Recurrent fusions in <i>PLAGL1</i> define a distinct subset of pediatric-type supratentorial neuroepithelial tumors

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/...

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Detalles Bibliográficos
Autores: Sievers P, Henneken SC, Blume C, Sill M, Schrimpf D, Stichel D, Okonechnikov K, Reuss DE, Benzel J, Maaß KK, Kool M, Sturm D, Zheng T, Ghasemi DR, Kohlhof-Meinecke P, Cruz O, Suñol M, Lavarino C, Ruf V, Boldt HB, Pagès M, Pouget C, Schweizer L, Kranendonk MEG, Akhtar N, Bunkowski S, Stadelmann C, Schüller U, Mueller WC, Dohmen H, Acker T, Harter PN, Mawrin C, Beschorner R, Brandner S, Snuderl M, Abdullaev Z, Aldape K, Gilbert MR, Armstrong TS, Ellison DW, Capper D, Ichimura K, Reifenberger G, Grundy RG, Jabado N, Krskova L, Zapotocky M, Vicha A, Varlet P, Wesseling P, Rutkowski S, Korshunov A, Wick W, Pfister SM, Jones DTW, von Deimling A, Pajtler KW, Sahm F
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Fundació Sant Joan de Déu
Repositorio:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
OAI Identifier:oai:fsjd.fundanetsuite.com:p19968
Acceso en línea:https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=19968
Access Level:acceso abierto
Palabra clave:Neuroepithelial tumor
Supratentorial
PLAGL1
EWSR1
FOXO1
EP300
Gene fusion
Descripción
Sumario: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.

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