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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 Deimling
Original Paper

Abstract

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.

Keywords

BRAF V600E mutation Brain tumor Pleomorphic xanthoastrocytoma Ganglioglioma 

Notes

Acknowledgments

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).

References

  1. 1.
    Allen JC, Judkins AR, Rosenblum MK et al (2006) Atypical teratoid/rhabdoid tumor evolving from an optic pathway ganglioglioma: case study. Neuro Oncol 8:79–82CrossRefPubMedGoogle Scholar
  2. 2.
    Basto D, Trovisco V, Lopes JM et al (2005) Mutation analysis of B-RAF gene in human gliomas. Acta Neuropathol 109:207–210CrossRefPubMedGoogle Scholar
  3. 3.
    Bowers DC, Gargan L, Kapur P et al (2003) Study of the MIB-1 labeling index as a predictor of tumor progression in pilocytic astrocytomas in children and adolescents. J Clin Oncol 21:2968–2973CrossRefPubMedGoogle Scholar
  4. 4.
    Chacko G, Chacko AG, Dunham CP et al (2007) Atypical teratoid/rhabdoid tumor arising in the setting of a pleomorphic xanthoastrocytoma. J Neurooncol 84:217–222CrossRefPubMedGoogle Scholar
  5. 5.
    Davies H, Bignell GR, Cox C et al (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954CrossRefPubMedGoogle Scholar
  6. 6.
    Dougherty MJ, Santi M, Brose MS et al (2010) Activating mutations in BRAF characterize a spectrum of pediatric low-grade gliomas. Neuro OncolGoogle Scholar
  7. 7.
    Eisenhardt AE, Olbrich H, Roring M et al (2010) Functional characterization of a BRAF insertion mutant associated with pilocytic astrocytoma. Int J CancerGoogle Scholar
  8. 8.
    El-Habr EA, Tsiorva P, Theodorou M et al (2010) Analysis of PIK3CA and B-RAF gene mutations in human astrocytomas: association with activation of ERK and AKT. Clin Neuropathol 29:239–245PubMedGoogle Scholar
  9. 9.
    Ewing I, Pedder-Smith S, Franchi G et al (2007) A mutation and expression analysis of the oncogene BRAF in pituitary adenomas. Clin Endocrinol (Oxf) 66:348–352CrossRefGoogle Scholar
  10. 10.
    Flaherty KT, Puzanov I, Kim KB et al (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363:809–819CrossRefPubMedGoogle Scholar
  11. 11.
    Forbes SA, Bhamra G, Bamford S et al (2008) The catalogue of somatic mutations in cancer (COSMIC). Curr Protoc Hum Genet, chap 10, unit 10 11Google Scholar
  12. 12.
    Forshew T, Tatevossian RG, Lawson AR et al (2009) Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas. J Pathol 218:172–181CrossRefPubMedGoogle Scholar
  13. 13.
    Furuta A, Takahashi H, Ikuta F et al (1992) Temporal lobe tumor demonstrating ganglioglioma and pleomorphic xanthoastrocytoma components. Case report. J Neurosurg 77:143–147CrossRefPubMedGoogle Scholar
  14. 14.
    Hagemann C, Gloger J, Anacker J et al (2009) RAF expression in human astrocytic tumors. Int J Mol Med 23:17–31PubMedGoogle Scholar
  15. 15.
    Hoeflich KP, Herter S, Tien J et al (2009) Antitumor efficacy of the novel RAF inhibitor GDC-0879 is predicted by BRAFV600E mutational status and sustained extracellular signal-regulated kinase/mitogen-activated protein kinase pathway suppression. Cancer Res 69:3042–3051CrossRefPubMedGoogle Scholar
  16. 16.
    Horbinski C, Hamilton RL, Nikiforov Y et al (2010) Association of molecular alterations, including BRAF, with biology and outcome in pilocytic astrocytomas. Acta Neuropathol 119:641–649CrossRefPubMedGoogle Scholar
  17. 17.
    Jacob K, Albrecht S, Sollier C et al (2009) Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours. Br J Cancer 101:722–733CrossRefPubMedGoogle Scholar
  18. 18.
    Jeuken J, van den Broecke C, Gijsen S et al (2007) RAS/RAF pathway activation in gliomas: the result of copy number gains rather than activating mutations. Acta Neuropathol 114:121–133CrossRefPubMedGoogle Scholar
  19. 19.
    Jones DT, Kocialkowski S, Liu L et al (2008) Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 68:8673–8677CrossRefPubMedGoogle Scholar
  20. 20.
