Browsing by Subject "Rhabdomyosarcoma"
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Item High-Resolution Array Comparative Genomic Hybridization Identifies Common Targets in Rhabdomyosarcoma(2012-08-15) Paulson, Vera Ashley; Cameron, ScottRhabdomyosarcoma (RMS) accounts for nearly 50 percent of the soft tissue sarcomas that affect children. There are two major histological variants, alveolar (ARMS) and embryonal (ERMS). Both are defined as sarcomas that show exclusive evidence of muscle differentiation, but differ in their pathogenesis and prognosis. ARMS typically occurs in adolescents, presents as disease of the extremities, has a higher risk of metastasis or treatment-resistance, and in 75% of cases, is characterized by the presence of the PAX3/7:FOXO1A translocation. ERMS is associated with a younger age at presentation, sites of disease other than the extremities, a more favorable clinical outcome, and the absence of consistent chromosomal translocations. Here we used high-density array-based comparative genomic hybridization to examine the genomes of RMS to identify common programs that drive tumor pathogenesis. [Keywords: Rhabdomyosarcoma; array CGH; CDKN2A/B; FGFR4; Ras; hedgehog; POU3F3; NF1; PAX3:FOXO1]Item Molecular Dissection of Rhabdomyosarcoma Tumorigenesis(2011-11-15) Edelman, Lauren Alexis; Galindo, ReneRhabdomyosarcoma is a tumor of skeletal muscle-type histogenesis and the most common pediatric soft tissue cancer. Rhabdomyosarcoma is often caused by one of two chromosomal translocations, t(1;32)(q35;q14) or t(2;13)(p36;q14), that are rhabdomyosarcoma - specific and diagnostic, and both drive equivalent PAX-FKHR fusion oncogenic transcription factors. Despite aggressive multimodal therapy, the 5-year survival rate of patients with advance-staged rhabdomyosarcoma remains less than 30% and has not improved in three decades. We intend to genetically characterize the molecular underpinnings of rhabdomyosarcoma to find new potential drug targets for treatment. Since PAX biology is structurally and functionally conserved (as is syncytial muscle development and structure), we have generated a new transgenic PAX-FKHR Drosophila model, which we have used to conduct a forward unbiased genetic screen to identify dominant modifiers of PAX-FKHR pathogenesis when expressed in growing muscle tissue. We also performed microarray analysis of fly PAX-FKHR tissue versus control tissue. We are now actively profiling genetic loci of interest for phenotypes in mammalian murine C2C12 myoblasts. After testing a subset of candidate genes identified in the screen, we have found that the genes identified as genetic modifiers of PAX-FKHR pathogenicity in the fly screen are indeed active in mammalian myoblast biology and PAX-FKHR pathobiology. These genes include loci normally involved in myogenesis and genes not previously correlated with mammalian skeletal muscle development or PAX biology. Our results suggest that the PAX-FKHR Drosophila transgenic model and genetic screening are revealing previously unknown gene targets that will likely underlie rhabdomyosarcoma pathogenesis. The discovery of new genes seminal to rhabdomyosarcoma pathobiology will be a valuable tool in the conceptual design of new therapies to target rhabdomyosarcoma and thus improve treatment.