Abstract
BackgroundThe 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.ObjectivesHere 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.ResultsA 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.ConclusionsThese data suggest that GGAA-microsatellite polymorphisms observed in human populations modulate EWS/FLI-mediated gene expression and may influence disease susceptibility in Ewing sarcoma.
Highlights
Ewing sarcoma is a prototypical chromosomal translocationassociated malignancy, in which virtually all cases harbor a balanced somatic translocation fusing the EWSR1 gene (EWS) to a member of the (E- twenty six) ETS-family of transcription factors, most commonly FLI1 (FLI) [1,2]
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
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. 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
Summary
Ewing sarcoma is a prototypical chromosomal translocationassociated malignancy, in which virtually all cases harbor a balanced somatic translocation fusing the EWSR1 gene (EWS) to a member of the (E- twenty six) ETS-family of transcription factors, most commonly FLI1 (FLI) [1,2]. Forty to fifty percent of genomic EWS/FLI binding sites are associated with these GGAA-microsatellites [7] and EWS/FLImediated DNA binding and gene expression is dependent on these repetitive GGAA response elements [5,8,9]. These findings collectively demonstrate an unprecedented link between microsatellite DNA and transcriptional dysregulation in Ewing sarcoma. 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
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