Differential gene expression in liposarcoma: Insight into pathways for dedifferentiation?
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10048 Background: Liposarcoma (LPS) dedifferentiation signifies conversion to a clinically aggressive phenotype, but the biologic processes required for this change have not been determined. We describe differential gene expression patterns between well-differentiated (WD) and dedifferentiated (DD) tumors to determine pathways involved in LPS dedifferentiation. Methods: From 1999 to 2006, 121 fatty tumors were resected at a single institution. Twenty tumors, consisting of atypical lipomatous tumors (ALT), WD LPS or DD LPS, were randomly selected and clinicopathologic characteristics were retrospectively reviewed. Gene expression profiling was performed on extracted RNA using the Affymetrix GeneChip platform. Differentially expressed genes were obtained and gene network analysis was done using GeneGO by MetaCore. Results: Median age was 59 years and 70% of cases were male. WD tumors, consisting of 3 ALT and 6 WD LPS, were compared with 11 DD LPS. After a median follow-up of 64 months, 7 patients had died of whom 6 had DD LPS. DD histology was associated with lower overall survival (p<0.05). Significance Analysis of Microarrays for WD tumors vs. DD LPS using a 0% false discovery rate showed differential expression of 188 genes. Network analysis of genes from WD tumors vs. DD LPS showed significant (p<0.001) differential regulation of glucose-activated transcription factor ChREBP (carbohydrate response element binding protein), a key element involved in lipogenesis, gluconeogenesis and glycolysis. There was also significant differential regulation of insulin signaling, PI3K-dependent and PKA signal transduction pathways and of amino acid, fatty acid and glucose metabolism pathways (p<0.05). These pathways, based on Gene Ontology cellular processes, mapped to gene networks primarily involved in lipid metabolism (p<0.05). Conclusions: Differential expression of genes involved in lipid metabolism networks is seen in DD LPS and changes in lipid metabolism may be associated with dedifferentiation. These differential gene expression patterns may help identify fatty tumors potentially at risk for progressing to a malignant or DD state and provide prognostic factors and therapeutic targets for patients with LPS.
Han, D., Bloom, G. C., Bui, M. M., Enkemann, S., Yamauchi, H., Han, G., ... Gonzalez, R. J.
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Han, Dale||Bloom, Gregory C||Bui, Marilyn M||Enkemann, Steven||Yamauchi, Hideko||Han, Gang||Conley, Anthony Paul||Zager, Jonathan S||Cheong, David||Reed, Damon R||Lavey, Robert S||Sondak, Vernon K||Letson, Douglas D||Gonzalez, Ricardo Jorge
