BACKGROUND: Malignant astrocytic gliomas in children show a remarkable biological and clinical diversity. Small in-frame insertions or missense mutations in the epidermal growth factor receptor gene (EGFR) have recently been identified in a distinct subset of pediatric-type bithalamic gliomas with a unique DNA methylation pattern. METHODS: Here, we investigated an epigenetically homogeneous cohort of malignant gliomas (n = 58) distinct from other subtypes and enriched for pediatric cases and thalamic location, in comparison with this recently identified subtype of pediatric bithalamic gliomas. RESULTS: EGFR gene amplification was detected in 16/58 (27%) tumors, and missense mutations or small in-frame insertions in EGFR were found in 20/30 tumors with available sequencing data (67%; 5 of them co-occurring with EGFR amplification). Additionally, 8 of the 30 tumors (27%) harbored an H3.1 or H3.3 K27M mutation (6 of them with a concomitant EGFR alteration). All tumors tested showed loss of H3K27me3 staining, with evidence of overexpression of the EZH inhibitory protein (EZHIP) in the H3 wildtype cases. Although some tumors indeed showed a bithalamic growth pattern, a significant proportion of tumors occurred in the unilateral thalamus or in other (predominantly midline) locations. CONCLUSIONS: Our findings present a distinct molecular class of pediatric-type malignant gliomas largely overlapping with the recently reported bithalamic gliomas characterized by EGFR alteration, but additionally showing a broader spectrum of EGFR alterations and tumor localization. Global H3K27me3 loss in this group appears to be mediated by either H3 K27 mutation or EZHIP overexpression. EGFR inhibition may represent a potential therapeutic strategy in these highly aggressive gliomas.

Clinical Cancer Genomics Laboratory University of California San Francisco San Francisco California USA

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

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

Clinical Cooperation Unit Pediatric Oncology German Cancer Research Center

Département de Biologie Univ Evry Université Paris Saclay Evry France

Département de Cancérologie de l'Enfant et de l'Adolescent Gustave Roussy Université Paris Saclay Villejuif France

Department of Histopathology Great Ormond Street Hospital for Children NHS Foundation Trust London UK

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

Department of Neurological Surgery University of California San Francisco San Francisco California USA

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

Department of Neuropathology Institute of Pathology University Hospital Heidelberg Heidelberg 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 NYU Langone Medical Center New York New York USA

Department of Pathology University of California San Francisco

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

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

Department of Pediatrics McGill University Montreal QC H4A 3J1 Canada

Developmental Biology and Cancer Research and Teaching Department UCL Great Ormond Street Institute of Child Health London UK

Division of Molecular Pathology Institute of Cancer Research London UK

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

Division of Pediatric Neurooncology German Cancer Consortium Heidelberg Germany

Frankfurt Cancer Institute Frankfurt am Main Germany

German Cancer Consortium Partner Site 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 Medical Genetics and Pathology University Hospital Basel Basel Switzerland

Institute of Diagnostic and Interventional Neuroradiology University Hospital Würzburg Würzburg Germany

Institute of Neurology Goethe University Frankfurt am Main Germany

Institute of Neuropathology Heinrich Heine University Düsseldorf Germany

Molecular Predictors and New Targets in Oncology INSERM Gustave Roussy Université Paris Saclay Villejuif France

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

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

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