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

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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.

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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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Acknowledgements

We thank Dr. Jeroen EM van Leeuwen for generously providing the phospho-p44/42 MAPK antibody, Jos Rijntjes for the immunohistochemical stainings, and Susan van de Kieboom-Hageman for construction of the tissue micro-arrays.

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Authors and Affiliations

  1. Department of Pathology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500, Nijmegen, The Netherlands

    Judith Jeuken, Sabine Gijsen, Sandra Boots-Sprenger & Pieter Wesseling

  2. Department of Pathology, University Hospital Gent, Ghent, Belgium

    Caroline van den Broecke

  3. Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Pieter Wesseling

Authors
  1. Judith Jeuken
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  2. Caroline van den Broecke
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  3. Sabine Gijsen
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  4. Sandra Boots-Sprenger
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  5. Pieter Wesseling
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Corresponding author

Correspondence to Judith Jeuken.

Additional information

This research was funded by the KWF Dutch Cancer Society grant KUN2004-3143. PW was sponsored by Dutch Cancer Society grant KUN2003-2975.

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Jeuken, J., van den Broecke, C., Gijsen, S. et al. RAS/RAF pathway activation in gliomas: the result of copy number gains rather than activating mutations. Acta Neuropathol 114, 121–133 (2007). https://doi.org/10.1007/s00401-007-0239-0

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  • DOI: https://doi.org/10.1007/s00401-007-0239-0

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