Molecular Alterations of PDGFA and PDGFRA in Gliomas
O Martinho, A Longatto-Filho, MBK Lambros, A Martins, C Pinheiro, A Silva, F Pardal, J Amorim, A Mackay, F Milanezi, N Tamber, K Fenwick, A Ashworth, JS Reis-Filho, JM Lopes, RM Reis. University of Minho, Braga, Portugal; Instituto Adolfo Lutz, Sao Paulo, Brazil; ICR, London, United Kingdom; Sao Marcos Hospital, Braga, Portugal; IPATIMUP, Porto, Portugal; Medical Faculty, University of Porto, Porto, Portugal
Background: Malignant gliomas are the most prevalent primary brain tumours, have an aggressive clinical course and lack effective treatment options. PDGF signalling is one of the key regulators of glioma development. The efficacy of anti-PDGFRA drugs for the management of patients with glioblastomas is currently being tested in clinical trials. The aims of this study were to determine the expression of PDGFRA and PDGFA and the underlying genetic mechanisms driving their expression in a large series of gliomas.
Design: We investigated the frequency of PDGFA and PDGFRA expression by immunohistochemistry in 169 gliomas and screened for PDGFRA gene mutations and gene amplification in 86 and 57 gliomas using a combination of direct sequencing, quantitative copy number PCR and microarray-based comparative genomic hybridisation.
Results: We found that PDGFA was largely expressed in different glioma histological types and its absence was associated with a poor prognosis. PDGFRA was significantly expressed at high levels in malignant astrocytic tumours. Moreover, we have observed the existence of putative PDGFA/PDGFRA autrocrine/paracrine loops in glioblastomas. Finally, although PDGFRA gene activating mutations were not found, PDGFRA gene amplification was observed in 21% of gliomas and was significantly associated with PDGFRA overexpression in diffuse astrocytomas.
Conclusions: The present study describes a comprehensive molecular analysis of PDGFA and PDGFRA in gliomas. Taken together, these results provide a molecular basis for anti-PDGFRA therapies in gliomas.
Tuesday, March 10, 2009 9:30 AM
Poster Session III # 197, Tuesday Morning