BACKGROUND: The term gliomatosis cerebri (GC), a radiology-defined highly infiltrating diffuse glioma, has been abandoned since molecular GC-associated features could not be established. METHODS: We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive clinical and (epi-)genetic characterization. RESULTS: Median overall survival (OS) was 15.5 months (interquartile range, 10.9-27.7) with a 2-year survival rate of 28%. Histopathological grading correlated significantly with median OS: CNS WHO grade II: 47.8 months (25.2-55.7); grade III: 15.9 months (11.4-26.3); grade IV: 10.4 months (8.8-14.4). By DNA methylation profiling (n = 49), most tumors were classified as pediatric-type diffuse high-grade glioma (pedHGG), H3-/IDH-wild-type (n = 31/49, 63.3%) with enriched subclasses pedHGG_RTK2 (n = 19), pedHGG_A/B (n = 6), and pedHGG_MYCN (n = 5), but only one pedHGG_RTK1 case. Within the pedHGG, H3-/IDH-wild-type subgroup, recurrent alterations in EGFR (n = 10) and BCOR (n = 9) were identified. Additionally, we observed structural aberrations in chromosome 6 in 16/49 tumors (32.7%) across tumor types. In the pedHGG, H3-/IDH-wild-type subgroup TP53 alterations had a significant negative effect on OS. CONCLUSIONS: Contrary to previous studies, our representative pediatric GC study provides evidence that GC has a strong predilection to arise on the background of specific molecular features (especially pedHGG_RTK2, pedHGG_A/B, EGFR and BCOR mutations, chromosome 6 rearrangements).

2nd Department of Pediatrics Semmelweis University Budapest Hungary

AbbVie Inc Oncology Development North Chicago IL U S A

Center of Radiology Department of Diagnostic and Interventional Radiology and Neuroradiology Hospital of Fulda Fulda Germany

Department of Neurosciences University of Turin Turin Italy

Department of Onco Hematology Gene and Cell Therapy Bambino Gesù Children's Hospital Rome Italy

Department of Oncology and Children's Research Centre University Children's Hospital Zurich Switzerland

Department of Paediatric Oncology Sir James Spence Institute of Child Health Royal Victoria Infirmary Queen Victoria Road Newcastle upon Tyne UK

Department of Pathology Amsterdam UMC Amsterdam The Netherlands

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

Department of Pediatric and Adolescent Medicine University Medical Center Mannheim Medical Faculty Mannheim Heidelberg University Mannheim Germany

Department of Pediatric and Adolescent Oncology Gustave Roussy Université Paris Saclay Villejuif France

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

Department of Pediatric Hematology and Oncology University Hospitals Leuven Belgium

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

Department of Pediatric Hematology Oncology and Stem Cell Transplantation University of Regensburg Regensburg Germany

Department of Pediatric Oncology and Hematology Saarland University Homburg Germany

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

Department of Pediatric Oncology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Pediatrics Clínica Universidad de Navarra Pamplona Spain

Department of Pediatrics Obstetrics and Gynecology Division of Pediatric Hematology and Oncology University Hospital Geneva Geneva Switzerland

Department of Radiation Oncology University of Leipzig Leipzig Germany

Department of Radiological Oncological and Anatomo Pathological Sciences Sapienza University Rome Italy

Department of Radiology and Nuclear Medicine Erasmus MC Rotterdam The Netherlands

Department of Radiotherapy and Radiation Oncology Faculty of Medicine and University Hospital Carl Gustav Carus Technical University Dresden Dresden Germany

Diagnostic and Interventional Neuroradiology Faculty of Medicine University of Augsburg Augsburg Germany

Division of Clinical Neuro Oncology Department of Neurology University Hospital Bonn Bonn Germany

Division of Hematology Oncology and Stem Cell Transplantation Children's Hospital Helsinki University Hospital Helsinki Finland

Division of Hematology Oncology Children's Hospital of Pittsburgh Pittsburgh PA U S A

Division of Molecular Pathology Institute of Cancer Research London UK

Division of Pediatric Glioma Research German Cancer Research Center Heidelberg Germany

Division of Pediatric Hematology and Oncology Department of Pediatrics and Adolescent Medicine Medical University of Graz Graz Austria

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

Division of Pediatric Hematology Oncology 1st Department of Pediatrics National and Kapodistrian University of Athens Aghia Sophia Children's Hospital Athens Greece

Division of Pediatric Hematology Oncology Institute of Oncology Istanbul University Istanbul Turkey

Division of Pediatric Neurooncology German Cancer Research Center Heidelberg Germany

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

Health Research Institute of Navarra Pamplona Navarra Spain

Hopp Children's Cancer Center Heidelberg Germany

Institute of Biostatistics and Clinical Research University of Münster Münster Germany

Institute of Diagnostic and Interventional Neuroradiology University of Würzburg Würzburg Germany

Institute of Neuropathology DGNN Brain Tumor Reference Center University of Bonn Medical Center Bonn Germany

National Center for Tumor Diseases Heidelberg Heidelberg Germany

Neuro Oncology Unit IRCSS Istituto Giannina Gaslini Genoa Italy

Neuroradiological Reference Center for the Pediatric Brain Tumor Studies of the German Society of Pediatric Oncology and Hematology University Augsburg Faculty of Medicine Germany

Neurosurgery Unit Bambino Gesù Children's Hospital Rome Italy

Oncological Neuroradiology and Advanced Diagnostics Unit Bambino Gesù Children's Hospital Rome Italy

Pathology Unit Bambino Gesù Children's Hospital Rome Italy

Pediatric and Adolescent Medicine Swabian Children's Cancer Center University Medical Center Augsburg Augsburg Germany

Pediatric Hematology and Oncology Department of Pediatrics University Hospital Würzburg Würzburg Germany

Pediatric Neuro Oncology Pediatric Cancer Center Barcelona Hospital Sant Joan de Deu Barcelona Spain

Pediatric Onco Hematology Department Pediatrics 3 University Hospital of Strasbourg Strasbourg France

Pediatric Oncology Department of Oncology KU Leuven Belgium

Pediatric Oncology Department University Hospital São João Porto Portugal

Pediatric Oncology Great Ormond Street Hospital for Children London UK

Pediatric Oncology Unit Fondazione IRCCS Istituto Nazionale dei Tumori Milano Italy

Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands

Solid Tumor Program Center for the Applied Medical Research Pamplona Navarra Spain

U981 Molecular Predictors and New Targets in Oncology Team Genomics and Oncogenesis of Pediatric Brain Tumors INSERM Gustave Roussy Université Paris Saclay Villejuif France

UMR CNRS 7021 Laboratory of Bioimagery and Pathologies Team tumor signaling and therapeutic targets University of Strasbourg Illkirch France

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Diffuse pediatric high-grade glioma of methylation-based RTK2A and RTK2B subclasses present distinct radiological and histomolecular features including Gliomatosis cerebri phenotype