peIF4E as an independent prognostic factor and a potential therapeutic target in diffuse infiltrating astrocytomas

Malignant transformation in tumors is a complex process requiring accumulation of numerous oncogenic abnormalities. Brain tumors show considerable phenotypic and genetic heterogeneity. In a series comprising diffuse infiltrating astrocytomas (DIA) and reactive gliosis, we investigated the main factors associated with signaling pathways. We assessed expression levels and their association with tumor progression and survival. We studied 19 grade II astrocytomas, 25 anaplastic astrocytomas (grade III), 60 glioblastomas (grade IV), and 15 cases of reactive gliosis. Epidermal growth factor receptor (EGFR), pMAPK, 4E-BP1, p4E-BP1, pS6, eIF4E, and peIF4E expression levels were evaluated using immunohistochemistry. Expression levels were semiquantitatively evaluated using a histoscore. Immunohistochemistry and PCR were used for IDH1 mutations. Statistical analysis was based on the following tests: chi-square, Student's t, Pearson correlation, Spearman's rho, and Mann-Whitney; ROC and Kaplan-Meier curves were constructed. A significant increase was observed between grades for expression of total and phosphorylated 4E-BP1 and for eIF4E, Ki67, EGFR, and cyclin D1. Although expression of EGFR, eIF4E, and Ki67 correlated with survival, only peIF4E was an independent predictor of survival in the multivariate analysis. Combining the evaluation of different proteins enables us to generate helpful diagnostic nomograms. In conclusion, cell signaling pathways are activated in DIAs; peIF4E is an independent prognostic factor and a promising therapeutic target. Joint analysis of the expression of 4E-BP1 and peIF4E could be helpful in the diagnosis of glioblastoma multiforme in small biopsy samples.