Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/β-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.

Aix Marseille Univ APHM CNRS INP Inst Neurophysiopathol CHU Timone Service d'Anatomie Pathologique et de Neuropathologie Marseille France

Clinical Cooperation Unit Neuropathology German Consortium for Translational Cancer Research Heidelberg Germany

Clinical Cooperation Unit Pediatric Oncology German Consortium for Translational Cancer Research Heidelberg Germany

Department of Clinical Pathology Kuopio University Hospital and Unit of Pathology Institute of Clinical Medicine University of Eastern Finland Kuopio Finland

Department of Developmental Biology and Cancer UCL GOS Institute of Child Health University College London London UK

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

Department of Neurodegenerative Disease UCL Queen Square Institute of Neurology Queen Square London UK

Department of Neuropathology Institute of Pathology University Hospital Heidelberg Heidelberg Germany

Department of Oncology Pathology Karolinska Institutet Stockholm Sweden

Department of Pathology Amsterdam University Medical Centers Location VUmc and Brain Tumor Center Amsterdam Amsterdam The Netherlands

Department of Pathology and Laboratory Medicine The Aga Khan University Karachi Pakistan

Department of Pathology and Laboratory Medicine The University of British Colombia Vancouver Canada

Department of Pathology and Molecular Medicine 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Pathology NYU Langone Medical Center New York NY USA

Department of Pathology Rigshospitalet Copenhagen Denmark

Department of Pediatric Haematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Pediatric Hematology and Oncology Alder Hey Children's NHS Foundation Trust Liverpool UK

Department of Pediatric Hematology and Oncology University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Pediatric Hematology Oncology Valley Children's Hospital Madera CA USA

Department of Pediatric Oncology and Hematology Charité Universitätsmedizin Berlin Corporate Member of Freie Universität Berlin Humboldt Universität zu Berlin and Berlin Institute of Health Berlin Germany

Department of Pediatric Oncology and Hematology Skåne University Hospital Lund University Lund Sweden

Department of Pediatric Oncology Hematology Immunology and Pulmonology University Hospital Heidelberg Heidelberg Germany

Department of Pediatric Oncology Hematology Immunology Olgahospital Klinikum Stuttgart Stuttgart Germany

Department of Pediatrics and Adolescent Medicine Comprehensive Cancer Center and Comprehensive Center for Pediatrics Medical University of Vienna 1090 Vienna Austria

Department of Pediatrics Pediatric Hematology and Oncology Ward Kuopio University Hospital and Institute of Clinical Medicine University of Eastern Finland Kuopio Finland

Department of Radiology Alder Hey Children's NHS Foundation Trust Liverpool UK

Division of Cancer Sciences University of Manchester Manchester Academic Health Science Centre Manchester UK

Division of Neuropathology and Neurochemistry Department of Neurology Medical University of Vienna Vienna Austria

Division of Neuropathology Department of Pathology University of California San Francisco 513 Parnassus Ave Health Sciences West 451 San Francisco CA 94143 USA

Division of Neuropathology National Hospital for Neurology and Neurosurgery University College London Hospitals NHS Foundation Trust Queen Square London UK

Division of Pediatric Glioma Research Im Neuenheimer Feld 280 69120 Heidelberg Germany

Division of Pediatric Hematology and Oncology University Medical Center Göttingen Göttingen Germany

Division of Pediatric Neurooncology German Cancer Consortium Heidelberg Germany

Faculty of Biosciences Heidelberg University Heidelberg Germany

Geoffrey Jefferson Brain Research Centre Division of Neuroscience and Experimental Psychology Faculty of Biology Medicine and Health University of Manchester Manchester UK

Hopp Children's Cancer Center Heidelberg Im Neuenheimer Feld 280 69120 Heidelberg Germany

Institut de Pathologie Multisite Site Est Groupement Hospitalier Est Hospices Civils de Lyon Lyon France

Institute of Neuropathology University Medical Center Hamburg Eppendorf Hamburg Germany

KiTZ Clinical Trial Unit Department of Pediatric Hematology and Oncology Heidelberg University Hospital Heidelberg Germany

Murdoch Children's Research Institute and Department of Paediatrics University of Melbourne Royal Children's Hospital Melbourne Australia

Prague Brain Tumor Research Group 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands

Research Institute Children's Cancer Center Hamburg Hamburg Germany

University of Bordeaux Bordeaux Institute of Oncology INSERM U1312 Université de Bordeaux 146 rue Leo Saignat Case 76 33076 Bordeaux France

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Acta Neuropathol. 2023 Apr;145(4):511-514. doi: 10.1007/s00401-023-02538-4. PubMed

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Central Nervous System Tumours (2021) WHO classification of tumours, 5th edition, volume 6. Edited by the WHO Classification of Tumours Editorial Board. 2021: International Agency for Research on Cancer

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