Highlights d Proteogenomics characterization of 218 pediatric brain tumor samples of 7 histologies d Proteomic clusters reveal actionable biological features spanning histological boundaries d Proteomics reveal downstream effects of DNA alterations not evident in transcriptomics d Kinase activity analyses provide insights into pathway activities and druggable targets
We performed a comprehensive proteogenomic analysis across seven major types of childhood brain tumors for a deeper understanding of their functional biology. Whole genome seq, RNAseq, quantitative proteomic and phosphoproteomic profiling were performed on 219 fresh frozen tumor samples representing the histologic diagnoses of: low grade astrocytoma (93), ependymoma (32), high grade astrocytoma (26), medulloblastoma (22), ganglioglioma (18), craniopharyngioma (16) and atypical teratoid rhabdoid tumor (12). Characterization of the tumor microenvironment through multi-omics based deconvolution analyses revealed 5 distinct tumor clusters associated with different populations of infiltrating immune cells: Cold-medullo, Cold-mixed, Epithelial, Neuronal and Hot. The two cold-tumor clusters have the lowest immune cell infiltration, one characterized by the enrichment of medulloblastoma tumors; while the other is a mixture of ependymoma, ATRT, HGG and medulloblastoma. The Epithelial group, on the other hand, was enriched in craniopharyngioma samples, an epithelium derived tumor. Interestingly, the RNA levels of PD-1 and CTLA4 were significantly upregulated in this Epithelial group, confirming that craniopharingioma could potentially benefit from anti PD-1 and/or CTLA-4 therapies as previously reported. LLG and ganglioglioma were allocated into two groups of Neuronal and Hot, the former characterized by the presence of neuronal cells, and the latter by the presence of macrophages, microglia, and dendritic cells. Adenosine producers (e.g., ENTPD1 and NT5E), which act as inhibitory immune checkpoint molecular, showed up-regulation in the Hot cluster based on both RNAseq and proteome data, suggesting patients in this group might benefit from adenosine reducing treatments. Among LGG tumors, there is a significant difference between microglial and macrophage polarization across BRAF statuses: BRAF-fusion promoted more pro-regenerative (immune suppressive) microglia than pro-inflammatory microglia, while BRAF-V600E promoted more pro-regenerative macrophages than pro-inflammatory macrophages, implying different immunosuppressive mechanisms in the BRAF-V600E and fusion tumors. This study reports the first large-scale deep comprehensive proteogenomic analysis crossing traditional histologic boundaries to uncover foundational pediatric brain tumor biology relating to tumor microenvironment. The incorporation of the proteomic and phosphoproteomic dimension into this large-scale multi-omic study adds functional insight that helps drive translational efforts. Citation Format: Francesca Petralia, Nicole Tignor, Boris Reva, Pichai Raman, Shrabanti Chowdhury, Dmitry Rykunov, Azra Krek, Weiping Ma, Jiayi Ji, Xiaoyu Song, Yuankun Zhu, Jo Lynne Rokita, Antonio Colaprico, Anna Calinawan, Jeffrey R. Whiteaker, Richard G. Ivey, Zeynep Gumus, Selim Kalayci, Gonzalo L. Garcia, Seungyeul Yoo, Lizabeth Katsnelson, Ying Wang, Jacob J. Kennedy, Uliana J. Voytovich, Lei Zhao, Felipe Leprevost, Hui-Yin Chang, Krutika S. Gaonkar, Elizabeth M. Appert, Ximena Cuellar, Jena Lilly, Jun Zhu, Eric E. Schadt, Medhi Mesri, Emily Boja, Tara Hiltka, Henry Rodriguez, Li Ding, Antonio Iavarone, Maciej Wiznerowicz, Alexey I. Nesvizhskii, David Fenyo, Steven Gygi, Amanda Paulovich, Adam C. Resnick, Phillip B. Storm, Brian Rood, Pei Wang, Children's Brain Tumor Tissue Consortium and Clinical Proteomic Tumor Analysis Consortium. Integrated proteogenomic characterization across seven histological types of pediatric brain tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 445.
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.
Childhood cancers and structural birth defects share a common context of altered developmental biology, but the potential role of shared, genetic alterations and/or pathways across pediatric cancers and birth defects is not well explored. It is increasingly critical that genomic data are paired with high-quality clinical data to drive translational research by elucidating the relationship between genomic alterations, treatments, outcomes, and other phenotypic characteristics. The NIH Common Fund Gabriella Miller Kids First Program represents a first-in-kind national, collaborative initiative focused on large-scale clinical and genomic data sharing for childhood cancers and structural birth defects. As part of this program, the Kids First Data Resource Center (DRC) is charged with empowering collaborative discovery across Kids First datasets. Through newly developed cloud-based platforms, researchers will be able to rapidly and interactively access standardized and harmonized clinical and genomic data. A better understanding of common developmental programs could spur advancements in prevention, detection, and therapeutics that will improve the outcomes of affected children and families. Approximately 8,000 patient samples were available at the launch of the Kids First DRC portal, with an initial focus on whole genome sequencing (WGS) of trios and families. More than 25,000 WGS are expected to be processed by 2019, making the DRC one of the largest pediatric data resources of its kind across a diversity of diseases. The rise of cloud-based computing has greatly reduced the burden on the researcher of large-scale genomic harmonization. In normal operations, the DRC is capable of running two hundred workflows simultaneously with considerable scalability on demand. Additionally, there is a strong focus on harmonizing and structuring seemingly disparate clinical and phenotypic data types to make them more interoperable, discoverable and reusable by using ontologies. The data in the DRC is expertly curated and mapped to existing data standards, including NCI Thesaurus (NCIt), Human Phenotype Ontology (HPO), Monarch Disease Ontology (MONDO), and Uber-anatomy Ontology (Uberon). This allows for increased interoperability and semantic structure of the data. For example, MONDO integrates numerous disease terminologies into a single merged ontology, including the NCIt. The combination of harmonized genomic and clinical data across pediatric cancers and structural birth defect provides a key foundation for exploring and developing new methods to better understand the relationships between germline variants, cancer risk, and associated treatments and outcomes. Community standardization of this modeling is ongoing as part of GA4GH, and is critical for implementation of improved interpretation in EHR systems, for example via HL7 FHIR. Citation Format: Allison P. Heath, Deanne M. Taylor, Yuankun Zhu, Pichai Raman, Jena Lilly, Phillip Storm, Angela J. Waanders, Vincent Ferretti, Christina Yung, Michele Mattioni, Brandi Davis-Dusenbery, Zachary L. Flamig, Robert Grossman, Samuel L. Volchenboum, Sabine Mueller, Javad Nazarian, Nicole Vasilevsky, Melissa A. Haendel, Adam Resnick. Gabriella Miller Kids First Data Resource Center: Harmonizing clinical and genomic data to support childhood cancer and structural birth defect research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2464.
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 4,700 subjects, over 1,500 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 1,000 tumors and germline material is currently available with data generation for > 5,000 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.
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