Acta Neuropathologica

, Volume 114, Issue 2, pp 121–133 | Cite as

RAS/RAF pathway activation in gliomas: the result of copy number gains rather than activating mutations

  • Judith Jeuken
  • Caroline van den Broecke
  • Sabine Gijsen
  • Sandra Boots-Sprenger
  • Pieter Wesseling
Original Paper

Abstract

Aberrant RAS/RAF signaling has been reported to be important for many tumor types including gliomas. Activation of the RAS/RAF pathway can result from oncogenic mutations of RAS/RAF itself. However, such mutations have only occasionally been reported in gliomas. In order to further elucidate the role of RAS/RAF pathway activation in a histopathological and genetic spectrum of glioma subtypes (n = 93), we evaluated different types of aberrations in this pathway. Hotspot mutation analysis of BRAF, NRAS, KRAS, and HRAS revealed only two mutations, V600M in BRAF and G10E in NRAS, both occurring in pure oligodendroglial tumors. However, CGH analysis of 87 tumors revealed copy number gains including the above mentioned oncogenes in 38 of the neoplasms (44%) and including the upstream growth factors EGF, PDGF, IGF, FGF, TGF and/or their receptors in 46 tumors (53%). Phosphorylated MAPK (i.e. the activated compound downstream the RAS/RAF pathway) was detected by immunohistochemistry using tissue micro-arrays in the majority of gliomas. Interestingly, a significant correlation was found for nuclear MAPK-P staining and the number of these copy number gains (≤ 2 and ≥ 3). These results indicate that RAS/RAF pathway activation in gliomas is achieved much more frequently by copy number gains including RAS/RAF and/or upstream growth factor (receptor) than by activating RAS/RAF mutations.

Keywords

RAS BRAF Glioma Copy number gains Mutation 

Abbreviations

a-

anaplastic tumor (WHO grade III)

A

diffuse astrocytoma (WHO grade II)

BRAF

v-raf murine sarcoma viral oncogene homologue B1

E

ependymoma (WHO grade II)

EGF(R)

epidermal growth factor (receptor)

ERK

extracellular signal regulated kinase (= MAPK)

FGF(R)

fibroblast growth factor (receptor)

GBM

glioblastoma multiforme (WHO grade IV astrocytoma)

HRAS

v-Ha-ras Harvey rat sarcoma viral oncogene homologue

IGF(R)

insulin-like growth factor (receptor)

KRAS

v-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue

LOH

loss of heterozygosity

MAPK

mitogen-activated protein kinase (= ERK)

MEK

MAPK/extracellular signal regulated kinase (= MAPKK)

NRAS

neuroblastoma RAS viral (v-ras) oncogene homologue

O

oligodendroglioma (WHO grade II)

OA

oligoastrocytoma (WHO grade II)

PDGF(R)

platelet derived growth factor (receptor)

RAS

rat sarcoma viral oncogene homologue

RAF

v-raf murine sarcoma viral oncogene homologue

TGF(R)

transforming growth factor (receptor)

TMA

tissue micro-array

TP53

tumor protein 53

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Judith Jeuken
    • 1
  • Caroline van den Broecke
    • 2
  • Sabine Gijsen
    • 1
  • Sandra Boots-Sprenger
    • 1
  • Pieter Wesseling
    • 1
    • 3
  1. 1.Department of PathologyRadboud University Nijmegen Medical CentreNijmegenThe Netherlands
  2. 2.Department of PathologyUniversity Hospital GentGhentBelgium
  3. 3.Nijmegen Centre for Molecular Life SciencesRadboud University Nijmegen Medical CentreNijmegenThe Netherlands

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