecimen- and data-resources for pediatric brain tumors, the Children’s Brain Tumor Network and Pacific Pediatric Neuro-Oncology Consortium, in partnership with the Alex’s Lemonade Stand Foundation Childhood Cancer Data Lab, launched OpenPBTA, a global open science Pediatric Brain Tumor Atlas initiative to comprehensively define the molecular landscape of pediatric brain tumors. The initiative contains multi-modal analyses of research- and clinical-trial based DNA and RNA sequences from nearly 1,000 subjects (with 1,256 tumors) along with their longitudinal clinical data. The OpenPBTA’s open science framework for analysis tests the capacity of crowd-sourced collaborative architectures to advance more rapid, iterative and integrated discovery of the underlying mechanisms of disease across pediatric brain and spinal cord tumors. Since the launch of the project, OpenPBTA has collaboratively created reproducible workflows for integrated consensus SNV, CNV, and fusion calling, enabled RNA-Seq-based classification of medulloblastoma subtypes, and more than 25 additional DNA- and RNA-based analyses. The open-science platform and associated datasets and processed results provide a continuously updated, global view of the integrated cross-disease molecular landscape of pediatric brain tumors. Such biospecimen- and clinically-linked scalable data resources provide unprecedented collaborative opportunities for precision-based, personalized therapeutic discovery and drug development with the upcoming further integration of proteomic sample data (N >300) and drug response datasets, additionally diversifying the multimodal discovery potential of crowd-sourced approaches for accelerated impact for children with brain tumors.

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