配对的原发性和复发性脑膜瘤中驱动基因突变的比较基因组分析。

Comparative genomic analysis of driver mutations in matched primary and recurrent meningiomas.

作者信息

Loewenstern Joshua, Rutland John, Gill Corey, Arib Hanane, Pain Margaret, Umphlett Melissa, Kinoshita Yayoi, McBride Russell, Donovan Michael, Sebra Robert, Bederson Joshua, Fowkes Mary, Shrivastava Raj

机构信息

Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, NY, New York, USA.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY, New York, USA.

出版信息

Oncotarget. 2019 May 28;10(37):3506-3517. doi: 10.18632/oncotarget.26941.

Abstract

A significant proportion of low-grade WHO grade I and higher-grade WHO grade II or III meningiomas are at risk to develop post-resection recurrence. Though recent studies investigated genomic alterations within histological subtypes of meningiomas, few have compared genomic profiles of primary meningiomas matched to their recurrences. The present study aimed to identify oncogenic driver mutations that may indicate risk of meningioma recurrence and aggressive clinical course. Seventeen patients treated for low-grade ( = 8) or high-grade ( = 9) meningioma and underwent both primary and recurrent resection between 2007-2017 were reviewed. Tumor specimens ( = 38) underwent genomic sequencing of known oncogenic driver mutations. Primary and recurrent tumors were compared using matched-pair analyses for mutational associations with clinical outcomes including functional status, progression-free survival (PFS) and overall survival (OS). Most common driver mutations included and . There was no enrichment for any driver mutation from primary to recurrent tumor specimen. mutant meningiomas were associated with larger tumor size (8-fold increase), presence of vasogenic edema, and higher mitotic proliferation on univariate and independently on multivariate regression (p's < 0.05) after controlling for preoperative and tumor features. Tumors with driver mutations were associated with decreased functional status at last postoperative follow-up ( = 0.022) relative to presentation. Mutation status was not associated with PFS or OS on multivariate Cox regression, but rather with grade of resection ( = 0.046) for PFS. While primary and recurrent tumors exhibited similar driver mutations within patients, the identification of driver mutations associated with clinical outcomes is crucial for guiding potential targeted treatments in recurrent meningiomas.

摘要

世界卫生组织(WHO)I级低级别以及II级或III级更高级别脑膜瘤中有很大一部分存在切除后复发的风险。尽管最近的研究调查了脑膜瘤组织学亚型中的基因组改变,但很少有研究比较原发性脑膜瘤与其复发肿瘤的基因组图谱。本研究旨在识别可能表明脑膜瘤复发风险和侵袭性临床病程的致癌驱动突变。回顾了2007年至2017年间接受低级别(n = 8)或高级别(n = 9)脑膜瘤治疗并接受了原发性和复发性切除的17例患者。对38个肿瘤标本进行了已知致癌驱动突变的基因组测序。使用配对分析比较原发性和复发性肿瘤,以分析与包括功能状态、无进展生存期(PFS)和总生存期(OS)在内的临床结果的突变关联。最常见的驱动突变包括……和……。从原发性肿瘤标本到复发性肿瘤标本,没有任何驱动突变出现富集。在控制术前和肿瘤特征后,单因素和多因素回归分析(p值<0.05)显示,携带……突变的脑膜瘤与更大的肿瘤大小(增加8倍)、血管源性水肿的存在以及更高的有丝分裂增殖相关。与初次就诊时相比,携带……驱动突变的肿瘤在最后一次术后随访时功能状态下降(p = 0.022)。多因素Cox回归分析显示,突变状态与PFS或OS无关,但与PFS的切除分级相关(p = 0.046)。虽然原发性和复发性肿瘤在患者体内表现出相似的驱动突变,但识别与临床结果相关的驱动突变对于指导复发性脑膜瘤的潜在靶向治疗至关重要。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/debf/6544407/ca7028f2867d/oncotarget-10-3506-g001.jpg

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