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Abstract
Children diagnosed with brain tumors have the lowest overall survival of all pediatric cancers. Recent molecular studies have resulted in the discovery of recurrent driver mutations in many pediatric brain tumors. However, despite these molecular advances, the clinical outcomes of high grade tumors, including H3K27M diffuse midline glioma (H3K27M DMG), remain poor. To address the paucity of tissue for biological studies, we have established a comprehensive protocol for the coordination and processing of donated specimens at postmortem. Since 2010, 60 postmortem pediatric brain tumor donations from 26 institutions were coordinated and collected. Patient derived xenograft models and cell cultures were successfully created (76% and 44% of attempts respectively), irrespective of postmortem processing time. Histological analysis of mid-sagittal whole brain sections revealed evidence of treatment response, immune cell infiltration and the migratory path of infiltrating H3K27M DMG cells into other midline structures and cerebral lobes. Sequencing of primary and disseminated tumors confirmed the presence of oncogenic driver mutations and their obligate partners. Our findings highlight the importance of postmortem tissue donations as an invaluable resource to accelerate research, potentially leading to improved outcomes for children with aggressive brain tumors.
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1 Children’s National Hospital, Center for Genetic Medicine Research, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586); Children’s National Hospital, Brain Tumor Institute, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586)
2 Children’s National Hospital, Center for Genetic Medicine Research, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586); Children’s National Hospital, Brain Tumor Institute, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586); Dana-Farber Cancer Institute, Department of Pediatric Oncology, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910)
3 Children’s National Hospital, Center for Genetic Medicine Research, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586); Children’s National Hospital, Brain Tumor Institute, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586); The George Washington University School of Medicine and Health Sciences, Washington, USA (GRID:grid.253615.6) (ISNI:0000 0004 1936 9510)
4 Children’s National Hospital, Department of Pathology, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586); The George Washington University School of Medicine and Health Sciences, Washington, USA (GRID:grid.253615.6) (ISNI:0000 0004 1936 9510)
5 Children’s National Hospital, Brain Tumor Institute, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586); Children’s National Hospital, Center for Cancer and Immunology Research, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586)
6 Children’s National Hospital, Center for Genetic Medicine Research, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586); PTC Therapeutics, South Plainfield, USA (GRID:grid.417479.8) (ISNI:0000 0004 0465 0940)
7 Children’s National Hospital, Center for Genetic Medicine Research, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586)
8 Children’s Hospital of Philadelphia, Center for Data-Driven Discovery in Biomedicine, Philadelphia, USA (GRID:grid.239552.a) (ISNI:0000 0001 0680 8770)
9 UCSF Benioff Children’s Hospital, Pediatric Hematology-Oncology and Neurology, San Francisco, USA (GRID:grid.414016.6) (ISNI:0000 0004 0433 7727); Children’s Hospital of Philadelphia, Division of Oncology, Philadelphia, USA (GRID:grid.239552.a) (ISNI:0000 0001 0680 8770)
10 University of Maryland School of Medicine, Department of Pathology and Neurology, Baltimore, USA (GRID:grid.411024.2) (ISNI:0000 0001 2175 4264)
11 Northwestern University, Feinberg School of Medicine, Chicago, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507)
12 NeuroMarkers PLLC, Houston, USA (GRID:grid.16753.36)
13 University of Arizona College of Medicine, Department of Pathology, Tucson, USA (GRID:grid.134563.6) (ISNI:0000 0001 2168 186X)
14 National Cancer Institute, Pediatric Oncology Branch, Bethesda, USA (GRID:grid.48336.3a) (ISNI:0000 0004 1936 8075)
15 Children’s National Hospital, Brain Tumor Institute, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586)
16 UCSF Benioff Children’s Hospital, Pediatric Hematology-Oncology and Neurology, San Francisco, USA (GRID:grid.414016.6) (ISNI:0000 0004 0433 7727); University Children’s Hospital Zürich, Department of Oncology, Children’s Research Center, Zurich, Switzerland (GRID:grid.412341.1) (ISNI:0000 0001 0726 4330)
17 Children’s National Hospital, Center for Genetic Medicine Research, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586); University Children’s Hospital Zürich, Department of Oncology, Children’s Research Center, Zurich, Switzerland (GRID:grid.412341.1) (ISNI:0000 0001 0726 4330); The George Washington University School of Medicine and Health Sciences, Washington, USA (GRID:grid.253615.6) (ISNI:0000 0004 1936 9510)