Molecular Features of Ewing Sarcoma

The World Health Organization identifies the presence of a gene fusion involving EWSR1 or FUS and a gene in the ETS family as a defining element of Ewing sarcoma.[26] The EWSR1 gene located on chromosome 22 band q12 is a member of the FET family (FUS, EWSR1, TAF15) of RNA-binding proteins.[27] Characteristically, the amino terminus of the EWSR1 gene is juxtaposed with the carboxy terminus of a gene from the ETS family of DNA-binding transcription factors (see Table 6). The FLI1 gene located on chromosome 11 band q24 is a member of the ETS family and is the ETS family fusion partner for EWSR1 in 85% to 90% of pediatric cases of Ewing sarcoma.[28-30] Other ETS family members that may combine with the EWSR1 gene are ERG, ETV1, ETV4, and FEV.[31] Rarely, FUS, another FET family member, can substitute for EWSR1.[32] Finally, there are a few rare cases in which EWSR1 has translocated with partners that are not members of the ETS family of oncogenes. These tumors are thought to be distinct from Ewing sarcoma and are discussed separately. For more information, see the Undifferentiated Small Round Cell (Ewing-Like) Sarcomas section.

The EWSR1::FLI1 translocation associated with Ewing sarcoma can occur at several potential breakpoints in each of the genes that join to form the novel segment of DNA. Once thought to be significant,[33] two large series have shown that the EWSR1::FLI1 translocation breakpoint site is not an adverse prognostic factor.[34,35]

Besides the consistent aberrations involving the EWSR1 gene, secondary numerical and structural chromosomal aberrations are observed in most cases of Ewing sarcoma. Chromosome gains are more common than chromosome losses, and structural chromosome imbalances are also observed.[36] Two of the more common chromosome aberrations are those involving chromosome 8 or chromosomes 1 and 16.[36]

The genomic landscape of Ewing sarcoma is characterized by a relatively silent genome, with a paucity of variants in pathways that might be amenable to treatment with novel targeted therapies.[28-30] Recurring genomic alterations are described below. For some of these genomic alterations, claims of prognostic significance have been made. However, these claims need to be viewed cautiously because of the relatively small size of most studies, the low frequency of many of the genomic alterations, the variable use of tumor tissue from diagnosis versus relapse specimens, and the need to consider clinical prognostic factors such as tumor size and the presence of metastatic disease.

Ewing sarcoma translocations can all be found with standard cytogenetic analysis. A fluorescence in situ hybridization (FISH) rapid analysis looking for a break apart of the EWSR1 gene is now frequently done to confirm the diagnosis of Ewing sarcoma molecularly.[45] This test result must be considered with caution, however. Ewing sarcomas that harbor FUS translocations will have negative tests because the EWSR1 gene is not translocated in those cases. In addition, other small round tumors also contain translocations of different ETS family members with EWSR1, such as desmoplastic small round cell tumor, clear cell sarcoma, extraskeletal myxoid chondrosarcoma, and myxoid liposarcoma, all of which may be positive with a EWSR1 FISH break-apart probe. A detailed analysis of 85 patients with small round blue cell tumors that were negative for EWSR1 rearrangement by FISH (with an EWSR1 break-apart probe) identified eight patients with FUS rearrangements.[46] Four patients who had EWSR1::ERG fusions were not detected by FISH with an EWSR1 break-apart probe. The authors do not recommend relying solely on EWSR1 break-apart probes for analyzing small round blue cell tumors with strong immunohistochemical positivity for CD99. Next-generation sequencing assays, including dedicated fusion panels, are now commonly used in the evaluation of these tumors.

For information about the treatment of Ewing sarcoma, see Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue Treatment.