title: Bioinformatic analysis of patient-derived ASPS gene expressions and ASPL-TFE3 fusion transcript levels identify potential therapeutic targets.
abstract: Gene expression data, collected from ASPS tumors of seven different patients and from one immortalized ASPS cell line (ASPS-1), was analyzed jointly with patient ASPL-TFE3 (t(X;17)(p11;q25)) fusion transcript data to identify disease-specific pathways and their component genes. Data analysis of the pooled patient and ASPS-1 gene expression data, using conventional clustering methods, revealed a relatively small set of pathways and genes characterizing the biology of ASPS. These results could be largely recapitulated using only the gene expression data collected from patient tumor samples. The concordance between expression measures derived from ASPS-1 and both pooled and individual patient tumor data provided a rationale for extending the analysis to include patient ASPL-TFE3 fusion transcript data. A novel linear model was exploited to link gene expressions to fusion transcript data and used to identify a small set of ASPS-specific pathways and their gene expression. Cellular pathways that appear aberrantly regulated in response to the t(X;17)(p11;q25) translocation include the cell cycle and cell adhesion. The identification of pathways and gene subsets characteristic of ASPS support current therapeutic strategies that target the FLT1 and MET, while also proposing additional targeting of genes found in pathways involved in the cell cycle (CHK1), cell adhesion (ARHGD1A), cell division (CDC6), control of meiosis (RAD51L3) and mitosis (BIRC5), and chemokine-related protein tyrosine kinase activity (CCL4).
authors.affiliation: Developmental Therapeutics Program, National Cancer Institute, Frederick National Laboratory for Cancer Research (FNLCR), Frederick, MD, USA. covelld@mail.nih.gov
authors.forename: David G
authors.initials: DG
authors.lastname: Covell
authors.forename: Anders
authors.initials: A
authors.lastname: Wallqvist
authors.forename: Susan
authors.initials: S
authors.lastname: Kenney
authors.forename: David T
authors.initials: DT
authors.lastname: Vistica
mesh_terms: D000328:Adult; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D002448:Cell Adhesion; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics; D002461:Cell Line, Transformed; D054407:Chemokine CCL4 / Q000235:genetics; D002886:Chromosomes, Human, Pair 17; D019295:Computational Biology; D004268:DNA-Binding Proteins / Q000235:genetics; D057225:Data Mining; D015870:Gene Expression; D053263:Gene Regulatory Networks; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D008957:Models, Genetic; D019042:Muscle Neoplasms / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics*; D018234:Sarcoma, Alveolar Soft Part / Q000235:genetics*; D000077022:Survivin; D014178:Translocation, Genetic; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha / Q000235:genetics
chemical_list: C569638:ARHGDIA protein, human; C107489:BIRC5 protein, human; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D018797:Cell Cycle Proteins; D054407:Chemokine CCL4; D004268:DNA-Binding Proteins; D051034:Inhibitor of Apoptosis Proteins; D015514:Oncogene Proteins, Fusion; C112629:RAD51D protein, human; D012333:RNA, Messenger; D000077022:Survivin; C069203:TFE3 protein, human; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; C501162:FLT1 protein, human; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D040281:Vascular Endothelial Growth Factor Receptor-1