TY - JOUR
T1 - Clear cell meningiomas are defined by a highly distinct DNA methylation profile and mutations in SMARCE1
AU - The German Consortium “Aggressive Meningiomas”
AU - Sievers, Philipp
AU - Sill, Martin
AU - Blume, Christina
AU - Tauziede-Espariat, Arnault
AU - Schrimpf, Daniel
AU - Stichel, Damian
AU - Reuss, David E.
AU - Dogan, Helin
AU - Hartmann, Christian
AU - Mawrin, Christian
AU - Hasselblatt, Martin
AU - Stummer, Walter
AU - Schick, Uta
AU - Hench, Jürgen
AU - Frank, Stephan
AU - Ketter, Ralf
AU - Schweizer, Leonille
AU - Schittenhelm, Jens
AU - Puget, Stéphanie
AU - Brandner, Sebastian
AU - Jaunmuktane, Zane
AU - Küsters, Benno
AU - Abdullaev, Zied
AU - Pekmezci, Melike
AU - Snuderl, Matija
AU - Ratliff, Miriam
AU - Herold-Mende, Christel
AU - Unterberg, Andreas
AU - Aldape, Kenneth
AU - Ellison, David W.
AU - Wesseling, Pieter
AU - Reifenberger, Guido
AU - Wick, Wolfgang
AU - Perry, Arie
AU - Varlet, Pascale
AU - Pfister, Stefan M.
AU - Jones, David T.W.
AU - von Deimling, Andreas
AU - Sahm, Felix
N1 - Funding Information: For excellent technical support we sincerely thank the Microarray Unit of the German Cancer Research Center (DKFZ) Genomics and Proteomics Core Facility, as well as L. D?rner, Lea Hoffmann, Moritz Schalles and A. Habel (Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany). This study was supported by the Hertie Network of Excellence in Clinical Neuroscience, the German Cancer Aid (70112956), and the Else Kr?ner-Fresenius Stiftung (EKFS 2015_A60). P. Sievers is a fellow of the Hertie Academy of Excellence in Clinical Neuroscience. F. Sahm is a fellow of the Else Kr?ner Excellence Program of the Else Kr?ner-Fresenius Stiftung (EKFS 2017_EKES.24). S. Brandner and Z. Jaunmuktane are supported by the UK Department of Health?s NIHR Biomedical Research Centre?s funding scheme to UCLH. A proportion of data were obtained from University College London NHS Foundation Trust as part of the UK Brain Archive Information Network (BRAIN UK) which is funded by the Medical Research Council and Brain Tumour Research. BRAIN UK reference number: 19/002. Funding Information: For excellent technical support we sincerely thank the Microarray Unit of the German Cancer Research Center (DKFZ) Genomics and Proteomics Core Facility, as well as L. Dörner, Lea Hoffmann, Moritz Schalles and A. Habel (Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany). This study was supported by the Hertie Network of Excellence in Clinical Neuroscience, the German Cancer Aid (70112956), and the Else Kröner-Fresenius Stiftung (EKFS 2015_A60). P. Sievers is a fellow of the Hertie Academy of Excellence in Clinical Neuroscience. F. Sahm is a fellow of the Else Kröner Excellence Program of the Else Kröner-Fresenius Stiftung (EKFS 2017_EKES.24). S. Brandner and Z. Jaunmuktane are supported by the UK Department of Health’s NIHR Biomedical Research Centre’s funding scheme to UCLH. A proportion of data were obtained from University College London NHS Foundation Trust as part of the UK Brain Archive Information Network (BRAIN UK) which is funded by the Medical Research Council and Brain Tumour Research. BRAIN UK reference number: 19/002. Publisher Copyright: © 2020, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/2
Y1 - 2021/2
N2 - Clear cell meningioma represents an uncommon variant of meningioma that typically affects children and young adults. Although an enrichment of loss-of-function mutations in the SMARCE1 gene has been reported for this subtype, comprehensive molecular investigations are lacking. Here we describe a molecularly distinct subset of tumors (n = 31), initially identified through genome-wide DNA methylation screening among a cohort of 3093 meningiomas, of which most were diagnosed histologically as clear cell meningioma. This cohort was further supplemented by an additional 11 histologically diagnosed clear cell meningiomas for analysis (n = 42). Targeted DNA sequencing revealed SMARCE1 mutations in 33/34 analyzed samples, accompanied by a nuclear loss of expression determined via immunohistochemistry and a decreased SMARCE1 transcript expression in the tumor cells. Analysis of time to progression or recurrence of patients within the clear cell meningioma group (n = 14) in comparison to those with meningioma WHO grade 2 (n = 220) revealed a similar outcome and support the assignment of WHO grade 2 to these tumors. Our findings indicate the existence of a highly distinct epigenetic signature of clear cell meningiomas, separate from all other variants of meningiomas, with recurrent mutations in the SMARCE1 gene. This suggests that these tumors may arise from a different precursor cell population than the broad spectrum of the other meningioma subtypes.
AB - Clear cell meningioma represents an uncommon variant of meningioma that typically affects children and young adults. Although an enrichment of loss-of-function mutations in the SMARCE1 gene has been reported for this subtype, comprehensive molecular investigations are lacking. Here we describe a molecularly distinct subset of tumors (n = 31), initially identified through genome-wide DNA methylation screening among a cohort of 3093 meningiomas, of which most were diagnosed histologically as clear cell meningioma. This cohort was further supplemented by an additional 11 histologically diagnosed clear cell meningiomas for analysis (n = 42). Targeted DNA sequencing revealed SMARCE1 mutations in 33/34 analyzed samples, accompanied by a nuclear loss of expression determined via immunohistochemistry and a decreased SMARCE1 transcript expression in the tumor cells. Analysis of time to progression or recurrence of patients within the clear cell meningioma group (n = 14) in comparison to those with meningioma WHO grade 2 (n = 220) revealed a similar outcome and support the assignment of WHO grade 2 to these tumors. Our findings indicate the existence of a highly distinct epigenetic signature of clear cell meningiomas, separate from all other variants of meningiomas, with recurrent mutations in the SMARCE1 gene. This suggests that these tumors may arise from a different precursor cell population than the broad spectrum of the other meningioma subtypes.
KW - Brain tumor
KW - Clear cell
KW - DNA methylation profile
KW - Meningioma
KW - SMARCE1
UR - http://www.scopus.com/inward/record.url?scp=85097560192&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s00401-020-02247-2
DO - https://doi.org/10.1007/s00401-020-02247-2
M3 - Article
C2 - 33319313
SN - 0001-6322
VL - 141
SP - 281
EP - 290
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 2
ER -