Pediatric ependymomas frequently develop in the cerebellum and are currently treated using non‐specific therapies, in part, because few somatically mutated driver genes are present, and the underlying pathobiology is poorly described. Circular RNAs (circRNAs) constitute as a large class of primarily non‐coding RNAs with important roles in tumorigenesis, but they have not been described in pediatric ependymomas. To advance our molecular understanding of ependymomas, we performed Next Generation Sequencing of rRNA‐depleted total RNA of 10 primary ependymoma and three control samples. CircRNA expression patterns were correlated to disease stage, outcome, age, and gender. We found a profound global downregulation of circRNAs in ependymoma relative to control samples. Many differentially expressed circRNAs were discovered and circSMARCA5 and circ‐FBXW7, which are described as tumor suppressors in glioma and glioblastomas in adults, were among the most downregulated. Moreover, patients with a dismal outcome clustered separately from patients with a good prognosis in unsupervised hierarchical cluster analyses. Next, NanoString nCounter experiments were performed, using a custom‐designed panel targeting 66 selected circRNAs, on a larger cohort that also included medulloblastomas and pilocytic astrocytomas. These experiments indicated that circRNA expression profiles are different among distinct pediatric brain tumor subtypes. In particular, circRNAs derived from RMST, LRBA, WDR78, DRC1 and BBS9 genes were specifically upregulated in ependymomas. In conclusion, circRNAs have different expression profiles in ependymomas relative to controls and between survivors and patients with a dismal outcome, suggesting that circRNAs could be exerted as diagnostic and prognostic biomarkers in the future if further validated in larger cohorts.

中文翻译：

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小儿室管膜瘤中不同的环状 RNA 表达谱

小儿室管膜瘤经常发生在小脑，目前使用非特异性疗法进行治疗，部分原因是几乎没有体细胞突变的驱动基因存在，并且潜在的病理学描述也很差。环状RNA（circRNA）是一大类主要的非编码RNA，在肿瘤发生中起重要作用，但尚未在儿科室管膜瘤中描述它们。为了推进我们对室管膜瘤的分子理解，我们对 10 个原发性室管膜瘤和三个对照样本的 rRNA 耗尽总 RNA 进行了下一代测序。circRNA 表达模式与疾病分期、结果、年龄和性别相关。我们发现相对于对照样本，室管膜瘤中的 circRNA 存在显着的全局下调。发现了许多差异表达的 circRNA，circSMARCA5 和 circ-FBXW7，被描述为成人胶质瘤和胶质母细胞瘤中的肿瘤抑制因子，是下调幅度最大的。此外，在无监督的分层聚类分析中，预后不佳的患者与预后良好的患者分开聚类。接下来，NanoString nCounter 实验使用定制设计的面板针对 66 个选定的 circRNA，在一个更大的队列中进行，该队列还包括成神经管细胞瘤和毛细胞星形细胞瘤。这些实验表明，不同的儿科脑肿瘤亚型之间的 circRNA 表达谱是不同的。尤其是，circRNAs 来源于 在无监督的分层聚类分析中，将预后不佳的患者与预后良好的患者分开进行聚类。接下来，NanoString nCounter 实验使用定制设计的面板针对 66 个选定的 circRNA，在一个更大的队列中进行，该队列还包括成神经管细胞瘤和毛细胞星形细胞瘤。这些实验表明，不同的儿科脑肿瘤亚型之间的 circRNA 表达谱是不同的。尤其是，circRNAs 来源于 在无监督的分层聚类分析中，将预后不佳的患者与预后良好的患者分开进行聚类。接下来，NanoString nCounter 实验使用定制设计的面板针对 66 个选定的 circRNA，在一个更大的队列中进行，该队列还包括成神经管细胞瘤和毛细胞星形细胞瘤。这些实验表明，不同的儿科脑肿瘤亚型之间的 circRNA 表达谱是不同的。尤其是，circRNAs 来源于RMST、LRBA、WDR78、DRC1和BBS9基因在室管膜瘤中特异性上调。总之，circRNAs 在室管膜瘤中的表达谱与对照组以及幸存者和预后不佳的患者之间具有不同的表达谱，这表明如果在更大的队列中进一步验证，circRNAs 可以在未来用作诊断和预后生物标志物。