Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial neuroepithelial tumors.
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Sievers Philipp, Henneken Sophie C, Blume Christina, Sill Martin, Schrimpf Daniel, Stichel Damian, Okonechnikov Konstantin, Reuss David E, Benzel Julia, Maaß Kendra K, Kool Marcel, Sturm Dominik, Zheng Tuyu, Ghasemi David R, Kohlhof-Meinecke Patricia, Cruz Ofelia, Suñol Mariona, Lavarino Cinzia, Ruf Viktoria, Boldt Henning B, Pagès Mélanie, Pouget Celso, Schweizer Leonille, Kranendonk Mariëtte E G, Akhtar Noreen, Bunkowski Stephanie, Stadelmann Christine, Schüller Ulrich, Mueller Wolf C, Dohmen Hildegard, Acker Till, Harter Patrick N, Mawrin Christian, Beschorner Rudi, Brandner Sebastian, Snuderl Matija, Abdullaev Zied, Aldape Kenneth, Gilbert Mark R, Armstrong Terri S, Ellison David W, Capper David, Ichimura Koichi, Reifenberger Guido, Grundy Richard G, Jabado Nada, Krskova Lenka, Zapotocky Michal, Vicha Ales, Varlet Pascale, Wesseling Pieter, Rutkowski Stefan, Korshunov Andrey, Wick Wolfgang, Pfister Stefan M, Jones David T W, von Deimling Andreas, Pajtler Kristian W, Sahm Felix
Аннотация
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.