Activated growth signaling pathway expression in Ewing sarcoma and clinical outcome

摘要

Background: In Ewing sarcoma (EWS) most of the research on signaling pathways has been performed on cell lines or animal models. The objective of the current study was to determine the relation between clinical outcome and the expression of proteins involved in active growth signaling pathways. Methods: A paraffin-embedded microarray of 45 human primary EWS tissue specimens was stained with the antibodies against c-KIT, AKT, p-AKT, p-mTOR, IGF-1R, IGFBP-3, MAPK, p27 KIP1, and p70S6 kinase. Immunohistochemical staining was correlated with patient overall survival (OS). Results: In the univariate analysis 3 variables showed statistical significance to predict survival: presence of metastasis, p-mTOR, and p27 KIP1. A positive stain for p-mTOR (hazard ratio of 4.74 [95% CI (57, 121)]) was significantly (log-rank test with a P=0.029) associated with better OS. Also, a positive stain for p27 KIP1 (hazard ratio of 6.87 [95% CI (77, 136)] was significantly (log-rank test with a P=0.009) associated with better OS. Multivariate analysis showed metastasis (HR: 4.3; 95% CI: 0.99, 19; P=0.05), p-mTOR (HR: 4.8 with 95% CI: 0.6, 38; P=0.13) and p27 (HR: 5.3; 95% CI: 1.37, 20; P=0.01) as independent prognostic factors of outcome. Conclusions: In our series, p-mTOR and p27 KIP1 protein overexpression were independently associated with better survival.