Abstract

The diagnosis of ependymoma has moved from a purely histopathological review with limited prognostic value to an integrated diagnosis, relying heavily on molecular information. However, as the integrated approach is still novel and some molecular ependymoma subtypes are quite rare, few studies have correlated integrated pathology and clinical outcome, often focusing on small series of single molecular types. We collected data from 2023 ependymomas as classified by DNA methylation profiling, consisting of 1736 previously published and 287 unpublished methylation profiles. Methylation data and clinical information were correlated, and an integrated model was developed to predict progression-free survival. Patients with EPN-PFA, EPN-ZFTA, and EPN-MYCN tumors showed the worst outcome with 10-year overall survival rates of 56%, 62%, and 32%, respectively. EPN-PFA harbored chromosome 1q gains and/or 6q losses as markers for worse survival. In supratentorial EPN-ZFTA, a combined loss of CDKN2A and B indicated worse survival, whereas a single loss did not. Twelve out of 200 EPN-ZFTA (6%) were located in the posterior fossa, and these tumors relapsed or progressed even earlier than supratentorial tumors with a combined loss of CDKN2A/B. Patients with MPE and PF-SE, generally regarded as non-aggressive tumors, only had a 10-year progression-free survival of 59% and 65%, respectively. For the prediction of the 5-year progression-free survival, Kaplan-Meier estimators based on the molecular subtype, a Support Vector Machine based on methylation, and an integrated model based on clinical factors, CNV data, and predicted methylation scores achieved balanced accuracies of 66%, 68%, and 73%, respectively. Excluding samples with low prediction scores resulted in balanced accuracies of over 80%. In sum, our large-scale analysis of ependymomas provides robust information about molecular features and their clinical meaning. Our data are particularly relevant for rare and hardly explored tumor subtypes and seemingly benign variants that display higher recurrence rates than previously believed.

中文翻译：

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2023 年室管膜瘤队列的分子特征和改进的生存预测

摘要

室管膜瘤的诊断已从预后价值有限的纯粹组织病理学检查转变为严重依赖分子信息的综合诊断。然而，由于综合方法仍然新颖，并且一些分子室管膜瘤亚型相当罕见，因此很少有研究将综合病理学和临床结果相关联，通常集中于单分子类型的小系列研究。我们收集了 2023 个室管膜瘤的数据，按 DNA 甲基化图谱分类，其中包括 1736 个先前发表的甲基化图谱和 287 个未发表的甲基化图谱。将甲基化数据和临床信息相关联，并开发了一个综合模型来预测无进展生存期。EPN-PFA、EPN-ZFTA 和 EPN-MYCN 肿瘤患者的预后最差，10 年总生存率分别为 56%、62% 和 32%。EPN-PFA 将染色体 1q 增加和/或 6q 损失作为生存较差的标志。在幕上 EPN-ZFTA 中， CDKN2A和B的联合缺失表明生存率较差，而单一缺失则不然。200 个 EPN-ZFTA 中有 12 个（6%）位于后颅窝，这些肿瘤的复发或进展甚至比幕上肿瘤更早，同时伴有CDKN2A/B的缺失。MPE 和 PF-SE 患者通常被认为是非侵袭性肿瘤，其 10 年无进展生存率分别仅为 59% 和 65%。对于5年无进展生存期的预测，基于分子亚型的Kaplan-Meier估计器、基于甲基化的支持向量机以及基于临床因素、CNV数据和预测甲基化评分的集成模型取得了平衡的精度分别为 66%、68% 和 73%。排除预测得分较低的样本后，平衡准确度超过 80%。总之，我们对室管膜瘤的大规模分析提供了有关分子特征及其临床意义的可靠信息。我们的数据与罕见且难以探索的肿瘤亚型和看似良性的变异特别相关，这些变异的复发率比之前认为的要高。