Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.

Bioinformatics and Omics Data Analytics German Cancer Research Center Heidelberg Germany

Charité Universitätsmedizin Berlin corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin Institute of Neuropathology Berlin Germany

Children's Brain Tumour Research Centre University of Nottingham Nottingham UK

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

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

Department of Clinical Research University of Southern Denmark Odense Denmark

Department of Human Genetics McGill University Montreal QC H3A 1B1 Canada

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

Department of Neurology and Neurooncology Program National Center for Tumor Diseases Heidelberg University Hospital Heidelberg Germany

Department of Neuropathology GHU Paris Psychiatry and Neurosciences Sainte Anne Hospital Paris France

Department of Neuropathology Institute of Pathology University Hospital Heidelberg Heidelberg Germany

Department of Neuropathology Otto Von Guericke University Magdeburg Germany

Department of Neuropathology University of Tübingen Tübingen Germany

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

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

Department of Pathology CHRU Nancy France

Department of Pathology Hospital Sant Joan de Déu Esplugues de Llobregat Barcelona Spain

Department of Pathology Klinikum Stuttgart Stuttgart Germany

Department of Pathology NYU Langone Medical Center New York NY USA

Department of Pathology Odense University Hospital Odense Denmark

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

Department of Pathology University Medical Center Utrecht Utrecht The Netherlands

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 University Medical Center Hamburg Eppendorf Hamburg Germany

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

Department of Pediatric Oncology Hospital Sant Joan de Déu Esplugues de Llobregat Barcelona Spain

Department of Pediatrics McGill University Montreal QC H4A 3J1 Canada

Division of Brain Tumor Translational Research National Cancer Center Research Institute Chuo ku Tokyo Japan

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

Division of Pediatric Neurooncology German Cancer Consortium Heidelberg Germany

Faculty of Biosciences Heidelberg University 69117 Heidelberg Germany

Frankfurt Cancer Institute University Hospital Goethe University Frankfurt am Main Frankfurt am Main Germany

German Cancer Consortium Heidelberg Germany

German Cancer Consortium Partner Site Essen Düsseldorf Essen Düsseldorf Germany

German Cancer Consortium Partner site Frankfurt Mainz Frankfurt am Main Germany

German Cancer Research Center Heidelberg Germany

Hopp Children's Cancer Center Heidelberg Heidelberg Germany

Institute for Neuropathology University Medical Centre Göttingen Göttingen Germany

Institute of Neurology University Hospital Goethe University Frankfurt am Main Frankfurt am Main Germany

Institute of Neuropathology Heinrich Heine University Düsseldorf Germany

Institute of Neuropathology Ludwig Maximilian University Munich Germany

Institute of Neuropathology University Medical Center Hamburg Eppendorf Hamburg Germany

Institute of Neuropathology University of Giessen Giessen Germany

Laboratory of Molecular Oncology Hospital Sant Joan de Déu Esplugues de Llobregat Barcelona Spain

Laboratory of Pathology Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD USA

Laboratory of Translational Research in Pediatric Oncology SIREDO INSERM U830 Institut Curie Paris Sciences Lettres University Paris France

Manchester Royal Infirmary Manchester University NHS Foundation Trust Manchester UK

Neuro Oncology Branch National Cancer Institute Bethesda MD USA

Paul Flechsig Institute of Neuropathology University Hospital and Faculty of Medicine Leipzig Germany

Pediatric Glioma Research Group German Cancer Research Center Heidelberg Germany

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

Shaukat Khanum Memorial Cancer Hospital and Research Centre Lahore Pakistan

The Research Institute of the McGill University Health Center Montreal QC H4A 3J1 Canada

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Comparative Clinical and Imaging-Based Evaluation of Therapeutic Modalities in CNS Embryonal Tumours With PLAGL Amplification

CNS Embryonal Tumor with PLAGL Amplification, a New Tumor in Children and Adolescents: Insights from a Comprehensive MRI Analysis

Amplification of the PLAG-family genes-PLAGL1 and PLAGL2-is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification