Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue tumors that arise from neurofibromas in patients with neurofibromatosis but also occur sporadically. Malignant transformation is a life threatening complication in patients with neurofibromatosis. The transformation of neurofibromas into MPNSTs is not completely understood at a molecular level. The goal of this study is to identify genes that will serve as molecular markers for progression of neurofibroma to MPNST, and to identify novel potential therapeutic targets. Gene expression profiling using 43000 spot cDNA microarrays was performed on 32 cases of MPNSTs, 23 schwannomas, 20 neurofibromas and 16 synovial sarcomas. Using unsupervised hierarchical clustering, most tumors grouped together according to tumor type. There appear to be at least two subtypes of MPNSTs. Analysis employing ‘significance analysis of microarrays' identified genes that were differentially expressed in various nerve sheath tumors. A major trend in transformation from neurofibroma towards MPNST is accompanied by the loss of expression of a large number of genes, rather than widespread de novo increase in gene expression upon transformation. NF1 is one of the genes for which loss of expression was noticed in most of the MPNSTS. Potential signaling pathways were identified using ‘Gene Set Enrichment Analysis' method. The expression of genes associated with MET and TFGB signaling pathways in the majority of neurofibromas, but not in MPNST, suggest that these pathways are affected during malignant transformation. A detailed list of genes and the signaling pathways that are associated with various nerve sheath tumors will be discussed.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]