A longitudinal single-cell and spatial multiomic atlas of pediatric high-grade glioma.

Pediatric high-grade glioma (pHGG) is an incurable central nervous system malignancy that is a leading cause of pediatric cancer death. While pHGG shares many similarities to adult glioma, it is increasingly recognized as a molecularly distinct, yet highly heterogeneous disease. In this study, we longitudinally profiled a molecularly diverse cohort of 16 pHGG patients before and after standard therapy through single-nucleus RNA and ATAC sequencing, whole-genome sequencing, and CODEX spatial proteomics to capture the evolution of the tumor microenvironment during progression following treatment. We found that the canonical neoplastic cell phenotypes of adult glioblastoma are insufficient to capture the range of tumor cell states in a pediatric cohort and observed differential tumor-myeloid interactions between malignant cell states. We identified key transcriptional regulators of pHGG cell states and did not observe the marked proneural to mesenchymal shift characteristic of adult glioblastoma. We showed that essential neuromodulators and the interferon response are upregulated post-therapy along with an increase in non-neoplastic oligodendrocytes. Through in vitro pharmacological perturbation, we demonstrated novel malignant cell-intrinsic targets. This multiomic atlas of longitudinal pHGG captures the key features of therapy response that support distinction from its adult counterpart and suggests therapeutic strategies which are targeted to pediatric gliomas.

Recent Developments in Blood Biomarkers in Neuro-oncology.

PURPOSE OF REVIEW: Given the invasive and high-risk nature of brain surgery, the need for non-invasive biomarkers obtained from the peripheral blood is greatest in tumors of the central nervous system (CNS). In this comprehensive review, we highlight recent advances in blood biomarker development for adult and pediatric brain tumors. RECENT FINDINGS: We summarize recent blood biomarker development for CNS tumors across multiple key analytes, including peripheral blood mononuclear cells, cell-free DNA, cell-free RNA, proteomics, circulating tumor cells, and tumor-educated platelets. We also discuss methods for enhancing blood biomarker detection through transient opening of the blood-brain barrier. Although blood-based biomarkers are not yet used in routine neuro-oncology practice, this field is advancing rapidly and holds great promise for improved and non-invasive management of patients with brain tumors. Prospective and adequately powered studies are needed to confirm the clinical utility of any blood biomarker prior to widespread clinical implementation.

OpenPBTA: The Open Pediatric Brain Tumor Atlas.

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.

Informatics Methods and Infrastructure Needed to Study Factors Associated with High Incidence of Pediatric Brain and Central Nervous System Tumors in Kentucky.

Pediatric brain and central nervous system tumors (PBCNSTs) are the most common solid tumors and are the leading cause of disease-related death in US children. PBCNST incidence rates in Kentucky are significantly higher than in the United States as a whole, and are even higher among Kentucky's Appalachian children. To understand and eventually eliminate such disparities, population-based research is needed to gain a thorough understanding of the epidemiology and etiology of the disease. This multi-institutional population-based retrospective cohort study is designed to identify factors associated with the high incidence of PBCNST in Kentucky, leveraging the infrastructure provided by the Kentucky Cancer Registry, its Virtual Tissue Repository (VTR), and the National Institutes of Health Gabriella Miller Kids First Data Resource Center (DRC). Spatiotemporal scan statistics have been used to explore geographic patterns of risk measured by standardized incidence ratios (SIRs) with 95% confidence intervals. The VTR is being used to collect biospecimens for the population-based cohort of PBCNST tissues that are being sequenced by Center for Data Driven Discovery in Biomedicine (D3b) at the Children's Hospital of Philadelphia (CHOP) with support from the Kids First DRC. After adjusting for demographic factors, we assess their potential relationship to environmental factors. We have identified regions in north-central and eastern Appalachian Kentucky where children experienced a significant increased risk of developing PBCNST from 1995-2017 (SIR, 1.48; 95% CI, 1.34-1.62). The VTR has been successful in the collection of a population-based cohort of 215 PBCNST specimens. Timely establishment of legal agreements for data sharing and tissue acquisition proved to be challenging which has been somewhat mitigated by the adoption of national agreement templates. Coronavirus disease 2019 (COVID-19) severely limited the generation of sequencing results due to laboratory shutdowns. However, tissue specimens processed before the shutdown indicated that punches were inferior to scrolls for generating enough quality material for DNA and RNA extraction. Informatics infrastructures that were developed have demonstrated the feasibility of our approach to generate and retrieve molecular results. Our study shows that population-based studies using historical tissue specimens are feasible and practical, but require significant investments in technical infrastructures.