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.

室管膜瘤包括沿整个神经轴发生的一组异质中枢神经系统 (CNS) 肿瘤。近年来，广泛的（表观）基因组分析工作已经确定了几个以不同分子改变和/或模式为特征的室管膜瘤分子组。基于大量全基因组 DNA 甲基化数据的无监督可视化，我们确定了一组高度不同的儿科肿瘤 ( n =  40)，形成了一个与所有已建立的 CNS 肿瘤类型分开的簇，其中很大一部分是组织病理学诊断为室管膜瘤。RNA测序揭示了涉及多形性腺瘤基因样1（PLAGL1 ）的反复融合) 分析的 20 个样本中有 19 个中的基因，最常见的融合是EWSR1:PLAGL1 ( n =  13)。五个肿瘤显示出PLAGL1:FOXO1融合，一个显示出PLAGL1:EP300融合。在这些肿瘤中注意到PLAGL1的高转录水平，同时过表达受 PLAGL1 调节的印迹基因H19和IGF2 。对有足够材料的病例进行组织病理学检查 ( n = 16）展示了具有主要室管膜瘤样特征的广泛形态学谱。免疫组化显示，肿瘤为 GFAP 阳性，OLIG2 和 SOX10 阴性。在 3/16 的病例中，检测到 EMA 呈点状阳性。我们系列中的所有肿瘤都位于幕上隔室。诊断时患者的中位年龄为 6.2 岁。中位无进展生存期为 35 个月（11 名有可用数据的患者）。总之，我们的研究结果表明存在一组新的幕上神经上皮肿瘤，其特征是复发性PLAGL1融合并在儿科患者中富集。