Open Access

Philipp Sievers, Sophie C. Henneken, Christina Blume, Martin Sill, Daniel Schrimpf, Damian Stichel, Konstantin Okonechnikov, David 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. Boldt, Mélanie Pagès, Celso Pouget, Leonille Schweizer, Mariëtte E. G. Kranendonk, Noreen Akhtar, Stephanie Bunkowski, Christine Stadelmann, Ulrich Schüller, Wolf C. Müller, Hildegard Dohmen, Till Acker, Patrick Nikolaus 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 Pfister, David T. W. Jones, Andreas von Deimling, Kristian Wilfried Pajtler, Felix Sahm

• 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.