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Clinical impact of targeted amplicon sequencing for meningioma as a practical clinical-sequencing system

机译：靶向扩增子测序对脑膜瘤的临床影响作为实用的临床测序系统

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Recent genetic analyses using next-generation sequencers have revealed numerous genetic alterations in various tumors including meningioma, which is the most common primary brain tumor. However, their use as routine laboratory examinations in clinical applications for tumor genotyping is not cost effective. To establish a clinical sequencing system for meningioma and investigate the clinical significance of genotype, we retrospectively performed targeted amplicon sequencing on 103 meningiomas and evaluated the association with clinicopathological features. We designed amplicon-sequencing panels targeting eight genes including NF2 (neurofibromin 2), TRAF7, KLF4, AKT1, and SMO. Libraries prepared with genomic DNA extracted from PAXgene-fixed paraffin-embedded tissues of 103 meningioma specimens were sequenced using the Illumina MiSeq. NF2 loss in some cases was also confirmed by interphase-fluorescent in situ hybridization. We identified NF2 loss and/or at least one mutation in NF2, TRAF7, KLF4, AKT1, and SMO in 81 out of 103 cases (79%) by targeted amplicon sequencing. On the basis of genetic status, we categorized meningiomas into three genotype groups: NF2 type, TRAKLS type harboring mutation in TRAF7, AKT1, KLF4, and/or SMO, and 鈥榥ot otherwise classified鈥?type. Genotype significantly correlated with tumor volume, tumor location, and magnetic resonance imaging findings such as adjacent bone change and heterogeneous gadolinium enhancement, as well as histopathological subtypes. In addition, multivariate analysis revealed that genotype was independently associated with risk of recurrence. In conclusion, we established a rapid clinical sequencing system that enables final confirmation of meningioma genotype within 7 days turnaround time. Our method will bring multiple benefits to neuropathologists and neurosurgeons for accurate diagnosis and appropriate postoperative management.
机译：最近使用下一代测序仪进行的遗传分析显示，包括脑膜瘤在内的各种肿瘤均发生了许多遗传改变，脑膜瘤是最常见的原发性脑部肿瘤。然而，在临床应用中将其用作常规的实验室检查以进行肿瘤基因分型不是具有成本效益的。为了建立脑膜瘤的临床测序系统并研究基因型的临床意义，我们回顾性分析了103例脑膜瘤的靶向扩增子序列，并评估了其与临床病理特征的相关性。我们设计了针对八个基因的扩增子测序小组，其中包括NF2（神经纤维蛋白2），TRAF7，KLF4，AKT1和SMO。使用Illumina MiSeq对从103个脑膜瘤标本的PAXgene固定石蜡包埋的组织中提取的基因组DNA提取的文库进行测序。在某些情况下，通过相间荧光原位杂交也证实了NF2的损失。我们通过靶向扩增子测序鉴定了103例病例中的81例（79％）中的NF2丢失和/或NF2，TRAF7，KLF4，AKT1和SMO中的至少一个突变。根据遗传状况，我们将脑膜瘤分为三个基因型组：NF2型，在TRAF7，AKT1，KLF4和/或SMO中带有突变的TRAKLS型，以及“其他分类”型。基因型与肿瘤体积，肿瘤位置和磁共振成像发现（例如相邻的骨变化和异质g增强）以及组织病理学亚型显着相关。此外，多变量分析显示基因型与复发风险独立相关。总之，我们建立了一个快速的临床测序系统，可以在7天的周转时间内最终确认脑膜瘤基因型。我们的方法将为神经病理学家和神经外科医师带来诸多好处，以进行准确的诊断和适当的术后管理。

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