Pediatric brain and spinal cancers are collectively 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 (CBTN) and Pacific Pediatric Neuro-Oncology Consortium (PNOC) created a systematic process for tumor biobanking, model generation, and sequencing with immediate access to harmonized data. We leverage these data to establish OpenPBTA, an open collaborative project with over 40 scalable analysis modules that genomically characterize 1,074 pediatric brain tumors. Transcriptomic classification reveals universal TP53 dysregulation in mismatch repair-deficient hypermutant high-grade gliomas and TP53 loss as a significant marker for poor overall survival in ependymomas and H3 K28-mutant diffuse midline gliomas. Already being actively applied to other pediatric cancers and PNOC molecular tumor board decision-making, OpenPBTA is an invaluable resource to the pediatric oncology community.
Display omitted
•OpenPBTA collaborative analyses establish resource for 1,074 pediatric brain tumors•NGS-based WHO-aligned integrated diagnoses generated for 644 of 1,074 tumors•RNA-Seq analysis infers medulloblastoma subtypes, TP53 status, and telomerase activity•OpenPBTA will accelerate therapeutic translation of genomic insights
The OpenPBTA is a global, collaborative open-science initiative that brought together researchers and clinicians to genomically characterize 1,074 pediatric brain tumors and 22 patient-derived cell lines. Shapiro et al. create over 40 open-source, scalable modules to perform cancer genomics analyses and provide a richly annotated somatic dataset across 58 brain tumor histologies. The OpenPBTA framework can be used as a model for large-scale data integration to inform basic research, therapeutic target identification, and clinical translation.
We report a comprehensive proteogenomics analysis, including whole-genome sequencing, RNA sequencing, and proteomics and phosphoproteomics profiling, of 218 tumors across 7 histological types of ...childhood brain cancer: low-grade glioma (n = 93), ependymoma (32), high-grade glioma (25), medulloblastoma (22), ganglioglioma (18), craniopharyngioma (16), and atypical teratoid rhabdoid tumor (12). Proteomics data identify common biological themes that span histological boundaries, suggesting that treatments used for one histological type may be applied effectively to other tumors sharing similar proteomics features. Immune landscape characterization reveals diverse tumor microenvironments across and within diagnoses. Proteomics data further reveal functional effects of somatic mutations and copy number variations (CNVs) not evident in transcriptomics data. Kinase-substrate association and co-expression network analysis identify important biological mechanisms of tumorigenesis. This is the first large-scale proteogenomics analysis across traditional histological boundaries to uncover foundational pediatric brain tumor biology and inform rational treatment selection.
Display omitted
•Proteogenomics characterization of 218 pediatric brain tumor samples of 7 histologies•Proteomic clusters reveal actionable biological features spanning histological boundaries•Proteomics reveal downstream effects of DNA alterations not evident in transcriptomics•Kinase activity analyses provide insights into pathway activities and druggable targets
Integrative proteogenomics analysis of pediatric tumors identifies common underlying biological processes and potential treatments as well as the functional effects of somatic mutations and CNVs driving tumorigenesis.
Abstract BACKGROUND Pediatric brain and spinal cord tumors are the leading cause of cancer-related mortality in children. An incomplete understanding of brain tumor biology and associated limited ...access to high-quality biological samples for research are the main factors driving the lack of clinical therapeutic development for pediatric brain tumors that recur or progress. Post-mortem tissue donation provides an unprecedented resource for addressing some of these limitations. METHODS The Gift from a Child (GFAC) program by the Swifty Foundation has a unique mission to increase post-mortem pediatric brain tissue donations through advocacy as well as the education of clinicians and families. Through GFAC’s strategic collaboration with the Children’s Brain Tumor Network (CBTN), CBTN has leveraged postmortem tissue to expand the Pediatric Brain Tumor Atlas (PBTA), a cross-histology multi-omics atlas resource. As part of the effort CBTN has sequenced and released data for over 350 post-mortem pediatric brain tumor specimens including multiple brain region sampling cases with specimen and sequencing quality metrics. RESULTS Here we present an assessment of postmortem samples and available multi-omic data on postmortem samples within the PBTA dataset. Data have been harmonized and released with no publication embargo. To access data, researchers can utilize existing open source data resources and platforms including PedCbioPortal and OpenPedCan to: (1) Identify tumor spatial and temporal specific alterations (2) Establish tumor evolution trajectory leading to therapeutic resistance and tumor progression; (3) Understand tumor heterogeneity longitudinally across multiple ‘omics layers; and (4) Identify and request specimens and derived tumor models. CONCLUSIONS Together, we present the largest deeply characterized cohort of postmortem pediatric brain tumor samples as powerful expansion of the PBTA cohort of >3,000 pediatric brain tumors. CBTN’s open-science model supported by the GFAC mission highlights the value and utility of autopsy-based specimen collection on behalf of improving outcomes for children with brain tumors.
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.
Abstract
Pediatric brain tumor preclinical development has suffered from the lack of robust in vitro and in vivo models that span the large number of brain tumor histologies. Opportunities for ...precision medicine approaches for solid and brain tumors are expanding, including immunotherapies, so it is essential to maximize access to preclinical models for studies of specificity, efficacy, and safety of treatments in ways that align patient models to patient samples and their clinical course. The Children’s Brain Tumor Network (CBTN) seeks to accelerate pediatric brain tumor research and discovery through support of the tumor model development program paired with molecularly characterized patient samples and longitudinal clinical data. This program focuses on the generation, characterization, and distribution of diverse models to investigators worldwide. Here we present currently available preclinical model resources comprising over 150 cell lines, organoids, and patient derived xenografts (PDX) developed and/or propagated at D3b at CHOP on behalf of CBTN. This platform maximizes the use of tumor tissue to generate a combination of cell lines, organoids and/or xenograft models grown in animals. To date, consortium-supported lines have been provided internationally to over 50 projects, encompassing basic biology and translational studies. Molecular data (whole genome sequencing and RNAseq) is currently available for over 80 models and a substantial portion of that cohort undergoes additional large-scale data generation and drug testing through collaborative work with Childhood Cancer Model Atlas, ProCan, and National Center for Advancing Translational Sciences. All models’ data are accompanied with patient molecular and clinical longitudinal information accessible through Kids First Data Resource, CAVATICA and PedcBio portals. This open-source repository model is an example of a unique research partnership supported by patients and their families and built with one mission – to accelerate therapeutic discovery for children suffering from brain tumors.
Abstract
Subsets of pediatric cancers, including high grade glioma (pHGG), have high rates of uniquely long telomeres, associated with ATRX gene mutations and alternative lengthening of telomeres ...(ALT). Ultimately, these cancers may benefit from a therapy stratification approach. In order to identify and further characterize pediatric brain tumors with telomere lengthening (TL), we determined the intratelomeric content in silico from paired WGS of 918 tumors from CBTTC Pediatric Brain Tumor Atlas (PBTA). The results were highly concordant with experimental assays to determine ALT in a subset of 45 pHGG tumors from the set. Overall, 13% of the PBTA cohort had telomere lengthening. We confirmed the highest rate of TL (37%) in the pHGG cohort (37/100 tumors; 30/82 patients). There was no statistical difference in age, gender or survival in subset analysis. As expected, the patient pHGG tumors with telomere lengthening were enriched for ATRX mutations (60%, q= 1.76e-3). However, 6 tumors without ATRX mutation also had normal protein expression, suggesting a different mechanism of inactivation or TL. The pHGG tumors with telomere lengthening had increased mutational burden (q=8.98e-3) and included all known pHGG cases (n=6) in the cohort with replication repair deficiencies. Of interest, the second highest rate of telomere lengthening was 9 subjects (24%) in the craniopharyngioma cohort. None of the craniopharyngioma tumors had ATRX mutations or low ATRX expression, and 55% of those with TL had CTNNB1 mutations. Finally, lower rates of telomere lengthening were found in medulloblastoma (10%), ependymoma (10%), low grade astrocytoma (8%) and ganglioglioma (7/47, 15%).
Abstract
Pediatric central nervous system cancers are the leading disease-related cause of death in children and there is urgent need for curative therapeutic strategies for these tumors. To address ...the urgency, Children’s Brain Tumor Network (CBTN) has advanced an open science model to accelerate the research discovery for pediatric brain tumors. In first phase of Open Pediatric Brain Tumor Atlas (OpenPBTA) effort CBTN together with Pacific Pediatric Neuro-Oncology Consortium (PNOC) and Gabriella Miller Kids First Data Resource Center (KFDRC) created and characterized over 1000 clinically annotated pediatric brain tumors.
