BACKGROUND: The genetics involved in Ewing sarcoma susceptibility and prognosis are poorly understood. EWS/FLI and related EWS/ETS chimeras upregulate numerous gene targets via promoter-based GGAA-microsatellite response elements. These microsatellites are highly polymorphic in humans, and preliminary evidence suggests EWS/FLI-mediated gene expression is highly dependent on the number of GGAA motifs within the microsatellite.
OBJECTIVES: Here we sought to examine the polymorphic spectrum of a GGAA-microsatellite within the NR0B1 promoter (a critical EWS/FLI target) in primary Ewing sarcoma tumors, and characterize how this polymorphism influences gene expression and clinical outcomes.
RESULTS: A complex, bimodal pattern of EWS/FLI-mediated gene expression was observed across a wide range of GGAA motifs, with maximal expression observed in constructs containing 20-26 GGAA motifs. Relative to white European and African controls, the NR0B1 GGAA-microsatellite in tumor cells demonstrated a strong bias for haplotypes containing 21-25 GGAA motifs suggesting a relationship between microsatellite function and disease susceptibility. This selection bias was not a product of microsatellite instability in tumor samples, nor was there a correlation between NR0B1 GGAA-microsatellite polymorphisms and survival outcomes.
CONCLUSIONS: These data suggest that GGAA-microsatellite polymorphisms observed in human populations modulate EWS/FLI-mediated gene expression and may influence disease susceptibility in Ewing sarcoma.
Adolescent, Age Factors, Alleles, Case-Control Studies, Cell Transformation, Neoplastic, Child, Child, Preschool, DAX-1 Orphan Nuclear Receptor, Female, Gene Expression, Genetic Loci, Genomics, Humans, Linkage Disequilibrium, Male, Microsatellite Repeats, Models, Biological, Nucleotide Motifs, Oncogene Proteins, Fusion, Polymorphism, Genetic, Prognosis, Proto-Oncogene Protein c-fli-1, RNA-Binding Protein EWS, Sarcoma, Ewing, Young Adult
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Monument, Michael J.; Johnson, Kirsten M.; McIlvaine, Elizabeth; Abegglen, Lisa; Watkins, W. Scott; Jorde, Lynn B.; Womer, Richard B.; Beeler, Natalie; Monovich, Laura; Lawlor, Elizabeth R.; Bridge, Julia A.; Schiffman, Joshua D.; Krailo, Mark D; Randall, R. Lor; and Lessnick, Stephen L., "Clinical and biochemical function of polymorphic NR0B1 GGAA-microsatellites in Ewing sarcoma: a report from the Children's Oncology Group." (2014). Journal Articles: Pathology and Microbiology. 4.