Clinical and Biochemical Function of Polymorphic NR0B1 GGAA-Microsatellites in Ewing Sarcoma: A Report from the Children's Oncology Group

@article{Monument2014ClinicalAB,
  title={Clinical and Biochemical Function of Polymorphic NR0B1 GGAA-Microsatellites in Ewing Sarcoma: A Report from the Children's Oncology Group},
  author={Michael J. Monument and Kirsten M. Johnson and Elizabeth Mcilvaine and Lisa M. Abegglen and W. Scott Watkins and Lynn B. Jorde and Richard B Womer and Natalie Beeler and Laura Monovich and Elizabeth R. Lawlor and Julia A Bridge and Joshua D. Schiffman and Mark Krailo and R Lor Randall and S. Lessnick},
  journal={PLoS ONE},
  year={2014},
  volume={9}
}
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… 
Identification of two types of GGAA-microsatellites and their roles in EWS/FLI binding and gene regulation in Ewing sarcoma
TLDR
The data suggest EWS/FLI binds to “promoter- like” and “enhancer-like” microsatellites to mediate activation and repression of target genes through different regulatory mechanisms, which clarifies the role of GGAA-microsatellite on a global genomic scale.
Role for the EWS domain of EWS/FLI in binding GGAA-microsatellites required for Ewing sarcoma anchorage independent growth
TLDR
It is demonstrated in Ewing Sarcoma cells that EWS/FLI activates gene targets through binding at associated GGAA-microsatellites, and these repetitive sequences are necessary for Ewing sarcoma cell proliferation and anchorage-independent growth, and a previously unknown role for the EWS portion of the fusion protein as critical in binding at EWS /FLI targets is shown.
Sequencing Overview of Ewing Sarcoma: A Journey across Genomic, Epigenomic and Transcriptomic Landscapes
TLDR
Using sequencing, novel predictive markers and candidates for immuno- and targeted therapy were identified and combined into a comprehensive overview of Ewing sarcoma.
EWS/FLI1 Target Genes and Therapeutic Opportunities in Ewing Sarcoma
TLDR
This work describes a selection of EWS/FLI1 targets, their functional role, and their potential clinical relevance and discusses their role in other types of cancer as well as the need for further studies to be performed in order to achieve a broader understanding of their particular contribution to Ewing sarcoma development.
Gene expression and immunohistochemical analyses identify SOX2 as major risk factor for overall survival and relapse in Ewing sarcoma patients
TLDR
High SOX2 expression constitutes an independent prognostic biomarker for EwS patients with poor outcomes and may help to identify patients with localised disease who are at high risk for tumour relapse within the first two years after diagnosis.
Transcriptomic analysis functionally maps the intrinsically disordered domain of EWS/FLI and reveals novel transcriptional dependencies for oncogenesis
EWS/FLI is the pathognomic fusion oncoprotein that drives Ewing sarcoma. The amino-terminal EWS portion coordinates transcriptional regulation and the carboxy-terminal FLI portion contains an ETS
Are EWSR1-NFATc2-positive sarcomas really Ewing sarcomas?
TLDR
IMmunohistochemical detection of anti-PAX7 immunohistochemistry is a sensitive marker for Ewing sarcoma, and analyses strongly suggest that EWSR1-NFATc2-positive sarcomas constitute a tumor entity distinct from Ewing Sarcoma.
Oncogenic hijacking of a developmental transcription factor evokes therapeutic vulnerability for ROS-induction in Ewing sarcoma
TLDR
It is discovered that SOX6 interferes with the antioxidant system resulting in constitutively elevated reactive oxygen species (ROS) levels that create a therapeutic vulnerability toward the ROS-inducing drug Elesclomol.
Combined experience of six independent laboratories attempting to create an Ewing sarcoma mouse model
TLDR
Data is presented from six independent laboratories seeking an alternative approach to express EWS-FLI1 in different murine tissues using the Runx2, Col1a2.3, Col 1a3.6, Prx1, CAG, Nse, NEFL, Dermo1, P0, Sox9 and Osterix promoters to target E WS- FLI1 or Cre expression.
EWS/FLI mediated reprogramming of 3D chromatin promotes an altered transcriptional state in Ewing sarcoma
TLDR
Local chromatin features provide the basis for transcriptional heterogeneity in regulation of direct EWS/FLI target genes across different Ewing sarcoma cell lines and support the notion that fusion transcription factors serve as master regulators through three-dimensional reprogramming of chromatin.
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The data suggest that GGAA microsatellite polymorphisms in the NR0B1 gene might influence disease susceptibility and prognosis in Ewing sarcoma in unanticipated ways.
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TLDR
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