Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial neuroepithelial tumors

Philipp Sievers, Sophie C. Henneken, Christina Blume, Martin Sill, Daniel Schrimpf, Damian Stichel, Konstantin Okonechnikov, David E. Reuss, Julia Benzel, Kendra K. Maaß, Marcel Kool, Dominik Sturm, Tuyu Zheng, David R. Ghasemi, Patricia Kohlhof-Meinecke, Ofelia Cruz, Mariona Suñol, Cinzia Lavarino, Viktoria Ruf, Henning B. BoldtMélanie Pagès, Celso Pouget, Leonille Schweizer, Mariëtte E.G. Kranendonk, Noreen Akhtar, Stephanie Bunkowski, Christine Stadelmann, Ulrich Schüller, Wolf C. Mueller, Hildegard Dohmen, Till Acker, Patrick N. Harter, Christian Mawrin, Rudi Beschorner, Sebastian Brandner, Matija Snuderl, Zied Abdullaev, Kenneth Aldape, Mark R. Gilbert, Terri S. Armstrong, David W. Ellison, David Capper, Koichi Ichimura, Guido Reifenberger, Richard G. Grundy, Nada Jabado, Lenka Krskova, Michal Zapotocky, Ales Vicha, Pascale Varlet, Pieter Wesseling, Stefan Rutkowski, Andrey Korshunov, Wolfgang Wick, Stefan M. Pfister, David T.W. Jones, Andreas von Deimling, Kristian W. Pajtler, Felix Sahm*

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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.

TidsskriftActa Neuropathologica
Udgave nummer5
Sider (fra-til)827-839
StatusUdgivet - nov. 2021

Bibliografisk note

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 I. Leis and M. Schalles (Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany). 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.


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