Translational Neuro-Oncology Laboratory, Department of Neurosurgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
Stephen E. and Catherine Pappas Center for Neuro-Oncology, Divisions of Hematology/Oncology and Neuro-Oncology, Departments of Medicine and Neurology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
Acta Neuropathol. 2018 Nov;136(5):779-792. doi: 10.1007/s00401-018-1899-7. Epub 2018 Aug 19.
Progressive meningiomas that have failed surgery and radiation have a poor prognosis and no standard therapy. While meningiomas are more common in females overall, progressive meningiomas are enriched in males. We performed a comprehensive molecular characterization of 169 meningiomas from 53 patients with progressive/high-grade tumors, including matched primary and recurrent samples. Exome sequencing in an initial cohort (n = 24) detected frequent alterations in genes residing on the X chromosome, with somatic intragenic deletions of the dystrophin-encoding and muscular dystrophy-associated DMD gene as the most common alteration (n = 5, 20.8%), along with alterations of other known X-linked cancer-related genes KDM6A (n =2, 8.3%), DDX3X, RBM10 and STAG2 (n = 1, 4.1% each). DMD inactivation (by genomic deletion or loss of protein expression) was ultimately detected in 17/53 progressive meningioma patients (32%). Importantly, patients with tumors harboring DMD inactivation had a shorter overall survival (OS) than their wild-type counterparts [5.1 years (95% CI 1.3-9.0) vs. median not reached (95% CI 2.9-not reached, p = 0.006)]. Given the known poor prognostic association of TERT alterations in these tumors, we also assessed for these events, and found seven patients with TERT promoter mutations and three with TERT rearrangements in this cohort (n = 10, 18.8%), including a recurrent novel RETREG1-TERT rearrangement that was present in two patients. In a multivariate model, DMD inactivation (p = 0.033, HR = 2.6, 95% CI 1.0-6.6) and TERT alterations (p = 0.005, HR = 3.8, 95% CI 1.5-9.9) were mutually independent in predicting unfavorable outcomes. Thus, DMD alterations identify a subset of progressive/high-grade meningiomas with worse outcomes.
手术和放疗失败的进行性脑膜瘤预后不良，且尚无标准疗法。虽然脑膜瘤在女性中更为常见，但进行性脑膜瘤在男性中更为常见。我们对 53 名进展/高级别肿瘤患者的 169 例脑膜瘤进行了全面的分子特征分析，包括匹配的原发和复发性样本。在一个初始队列（n=24）中进行的外显子组测序检测到位于 X 染色体上的基因频繁发生改变，其中肌营养不良蛋白编码和肌肉营养不良相关的 DMD 基因突变的体细胞基因内缺失是最常见的改变（n=5，20.8%），此外还改变了其他已知的 X 连锁癌症相关基因 KDM6A（n=2，8.3%）、DDX3X、RBM10 和 STAG2（n=1，4.1%）。最终在 53 例进展性脑膜瘤患者中的 17 例（32%）检测到 DMD 失活（通过基因组缺失或蛋白表达缺失）。重要的是，携带 DMD 失活的肿瘤患者的总生存期（OS）短于野生型患者[5.1 年（95%CI 1.3-9.0）与中位未达到（95%CI 2.9-未达到，p=0.006)]。鉴于这些肿瘤中 TERT 改变与预后不良的已知相关性，我们还评估了这些事件，并在该队列中发现了 7 例患者存在 TERT 启动子突变和 3 例 TERT 重排（n=10，18.8%），包括两个患者存在的新型 RETREG1-TERT 重排。在多变量模型中，DMD 失活（p=0.033，HR=2.6，95%CI 1.0-6.6）和 TERT 改变（p=0.005，HR=3.8，95%CI 1.5-9.9）在预测不良结局方面是相互独立的。因此，DMD 改变可识别出一组具有更差结局的进行性/高级别脑膜瘤。
