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
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
PURPOSE: Pediatric high grade glioma (pHGG) remains a fatal disease. Increasing the number of patient derived tumor models and reagents will encourage research in pHGG and support the ...translation of basic science research discoveries. This work describes a recent multi-institution initiative to provide such a resource. METHODS: pHGG tumors with associated clinical data were prospectively collected and sequenced through the Children’s Brain Tumor Tissue Consortium (CBTTC) and Pediatric Brain Tumor Atlas (PBTA) with data deposited into PedcBioPortal for easy access and visualization. Primary tumor was dissociated and cultured to create both adherent and glioma stem cell lines analyzed by targeted and WGS/RNA sequencing. A tissue microarray (TMA) of primary pHGG tumors was created and examined by immunohistochemistry. RESULTS: The pHGG set included 81 collection events (70 patients, 54% at diagnosis, median age of 11 yrs, 52% female, 43% hemispheric). Analysis of somatic mutations and copy number alterations of known glioma genes were of expected distribution (36% H3.3, 47% TP53, 24% ATRX and 7% BRAF V600E variants). There were rare germline variants in mismatch repair genes with resultant tumor hyper-mutation. At least one established adherent and/or suspension glioma stem cell line was generated from 22 (31%) patients and validated by targeted sequencing for driver pHGG mutations. A subset of lines had WGS and RNAseq profiling which computationally clustered with their parental primary tumors. The lines’ cell biology makeup and in vivo tumor formation was also evaluated. A pHGG TMA (n=77), including 37 (53%) of the sequenced pHGG tumors, showed concordance with mutation status when stained for ATRX, H3.3 K27M and TP53. CONCLUSION: The CBTTC and PBTA have created a freely available integrated resource of characterized pHGG primary tumors, corresponding cell lines and archival fixed tissue to advance translational research for pHGG.
Abstract
The Children’s Brain Tumor Network (formerly known as Children’s Brain Tumor Consortium- CBTTC) is a global organization pioneering a model of open-science medical research to improve ...treatment and discover cures. Started in 2011, our objective was to utilize a regulatory, agreement, and governance architecture to remove existing research barriers that slowed down the pace of research and collaboration. Our network now includes 17 institutions working together to empower research. As of December 2019, over 3,600 subjects have been enrolled resulting in collection of over 45,000 specimens. Clinical data collection is longitudinal and includes medical history, diagnosis, treatment, pathology slides and reports, radiology imaging and reports, and outcome data. The tissue is collected flash-frozen, in freezing media, and fresh for the generation of pre-clinical models including cell lines. Blood is collected from the subject, with blood or saliva collected from the parents for germline comparison. Additionally, the Children’s Brain Tumor Network- Pediatric Brain Tumor Atlas has generated 952 WGS and RNAseq, 221 proteomics, with annotated clinical data. All of this data, both generated raw and processed data, has been made available broadly to the scientific community via cloud-based platforms, including the Gabriella Miller Kids First Data Resource Portal, Cavatica, and PedCbioportal. As of January 2020, we have 45 approved biospecimen requests and 80 genomic/molecular data requests. In summary, the Children’s Brain Tumor Network’s goal is to accelerate the pace of discovery by providing resources and expanding the network of scientists working towards a cure.
Abstract
BACKGROUND
Pediatric high grade glioma (pHGG) remains a fatal disease. Access to richly annotated biospecimens and patient derived tumor models will accelerate pHGG research and support ...translation of research discoveries. This work describes the pediatric high grade glioma set of the Children’s Brain Tumor Tissue Consortium (CBTTC) from the first release of the Pediatric Brain Tumor Atlas (PBTA).
METHODS
pHGG tumors with associated clinical data and imaging were prospectively collected through the CBTTC and analyzed as the Pediatric Brain Tumor Atlas (PBTA) with processed genomic data deposited into PedcBioPortal for broad access and visualization. Matched tumor was cultured to create high grade glioma cell lines analyzed by targeted and WGS and RNA-seq. A tissue microarray (TMA) of primary pHGG tumors was also created.
RESULTS
The pHGG set includes 87 collection events (73 patients, 60% at diagnosis, median age of 9 yrs, 55% female, 46% hemispheric). Operative reports, pathology reports and histology images are available for nearly all cases. Pre- and post-operative MRI images and reports are also available for a subset. Tumor WGS/RNAseq is available for 70 subjects. Analysis of somatic mutations and copy number alterations of known glioma genes were of expected distribution (36% H3.3, 47% TP53, 24% ATRX and 7% BRAFV600E variants). In our panel of pHGG, six patients (8 tumors) harbored germline mismatch repair mutations with tumor hyper-mutation. A pHGG TMA (n=77), includes 36 patient tumors with matched sequencing. At least one established glioma cell line was generated from 23 patients (32%). Unique reagents include those derived from a H3.3 G34R glioma and from tumors with mismatch repair deficiency.
CONCLUSION
The CBTTC and PBTA have created an openly available integrated resource of over 2,000 tumors, including a rich set of pHGG primary tumors, corresponding cell lines and archival fixed tissue to advance translational research for pHGG.
Abstract
The Pediatric Brain Tumor Atlas (PBTA), created as a multi-center effort by the Children’s Brain Tumor Tissue Consortium (CBTTC) and Pacific Pediatric Neuro-Oncology Consortium (PNOC) and ...supported by the Gabriella Miller Kids First Data Resource Center (DRC), has the initial goal of comprehensively characterizing over 1,600 clinically annotated pediatric brain tumor samples and making the data publicly available to cancer researchers worldwide in near real time and without embargo. PBTA comprises comprehensive clinical data in addition to whole exome sequencing, whole genome sequencing (WGS), RNA sequencing (RNASeq), miRNA sequencing, and proteomics. To address the need to inform novel discovery and clinical implementation of genomic approaches for diagnostic/therapeutic purposes, PBTA utilizes the cloud-based research environment of the Gabriella Miller Kids First DRC to provide near real-time integration, dissemination, processing, and sharing of associated petabyte-scale harmonized data. The PBTA initiative leverages the DRC platform’s users to access their dbGAP approved use of TARGET and other pediatric cancer datasets hosted by NCI’s Cancer Genomics’ Cloud and Genomic Data Commons, allowing for cross-disease studies. Processed annotations is further enabled for the PBTA via PedcBioPortal, a data visualization/analysis application further integrating additional public and deposited datasets. In its first data release are over 30 different types of pediatric brain tumors representing over 1,000 subjects. This data is available on the Kids First DRC Portal and PedcBioPortal and users can seamlessly move between applications. Data types include those for matched tumor/normal samples, such as WGS, RNASeq, proteomics, longitudinal clinical data, imaging data (MRIs and radiology reports), histology slide images, and pathology reports. CBTTC/PNOC promote real-time data release and collaborative discovery via shared resources. The combination of cloud-based analytic platforms with data from both genomics and clinical practice serves to define a new paradigm for accelerated pediatric cancer translational research.
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