The children's brain tumor network (CBTN) - Accelerating research in pediatric central nervous system tumors through collaboration and open science

Pediatric brain tumors are the leading cause of cancer-related death in children in the United States and contribute a disproportionate number of potential years of life lost compared to adult cancers. Moreover, survivors frequently suffer long-term side effects, including secondary cancers. The Children's Brain Tumor Network (CBTN) is a multi-institutional international clinical research consortium created to advance therapeutic development through the collection and rapid distribution of biospecimens and data via open-science research platforms for real-time access and use by the global research community. The CBTN's 32 member institutions utilize a shared regulatory governance architecture at the Children's Hospital of Philadelphia to accelerate and maximize the use of biospecimens and data. As of August 2022, CBTN has enrolled over 4700 subjects, over 1500 parents, and collected over 65,000 biospecimen aliquots for research. Additionally, over 80 preclinical models have been developed from collected tumors. Multi-omic data for over 1000 tumors and germline material are currently available with data generation for > 5000 samples underway. To our knowledge, CBTN provides the largest open-access pediatric brain tumor multi-omic dataset annotated with longitudinal clinical and outcome data, imaging, associated biospecimens, child-parent genomic pedigrees, and in vivo and in vitro preclinical models. Empowered by NIH-supported platforms such as the Kids First Data Resource and the Childhood Cancer Data Initiative, the CBTN continues to expand the resources needed for scientists to accelerate translational impact for improved outcomes and quality of life for children with brain and spinal cord tumors.


Introduction
Brain and other central nervous system (CNS) tumors are the leading cause of cancer-related death in children and frequently result in substantial long-term morbidity and disability [1] . Despite scientific advances in brain tumor biology across a large number of tumor types and histologies, improvements in long-term survival and quality of life for CNS tumors have remained elusive compared to other childhood cancers. Barriers to therapeutic advancement include lack of clinically-annotated biospecimens, insufficient preclinical models, and siloed, disconnected datasets [2] .
The mission of the Children's Brain Tumor Network (CBTN, https: //cbtn.org/ ), launched in 2011 as the Children's Brain Tumor Tissue Consortium (CBTTC), is to serve as a collaborative multi-institutional research consortium with a publicly-accessible biosample and data repository dedicated to the study and treatment of childhood brain tumors. CBTN seeks to address critical unmet needs for integrated, large-scale biospecimen, multi-omic, and longitudinally clinically-annotated resources. As of 2022, the CBTN comprises 32 member institutions within the United States, Italy, Switzerland, and Australia. To overcome the challenges of global, collaborative research and siloed resources, CBTN spearheaded the development of cloud-based informatics and data applications that allow researchers to access and collaboratively analyze datasets. As such, CBTN's foundation of "Innovation through Collaboration" is being realized through its creation of a state-of-the-art biorepository, innovative analytics platforms, and real-time sharing of data and specimens. By design, CBTN initiatives build upon the success of The Cancer Genome Atlas (TCGA) and Therapeutically Applicable Research To Generate Effective Treatments

Collaborative biobanking with the CBTN
Patients are consented by one of 32 participating sites and enrolled on a local IRB-approved protocol which includes key language to enable prospective collection of, future research on, and sharing of, de-identified surgical specimens, patient demographics, medical history, diagnoses, treatments, and clinical imaging. CHOP reviews each site's regulatory documents prior to submission and maintains copies along with annual approvals. When possible, site-enabled workflows support the generation of cell lines, organoids, and/or patient-derived orthotopic xenografts from available tissue ( Fig. 1 A).

Creation of the Pediatric Brain Tumor Atlas (PBTA)
Created as a multi-center, multi-omic effort, the CBTN's Pediatric Brain Tumor Atlas (PBTA) includes matched tumor-normal whole genome sequencing (WGS), tumor RNA-Seq, methylation, and proteomics, as well as longitudinal clinical data, images (MRIs, histology slides images, radiology reports), and pathology reports [3] . The first PBTA dataset release of nearly ( Fig. 1 B). A second dataset of nearly 5000 samples including tumor/normal WGS and RNA-seq, as well as parental germline WGS, jointly sponsored by GMKF and CCDI [4] , along with methylation data for > 1700 tumors, will be released with no embargo. Additionally, building upon an initial proteogenomic PBTA dataset generated in partnership with the NCI's Clinical Proteomic Tumor Analysis Consortium (CPTAC) [5] , a large > 400 sample proteogenomic cohort is underway.
In partnership with CHOP's Center for Data Driven Discovery and Biomedicine (D3b) and the NIH GMKF Data Resource Center, the PBTA data has been integrated into cloud-based resources within the GMKF portal ( http://kidsfirstdrc.org/ ) enabling cross-disease analysis with other GMKF datasets or those hosted by NCI's cloud resources, such as TCGA and TARGET. In 2019, Researchers at D3b and Alex's Lemonade Stand Foundation's Childhood Cancer Data Lab launched the Open Pediatric Brain Tumor Atlas (OpenPBTA). OpenPBTA is a first-inkind, open-science, collaborative analysis and manuscript-writing effort to comprehensively analyze PBTA tumors [6] . OpenPBTA openly provides reproducible workflows and processed data on GitHub, PedcBioportal, and CAVATICA supporting multiple research publications as well as informing clinical trial decision-making in molecular tumor boards [7] . OpenPBTA's success has paved the way for additional efforts such as OpenPedCan [8] currently informing the new pediatric Molecular Targets Platform ( https: //moleculartargets.ccdi.cancer.gov/ ) developed with the CCDI in support of the Research to Accelerate Cures and Equity (RACE) for Children Act [9] and the Schwannomatosis Open Research Collaborative led by SAGE Bionetworks [10] . CBTN promotes releasing data without embargo periods, allowing near real-time integration, dissemination, processing, and sharing of associated petabyte-scale harmonized data.
As of 2022, CBTN has supported 190 data projects and 111 biospecimen projects ( Fig. 1 C-D) spanning > 25,000 biosamples. CBTN-collected biospecimens are available for request via a common approval process by both members and non-members. Such common workflows have led to the publication of > 100 scientific articles and 25 abstracts in > 30 peer-reviewed journals.