Genomic studies of high-grade/progressive meningiomas have reported a heterogeneous mutation spectrum, identifying few recurrently mutated genes. Most studies have been underpowered to detect genomic subclasses of aggressive meningiomas due to relatively small number of available samples. Here, we present a genomic survey of one of the largest multi-institutional cohorts of high-grade/progressive meningiomas to date. 850 high-grade/progressive meningiomas, including 441 WHO grade 2 and 176 WHO grade 3 meningiomas and 220 progressive WHO grade 1 meningiomas, were tested as part of a clinical testing program by hybridization capture of 406 cancer-related genes to detect base substitutions, indels, amplifications, deletions, and rearrangements. Information from pathology reports, histopathology review, and patient clinical data was assessed. Genomic analyses converged to identify at least three distinct patterns of biologically-aggressive meningiomas. The first and most common contained NF2-mutant tumors (n = 426, 50%), was associated with male sex (64.4% %, p = 0.0001) and often harbored additional mutations in CDKN2A/B (24%), and the chromatin regulators ARID1A (9%), and KDM6A (6%). A second group (NF2-agnostic) featured TERT promoter (TERTp; n = 56) or TP53 mutations (n = 25) and were either NF2-mutant or wild-type, and displayed no association with either sex (p = 0.39). The remaining group generally lacked NF2 mutations, and accounted for 40% of the cases—with three subgroups. One consistent primarily of grade 3 lesions harboring alterations in chromatin regulators BAP1 (n = 22) or PBRM1 (n = 16). A second subgroup contained AKT1 (n = 26), PIK3CA (n = 14) and SMO (n = 7) mutant skull-based meningiomas, and a third mixed subgroup included 237 meningiomas with a heterogeneous spectrum of low frequency and non-recurrent alterations. Our findings indicate that the patterns of genomic alterations in high-grade/progressive meningiomas commonly group into three different categories. The most common NF2-associated canonical group frequently harbored CDKN2A/B alterations, which is potentially amenable to targeted therapies. An NF2-agnostic group harbored frequent TERTp and TP53 mutations. The final subclass, distinct from the canonical NF2 mutant associated pathway, was partly characterized by BAP1/PBRM1 alterations (rhabdoid/papillary histology) or skull-base disease. Overall, these data increase our understanding of the pathobiology of high-grade/progressive meningiomas and can guide the design of clinical trials. Reviewed and approved by Western IRB; Protocol No. 20152817.

中文翻译：

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高级别/进行性脑膜瘤的不同基因组亚类：NF2 相关、NF2 排除和 NF2 不可知


高级别/进行性脑膜瘤的基因组研究报告了异质突变谱，识别出很少的反复突变基因。由于可用样本数量相对较少，大多数研究不足以检测侵袭性脑膜瘤的基因组亚类。在这里，我们对迄今为止最大的多机构高级别/进行性脑膜瘤队列之一进行了基因组调查。作为临床测试计划的一部分，通过杂交捕获 406 个癌症相关基因来检测碱基替换，对 850 个高级/进展性脑膜瘤进行了测试，其中包括 441 个 WHO 2 级和 176 个 WHO 3 级脑膜瘤和 220 个进展性 WHO 1 级脑膜瘤。插入缺失、扩增、删除和重排。评估了病理报告、组织病理学检查和患者临床数据的信息。基因组分析最终确定了至少三种不同的生物侵袭性脑膜瘤模式。第一个也是最常见的包含 NF2 突变的肿瘤 (n = 426, 50%)，与男性相关 (64.4% %，p = 0.0001)，并且通常在 CDKN2A/B (24%) 和染色质中含有其他突变调节器 ARID1A (9%) 和 KDM6A (6%)。第二组（与 NF2 无关）具有 TERT 启动子（TERTp；n = 56）或 TP53 突变（n = 25），并且是 NF2 突变型或野生型，并且与任一性别均没有关联（p = 0.39）。剩下的一组通常缺乏 NF2 突变，占病例的 40%，分为三个亚组。一种主要一致的 3 级病变，包含染色质调节因子 BAP1 (n = 22) 或 PBRM1 (n = 16) 的改变。 第二个亚组包含 AKT1 (n = 26)、PIK3CA (n = 14) 和 SMO (n = 7) 突变颅骨脑膜瘤，第三个混合亚组包含 237 个具有低频和非复发性改变异质谱的脑膜瘤。我们的研究结果表明，高级别/进行性脑膜瘤的基因组改变模式通常分为三个不同的类别。最常见的 NF2 相关典型群体经常含有 CDKN2A/B 改变，这可能适合靶向治疗。 NF2 不可知组存在频繁的 TERTp 和 TP53 突变。最后一个亚类与典型的 NF2 突变相关通路不同，其部分特征是 BAP1/PBRM1 改变（横纹肌样/乳头状组织学）或颅底疾病。总体而言，这些数据增加了我们对高级别/进展性脑膜瘤病理学的理解，并可以指导临床试验的设计。经Western IRB审核批准；协议号 20152817。