Acta Neuropathologica

, Volume 121, Issue 3, pp 397–405 | Cite as

Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma

  • Genevieve Schindler
  • David Capper
  • Jochen Meyer
  • Wibke Janzarik
  • Heymut Omran
  • Christel Herold-Mende
  • Kirsten Schmieder
  • Pieter Wesseling
  • Christian Mawrin
  • Martin Hasselblatt
  • David N. Louis
  • Andrey Korshunov
  • Stefan Pfister
  • Christian Hartmann
  • Werner Paulus
  • Guido Reifenberger
  • Andreas von DeimlingEmail author
Original Paper


Missense mutations of the V600E type constitute the vast majority of tumor-associated somatic alterations in the v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) gene. Initially described in melanoma, colon and papillary thyroid carcinoma, these alterations have also been observed in primary nervous system tumors albeit at a low frequency. We analyzed exon 15 of BRAF spanning the V600 locus by direct sequencing in 1,320 adult and pediatric tumors of the nervous system including various types of glial, embryonal, neuronal and glioneuronal, meningeal, adenohypophyseal/sellar, and peripheral nervous system tumors. A total of 96 BRAF mutations were detected; 93 of the V600E type and 3 cases with a three base pair insertion between codons 599 and 600. The highest frequencies of BRAF V600E mutations were found in WHO grade II pleomorphic xanthoastrocytomas (42/64; 66%) and pleomorphic xanthoastrocytomas with anaplasia (15/23; 65%), as well as WHO grade I gangliogliomas (14/77; 18%), WHO grade III anaplastic gangliogliomas (3/6) and pilocytic astrocytomas (9/97; 9%). In pilocytic astrocytomas BRAF V600E mutation was strongly associated with extra-cerebellar location (p = 0.009) and was most frequent in diencephalic tumors (4/12; 33%). Glioblastomas and other gliomas were characterized by a low frequency or absence of mutations. No mutations were detected in non-glial tumors, including embryonal tumors, meningiomas, nerve sheath tumors and pituitary adenomas. The high mutation frequencies in pleomorphic xanthoastrocytomas, gangliogliomas and extra-cerebellar pilocytic astrocytomas implicate BRAF V600E mutation as a valuable diagnostic marker for these rare tumor entities. Future clinical trials should address whether BRAF V600E mutant brain tumor patients will benefit from BRAF V600E-directed targeted therapies.


BRAF V600E mutation Brain tumor Pleomorphic xanthoastrocytoma Ganglioglioma 



We would like to thank Kerstin Lindenberg and Britta Friedensdorf for excellent technical assistance. We thank the tissuebank of the National Center of Tumor Diseases Heidelberg for supplying us with tumor material. This work was supported by the Bundesministerium für Bildung und Forschung (BMBF–01ES0730 and 01GS0883).


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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Genevieve Schindler
    • 3
  • David Capper
    • 1
    • 2
  • Jochen Meyer
    • 2
  • Wibke Janzarik
    • 12
    • 13
  • Heymut Omran
    • 12
    • 14
  • Christel Herold-Mende
    • 4
  • Kirsten Schmieder
    • 3
  • Pieter Wesseling
    • 5
  • Christian Mawrin
    • 6
  • Martin Hasselblatt
    • 7
  • David N. Louis
    • 8
  • Andrey Korshunov
    • 2
  • Stefan Pfister
    • 9
    • 10
  • Christian Hartmann
    • 1
    • 2
  • Werner Paulus
    • 7
  • Guido Reifenberger
    • 11
  • Andreas von Deimling
    • 1
    • 2
    Email author
  1. 1.Department of Neuropathology, Institute of PathologyRuprecht-Karls-University HeidelbergHeidelbergGermany
  2. 2.Clinical Cooperation Unit Neuropathology G380German Cancer Research CenterHeidelbergGermany
  3. 3.Department of NeurosurgeryMedical Faculty of the Ruprecht-Karls-University HeidelbergMannheimGermany
  4. 4.Division of Neurosurgical Research, Department of NeurosurgeryRuprecht-Karls-University HeidelbergHeidelbergGermany
  5. 5.Department of Pathology, Nijmegen Center for Molecular Life Sciences (NCMLS)Radboud University Nijmegen Medical CentreNijmegenThe Netherlands
  6. 6.Department of NeuropathologyOtto-von-Guericke-University MagdeburgMagdeburgGermany
  7. 7.Institute of NeuropathologyUniversity Hospital MünsterMünsterGermany
  8. 8.Department of PathologyMassachusetts General Hospital and Harvard Medical SchoolBostonUSA
  9. 9.Division Molecular GeneticsGerman Cancer Research CenterHeidelbergGermany
  10. 10.Pediatric Hematology and OncologyHeidelberg University HospitalHeidelbergGermany
  11. 11.Department of NeuropathologyHeinrich Heine UniversityDüsseldorfGermany
  12. 12.Department of Pediatric Neurology and Muscle DisordersUniversity Hospital FreiburgFreiburgGermany
  13. 13.Department of NeurologyUniversity Hospital FreiburgFreiburgGermany
  14. 14.Klinik und Poliklinik für Allgemeine PädiatrieUniversity Hospital MünsterMünsterGermany

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