Advertisement

Acta Neuropathologica

, Volume 118, Issue 3, pp 401–405 | Cite as

Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma

  • Andrey Korshunov
  • Jochen Meyer
  • David Capper
  • Arne Christians
  • Marc Remke
  • Hendrik Witt
  • Stefan Pfister
  • Andreas von DeimlingEmail author
  • Christian Hartmann
Original Paper

Abstract

Separation of pilocytic astrocytoma from diffuse astrocytomas frequently poses problems mostly related to small sample size. Precise classification and grading are essential due to different therapeutic strategies prompted by diagnoses of pilocytic astrocytoma WHO grade I, diffuse astrocytomas WHO grade II or anaplastic astrocytoma WHO grade III. Recently, genomic aberrations with a high specificity for distinct glioma entities have been described. Pilocytic astrocytomas carry a duplication at chromosome band 7q34 containing a BRAF–KIAA1549 gene fusion in the majority of cases. IDH1 mutations are observed very frequently in adult astrocytomas and IDH2 mutations have been reported in some astrocytomas. We examined a series of 120 astrocytomas including 70 pilocytic astrocytomas WHO grade I and 50 diffuse astrocytomas WHO grade II for both, BRAF–KIAA1549 fusion with a newly developed FISH assay and mutations in IDH1 and IDH2 by direct sequencing. Pilocytic astrocytomas contained the BRAF fusion in 49 cases (70%) but neither IDH1 nor IDH2 mutations. Astrocytomas WHO grade II exhibited IDH1 mutations in 38 cases (76%) but neither IDH2 mutations nor BRAF fusions. Thus, combined molecular analysis of BRAF and IDH1 is a sensitive and highly specific approach to separate pilocytic astrocytoma from diffuse astrocytoma.

Keywords

BRAF IDH1 IDH2 Pilocytic astrocytoma Diffuse astrocytoma 

Notes

Acknowledgments

We wish to thank F. Mößler, K. Lindenberg, A. Wittman and B. Walter for skillful technical assistance. This work was supported by the Bundesministerium für Bildung und Forschung (BMBF–01ES0730) to AvD and CH and by a grant from the “Tour der Hoffnung” to SP.

References

  1. 1.
    Balss J, Meyer J, Mueller W et al (2008) Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 116:597–602PubMedCrossRefGoogle Scholar
  2. 2.
    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
  3. 3.
    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
  4. 4.
    Hayne C, Tzivion G, Luo Z (2000) Raf-1/MEK/MAPK pathway is necessary for the G2/M transition induced by nocodazole. J Biol Chem 275:31876–31882PubMedCrossRefGoogle Scholar
  5. 5.
    Hayostek CJ, Shaw EG, Scheithauer B et al (1993) Astrocytomas of the cerebellum. A comparative clinicopathologic study of pilocytic and diffuse astrocytomas. Cancer 72:856–869PubMedCrossRefGoogle Scholar
  6. 6.
    Ichimura K, Pearson DM, Kocialkowski S et al (2009) IDH1 mutations are present in the majority of common adult gliomas but are rare in primary glioblastomas. Neuro Oncol (epub ahead of print)Google Scholar
  7. 7.
    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
  8. 8.
    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 (epub ahead of print)Google Scholar
  9. 9.
    Kruchko C, Brem S, Lee H et al (2008) Statistical report: primary brain tumors in the United States, 2000–2004, Hinsdale: Central Brain Tumor Registry of the United States (CBTRUS)Google Scholar
  10. 10.
    Lee SM, Koh HJ, Park DC et al (2002) Cytosolic NADP(+)-dependent isocitrate dehydrogenase status modulates oxidative damage to cells. Free Radic Biol Med 32:1185–1196PubMedCrossRefGoogle Scholar
  11. 11.
    Louis DN et al (2007) WHO classification of tumours of the central nervous system, 4th edn. World Health Organization classification of tumours. International Agency for Research on Cancer, LyonGoogle Scholar
  12. 12.
    Palma L, Russo A, Celli P (1984) Prognosis of the so-called “diffuse” cerebellar astrocytoma. Neurosurgery 15:315–317PubMedCrossRefGoogle Scholar
  13. 13.
    Parsons DW, Jones S, Zhang X et al (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812PubMedCrossRefGoogle Scholar
  14. 14.
    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
  15. 15.
    Sievert AJ, Jackson EM, Gai X et al (2009) Duplication of 7q34 in pediatric low-grade astrocytomas detected by high-density single-nucleotide polymorphism-based genotype arrays results in a novel BRAF fusion gene. Brain Pathol (epub ahead of print)Google Scholar
  16. 16.
    Watanabe T, Nobusawa S, Kleihues P et al (2009) IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol 174:1149–1153PubMedCrossRefGoogle Scholar
  17. 17.
    Yan H, Parsons DW, Jin G et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773PubMedCrossRefGoogle Scholar
  18. 18.
    Zhao S, Lin Y, Xu W et al (2009) Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science 324:261–265PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Andrey Korshunov
    • 1
    • 2
  • Jochen Meyer
    • 2
  • David Capper
    • 1
  • Arne Christians
    • 2
  • Marc Remke
    • 3
  • Hendrik Witt
    • 3
  • Stefan Pfister
    • 3
    • 4
  • Andreas von Deimling
    • 1
    • 2
    Email author
  • Christian Hartmann
    • 1
    • 2
  1. 1.Department of Neuropathology, Institute of PathologyRuprecht-Karls-Universität HeidelbergHeidelbergGermany
  2. 2.Clinical Cooperation Unit Neuropathology G380German Cancer Research CenterHeidelbergGermany
  3. 3.Division Molecular GeneticsGerman Cancer Research CenterHeidelbergGermany
  4. 4.Department of Pediatric Oncology, Hematology and ImmunologyRuprecht-Karls-Universität HeidelbergHeidelbergGermany

Personalised recommendations