Ewing sarcoma is defined by the presence of a fusion gene, most commonly EWSR1/FLI1.

Ewing sarcoma is a tumor of the bone (most commonly) or soft tissue and is defined by the presence of the fusion gene EWSR1/FLI1 or other less common FET/ETS family fusions.

Thought to be derived from a neural crest or mesenchymal cell of origin, although the exact cell of origin is still a source of debate.

Ewing tumors arise most commonly from a translocation of chromosomes 11 and 22, resulting in the generation of the fusion gene EWSR1/FLI1. Recent evidence has demonstrated that ~40% of Ewing tumors FET/ETS fusions arise from chromoplexy.

Ewing sarcoma is a rare subtype of sarcoma. It is the second most common primary bone sarcoma in pediatric patients and can also occur in the soft tissue. In the United States, there are 200-250 newly diagnosed cases annually. Ewing sarcoma most commonly occurs in the AYA (adolescent and young adult) patient population, with a peak incidence at 15 years of age. This tumor can also less commonly occur in older adults, with a second smaller peek in incidence in patients older than 35 years. There are no known environmental exposures known to cause Ewing sarcoma.

Ewing sarcoma can arise in the bone or soft tissue. Bone lesions are the most common and occur most often in the pelvis or femur. Common locations for soft tissue Ewing sarcoma include the buttock, thigh and chest wall. Many other bone and soft tissue primary locations for Ewing tumors have been reported but are less common.
70-75% of Ewing tumors present as a single, localized mass. The remaining ~25% of patients present with upfront metastatic disease in the lung or bone/bone marrow, as noted on imaging (PET and CT scans) and bilateral bone marrow biopsies obtained for disease staging.

Uniform sheets of small, round blue cells, often (95%) CD99+ and (100%) Tdt- by immunohistochemistry staining. EWSR1 break-apart FISH probes are commonly used diagnostically to detect the presence of the EWS-containing fusion (most commonly EWSR1/FLI1). FISH probes are not as reliable for detecting EWSR1/ERG or non-EWSR1 FET/ETS fusions. Tumor sequencing is thus also used to more precisely define the fusion present in FISH "negative" cases.

Additionally, mutations in the following genes have been described in subsets of Ewing tumors: STAG2, TP53, EZH2, and deletions inCDKN2A.

Localized Ewing sarcoma is currently treated with alternating, compressed cycles of multi-agent chemotherapy, such as VDC/IE (vincristine, doxorubicin, cyclophosphamide/ifosfamide, etoposide). Ewing tumors are sensitive to radiation and local control is achieved by surgery and/or radiation therapy.
Ongoing clinical trials aim to improve the outcomes for patients with upfront metastatic and relapsed Ewing sarcoma. These trials include international efforts to determine the most effective chemotherapy backbone for patients with relapsed Ewing sarcoma. Novel single agents include those attempting to target the EWSR1/FLI1 fusion itself.

Current survival estimates for patients with primary, localized Ewing sarcoma is ~70%. Survival for patients with upfront metastatic or relapsed Ewing sarcoma is only 10-30%.

about 85% of Ewing tumors show a t(11;22)(q24;q12); the translocation results in the fusion of the EWSR1 gene with the transcription factor gene FLI1, leading to a hybrid transcript and an oncogenic chimeric protein. Other more rare FET-ETS family member fusions have been described, such as: t(21;22)(q12;q12) and t(7;22)(p22;q12), leading to the fusions EWSR1/ERG and EWSR1/ETV1, respectively.

Additional anomalies in Ewings tumors mainly consist in chromosome gains: +8 (45% of the cases) and, with a much lower frequency, trisomies 2, 5, 7, 9, 12 (between 10 and 15% of the cases); trisomy 1q, through unbalanced t(1q;16q), is observed in about 25% of the cases

Germline Mutations
~13% of patients with Ewing sarcoma have been found to have germline mutations. These germline mutations are enriched in genes associated with DNA damage repair. The pathogenicity of such mutations remains a subject of ongoing investigation

The following genes have been identified as involved FET or ETS family members comprising various FET-ETS fusions: EWSR1, FLI1, ERG, ETV1, ETV4, FEV, FUS

EWSR1 (Ewing sarcoma breakpoint region 1)

22q12.2

Contains both a transcriptional activation domain and an RNA-binding domain.

FLI1 (Friend leukemia virus integration 1)

11q24.3

Member of the ETS family of transcription factors.

ERG (v-ets erythroblastosis virus E26 oncogene like (avian))

21q22.2

Member of the ETS family of transcription factors.

ETV1 (Ets variant 1)

7p21.2

Member of the ETS family of transcription factors.

ETV4 (Ets variant 4)

17q21.31

ETV4 serves as a transcriptional activator.

FEV (fifth ewing variant)

2q35

Member of the ETS family of transcription factors.

FUS (fused in sarcoma)

16p11.2

The FUS protein binds to DNA and participates in transcription.

The 5 portion of FET family members are fused to the 3 portion of ETS family members to generate a FET-ETS fusion oncogene, most commonly (85%) EWSR1/FLI1.

FUSR1/ERG t(16;21)

TGFBR2 (TGF-beta receptor II) expression is one example of a gene/protein classically repressed by EWS-R1/FLI1.