Related Experiment Videos
Clinical and biochemical function of polymorphic NR0B1 GGAA-microsatellites in Ewing sarcoma: a report from the
Michael J Monument1, Kirsten M Johnson2, Elizabeth McIlvaine3
1Sarcoma Services, Department of Orthopedic Surgery, University of Utah, Salt Lake City, Utah, United States of America; Center for Children's Cancer Research, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, United States of America.
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.
Insights
Genetic variations in GGAA-microsatellites within the NR0B1 promoter influence gene expression in Ewing sarcoma. These microsatellite polymorphisms may impact Ewing sarcoma susceptibility but do not correlate with survival outcomes.
Area of Science:
- Genetics
- Cancer Biology
- Molecular Oncology
Background:
- Ewing sarcoma genetics and prognosis remain largely unknown.
- EWS/ETS chimeras, including EWS/FLI, regulate gene targets through GGAA-microsatellite elements.
- Human GGAA-microsatellites exhibit high polymorphism, potentially affecting EWS/FLI gene expression based on motif number.
Purpose of the Study:
- To investigate the polymorphic variations of a GGAA-microsatellite in the NR0B1 promoter in Ewing sarcoma.
- To determine how NR0B1 GGAA-microsatellite polymorphisms affect gene expression and clinical outcomes.
Main Methods:
- Analysis of GGAA-microsatellite polymorphism spectrum in NR0B1 promoter in primary Ewing sarcoma tumors.
- Assessment of EWS/FLI-mediated gene expression across varying GGAA motif counts.
- Comparison of microsatellite allele frequencies in tumor cells versus control populations.
Main Results:
- A bimodal pattern of EWS/FLI gene expression was observed, peaking with 20-26 GGAA motifs.
- Ewing sarcoma tumors showed a bias towards NR0B1 GGAA-microsatellites with 21-25 motifs compared to controls.
- No correlation was found between NR0B1 GGAA-microsatellite polymorphisms and patient survival.
Conclusions:
- GGAA-microsatellite polymorphisms modulate EWS/FLI-mediated gene expression.
- These polymorphisms may play a role in Ewing sarcoma susceptibility.
- Microsatellite instability did not account for the observed selection bias in tumor samples.