1Department of Neurology, Laboratory of Molecular and Cellular Biology, University of São Paulo, São Paulo, Brazil.
2Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan.
J Neurosurg. 2022 Aug 26;138(3):649-662. doi: 10.3171/2022.7.JNS22953. Print 2023 Mar 1.
The authors searched for genetic and transcriptional signatures associated with tumor progression and recurrence in their cohort of patients with meningiomas, combining the analysis of targeted exome, NF2-LOH, transcriptome, and protein expressions.
The authors included 91 patients who underwent resection of intracranial meningioma at their institution between June 2000 and November 2007. The search of somatic mutations was performed by Next Generation Sequencing through a customized panel and multiplex ligation-dependent probe amplification for NF2 loss of heterozygosity. The transcriptomic profile was analyzed by QuantSeq 3' mRNA-Seq. The differentially expressed genes of interest were validated at the protein level analysis by immunohistochemistry.
The transcriptomic analysis identified an upregulated set of genes related to metabolism and cell cycle and downregulated genes related to immune response and extracellular matrix remodeling in grade 2 (atypical) meningiomas, with a significant difference in recurrent compared with nonrecurrent cases. EZH2 nuclear positivity associated with grade 2, particularly with recurrent tumors and EZH2 gene expression level, correlated positively with the expression of genes related to cell cycle and negatively to genes related to immune response and regulation of cell motility.
The authors identified modules of dysregulated genes in grade 2 meningiomas related to the activation of oxidative metabolism, cell division, cell motility due to extracellular remodeling, and immune evasion that were predictive of survival and exhibited significant correlations with EZH2 expression.
作者通过分析靶向外显子、NF2-杂合性缺失、转录组和蛋白质表达，在其脑膜瘤患者队列中寻找与肿瘤进展和复发相关的遗传和转录特征。
作者纳入了 91 例 2000 年 6 月至 2007 年 11 月在该机构接受颅内脑膜瘤切除术的患者。通过定制面板和 NF2 杂合性缺失的多重连接依赖性探针扩增进行下一代测序，搜索体细胞突变。通过 QuantSeq 3' mRNA-Seq 分析转录组谱。通过免疫组织化学对感兴趣的差异表达基因进行蛋白质水平分析验证。
转录组分析鉴定出一组与代谢和细胞周期上调相关的基因，以及与免疫反应和细胞外基质重塑下调相关的基因，在 2 级（非典型）脑膜瘤中复发与非复发病例之间存在显著差异。EZH2 核阳性与 2 级相关，尤其是与复发肿瘤和 EZH2 基因表达水平相关，与与细胞周期相关的基因表达呈正相关，与与免疫反应和细胞迁移调节相关的基因表达呈负相关。
作者鉴定了与氧化代谢、细胞分裂、细胞运动（由于细胞外重塑）和免疫逃避激活相关的失调基因模块，这些基因模块与生存相关，并与 EZH2 表达存在显著相关性。
