Acta Neuropathologica

, Volume 125, Issue 3, pp 351–358 | Cite as

Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations

  • David E. Reuss
  • Rosario M. Piro
  • David T. W. Jones
  • Matthias Simon
  • Ralf Ketter
  • Marcel Kool
  • Albert Becker
  • Felix Sahm
  • Stefan Pusch
  • Jochen Meyer
  • Christian Hagenlocher
  • Leonille Schweizer
  • David Capper
  • Phillipp Kickingereder
  • Jana Mucha
  • Christian Koelsche
  • Natalie Jäger
  • Thomas Santarius
  • Patrick S. Tarpey
  • Philip J. Stephens
  • P. Andrew Futreal
  • Ruth Wellenreuther
  • Jürgen Kraus
  • Doris Lenartz
  • Christel Herold-Mende
  • Christian Hartmann
  • Christian Mawrin
  • Nathalia Giese
  • Roland Eils
  • V. Peter Collins
  • Rainer König
  • Otmar D. Wiestler
  • Stefan M. Pfister
  • Andreas von Deimling
Original Paper

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

Meningioma Secretory KLF4 TRAF7 NF2 Krüppel-like factor 4 

Supplementary material

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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)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • David E. Reuss
    • 1
    • 2
  • Rosario M. Piro
    • 3
    • 4
  • David T. W. Jones
    • 5
  • Matthias Simon
    • 6
  • Ralf Ketter
    • 7
  • Marcel Kool
    • 5
  • Albert Becker
    • 8
  • Felix Sahm
    • 1
    • 2
  • Stefan Pusch
    • 1
    • 2
  • Jochen Meyer
    • 2
  • Christian Hagenlocher
    • 2
  • Leonille Schweizer
    • 1
    • 2
  • David Capper
    • 1
    • 2
  • Phillipp Kickingereder
    • 1
    • 2
  • Jana Mucha
    • 2
  • Christian Koelsche
    • 1
    • 2
  • Natalie Jäger
    • 3
  • Thomas Santarius
    • 9
  • Patrick S. Tarpey
    • 10
  • Philip J. Stephens
    • 10
  • P. Andrew Futreal
    • 10
  • Ruth Wellenreuther
    • 11
  • Jürgen Kraus
    • 12
  • Doris Lenartz
    • 13
  • Christel Herold-Mende
    • 14
  • Christian Hartmann
    • 15
  • Christian Mawrin
    • 16
  • Nathalia Giese
    • 17
  • Roland Eils
    • 3
    • 4
  • V. Peter Collins
    • 18
  • Rainer König
    • 3
    • 4
  • Otmar D. Wiestler
    • 19
  • Stefan M. Pfister
    • 5
    • 20
  • Andreas von Deimling
    • 1
    • 2
  1. 1.Department of Neuropathology, Institute of PathologyRuprecht-Karls-University HeidelbergHeidelbergGermany
  2. 2.Clinical Cooperation Unit NeuropathologyGerman Cancer Institute (DKFZ)HeidelbergGermany
  3. 3.Division of Theoretical BioinformaticsGerman Cancer Research Center (DKFZ)HeidelbergGermany
  4. 4.Institute of Pharmacy and Molecular Biotechnology, and Bioquant CenterUniversity of HeidelbergHeidelbergGermany
  5. 5.Division of Pediatric NeurooncologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
  6. 6.Department of NeurosurgeryUniversity of BonnBonnGermany
  7. 7.Klinik für NeurochirurgieUniversitätsklinikum des SaarlandesSaarlandGermany
  8. 8.Department of NeuropathologyUniversity of BonnBonnGermany
  9. 9.Department of NeurosurgeryAddenbrooke’s HospitalCambridgeUK
  10. 10.Cancer Genome Project, Wellcome Trust Sanger InstituteHinxton, CambridgeUK
  11. 11.Department of Molecular Genome AnalysisGerman Cancer Research Center (DKFZ)HeidelbergGermany
  12. 12.Medizinisches Versorgungszentrum für Neurologie und PsychiatrieBremenGermany
  13. 13.Department of NeurosurgeryUniversity Hospital of CologneCologneGermany
  14. 14.Department of NeurosurgeryUniversity Hospital HeidelbergHeidelbergGermany
  15. 15.Department for NeuropathologyInstitute of Pathology, Medizinische Hochschule HannoverHannoverGermany
  16. 16.Department of NeuropathologyOtto von Guericke University MagdeburgMagdeburgGermany
  17. 17.Chirurgische Universitätsklinik, Universität HeidelbergHeidelbergGermany
  18. 18.Division of Molecular Histopathology, Department of PathologyUniversity of CambridgeCambridgeUK
  19. 19.German Cancer Research Center (DKFZ)HeidelbergGermany
  20. 20.Department of Pediatric Oncology, Hematology and ImmunologyHeidelberg University HospitalHeidelbergGermany

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