Acta Neuropathologica Communications | 2021
Sporadic multiple meningiomas harbor distinct driver mutations
Abstract
© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. In a small fraction of patients, intracranial meningiomas arise as multiple and spatially distinct masses therefore presenting a unique management challenge [9, 12, 19]. A recently-published, (Surveillance, Epidemiology, and End Results) SEER-based study has reported that patients with multiple meningiomas (MM) have substantially reduced overall survival when compared to patients with single meningiomas [14]. Patients may develop multiple meningiomas in sporadic or hereditary forms. Familial syndromes that are commonly associated with MM are neurofibromatosis type 2 (NF2) and familial meningiomatosis in patients with germline NF2 and SMARCB1 mutations, respectively [2, 15]. While the mutational landscape of single meningiomas has been extensively studied [3–5, 10, 20], understanding of the molecular pathogenesis of sporadic MM remains incomplete. Older studies and case reports have reported molecular testing in patients with sporadic MM that have principally been focused on tumors with NF2 mutations [8, 16–18]. However, to our knowledge, no molecular profiling in a case series of spatially separated MM, composed of different histological subtypes, has been performed. The objective of this study is to elucidate the genetic features of sporadic MM, defined as the presence of ≥ 2 spatially separated synchronous or metachronous lesions. This series includes 17 resected sporadic meningiomas from eight patients (seven females and one male) that were identified by a record search for patients with MM. All patients presented with synchronous, spatially separated meningiomas without evidence of tumor bridging, as reviewed on MR-imaging. The patients had no significant prior radiation exposure and the tumors did not arise in patients who met the clinical criteria for the diagnosis of familial schwannomatosis or neurofibromatosis type 2 [6]. In addition, upon reviewing cranial and spinal MR images, no patient had other intraor extracranial tumors associated with hereditary meningioma syndromes such as schwannomas or ependymomas. Fresh frozen tumor tissue was available from all 17 meningiomas and was retrieved from the archives of the Institute for Pathology at the University Hospital Dresden upon approval of the local ethics committee. Two board-certified pathologists confirmed the pathologic diagnosis of each case. All tumors were classified according to the 2016 WHO classification of tumors of the central nervous system [11]. The tumor DNA was purified using AllPrep® DNA Universal Kit for fresh frozen tissue (Qiagen, Germantown MD) following the manufacturer’s instructions. The regions of interest were amplified using a custom designed amplikon panel according to the protocol “QIAseq Targeted DNA V3 Panel, May 2017” (QIAGEN, Hilden, Germany). The panel was custom-designed by our group and manufactured by QIAGEN. The panel covers either mutation hotspots or—where loss of function is a known mechanism of action—whole genes. The following meningioma-relevant genes are included: AKT1, ATRX, CDKN2A, KLF4, NF1, NF2, PIK3CA, PIK3R1, POLR2A, PTEN, SMARCB1, SMO, STAG2, SUFU, TP53, TRAF7, and TERT promotor. Open Access