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INTRODUCTION

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Ewing sarcoma was first described in 1921 by James Ewing as a radiosensitive malignancy of the bone. Since that initial description, insights into the biology of this tumor have expanded the definition of this disease. Based upon our current understanding, Ewing sarcoma comprises a family of tumors that share a common set of chromosomal translocations that are believed to be the originating event driving the pathogenesis of these tumors (see below). Ewing sarcomas may arise in the bone or soft tissues throughout the body. They may be undifferentiated (pathologically termed Ewing sarcoma) or show evidence of neural differentiation (pathologically termed primitive neuroectodermal tumor, or PNET). Moreover, a subset of these tumors that arise in the chest wall have historically been referred to as Askin tumors. As Ewing sarcoma, PNET, and Askin tumors are now understood to share the same fundamental biology, the principles that drive the management of patients with these tumors are largely identical. Therefore, except where relevant differences exist, this chapter will refer to these tumors simply as Ewing sarcoma. This is in contradistinction to a more recently recognized group of tumors that have been classified as Ewing-like sarcomas. These tumors harbor different genetic translocations and are biologically distinct from Ewing sarcoma, and little is known about their optimal management. Further discussion of Ewing-like sarcomas is outside the scope of this chapter.

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PATHOGENESIS

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The hallmark feature of Ewing sarcoma is the presence of 1 of several recurrent chromosomal translocations involving members of the TET transcription factor family (TLS, EWSR1, TAF15) and ETS transcription factor gene family members (eg, FLI1, ERG, ETV1, E1AF, and FEV). The translocation results in a novel chimeric transcription factor that brings the activation domain of the TET family with the DNA binding domain of the ETS family member. The most common translocation involves EWSR1 on chromosome 22 with FLI1 on chromosome 11, leading to the classic t(11;22) translocation. An EWSR1/FLI1 (often referred to as EWS-FLI1) fusion is detectable in at least 85% of cases of Ewing sarcoma, with less common EWS-ETS fusions seen in the remaining cases. These fusions are believed to be the initiating event in the development of these tumors. These chimeric fusion proteins function as transcription factors that establish a unique, aberrant oncogenic gene expression program and have roles in alternative splicing and responsiveness to genotoxic stress. Moreover, the presence of the fusion leads to an increased dependence on IGF1R signaling and to increased sensitivity to DNA damaging agents, both of which have led to clinical trials of approaches exploiting these potential vulnerabilities (see below). In addition to the primary EWS-ETS fusion, a number of cooperating genetic events have been described in a subset of Ewing sarcomas including STAG2 and TP53 mutations, and deletion of CDKN2A.

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EPIDEMIOLOGY

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Ewing sarcoma is a rare disease, with approximately 250 ...

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