    Jones DT, Kocialkowski S, Liu L et al (2009) Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene 28:2119–2123CrossRefPubMedGoogle Scholar
  21. 21.
    Knobbe CB, Reifenberger J, Reifenberger G (2004) Mutation analysis of the Ras pathway genes NRAS, HRAS, KRAS and BRAF in glioblastomas. Acta Neuropathol 108:467–470CrossRefPubMedGoogle Scholar
  22. 22.
    Kordek R, Biernat W, Sapieja W et al (1995) Pleomorphic xanthoastrocytoma with a gangliomatous component: an immunohistochemical and ultrastructural study. Acta Neuropathol 89:194–197CrossRefPubMedGoogle Scholar
  23. 23.
    Korshunov A, Meyer J, Capper D et al (2009) Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Acta Neuropathol 118:401–405CrossRefPubMedGoogle Scholar
  24. 24.
    Kubo T, Kuroda Y, Kokubu A et al (2009) Resequencing analysis of the human tyrosine kinase gene family in pancreatic cancer. Pancreas 38:e200–e206CrossRefPubMedGoogle Scholar
  25. 25.
    Lindboe CF, Cappelen J, Kepes JJ (1992) Pleomorphic xanthoastrocytoma as a component of a cerebellar ganglioglioma: case report. Neurosurgery 31:353–355CrossRefPubMedGoogle Scholar
  26. 26.
    Louis DN, Ohgaki H, Wiestler OD et al (2007) WHO classification of tumors of the central nervous system. IARC, LyonGoogle Scholar
  27. 27.
    Michaloglou C, Vredeveld LC, Mooi WJ et al (2008) BRAF(E600) in benign and malignant human tumours. Oncogene 27:877–895CrossRefPubMedGoogle Scholar
  28. 28.
    Michaloglou C, Vredeveld LC, Soengas MS et al (2005) BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436:720–724CrossRefPubMedGoogle Scholar
  29. 29.
    Montagut C, Settleman J (2009) Targeting the RAF–MEK–ERK pathway in cancer therapy. Cancer Lett 283:125–134CrossRefPubMedGoogle Scholar
  30. 30.
    Murray JC, Donahue DJ, Malik SI et al (2010) Temporal lobe pleomorphic xanthoastrocytoma and acquired BRAF mutation in an adolescent with the constitutional 22q11.2 deletion syndrome. J NeurooncolGoogle Scholar
  31. 31.
    Perry A, Giannini C, Scheithauer BW et al (1997) Composite pleomorphic xanthoastrocytoma and ganglioglioma: report of four cases and review of the literature. Am J Surg Pathol 21:763–771CrossRefPubMedGoogle Scholar
  32. 32.
    Pfister S, Janzarik WG, Remke M et al (2008) BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest 118:1739–1749CrossRefPubMedGoogle Scholar
  33. 33.
    Robinson JP, VanBrocklin MW, Guilbeault AR et al (2010) Activated BRAF induces gliomas in mice when combined with Ink4a/Arf loss or Akt activation. Oncogene 29:335–344CrossRefPubMedGoogle Scholar
  34. 34.
    Schiffman JD, Hodgson JG, VandenBerg SR et al (2010) Oncogenic BRAF mutation with CDKN2A inactivation is characteristic of a subset of pediatric malignant astrocytomas. Cancer Res 70:512–519CrossRefPubMedGoogle Scholar
  35. 35.
    Sugita Y, Irie K, Ohshima K et al (2009) Pleomorphic xanthoastrocytoma as a component of a temporal lobe cystic ganglioglioma: a case report. Brain Tumor Pathol 26:31–36CrossRefPubMedGoogle Scholar
  36. 36.
    Tannapfel A, Sommerer F, Benicke M et al (2003) Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut 52:706–712CrossRefPubMedGoogle Scholar
  37. 37.
    Vajtai I, Varga Z, Aguzzi A (1997) Pleomorphic xanthoastrocytoma with gangliogliomatous component. Pathol Res Pract 193:617–621PubMedGoogle Scholar
  38. 38.
    Weber RG, Hoischen A, Ehrler M et al (2007) Frequent loss of chromosome 9, homozygous CDKN2A/p14(ARF)/CDKN2B deletion and low TSC1 mRNA expression in pleomorphic xanthoastrocytomas. Oncogene 26:1088–1097CrossRefPubMedGoogle Scholar
  39. 39.
    Yang H, Higgins B, Kolinsky K et al (2010) RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res 70:5518–5527CrossRefPubMedGoogle Scholar
  40. 40.
    Yu J, Deshmukh H, Gutmann RJ et al (2009) Alterations of BRAF and HIPK2 loci predominate in sporadic pilocytic astrocytoma. Neurology 73:1526–1531CrossRefPubMedGoogle Scholar

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
  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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