Assuntos
Neoplasias Encefálicas , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Humanos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/diagnóstico por imagem , Masculino , Feminino , AdultoRESUMO
A novel methylation class, "neuroepithelial tumor, with PLAGL1 fusion" (NET-PLAGL1), has recently been described, based on epigenetic features, as a supratentorial pediatric brain tumor with recurrent histopathological features suggesting an ependymal differentiation. Because of the recent identification of this neoplastic entity, few histopathological, radiological and clinical data are available. Herein, we present a detailed series of nine cases of PLAGL1-fused supratentorial tumors, reclassified from a series of supratentorial ependymomas, non-ZFTA/non-YAP1 fusion-positive and subependymomas of the young. This study included extensive clinical, radiological, histopathological, ultrastructural, immunohistochemical, genetic and epigenetic (DNA methylation profiling) data for characterization. An important aim of this work was to evaluate the sensitivity and specificity of a novel fluorescent in situ hybridization (FISH) targeting the PLAGL1 gene. Using histopathology, immunohistochemistry and electron microscopy, we confirmed the ependymal differentiation of this new neoplastic entity. Indeed, the cases histopathologically presented as "mixed subependymomas-ependymomas" with well-circumscribed tumors exhibiting a diffuse immunoreactivity for GFAP, without expression of Olig2 or SOX10. Ultrastructurally, they also harbored features reminiscent of ependymal differentiation, such as cilia. Different gene partners were fused with PLAGL1: FOXO1, EWSR1 and for the first time MAML2. The PLAGL1 FISH presented a 100% sensitivity and specificity according to RNA sequencing and DNA methylation profiling results. This cohort of supratentorial PLAGL1-fused tumors highlights: 1/ the ependymal cell origin of this new neoplastic entity; 2/ benefit of looking for a PLAGL1 fusion in supratentorial cases of non-ZFTA/non-YAP1 ependymomas; and 3/ the usefulness of PLAGL1 FISH.
Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Ependimoma , Glioma Subependimal , Neoplasias Supratentoriais , Criança , Humanos , Neoplasias Encefálicas/genética , Proteínas de Ciclo Celular , Neoplasias do Sistema Nervoso Central/genética , Ependimoma/patologia , Hibridização in Situ Fluorescente , Neoplasias Supratentoriais/patologia , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
GSCs play an important role in GBM recurrence. Understanding the resistance mechanisms in these cells is therefore crucial for radiation therapy optimization. In this study, using patient-derived GSCs, we demonstrate that GDF15, a cytokine belonging to the TGF-ß superfamily, is regulated by irradiation (IR) and the transcription factor WWTR1/TAZ. Blocking WWTR1/TAZ using specific siRNAs significantly reduces GDF15 basal expression and reverses the upregulation of this cytokine induced by IR. Furthermore, we demonstrate that GDF15 plays an important role in GSC radioresistance. Targeting GDF15 expression by siRNA in GSCs expressing high levels of GDF15 sensitizes the cells to IR. In addition, we also found that GDF15 expression is critical for GSC spheroid formation, as GDF15 knockdown significantly reduces the number of GSC neurospheres. This study suggests that GDF15 targeting in combination with radiotherapy may be a feasible approach in patients with GBM.