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A subset of pediatric-type thalamic gliomas share a distinct DNA methylation profile, H3K27me3 loss and frequent alteration of EGFR
P. Sievers, M. Sill, D. Schrimpf, D. Stichel, DE. Reuss, D. Sturm, J. Hench, S. Frank, L. Krskova, A. Vicha, M. Zapotocky, B. Bison, D. Castel, J. Grill, MA. Debily, PN. Harter, M. Snuderl, CM. Kramm, G. Reifenberger, A. Korshunov, N. Jabado, P....
Language English Country Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't
NLK
Free Medical Journals
from 1999 to 1 year ago
PubMed Central
from 1999 to 1 year ago
Europe PubMed Central
from 1999 to 1 year ago
Open Access Digital Library
from 1999-01-01
Medline Complete (EBSCOhost)
from 2004-01-01 to 1 year ago
- MeSH
- Child MeSH
- ErbB Receptors genetics MeSH
- Genes, erbB-1 MeSH
- Glioma * genetics MeSH
- Histones genetics MeSH
- Humans MeSH
- DNA Methylation MeSH
- Mutation MeSH
- Brain Neoplasms * genetics MeSH
- Thalamus MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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 Cooperation Unit Pediatric Oncology German Cancer Research Center
Département de Biologie Univ Evry Université Paris Saclay Evry France
Department of Human Genetics McGill University Montreal QC H3A 1B1 Canada
Department of Pathology NYU Langone Medical Center New York New York USA
Department of Pathology University of California San Francisco
Department of Pediatrics McGill University Montreal QC H4A 3J1 Canada
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 Neurology Goethe University Frankfurt am Main Germany
Institute of Neuropathology Heinrich Heine University Düsseldorf Germany
Pediatric Glioma Research Group German Cancer Research Center Heidelberg Germany
Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands
The Research Institute of the McGill University Health Center Montreal QC H4A 3J1 Canada
References provided by Crossref.org
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- $a A subset of pediatric-type thalamic gliomas share a distinct DNA methylation profile, H3K27me3 loss and frequent alteration of EGFR / $c P. Sievers, M. Sill, D. Schrimpf, D. Stichel, DE. Reuss, D. Sturm, J. Hench, S. Frank, L. Krskova, A. Vicha, M. Zapotocky, B. Bison, D. Castel, J. Grill, MA. Debily, PN. Harter, M. Snuderl, CM. Kramm, G. Reifenberger, A. Korshunov, N. Jabado, P. Wesseling, W. Wick, DA. Solomon, A. Perry, TS. Jacques, C. Jones, O. Witt, SM. Pfister, A. von Deimling, DTW. Jones, F. Sahm
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