TY  - JOUR
A1  - Sievers, Philipp
A1  - Henneken, Sophie C.
A1  - Blume, Christina
A1  - Sill, Martin
A1  - Schrimpf, Daniel
A1  - Stichel, Damian
A1  - Okonechnikov, Konstantin
A1  - Reuss, David
A1  - Benzel, Julia
A1  - Maaß, Kendra K.
A1  - Kool, Marcel
A1  - Sturm, Dominik
A1  - Zheng, Tuyu
A1  - Ghasemi, David R.
A1  - Kohlhof-Meinecke, Patricia
A1  - Cruz, Ofelia
A1  - Suñol, Mariona
A1  - Lavarino, Cinzia
A1  - Ruf, Viktoria
A1  - Boldt, Henning B.
A1  - Pagès, Mélanie
A1  - Pouget, Celso
A1  - Schweizer, Leonille
A1  - Kranendonk, Mariëtte E. G.
A1  - Akhtar, Noreen
A1  - Bunkowski, Stephanie
A1  - Stadelmann, Christine
A1  - Schüller, Ulrich
A1  - Müller, Wolf C.
A1  - Dohmen, Hildegard
A1  - Acker, Till
A1  - Harter, Patrick Nikolaus
A1  - Mawrin, Christian
A1  - Beschorner, Rudi
A1  - Brandner, Sebastian
A1  - Snuderl, Matija
A1  - Abdullaev, Zied
A1  - Aldape, Kenneth
A1  - Gilbert, Mark R.
A1  - Armstrong, Terri S.
A1  - Ellison, David W.
A1  - Capper, David
A1  - Ichimura, Koichi
A1  - Reifenberger, Guido
A1  - Grundy, Richard G.
A1  - Jabado, Nada
A1  - Krskova, Lenka
A1  - Zapotocky, Michal
A1  - Vicha, Ales
A1  - Varlet, Pascale
A1  - Wesseling, Pieter
A1  - Rutkowski, Stefan
A1  - Korshunov, Andrey
A1  - Wick, Wolfgang
A1  - Pfister, Stefan
A1  - Jones, David T. W.
A1  - Deimling, Andreas von
A1  - Pajtler, Kristian Wilfried
A1  - Sahm, Felix
T1  - Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial neuroepithelial tumors
T2  - Acta neuropathologica
N2  - Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.
KW  - Neuroepithelial tumor
KW  - Supratentorial
KW  - PLAGL1
KW  - EWSR1
KW  - FOXO1
KW  - EP300
KW  - Gene fusion
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/63766
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-637662
SN  - 1432-0533
N1  - We also thank the German Childhood Cancer Foundation for funding (“Molecular Neuropathology 2.0-Increasing diagnostic accuracy in paediatric neurooncology” (DKS 2015.01)). This study was supported by the Hertie Network of Excellence in Clinical Neuroscience. P. Sievers is a fellow of the Hertie Academy of Excellence in Clinical Neuroscience. S. C. Henneken and D. R. Ghasemi received scholarships of the Mildred-Scheel doctoral program of the German Cancer Aid and the German Academic Scholarship Foundation. This study was generously supported by ‘Ein Kiwi gegen Krebs’. S. Brandner was partly funded by the National Institute of Health Research (NIHR) UCLH/UCL Biomedical Research Centre. A subset of the human tissue was obtained from University College London NHS Foundation Trust as part of the UK Brain Archive Information Network (BRAIN UK, Ref: 19/001) which is funded by the Medical Research Council and Brain Tumour Research UK. U. Schüller was supported by the Fördergemeinschaft Kinderkrebszentrum Hamburg.
N1  - Open Access funding enabled and organized by Projekt DEAL.
VL  - 142
SP  - 827
EP  - 839
PB  - Springer
CY  - Berlin ; Heidelberg
ER  -