Pediatric low-grade gliomas (pLGG) are frequently driven by genetic alterations in the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway yet show unexplained variability in their clinical outcome. To address this, we characterized a cohort of >1,000 clinically annotated pLGG. Eighty-four percent of cases harbored a driver alteration, while those without an identified alteration also often exhibited upregulation of the RAS/MAPK pathway. pLGG could be broadly classified based on their alteration type. Rearrangement-driven tumors were diagnosed at a younger age, enriched for WHO grade I histology, infrequently progressed, and rarely resulted in death as compared with SNV-driven tumors. Further sub-classification of clinical-molecular correlates stratified pLGG into risk categories. These data highlight the biological and clinical differences between pLGG subtypes and opens avenues for future treatment refinement.

Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children 555 University Avenue Toronto ON M5G 1X8 Canada

Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children 555 University Avenue Toronto ON M5G 1X8 Canada; Department of Haematology Oncology The Hospital for Sick Children Toronto ON Canada

Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children 555 University Avenue Toronto ON M5G 1X8 Canada; Department of Haematology Oncology The Hospital for Sick Children Toronto ON Canada; 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children 555 University Avenue Toronto ON M5G 1X8 Canada; Department of Haematology Oncology The Hospital for Sick Children Toronto ON Canada; Children's Research Center University Children's Hospital Zurich Zurich Switzerland

Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children 555 University Avenue Toronto ON M5G 1X8 Canada; Department of Haematology Oncology The Hospital for Sick Children Toronto ON Canada; Department of Medical Biophysics University of Toronto Toronto ON Canada

Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children 555 University Avenue Toronto ON M5G 1X8 Canada; Department of Haematology Oncology The Hospital for Sick Children Toronto ON Canada; Department of Paediatrics University of Toronto Toronto ON Canada

Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children 555 University Avenue Toronto ON M5G 1X8 Canada; Department of Haematology Oncology The Hospital for Sick Children Toronto ON Canada; Department of Pediatric Hematology and Oncology Hospital Universitario Niño Jesús Madrid Spain

Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children 555 University Avenue Toronto ON M5G 1X8 Canada; Department of Laboratory Medicine and Pathobiology University of Toronto Toronto ON Canada

Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children 555 University Avenue Toronto ON M5G 1X8 Canada; Department of Laboratory Medicine and Pathobiology University of Toronto Toronto ON Canada; Department of Haematology Oncology The Hospital for Sick Children Toronto ON Canada

Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children 555 University Avenue Toronto ON M5G 1X8 Canada; Department of Laboratory Medicine and Pathobiology University of Toronto Toronto ON Canada; Department of Neurosurgery The Hospital for Sick Children Toronto ON Canada

Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children 555 University Avenue Toronto ON M5G 1X8 Canada; Department of Laboratory Medicine and Pathobiology University of Toronto Toronto ON Canada; Department of Pathology The Hospital for Sick Children Toronto ON Canada

Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children 555 University Avenue Toronto ON M5G 1X8 Canada; Department of Paediatric Laboratory Medicine The Hospital for Sick Children Toronto ON Canada

Department of Genomic Diagnostics Children's Hospital of Philadelphia Philadelphia PA USA; Center for Data Driven Discovery in Biomedicine Children's Hospital of Philadelphia Philadelphia PA USA; Department of Hematology Oncology and Stem Cell Transplant Ann and Robert H Lurie Children's Hospital of Chicago Chicago IL USA; Department of Pediatrics Feinberg School of Medicine Northwestern University Chicago IL USA

Department of Haematology Oncology The Hospital for Sick Children Toronto ON Canada; Department of Paediatrics University of Toronto Toronto ON Canada

Department of Laboratory Medicine and Pathobiology University of Toronto Toronto ON Canada; Department of Paediatric Laboratory Medicine The Hospital for Sick Children Toronto ON Canada

Department of Laboratory Medicine and Pathobiology University of Toronto Toronto ON Canada; Department of Pathology The Hospital for Sick Children Toronto ON Canada

Department of Laboratory Medicine and Pathobiology University of Toronto Toronto ON Canada; Department of Pathology The Hospital for Sick Children Toronto ON Canada; Department of Anatomical Pathology The Alfred Hospital Prahran VIC Australia

Department of Oncology St Jude Children's Research Hospital Memphis TN USA

Department of Paediatric Laboratory Medicine The Hospital for Sick Children Toronto ON Canada

Department of Pathology and Laboratory Medicine Children's Hospital of Philadelphia Philadelphia PA USA

Department of Pathology and Laboratory Medicine Children's Hospital of Philadelphia Philadelphia PA USA; Department of Genomic Diagnostics Children's Hospital of Philadelphia Philadelphia PA USA

Department of Pathology Memorial Sloan Kettering Cancer Center New York NY USA

Department of Pathology St Jude Children's Research Hospital Memphis TN USA

Department of Pediatrics Memorial Sloan Kettering Cancer Center New York NY USA

Department of Radiology The Hospital for Sick Children Toronto ON Canada; Department of Medical Imaging University of Toronto Toronto ON Canada

Department of Surgery University of Toronto Toronto ON Canada; Department of Neurosurgery The Hospital for Sick Children Toronto ON Canada

Radiation Medicine Program Princess Margaret Cancer Centre University Health Network Toronto ON Canada; Department of Radiation Oncology Faculty of Medicine University of Toronto Toronto ON Canada

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Cancer Cell. 2020 Apr 13;37(4):424-425. doi: 10.1016/j.ccell.2020.03.020. PubMed

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Clinical Characteristics and Outcomes of Central Nervous System Tumors Harboring NTRK Gene Fusions

Gliomatosis cerebri in children: A poor prognostic phenotype of diffuse gliomas with a distinct molecular profile

LOGGIC/FIREFLY-2: a phase 3, randomized trial of tovorafenib vs. chemotherapy in pediatric and young adult patients with newly diagnosed low-grade glioma harboring an activating RAF alteration

LOGGIC Core BioClinical Data Bank: Added clinical value of RNA-Seq in an international molecular diagnostic registry for pediatric low-grade glioma patients

DIPG-like MYB-altered diffuse astrocytoma with durable response to intensive chemotherapy

Integrated genomic analysis reveals actionable targets in pediatric spinal cord low-grade gliomas

Survival and functional outcomes in paediatric thalamic and thalamopeduncular low grade gliomas