title: ARID1A and TERT promoter mutations in dedifferentiated meningioma.
abstract: Unlike patients with World Health Organization (WHO) grade I meningiomas, which are considered benign, patients with WHO grade III meningiomas have very high mortality rates. The principles underlying tumor progression in meningioma are largely unknown, yet a detailed understanding of these mechanisms will be required for effective management of patients with these high grade lethal tumors. We present a case of an intraventricular meningioma that at first presentation displayed remarkable morphologic heterogeneity-composed of distinct regions independently fulfilling histopathologic criteria for WHO grade I, II, and III designations. The lowest grade regions had classic meningothelial features, while the highest grade regions were markedly dedifferentiated. Whereas progression in meningiomas is generally observed during recurrence following radiation and systemic medical therapies, the current case offers us a snapshot of histologic progression and intratumoral heterogeneity in a native pretreatment context. Using whole exome sequencing and high resolution array-based comparative genomic hybridization, we observed marked genetic heterogeneity between the various areas. Notably, in the higher grade regions we found increased aneuploidy with progressive loss of heterozygosity, the emergence of mutations in the TERT promoter, and compromise of ARID1A. These findings provide new insights into intratumoral heterogeneity in the evolution of malignant phenotypes in anaplastic meningiomas and potential pathways of malignant progression.
authors.affiliation: Division of Neuropathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Malak S
authors.initials: MS
authors.lastname: Abedalthagafi
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Wenya Linda
authors.initials: WL
authors.lastname: Bi
authors.affiliation: Division of Neuropathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Parker H
authors.initials: PH
authors.lastname: Merrill
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Gibson
authors.affiliation: Division of Neuropathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Rose
authors.affiliation: Division of Neuropathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Ziming
authors.initials: Z
authors.lastname: Du
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Francis
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Rose
authors.initials: R
authors.lastname: Du
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Dunn
authors.affiliation: Clinical Cytogenetics Laboratory, Center for Advanced Molecular Diagnostics, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Azra H
authors.initials: AH
authors.lastname: Ligon
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.affiliation: Division of Neuropathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: ssantagata@partners.org.
authors.forename: Sandro
authors.initials: S
authors.lastname: Santagata
mesh_terms: D004268:DNA-Binding Proteins; D018450:Disease Progression; D005260:Female; D006801:Humans; D008577:Meningeal Neoplasms / Q000235:genetics*; D008579:Meningioma / Q000235:genetics* / Q000473:pathology*; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D019098:Telomerase / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C112476:ARID1A protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C509186:TERT protein, human; D019098:Telomerase
keywords: Meningioma; SWI/SNF complex; anaplastic; chromatin remodeling; intratumoral heterogeneity