Department of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany.
Department of Neurosurgery, University of Cologne Medical Center, Cologne, Germany.
Acta Neuropathol. 2021 Mar;141(3):455-466. doi: 10.1007/s00401-020-02260-5. Epub 2021 Jan 22.
Two distinct genetically defined entities of ependymoma arising in the supratentorial compartment are characterized by the presence of either a C11orf95-RELA or a YAP-MAMLD1 fusion, respectively. There is growing evidence that supratentorial ependymomas without these genetic features exist. In this study, we report on 18 pediatric non-RELA/non-YAP supratentorial ependymomas that were systematically characterized by means of their histology, immunophenotype, genetics, and epigenomics. Comprehensive molecular analyses included high-resolution copy number analysis, methylation profiling, analysis of fusion transcripts by Nanostring technology, and RNA sequencing. Based upon histological and immunohistochemical features two main patterns were identified-RELA-like (n = 9) and tanycytic ependymomas (n = 6). In the RELA-like group histologically assigned to WHO grade III and resembling RELA-fused ependymomas, tumors lacked nuclear expression of p65-RelA as a surrogate marker for a pathological activation of the NF-κB pathway. Three tumors showed alternative C11orf95 fusions to MAML2 or NCOA1. A methylation-based brain tumor classifier assigned two RELA-like tumors to the methylation class "EP, RELA-fusion"; the others demonstrated no significant similarity score. Of the tanycytic group, 5/6 tumors were assigned a WHO grade II. No gene fusions were detected. Methylation profiling did not show any association with an established methylation class. We additionally identified two astroblastoma-like tumors that both presented with chromothripsis of chromosome 22 but lacked MN1 breaks according to FISH analysis. They revealed novel fusion events involving genes in chromosome 22. One further tumor with polyploid cytogenetics was interpreted as PFB ependymoma by the brain tumor methylation classifier but had no relation to the posterior fossa. Clinical follow-up was available for 16/18 patients. Patients with tanycytic and astroblastoma-like tumors had no relapse, while 2 patients with RELA-like ependymomas died. Our data indicate that in addition to ependymomas discovered so far, at least two more supratentorial ependymoma types (RELA-like and tanycytic) exist.
两种分别由 C11orf95-RELA 或 YAP-MAMLD1 融合引起的、在幕上部位发生的具有独特遗传定义的室管膜瘤实体，分别具有相应的特征。越来越多的证据表明，存在没有这些遗传特征的幕上室管膜瘤。在这项研究中，我们报告了 18 例儿科非 RELA/非 YAP 幕上室管膜瘤，通过组织学、免疫表型、遗传学和表观基因组学对其进行了系统表征。全面的分子分析包括高分辨率拷贝数分析、甲基化谱分析、Nanostring 技术融合转录本分析和 RNA 测序。基于组织学和免疫组织化学特征，确定了两种主要模式——RELA 样（n=9）和促纤维增生性室管膜瘤（n=6）。在组织学上被归类为 WHO 级 III 并类似于 RELA 融合的室管膜瘤的 RELA 样组中，肿瘤缺乏核表达 p65-RelA，作为 NF-κB 途径病理性激活的替代标志物。有 3 个肿瘤显示出替代的 C11orf95 融合到 MAML2 或 NCOA1。一个基于甲基化的脑肿瘤分类器将 2 个 RELA 样肿瘤分配到甲基化类别“EP、RELA 融合”；其余的肿瘤没有明显的相似性评分。在促纤维增生性组中，6/6 个肿瘤被归类为 WHO 级 II。没有检测到基因融合。甲基化谱分析没有显示与任何已建立的甲基化类别有任何关联。我们还鉴定了 2 个星形细胞瘤样肿瘤，它们都表现出染色体 22 的染色体重排，但根据 FISH 分析缺乏 MN1 断裂。它们揭示了涉及染色体 22 中基因的新融合事件。另一个具有多倍体细胞遗传学的肿瘤被脑肿瘤甲基化分类器解释为 PFB 室管膜瘤，但与后颅窝无关。对 18 例患者中的 16 例进行了临床随访。具有促纤维增生性和星形细胞瘤样肿瘤的患者没有复发，而 2 例 RELA 样室管膜瘤患者死亡。我们的数据表明，除了迄今为止发现的室管膜瘤外，至少还存在另外两种幕上室管膜瘤类型（RELA 样和促纤维增生性）。
