||Monument, MichaelJ.; Johnson, Kirsten M.; McIlvaine, E.; Abegglen, L.; Scott Watkins, W.; Womer, R. B.; Beeler, N.; Monovich, L.; Lawlor, E. R.; Bridge, J. A.; Schiffman, J. D.; Krailo, M. D... et.al.
||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 (acritical 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.
||Monument, M. J., Johnson, K. M., McIlvaine, E., Abegglen, L., Scott Watkins, W., Jorde, L.B., Womer, R. B., Beeler, N., Monovich, L., Lawlor, E. R., Bridge, J. A., Schiffman, J. D., Krailo, M. D., Lor Randall, R., & Lessnick, S. L. (2014). Clinical and biochemical function of polymorphic NR0B1 GGAA-microsatellites in Ewing sarcoma: A report from the Childrens Oncology Group. PLoS ONE, 9(8), E104378, 1-14.