Foundation Medicine Inc, 150 Second Street, Cambridge, MA, 02141, USA.
Translational Neuro-Oncology Laboratory, Department of Neurosurgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
Acta Neuropathol Commun. 2020 Oct 21;8(1):171. doi: 10.1186/s40478-020-01040-2.
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.
高级/进展性脑膜瘤的基因组研究报告了一种异质的突变谱，确定了少数经常发生突变的基因。由于可用样本数量相对较少，大多数研究的检测能力不足以发现侵袭性脑膜瘤的基因组亚类。在这里，我们展示了迄今为止最大的多机构高级/进展性脑膜瘤队列之一的基因组调查结果。
850 例高级/进展性脑膜瘤，包括 441 例世界卫生组织（WHO）2 级和 176 例 WHO 3 级脑膜瘤以及 220 例进展性 WHO 1 级脑膜瘤，作为临床检测计划的一部分进行了检测，该计划通过杂交捕获 406 种与癌症相关的基因来检测碱基替换、插入缺失、扩增、缺失和重排。评估了来自病理报告、组织病理学复查和患者临床数据的信息。
基因组分析结果一致，确定了至少三种具有生物学侵袭性的脑膜瘤模式。第一种也是最常见的模式是 NF2 突变型肿瘤（n=426，50%），与男性（64.4%，p=0.0001）相关，常伴有 CDKN2A/B 缺失（24%），以及染色质调节剂 ARID1A（9%）和 KDM6A（6%）。第二种模式为 NF2 非依赖模式，特征为 TERT 启动子（TERTp；n=56）或 TP53 突变（n=25），可为 NF2 突变型或野生型，与性别无关（p=0.39）。其余的组通常缺乏 NF2 突变，占病例的 40%，其中有三个亚组。一组主要为 3 级病变，存在染色质调节剂 BAP1（n=22）或 PBRM1（n=16）改变。第二个亚组包含 AKT1（n=26）、PIK3CA（n=14）和 SMO（n=7）突变的颅底脑膜瘤，第三个混合亚组包括 237 例具有混杂低频和非重现性改变的脑膜瘤。
我们的研究结果表明，高级/进展性脑膜瘤的基因组改变模式通常可分为三种不同的类别。最常见的与 NF2 相关的经典组常伴有 CDKN2A/B 的改变，这可能适用于靶向治疗。NF2 非依赖组中经常发生 TERTp 和 TP53 突变。最后一个亚组与经典的 NF2 突变相关途径不同，部分特征为 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/进展性脑膜瘤发病机制的认识，并可以指导临床试验的设计。
IRB 批准状态：经西方 IRB 审查和批准；协议编号 20152817。
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