title: RAS/RAF pathway activation in gliomas: the result of copy number gains rather than activating mutations.
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 (<or= 2 and >or= 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.
authors.affiliation: Department of Pathology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500, Nijmegen, The Netherlands. j.jeuken@pathol.umcn.nl
authors.forename: Judith
authors.initials: J
authors.lastname: Jeuken
authors.forename: Caroline
authors.initials: C
authors.lastname: van den Broecke
authors.forename: Sabine
authors.initials: S
authors.lastname: Gijsen
authors.forename: Sandra
authors.initials: S
authors.lastname: Boots-Sprenger
authors.forename: Pieter
authors.initials: P
authors.lastname: Wesseling
mesh_terms: D001483:Base Sequence; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics*; D018628:Gene Dosage; D005910:Glioma / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D020929:Mitogen-Activated Protein Kinase Kinases; D009154:Mutation; D009693:Nucleic Acid Hybridization; D010766:Phosphorylation; D046888:Tissue Array Analysis; D048490:raf Kinases / Q000235:genetics* / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; D048490:raf Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins