Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Department of Oncology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, USA.
Acta Neuropathol. 2022 Oct;144(4):733-746. doi: 10.1007/s00401-022-02484-7. Epub 2022 Aug 18.
Methylation profiling has radically transformed our understanding of tumors previously called central nervous system primitive neuro-ectodermal tumors (CNS-PNET). While this marks a momentous step toward defining key differences, reclassification has thrown treatment into disarray. To shed light on response to therapy and guide clinical decision-making, we report outcomes and molecular features of children with CNS-PNETs from two multi-center risk-adapted studies (SJMB03 for patients ≥ 3 years; SJYC07 for patients < 3 years) complemented by a non-protocol institutional cohort. Seventy patients who had a histological diagnosis of CNS-PNET or CNS embryonal tumor from one of the new categories that has supplanted CNS-PNET were included. This cohort was molecularly characterized by DNA methylation profiling (n = 70), whole-exome sequencing (n = 53), RNA sequencing (n = 20), and germline sequencing (n = 28). Clinical characteristics were detailed, and treatment was divided into craniospinal irradiation (CSI)-containing (SJMB03 and SJMB03-like) and CSI-sparing therapy (SJYC07 and SJYC07-like). When the cohort was analyzed in its entirety, no differences were observed in the 5-year survival rates even when CSI-containing therapy was compared to CSI-sparing therapy. However, when analyzed by DNA methylation molecular grouping, significant survival differences were observed, and treatment particulars provided suggestions of therapeutic response. Patients with CNS neuroblastoma with FOXR2 activation (CNS-NB-FOXR2) had a 5-year event-free survival (EFS)/overall survival (OS) of 66.7% ± 19.2%/83.3% ± 15.2%, and CIC rearranged sarcoma (CNS-SARC-CIC) had a 5-year EFS/OS both of 57.1% ± 18.7% with most receiving regimens that contained radiation (focal or CSI) and multidrug chemotherapy. Patients with high-grade neuroepithelial tumor with BCOR alteration (HGNET-BCOR) had abysmal responses to upfront chemotherapy-only regimens (5-year EFS = 0%), but survival extended with salvage radiation after progression [5-year OS = 53.6% ± 20.1%]. Patients with embryonal tumor with multilayered rosettes (ETMR) or high-grade glioma/glioblastoma multiforme (HGG/GBM) did not respond favorably to any modality (5-year EFS/OS = 10.7 ± 5.8%/17.9 ± 7.2%, and 10% ± 9.0%/10% ± 9.0%, respectively). As an accompaniment, we have assembled this data onto an interactive website to allow users to probe and query the cases. By reporting on a carefully matched clinical and molecular cohort, we provide the needed insight for future clinical management.
甲基化分析极大地改变了我们对以前称为中枢神经系统原始神经外胚层肿瘤 (CNS-PNET) 的肿瘤的认识。虽然这标志着定义关键差异的重要一步，但重新分类却使治疗陷入混乱。为了阐明对治疗的反应并指导临床决策，我们报告了来自两个多中心风险适应研究（SJMB03 适用于年龄≥3 岁的患者；SJYC07 适用于年龄<3 岁的患者）的 CNS-PNET 儿童的结果和分子特征，其中包括一个非协议机构队列。该队列的组织学诊断为 CNS-PNET 或 CNS 胚胎性肿瘤，属于取代 CNS-PNET 的新类别之一。该队列通过 DNA 甲基化分析（n=70）、全外显子组测序（n=53）、RNA 测序（n=20）和种系测序（n=28）进行了分子表征。详细描述了临床特征，并将治疗分为包含颅脊髓照射（CSI）的治疗（SJMB03 和 SJMB03 样）和 CSI 节约治疗（SJYC07 和 SJYC07 样）。当对整个队列进行分析时，即使将包含 CSI 的治疗与 CSI 节约治疗进行比较，5 年生存率也没有差异。然而，当按 DNA 甲基化分子分组进行分析时，观察到显著的生存差异，治疗细节提供了治疗反应的线索。FOXR2 激活的中枢神经系统神经母细胞瘤（CNS-NB-FOXR2）患者的 5 年无事件生存率（EFS）/总生存率（OS）为 66.7%±19.2%/83.3%±15.2%，而 CIC 重排肉瘤（CNS-SARC-CIC）的 5 年 EFS/OS 均为 57.1%±18.7%，大多数患者接受的治疗方案包含辐射（局部或 CSI）和多药化疗。具有 BCOR 改变的高级神经上皮肿瘤（HGNET-BCOR）患者对一线化疗方案的反应不佳（5 年 EFS=0%），但在进展后接受挽救性放疗可延长生存[5 年 OS=53.6%±20.1%]。具有多层玫瑰花结的胚胎性肿瘤（ETMR）或高级别胶质瘤/胶质母细胞瘤多形性（HGG/GBM）患者对任何治疗方式均无反应（5 年 EFS/OS=10.7%±5.8%/17.9%±7.2%和 10%±9.0%/10%±9.0%）。作为伴随，我们将这些数据整理到一个交互式网站上，以便用户进行探测和查询。通过报告精心匹配的临床和分子队列，我们为未来的临床管理提供了必要的见解。
