Acta Neuropathologica

, Volume 125, Issue 3, pp 351–358

Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations

Authors

  • David E. Reuss
    • Department of Neuropathology, Institute of PathologyRuprecht-Karls-University Heidelberg
    • Clinical Cooperation Unit NeuropathologyGerman Cancer Institute (DKFZ)
  • Rosario M. Piro
    • Division of Theoretical BioinformaticsGerman Cancer Research Center (DKFZ)
    • Institute of Pharmacy and Molecular Biotechnology, and Bioquant CenterUniversity of Heidelberg
  • David T. W. Jones
    • Division of Pediatric NeurooncologyGerman Cancer Research Center (DKFZ)
  • Matthias Simon
    • Department of NeurosurgeryUniversity of Bonn
  • Ralf Ketter
    • Klinik für NeurochirurgieUniversitätsklinikum des Saarlandes
  • Marcel Kool
    • Division of Pediatric NeurooncologyGerman Cancer Research Center (DKFZ)
  • Albert Becker
    • Department of NeuropathologyUniversity of Bonn
  • Felix Sahm
    • Department of Neuropathology, Institute of PathologyRuprecht-Karls-University Heidelberg
    • Clinical Cooperation Unit NeuropathologyGerman Cancer Institute (DKFZ)
  • Stefan Pusch
    • Department of Neuropathology, Institute of PathologyRuprecht-Karls-University Heidelberg
    • Clinical Cooperation Unit NeuropathologyGerman Cancer Institute (DKFZ)
  • Jochen Meyer
    • Clinical Cooperation Unit NeuropathologyGerman Cancer Institute (DKFZ)
  • Christian Hagenlocher
    • Clinical Cooperation Unit NeuropathologyGerman Cancer Institute (DKFZ)
  • Leonille Schweizer
    • Department of Neuropathology, Institute of PathologyRuprecht-Karls-University Heidelberg
    • Clinical Cooperation Unit NeuropathologyGerman Cancer Institute (DKFZ)
  • David Capper
    • Department of Neuropathology, Institute of PathologyRuprecht-Karls-University Heidelberg
    • Clinical Cooperation Unit NeuropathologyGerman Cancer Institute (DKFZ)
  • Phillipp Kickingereder
    • Department of Neuropathology, Institute of PathologyRuprecht-Karls-University Heidelberg
    • Clinical Cooperation Unit NeuropathologyGerman Cancer Institute (DKFZ)
  • Jana Mucha
    • Clinical Cooperation Unit NeuropathologyGerman Cancer Institute (DKFZ)
  • Christian Koelsche
    • Department of Neuropathology, Institute of PathologyRuprecht-Karls-University Heidelberg
    • Clinical Cooperation Unit NeuropathologyGerman Cancer Institute (DKFZ)
  • Natalie Jäger
    • Division of Theoretical BioinformaticsGerman Cancer Research Center (DKFZ)
  • Thomas Santarius
    • Department of NeurosurgeryAddenbrooke’s Hospital
  • Patrick S. Tarpey
    • Cancer Genome Project, Wellcome Trust Sanger Institute
  • Philip J. Stephens
    • Cancer Genome Project, Wellcome Trust Sanger Institute
  • P. Andrew Futreal
    • Cancer Genome Project, Wellcome Trust Sanger Institute
  • Ruth Wellenreuther
    • Department of Molecular Genome AnalysisGerman Cancer Research Center (DKFZ)
  • Jürgen Kraus
    • Medizinisches Versorgungszentrum für Neurologie und Psychiatrie
  • Doris Lenartz
    • Department of NeurosurgeryUniversity Hospital of Cologne
  • Christel Herold-Mende
    • Department of NeurosurgeryUniversity Hospital Heidelberg
  • Christian Hartmann
    • Department for NeuropathologyInstitute of Pathology, Medizinische Hochschule Hannover
  • Christian Mawrin
    • Department of NeuropathologyOtto von Guericke University Magdeburg
  • Nathalia Giese
    • Chirurgische Universitätsklinik, Universität Heidelberg
  • Roland Eils
    • Division of Theoretical BioinformaticsGerman Cancer Research Center (DKFZ)
    • Institute of Pharmacy and Molecular Biotechnology, and Bioquant CenterUniversity of Heidelberg
  • V. Peter Collins
    • Division of Molecular Histopathology, Department of PathologyUniversity of Cambridge
  • Rainer König
    • Division of Theoretical BioinformaticsGerman Cancer Research Center (DKFZ)
    • Institute of Pharmacy and Molecular Biotechnology, and Bioquant CenterUniversity of Heidelberg
  • Otmar D. Wiestler
    • German Cancer Research Center (DKFZ)
  • Stefan M. Pfister
    • Division of Pediatric NeurooncologyGerman Cancer Research Center (DKFZ)
    • Department of Pediatric Oncology, Hematology and ImmunologyHeidelberg University Hospital
    • Department of Neuropathology, Institute of PathologyRuprecht-Karls-University Heidelberg
    • Clinical Cooperation Unit NeuropathologyGerman Cancer Institute (DKFZ)
Original Paper

DOI: 10.1007/s00401-013-1093-x

Cite this article as:
Reuss, D.E., Piro, R.M., Jones, D.T.W. et al. Acta Neuropathol (2013) 125: 351. doi:10.1007/s00401-013-1093-x

Abstract

Meningiomas are among the most frequent intracranial tumors. The secretory variant of meningioma is characterized by glandular differentiation, formation of intracellular lumina and pseudopsammoma bodies, expression of a distinct pattern of cytokeratins and clinically by pronounced perifocal brain edema. Here we describe whole-exome sequencing analysis of DNA from 16 secretory meningiomas and corresponding constitutional tissues. All secretory meningiomas invariably harbored a mutation in both KLF4 and TRAF7. Validation in an independent cohort of 14 secretory meningiomas by Sanger sequencing or derived cleaved amplified polymorphic sequence (dCAPS) assay detected the same pattern, with KLF4 mutations observed in a total of 30/30 and TRAF7 mutations in 29/30 of these tumors. All KLF4 mutations were identical, affected codon 409 and resulted in a lysine to glutamine exchange (K409Q). KLF4 mutations were not found in 89 non-secretory meningiomas, 267 other intracranial tumors including gliomas, glioneuronal tumors, pituitary adenomas and metastases, 59 peripheral nerve sheath tumors and 52 pancreatic tumors. TRAF7 mutations were restricted to the WD40 domains. While KLF4 mutations were exclusively seen in secretory meningiomas, TRAF7 mutations were also observed in 7/89 (8 %) of non-secretory meningiomas. KLF4 and TRAF7 mutations were mutually exclusive with NF2 mutations. In conclusion, our findings suggest an essential contribution of combined KLF4 K409Q and TRAF7 mutations in the genesis of secretory meningioma and demonstrate a role for TRAF7 alterations in other non-NF2 meningiomas.

Keywords

MeningiomaSecretoryKLF4TRAF7NF2Krüppel-like factor 4

Supplementary material

401_2013_1093_MOESM1_ESM.xls (32 kb)
Supplementary material 1 (XLS 32 kb)
401_2013_1093_MOESM2_ESM.xls (43 kb)
Supplementary material 2 (XLS 43 kb)
401_2013_1093_MOESM3_ESM.docx (34 kb)
Supplementary material 3 (DOCX 34 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2013