The second phase of the OpenPBTA, through resource awards and collaboration across KFDRC, the NCI Childhood Cancer Data Initiative (CCDI), Clinical Proteomic Tumor Analysis Consortium (CPTAC), Center for Cancer Research and partnered institutions and foundations has expanded molecular characterization for an additional 1900 pediatric brain tumor patients and their families. This includes the processing and characterization of >8000 specimens across >50 brain tumor diagnoses. This expansion builds off multimodal data including whole genome, RNA, miRNA and methylation sequencing, proteomics, lipidomics and/or metabolomics. Molecular data is linked to longitudinal clinical data, imaging data, histology images, and pathology reports.
The data deposition in the cloud-based environment of the NCI’s CCDI and KFDRC to provide near real-time integration, dissemination, processing, and sharing capability. The approach leverages the DRC platform’s cloud-based computational environment through CAVATICA portal shareable pipelines. Data can be explored via PedcBioPortal, a data visualization/analysis application integrating additional public and deposited datasets.
This OpenPBTA expansion released with no embargo provides one of the largest deeply characterized cohorts of samples and associated clinical data for >3000 pediatric brain tumor patients. CBTN’s open-science, rapid-release model aims to accelerate pediatric biomarker and drug discovery research and supports clinical trial development on behalf of changing the outcome for kids with brain tumors.
Abstract
Pediatric brain tumor preclinical field suffered for years from the lack of in vitro and in vivo models. With the explosion of novel therapy approaches for solid and brain tumors, including ...the immunotherapies it is essential to maximize the access to preclinical models for preclinical specificity, efficacy as well and safety. One of the many ways the Children’s Brain Tumor Network (CBTN) accelerates the pediatric brain tumor research and discovery is through support of the tumor model development program. This program focuses on the generation, characterization, and distribution of diverse models to investigators worldwide provided free of charge. Here we present the resource platform with over 150 cell lines, organoids and patient derived xenografts (PDX) developed and/or propagated at D3b at CHOP on behalf of CBTN. This platform maximizes the tumor tissue use to generate a combination of cell line, organoids and/or xenograft models grown in animals. In recent years, consortium supported over 40 requests for cells lines used in basic biology and translational studies internationally. Current efforts focusing also on supporting large-scale data generation and testing through its collaborative model (Childhood Cancer Model Atlas, Procan, National Center for Advancing Translational Sciences) to maximize the molecular information available for each tumor model essential in preclinical screenings. The generated and returned to consortia data are bound with the deidentified patient clinical information and genomic data and freely available through Kid’s First Data, Cavatica and PedcBio portals. These efforts have already attracted interest from pharma stakeholders previously not observed in pediatric brain environment. This open-source repository model is an example of a unique research partnership supported by patients and their families and built with one mission to bring fast change to kids suffering from brain tumors.
INTRODUCTION:
The Children’s Brain Tumor Tissue Consortium (CBTTC) is a multi-institutional, international research collaboration comprised of 13 institutions utilizing an infrastructure of web based ...open source tools to accelerate pediatric brain tumor research. The CBTTC mission is to provide the largest accessible, de-identified, longitudinal clinical data set linked to available biospecimens and -omic data in the world.
METHODS:
Clinical data collection and protection of Personal Health Information (PHI) is a major research regulatory hurdle. The CBTTC database is protected by a custom designed electronic honest broker that maintains links from a subject to multiple research records in the physical biobank and data collection tool. Currently the CBTTC utilizes three interconnected open source tools; the biorepository portal, electronic honest broker and the harvest query tool. CBTTC biospecimen and clinical records are also connected via web-protocols to the pedCBioPortal, a genomic data visualization tool, and Cavatica, a cloud based infrastructure genomic data storage and analysis. These tools work concurrently and communicate over https protocols and complement well known research tools such as an enterprise laboratory management systems (LIMS) and REDCap for data management. They are further expanded to include imaging tools, pathology slide review, genomic analysis and file repository resources.
RESULTS:
The CBTTC integrates phenotypic and genomic data for pediatric brain tumors and associated biospecimens. The platform facilitates open ended longitudinal data collection currently reflecting 1,900 subjects and 9,140 specimens available for research. The CBTTC has empowered 16 unique hypothesis driven collaborative research projects to date (See:
www.cbttc.org
). Remarkably, researchers are able to link molecular biology findings with clinical information such as overall survival through the web-based interface.
DISCUSSION:
The web-platform based approach facilitates real-time collaboration with researchers around the world. The CBTTC continues to grow, with additional collaborating sites and data generation added each year.
PDF
