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Review
. 2010 Aug 12;29(32):4504-16.
doi: 10.1038/onc.2010.205. Epub 2010 Jun 14.

Recent advances in the molecular pathogenesis of Ewing's sarcoma

Affiliations
Review

Recent advances in the molecular pathogenesis of Ewing's sarcoma

E C Toomey et al. Oncogene. .

Abstract

Tumor development is a complex process resulting from interplay between mutations in oncogenes and tumor suppressors, host susceptibility factors, and cellular context. Great advances have been made by studying rare tumors with unique clinical, genetic, or molecular features. Ewing's sarcoma serves as an excellent paradigm for understanding tumorigenesis because it exhibits some very useful and important characteristics. For example, nearly all cases of Ewing's sarcoma contain the (11;22)(q24;q12) chromosomal translocation that encodes the EWS/FLI oncoprotein. Besides the t(11;22), however, many cases have otherwise simple karyotypes with no other demonstrable abnormalities. Furthermore, it seems that an underlying genetic susceptibility to Ewing's sarcoma, if it exists, must be rare. These two features suggest that EWS/FLI is the primary mutation that drives the development of this tumor. Finally, Ewing's sarcoma is an aggressive tumor that requires aggressive treatment. Thus, improved understanding of the pathogenesis of this tumor will not only be of academic interest, but may also lead to new therapeutic approaches for individuals afflicted with this disease. The purpose of this review is to highlight recent advances in understanding the molecular pathogenesis of Ewing's sarcoma, while considering the questions surrounding this disease that still remain and how this knowledge may be applied to developing new treatments for patients with this highly aggressive disease.

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Figures

Figure 1
Figure 1
Ewing's sarcoma fusion protein organization. The Ewing's sarcoma translocation product is the result of a chromosomal rearrangement involving the N-terminal transcriptional activation domain (TAD) of a TET family member (either TLS/FUS or more commonly EWS) and the C-terminal portion of an ETS family member (FLI, ERG, ETV1, ETV4, or FEV), including the ETS DNA binding domain (DBD).
Figure 2
Figure 2
Ewing's sarcoma transformation requires several distinct events. The EWS/FLI (or other TET/ETS) translocation is the central mediator of this process, dysregulating a number of genes that contribute to oncogenesis and tumor progression. A permissive cell type for EWS/FLI expression is also required. Cooperating mutations such as those in the RB and p53 pathways, as well as growth factor signaling (including IGF) likely contribute to the fully transformed phenotype.

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