title: Molecular characterization of PDGFR-alpha/PDGF-A and c-KIT/SCF in gliosarcomas.
abstract: Gliosarcomas are rare and poorly characterized malignant brain tumors that exhibit a biphasic tissue pattern with areas of gliomatous and sarcomatous differentiation. These tumors are histological variants of glioblastoma, displaying a similar genetic profile and dismal prognosis. Up-regulation of PDGFR subfamily of tyrosine kinase members, PDGFR-alpha and c-Kit, and their intracellular effectors RAS/RAF/MAPK has a crucial role in the cancer development. In addition, signal transduction mediated by activating mutations of c-Kit and PDGFR can be effectively blocked by specific tyrosine kinase inhibitors, such as Imatinib mesylate. The aim of this study was to characterize the molecular alterations of PDGFR signaling in gliosarcomas. Six cases were analyzed by immunohistochemistry for the expression of PDGFR-alpha, c-Kit and their ligands PDGF-A and SCF, respectively. The cases were further evaluated for the presence of activating mutations of PDGFR-alpha (exons 12 and 18) and c-kit (exons 9, 11, 13, and 17), as well as B-RAF (exons 11 and 15). Expression of PDGF-A was found in all cases and co-expression of PDGFR-alpha was observed in three cases. Four cases showed expression of SCF, and c-Kit was observed only in one case that also expressed SCF. Generally, immunoreaction predominates in the glial component. The mutational analysis of PDGFR-alpha showed the presence of an IVS17-50insT intronic insertion in two cases, one of them also with a 2472C > T silent mutation; this silent mutation was also found in another case. Glioma cell line analysis of IVS17-50insT insertion showed no influence on PDGFR-alpha gene splicing. No mutations were detected in c-kit and B-RAF oncogenes. Our results indicate that activating mutations of PDGFR-alpha, c-kit and B-RAF are absent in gliosarcomas. Nevertheless, the presence of a PDGFR-a/PDGFA and c-Kit/SCF autocrine/paracrine stimulation loop in a proportion of cases, supports the potential role of specific tyrosine kinase inhibitors in the treatment of gliosarcomas.
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal. rreis@ecsaude.uminho.pt
authors.forename: Rui M
authors.initials: RM
authors.lastname: Reis
authors.forename: Albino
authors.initials: A
authors.lastname: Martins
authors.forename: Susana A
authors.initials: SA
authors.lastname: Ribeiro
authors.forename: Diana
authors.initials: D
authors.lastname: Basto
authors.forename: Adhemar
authors.initials: A
authors.lastname: Longatto-Filho
authors.forename: Fernando C
authors.initials: FC
authors.lastname: Schmitt
authors.forename: José M
authors.initials: JM
authors.lastname: Lopes
mesh_terms: D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D004252:DNA Mutational Analysis; D004587:Electrophoresis, Agar Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018316:Gliosarcoma / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D009154:Mutation; D010982:Platelet-Derived Growth Factor / Q000235:genetics*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000235:genetics*
chemical_list: D004791:Enzyme Inhibitors; D010982:Platelet-Derived Growth Factor; D019089:Stem Cell Factor; C075278:platelet-derived growth factor A; D004247:DNA; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf