Abstract 4348: PDGF-Rα expression and activation of the MAPK pathway in disseminated pilocytic astrocytomas

Abstract

Abstract Background: Pilocytic astrocytomas (PA) are the most common pediatric tumors of the central nervous system. Approximately 5 % of patients with PA present a tumor dissemination. Although the disseminated growth is associated with severe clinical problems, the genetic alterations associated with this biological behaviour have never been investigated. As the histology of the disseminated PAs does not differ significantly to sporadic PAs, we analyzed the mitogen-activated protein kinase (MAPK) pathway for aberrations because genetic alterations of members of this pathway as BRAF and NF-1 have been found to be involved in the pathogenesis of non-disseminated PAs. Methods: Immunohistochemical analysis of the platelet-derived growth factor receptors alpha (PDGF-Rα) and beta (PDGF-Rβ), the epidermal growth factor receptor (EGF-R), and the downstream activated (phosphorylated) extracellular signal-regulated kinase (p-ERK) was performed in a cohort of 18 patients suffering disseminated PAs. In three patients, material of the primary tumor and of relapses could be studied. The BRAF gene was analyzed for mutations by single strand conformation analysis (SSCP) and for gene copy numbers by semiquantitative PCR with fluorescence labelled primers. Mutational hotspots of the K-RAS, H-RAS and N-RAS genes were also analyzed by SSCP. Results: Immunohistochemical analysis showed an increased PDGF-Rα expression in 71.4% of disseminated Pas, but no significant overexpression of EGF-R or PDGF-Rβ. A constitutive ERK phosphorylation was demonstrated in all disseminated PAs investigated. Molecular genetic analysis revealed V600E BRAF mutations in two tumors and an increased BRAF gene copy level in the majority of cases. No RAS mutations were found. Conclusions: This is the first report of molecular genetic analysis of the MAPK pathway in disseminated pilocytic astrocytomas. It underlines the important role of the upstream PDGF-Rα receptor and subsequent MAPK pathway in these gliomas. Its activation represents a potential target for novel strategies in the therapy of disseminated PAs. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4348.