Journal of Neuro-Oncology

, Volume 113, Issue 3, pp 353–358 | Cite as

BRAF alterations in pediatric low grade gliomas and mixed neuronal–glial tumors

  • Efthymios Dimitriadis
  • George A. Alexiou
  • Panagiota Tsotsou
  • Efthymia Simeonidi
  • Kalliopi Stefanaki
  • Amalia Patereli
  • Neofytos Prodromou
  • Nikolaos Pandis
Laboratory Investigation


Low grade astrocytomas are the most common brain tumor in children. Recent studies have identified alterations in the BRAF serine/threonine kinase gene that result in mitogen activated protein kinase pathway activation. Herewith, we investigated the genetic changes of BRAF in pediatric low grade gliomas and their relation to pathological findings and Ki-67 proliferation index. The results showed gene fusions between KIAA1549 and BRAF in 66.7 % of tumors. The majority involved the KIAA1549–BRAF exon 16-exon 9 variant. Fusion junction between KIAA1549 exon 15 and BRAF exon 9 was found in five tumors, in which the myxoid component was the predominant. This has not been previously reported. No significant correlation was found between specific KIAA1549 and BRAF fusion junctions and Ki-67 index. All of the samples included in this study were tested for the presence of the BRAFV600E mutation, and no positive sample was found.


