Autor(es):
Reis, R. M. 
; Martins, Albino ; Ribeiro, Susana A. ; Basto, Diana ; Longatto Filho, Adhemar ; Schmitt, Fernando C. ; Lopes, José M.
Data: 2005
Identificador Persistente: http://hdl.handle.net/1822/4020
Origem: RepositóriUM - Universidade do Minho
Assunto(s): Gliosarcoma; PDGFR-alfa; PDGF-A; c-Kit; SCF; BRAF
Descrição
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-α 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-α, c-Kit and their ligands PDGF-A and SCF,
respectively. The cases were further evaluated for the presence of activating mutations of PDGFR-α (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-α 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-α
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-α gene splicing. No mutations were detected in c-kit and B-RAF oncogenes. Our results indicate that activating
mutations of PDGFR-α, 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.
