Acta Neuropathologica

, Volume 121, Issue 3, pp 407–420

PI3K/AKT pathway alterations are associated with clinically aggressive and histologically anaplastic subsets of pilocytic astrocytoma

  • Erika F. Rodriguez
  • Bernd W. Scheithauer
  • Caterina Giannini
  • Amanda Rynearson
  • Ling Cen
  • Bridget Hoesley
  • Heather Gilmer-Flynn
  • Jann N. Sarkaria
  • Sarah Jenkins
  • Jin Long
  • Fausto J. Rodriguez
Original Paper

DOI: 10.1007/s00401-010-0784-9

Cite this article as:
Rodriguez, E.F., Scheithauer, B.W., Giannini, C. et al. Acta Neuropathol (2011) 121: 407. doi:10.1007/s00401-010-0784-9

Abstract

Pilocytic astrocytomas (PA) are well-differentiated gliomas having a favorable prognosis when compared with other diffuse or infiltrative astrocytomas. Molecular genetic abnormalities and activation of signaling pathways associated with clinically aggressive PA and histologically anaplastic PA have not been adequately studied. We performed molecular genetic, gene expression, and immunohistochemical studies using three PA subsets, including conventional PA (n = 43), clinically aggressive/recurrent PA (n = 24), and histologically anaplastic PA (n = 25). A clinical diagnosis of NF1 was present in 28% of anaplastic PA. Molecular cytogenetic studies demonstrated heterozygous PTEN/10q and homozygous p16 deletions in 6/19 (32%) and 3/15 (20%) cases of anaplastic PA, respectively, but in neither of the two other groups. BRAF duplication was identified in 33% of sporadic anaplastic PA and 63% of cerebellar examples. BRAFV600E mutation was absent in four (of 4) sporadic cases lacking duplication. IDH1R132H immunohistochemistry was negative in 16 (of 16) cases. Neither PDGFRA nor EGFR amplifications were present. pERK staining levels were similar among the three PA subsets, but a stepwise increase in cytoplasmic pAKT and to a lesser extent pS6 immunoreactivity was noted by immunohistochemistry in aggressive PA groups. This was particularly true in histologically anaplastic PA when compared with conventional PA (p < 0.001 and p = 0.005, respectively). In addition, PTEN expression at the mRNA level was decreased in histologically anaplastic PA when compared to the other groups (p = 0.05). In summary, activation of the PI3K/AKT in addition to MAPK/ERK signaling pathways may underlie biological aggressiveness in PA. Specifically, it may mediate the increased proliferative activity observed in histologically anaplastic PA.

Keywords

Pilocytic astrocytomaBrainNeurofibromatosisGliomaPTENAKT

Supplementary material

401_2010_784_MOESM1_ESM.tif (425 kb)
Supplementary Fig. 1: Validation of BRAF probe cocktail target site. PCR for three BAC clones used in BRAF probe design (a). Hybridization using non-neoplastic human metaphases demonstrates the expected labeling to the known BRAF gene locus in chromosomal region 7q34 (b) (TIFF 425 kb)
401_2010_784_MOESM2_ESM.tif (477 kb)
Supplementary Fig. 2: Sequencing results from a histologically anaplastic PA showed a BRAF gene exon 15 wild-type sequence. Arrow indicates BRAF gene nucleotide 1799 position (T) (TIFF 476 kb)

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Erika F. Rodriguez
    • 1
  • Bernd W. Scheithauer
    • 1
  • Caterina Giannini
    • 1
  • Amanda Rynearson
    • 1
  • Ling Cen
    • 2
  • Bridget Hoesley
    • 3
  • Heather Gilmer-Flynn
    • 3
  • Jann N. Sarkaria
    • 2
  • Sarah Jenkins
    • 4
  • Jin Long
    • 1
  • Fausto J. Rodriguez
    • 1
    • 5
  1. 1.Department of Anatomic Pathology and Laboratory MedicineMayo ClinicRochesterUSA
  2. 2.Department of Radiation OncologyMayo ClinicRochesterUSA
  3. 3.Advanced Genomics Technology CenterMayo ClinicRochesterUSA
  4. 4.Biomedical Statistics and InformaticsMayo ClinicRochesterUSA
  5. 5.Division of Neuropathology, Department of PathologyJohns Hopkins UniversityBaltimoreUSA