Low grade glioma Children BRAF Ki-67 


  1. 1.
    Alexiou GA, Moschovi M, Stefanaki K et al (2011) Epidemiology of pediatric brain tumors in Greece (1991–2008). Experience from the Agia Sofia Children’s Hospital. Cent Eur Neurosurg 72:1–4PubMedCrossRefGoogle Scholar
  2. 2.
    Lin A, Rodriguez FJ, Karajannis MA et al (2012) BRAF alterations in primary glial and glioneuronal neoplasms of the central nervous system with identification of 2 novel KIAA1549–BRAF fusion variants. J Neuropathol Exp Neurol 71:66–72PubMedCrossRefGoogle Scholar
  3. 3.
    Cin H, Meyer C, Herr R et al (2011) Oncogenic FAM131B-BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma. Acta Neuropathol 121:763–774PubMedCrossRefGoogle Scholar
  4. 4.
    Tihan T, Ersen A, Qaddoumi I et al (2012) Pathologic characteristics of pediatric intracranial pilocytic astrocytomas and their impact on outcome in 3 countries: a multi-institutional study. Am J Surg Pathol 36:43–55PubMedCrossRefGoogle Scholar
  5. 5.
    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 68:8673–8677PubMedCrossRefGoogle Scholar
  6. 6.
    Dahse R, Kromeyer-Hauschid K, Berndt A et al (2009) No incidence of BRAF mutations in salivary gland carcinomas: implications for anti-EGFR therapies. J Biomed Biotechnol 2009:501736PubMedCrossRefGoogle Scholar
  7. 7.
    Louis DN, Ohgaki H, Wiestler OD et al (2007) The 2007 WHO Classification of Tumours of the Central Nervous System. Acta Neuropathol 114:97–109PubMedCrossRefGoogle Scholar
  8. 8.
    Horbinski C, Hamilton RL, Nikiforov Y et al (2010) Association of molecular alterations, including BRAF, with biology and outcome in pilocytic astrocytomas. Acta Neuropathol 119:641–649PubMedCrossRefGoogle Scholar
  9. 9.
    Horbinski C, Hamilton RL, Lovell C, Burnham J, Pollack IF (2010) Impact of morphology, MIB-1, p53 and MGMT on outcome in pilocytic astrocytomas. Brain Pathol 20:581–588PubMedCrossRefGoogle Scholar
  10. 10.
    Komotar RJ, Mocco J, Jones JE, Zacharia BE, Tihan T, Feldstein NA et al (2005) Pilomyxoid astrocytoma: diagnosis, prognosis, and management. Neurosurg Focus 18:E7PubMedGoogle Scholar
  11. 11.
    Fisher PG, Tihan T, Goldthwaite PT et al (2008) Outcome analysis of childhood low-grade astrocytomas. Pediatr Blood Cancer 51:245–250PubMedCrossRefGoogle Scholar
  12. 12.
    Turner CD, Chordas CA, Liptak CC et al (2009) Medical, psychological, cognitive and educational late-effects in pediatric low-grade glioma survivors treated with surgery only. Pediatr Blood Cancer 53:417–423PubMedCrossRefGoogle Scholar
  13. 13.
    Dienstmann R, Tabernero J (2011) BRAF as a target for cancer therapy. Anticancer Agents Med Chem 11:285–295PubMedCrossRefGoogle Scholar
  14. 14.
    Bar EE, Lin A, Tihan T et al (2008) Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma. J Neuropathol Exp Neurol 67:878–887PubMedCrossRefGoogle Scholar
  15. 15.
    Jones DT, Gronych J, Lichter P et al (2012) MAPK pathway activation in pilocytic astrocytoma. Cell Mol Life Sci 69:1799–1811PubMedCrossRefGoogle Scholar
  16. 16.
    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 101:722–733PubMedCrossRefGoogle Scholar
  17. 17.
    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 218:172–181PubMedCrossRefGoogle Scholar
  18. 18.
    Yu J, Deshmukh H, Gutmann RJ, Emnett RJ, Rodriguez FJ, Watson MA, Nagarajan R, Gutmann DH (2009) Alterations of BRAF and HIPK2 loci predominate in sporadic pilocytic astrocytoma. Neurology 73:1526–1531PubMedCrossRefGoogle Scholar
  19. 19.
    Tatevossian RG, Lawson AR, Forshew T et al (2010) MAPK pathway activation and the origins of pediatric low-grade astrocytomas. J Cell Physiol 222:509–514PubMedGoogle Scholar
  20. 20.
    Horbinski C, Nikiforova MN, Hagenkord JM, Hamilton RL, Pollack IF (2012) Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas. Neuro Oncol 14:777–789PubMedCrossRefGoogle Scholar
  21. 21.
    Chappé C, Padovani L, Scavarda D, Forest F, Nanni-Metellus I, Loundou A, Mercurio S, Fina F, Lena G, Colin C, Figarella-Branger D (2013) Dysembryoplastic Neuroepithelial Tumors share with Pleomorphic Xanthoastrocytomas and Gangliogliomas BRAF(V600E) mutation and expression. Brain Pathol. doi: 10.1111/bpa.12048 PubMedGoogle Scholar
  22. 22.
    Hawkins C, Walker E, Mohamed N et al (2011) BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma. Clin Cancer Res 17:4790–4798PubMedCrossRefGoogle Scholar
  23. 23.
    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 28:2119–2123PubMedCrossRefGoogle Scholar
  24. 24.
    Tian Y, Rich BE, Vena N et al (2011) Detection of KIAA1549–BRAF fusion transcripts in formalin-fixed paraffin-embedded pediatric low-grade gliomas. J Mol Diagn 13:669–677PubMedCrossRefGoogle Scholar
  25. 25.
    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 118:1739–1749PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Efthymios Dimitriadis
    • 1
  • George A. Alexiou
    • 2
  • Panagiota Tsotsou
    • 1
  • Efthymia Simeonidi
    • 1
  • Kalliopi Stefanaki
    • 3
  • Amalia Patereli
    • 3
  • Neofytos Prodromou
    • 2
  • Nikolaos Pandis
    • 1
  1. 1.Department of GeneticsSaint Savvas HospitalAthensGreece
  2. 2.Department of NeurosurgeryChildren’s Hospital “Agia Sofia”AthensGreece
  3. 3.Department of PathologyChildren’s Hospital “Agia Sofia’’AthensGreece

Personalised recommendations