Diffuse pediatric-type high-grade gliomas (pedHGG), H3- and IDH-wildtype, encompass three main DNA-methylation-based subtypes: pedHGG-MYCN, pedHGG-RTK1A/B/C, and pedHGG-RTK2A/B. Since their first description in 2017 tumors of pedHGG-RTK2A/B have not been comprehensively characterized and clinical correlates remain elusive. In a recent series of pedHGG with a Gliomatosis cerebri (GC) growth pattern, an increased incidence of pedHGG-RTK2A/B (n = 18) was observed. We added 14 epigenetically defined pedHGG-RTK2A/B tumors to this GC series and provided centrally reviewed radiological, histological, and molecular characterization. The final cohort of 32 pedHGG-RTK2A/B tumors consisted of 25 pedHGG-RTK2A (78%) and seven pedHGG-RTK2B (22%) cases. The median age was 11.6 years (range, 4-17) with a median overall survival of 16.0 months (range 10.9-28.2). Seven of 11 of the newly added cases with imaging available showed a GC phenotype at diagnosis or follow-up. PedHGG-RTK2B tumors exhibited frequent bithalamic involvement (6/7, 86%). Central neuropathology review confirmed a diffuse glial neoplasm in all tumors with prominent angiocentric features in both subclasses. Most tumors (24/27 with available data, 89%) diffusely expressed EGFR with focal angiocentric enhancement. PedHGG-RTK2A tumors lacked OLIG2 expression, whereas 43% (3/7) of pedHGG-RTK2B expressed this glial transcription factor. ATRX loss occurred in 3/6 pedHGG-RTK2B samples with available data (50%). DNA sequencing (pedHGG-RTK2A: n = 18, pedHGG-RTK2B: n = 5) found EGFR alterations (15/23, 65%; predominantly point mutations) in both subclasses. Mutations in BCOR (14/18, 78%), SETD2 (7/18, 39%), and the hTERT promoter (7/19, 37%) occurred exclusively in pedHGG-RTK2A tumors, while pedHGG-RTK2B tumors were enriched for TP53 alterations (4/5, 80%). In conclusion, pedHGG-RTK2A/B tumors are characterized by highly diffuse-infiltrating growth patterns and specific radiological and histo-molecular features. By comprehensively characterizing methylation-based tumors, the chance to develop specific and effective therapy concepts for these detrimental tumors increases.

Cancer Research Platform for Pediatric Oncology and Hematology Faculty of Medicine Department of Pediatrics Gynecology and Obstetrics University of Geneva Geneva Switzerland

Department of Neuropathology GHU Paris Psychiatrie et Neurosciences Sainte Anne Hospital 1 Rue Cabanis 75014 Paris France

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 Medical Faculty Mannheim University Medical Center Mannheim Heidelberg University Mannheim Germany

Department of Pediatric and Adolescent Oncology Gustave Roussy Cancer Center 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 Heidelberg University Hospital Heidelberg Germany

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

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

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

Division of Molecular Pathology Institute of Cancer Research London UK

Division of Pediatric Glioma Research Hopp Children's Cancer Center Heidelberg 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 Neurooncology German Cancer Research Center Heidelberg Germany

German Cancer Research Center Heidelberg Germany

Hopp Children's Cancer Center Heidelberg Heidelberg Germany

Inserm UMR 1266 IMA Brain Institut de Psychiatrie et Neurosciences de Paris Paris France

Institute of Biostatistics and Clinical Research University of Münster Münster Germany

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

National Center for Tumor Diseases Heidelberg Germany

National Center for Tumor Diseases NCT Heidelberg a partnership between DKFZ and Heidelberg University Hospital 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 Faculty of Medicine University Augsburg Augsburg Germany

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

Pediatric Radiology Department Hôpital Necker Enfants Malades AP HP Paris France

Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands

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

Université Paris Cité UMR 1163 Institut Imagine and INSERM U1299 Paris France

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