Leiomyosarcoma is a malignant mesenchymal tumor composed of cells showing smooth muscle differentiation. This tumor usually occurs in middle-aged or older adults, and forms a significant percentage of retroperitoneal, vascular, extremity and uterine sarcomas. Leiomyosarcomas are most often associated with complex karyotypes with numerous chromosomal gains and losses. Some of these cytogenetic and molecular genetic aberrations correlate with histopathologic features and clinical outcomes. Identification of genetic alterations with specific identification of oncogenes and tumor suppressor genes may lead to additional insights into the tumorigenesis of leiomyosarcoma and the opportunity to confer the benefits of targeted therapy.

Purpose Malignant peripheral nerve sheath tumor (MPNST) is a rare sarcoma that lacks effective therapeutic strategies. We gain insight into the most recurrent genetically altered pathways with the purpose of scanning possible therapeutic targets. Experimental design We performed a microarray based-comparative genomic hybridization (aCGH) profiling of two cohorts of primary MPNST tissue samples including 25 patients treated at The University of Texas MD Anderson Cancer Center and 26 patients from Tianjin Cancer Hospital. IHC and cell biology detection and validation were performed on human MPNST tissues and cell lines. Results Genomic characterization of 51 MPNST tissue samples identified several frequently amplified regions harboring 2,599 genes and regions of deletion including 4,901 genes. At the pathway level, we identified a significant enrichment of copy number–altering events in the insulin-like growth factor 1 receptor (IGF1R) pathway, including frequent amplifications of the IGF1R gene itself. To validate the IGF1R pathway as a potential target in MPNSTs, we first confirmed that high IGF1R protein correlated with worse tumor-free survival in an independent set of samples using immunohistochemistry. Two MPNST cell lines (ST88-14 and STS26T) were used to determine the effect of attenuating IGF1R. Inhibition of IGF1R in ST88-14 cells using small interfering RNAs or an IGF1R inhibitor, MK-0646, led to significant decreases in cell proliferation, invasion, and migration accompanied by attenuation of the PI3K/AKT and MAPK pathways. Conclusion These integrated genomic and molecular studies provide evidence that the IGF1R pathway is a potential therapeutic target for patients with MPNST.