Clinical and biochemical function of polymorphic NR0B1 GGAA-microsatellites in Ewing sarcoma: A report from the Childrens Oncology Group

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Publication Type pre-print
School or College School of Medicine
Department Human Genetics
Creator Jorde, Lynn B.
Other Author 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.
Title Clinical and biochemical function of polymorphic NR0B1 GGAA-microsatellites in Ewing sarcoma: A report from the Childrens Oncology Group
Date 2014-01-01
Description 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.
Type Text
Publisher Public Library of Science (PLoS)
Volume 9
Issue 8
First Page 1
Last Page 14
Language eng
Bibliographic Citation 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.
Rights Management (c) Public Library of Science (PLoS)
Format Medium application/pdf
Format Extent 1,172,174 bytes
Identifier uspace,18900
ARK ark:/87278/s6q84p68
Setname ir_uspace
Date Created 2014-09-04
Date Modified 2014-09-10
ID 712667
Reference URL https://collections.lib.utah.edu/ark:/87278/s6q84p68
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