DMD genomic deletions characterize a subset of progressive/higher-grade meningiomas with poor outcome
DMD genomic deletions characterize a subset of progressive/higher-grade meningiomas with poor outcome
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DOI：
10.1007/s00401-018-1899-7
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发表时间：
2018-11-01
影响因子：
12.7
通讯作者：
Brastianos, Priscilla K.
中科院分区：
文献类型：
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作者：
Juratli, Tareq A.;McCabe, Devin;Brastianos, Priscilla K.
手术和放疗失败的进展性脑膜瘤预后差，没有标准治疗。虽然脑膜瘤总体上在女性中更常见，但进行性脑膜瘤在男性中更常见。我们对来自53例进行性/高级别肿瘤患者的169例脑膜瘤进行了全面的分子表征，包括匹配的原发和复发样本。在初始队列（n = 24）中的外显子组测序检测到X染色体上基因的频繁改变，肌营养不良蛋白编码和肌营养不良相关DMD基因的体细胞基因内缺失是最常见的改变（n = 5，20.8%），沿着的还有其他已知的X连锁癌症相关基因KDM 6A（n = 2，8.3%）、DDX 3X、RBM 10和STAG 2（n = 1，各4.1%）的改变。DMD失活（通过基因组缺失或蛋白表达缺失）最终在17/53例进行性脑膜瘤患者（32%）中检测到。重要的是，携带DMD失活的肿瘤患者的总生存期（OS）比野生型患者短[5.1年（95% CI 1.3-9.0）vs.未达到中位数（95% CI 2.9-未达到，p = 0.006）]。考虑到已知这些肿瘤中TERT改变的预后不良相关性，我们也评估了这些事件，并在该队列中发现7名患者存在TERT启动子突变，3名患者存在TERT重排（n = 10，18.8%），包括2名患者中存在的复发性新型RETREG 1-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）在预测不利结局方面相互独立。因此，DMD改变识别了预后较差的进行性/高级别脑膜瘤的子集。
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 [5.1years (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.