Elevated Expression of IRS2 in the Progression from Neurofibroma to Malignant Peripheral Nerve Sheath Tumor

Novel drugs to inhibit insulin receptor substrate (IRS) and focal adhesion kinase (FAK) pathways are emerging and will be sarcoma subtype-specific. As a result, defining expression of proteins in these pathways; in select tumors is important in order to formulate therapeutic approaches to malignant peripheral nerve sheath tumors (MPNSTs). Fifty-three patients with MPNSTs or neurofibromas (NFs), who were treated at our institution from 1994-2005, were identified. Tumor immonohistochemical staining for multiple key oncogenic proteins was performed and the sections were evaluated in a blinded fashion by a sarcoma pathologist (JDR) and correlated with survival. A total of 88% of MPNSTs expressed IRS2 compared to 48% of NFs. IRS2 expression was significantly higher in MPNSTs than in NFs (p=0.0009). However, IRS1 expression was significantly higher in NFs than MPNSTs (p=0.03). A trend toward an increase in FAK expression in MPNSTs was seen (p=0.11). No difference was seen between MPNSTs and NFs when evaluating the expression of phosphorylated focal adhesions kinase, vascular endothelial growth factor 3, insulin like growth factor receptor 1, neurofibromatosis 1. Univariate analysis of survival indicated that IRS2 and NF1 protein expression, patient age and tumor size were significantly correlated with outcome. MPNSTs have an elevated level of IRS2 and FAK and lower level of IRS1 compared to NFs These data demonstrate for the first time that IRS2 and FAK may be associated with malignant transformation of neurofibromas.