Growth Mechanisms of Schwann Cell Tumors in NF2

摘要

Patients with neurofibromatosis 2 (NF2) develop multiple schwannomas that, although benign, cause significant morbidity and mortality. In addition NF2 patients have numerous, small, Schwann cell tumorlets in the cauda equina. Previous studies have demonstrated inactivation of both NF2 alleles already occurs in the Schwann cell tumorlet stage, suggesting that additional genetic or epigenetic events are necessary for the development of frank schwannomas. In order to identify the mechanisms that promote this process, we compared gene expression of these two Schwann cell lesions in a single NF2 patient. We employed laser capture microdissection and cDNA microarray analysis, using the Affymterix platform. 130 differentially expressed genes were identified (p 0.01, >2 fold) and RT-PCR was used for validation of 5 of these genes. Analysis of the Gene Ontology and KEGG pathway terms associated with the upregulated genes (79 genes) identified many genes with known receptor, growth factor or signaling function. There was over-representation of genes involved in the phosphoinositide 3-kinase/Akt (PI3K/Akt) pathway in schwannomas and overexpression of several receptors that may function as autocrine loops for this pathway. Identification of autocrine loops that promote growth in NF2- associated schwannomas may aid in the development of targeted therapies for NF2 patients.