Ewing sarcomas are the second most frequent bone tumor of childhood that can also occur in soft tissue. They are highly aggressive with a survival of 30% for those with metastatic disease. They are genetically characterized by balanced reciprocal chromosomal translocations in which a member of the FET gene family is fused with an ETS transcription factor, with the most common translocation being the t(11;22)(q24;q12). The t(11;22) reciprocal translocation fuses the N-terminal transactivation domain of the Ewing sarcoma breakpoint region 1 protein (EWSR1) with the C-terminal DNA binding domain of the Friend leukemia integration 1 transcription factor (FLI1). The EWSR1-FLI1 fusion occurs in ∼90% of Ewing sarcoma cases and is a tumor-specific chimeric transcription factor that massively revamps the transcriptome. Therefore, the detection of EWSR1-FLI1 fusions is of important diagnostic value. Here, we present two pediatric Ewing sarcomas with atypical EWSR1-FLI1 fusions. The first case had a complex t(9;11;22)(q22;q24;q12) three-way translocation and a 1q jumping translocation by chromosome analysis. EWSR1 rearrangements using a EWSR1 break-apart FISH probe set revealed 5’ EWSR1 on der(22)(q12) and 3’ EWSR1 on der(9)(q22). Metaphase FISH using dual-color dual-fusion EWSR1-FLI1 FISH probe set revealed a EWSR1-FLI1 fusion at the derivative chromosome 22 involving the three-way translocation. 1q amplification by jumping translocations were confirmed by SNP microarray. The second case had a t(4;22)(q35;q12) reciprocal translocation and tetrasomy 8 by chromosome analysis. EWSR1 rearrangements using a EWSR1 break-apart FISH probe set revealed 5’ EWSR1 on der(22)(q12) and 3’ EWSR1 on der(4)(q35). Metaphase FISH using dual-color dual-fusion EWSR1-FLI1 FISH probe set revealed a EWSR1-FLI1 fusion at the derivative chromosome 22 involving the 4;22 translocation. Both cases had EWSR1-FLI1 gene fusions detected by Nanostring gene fusion panel. Recognizing complex and cryptic EWSR1-FLI1 gene fusions using various diagnostic methods is important for diagnosis, prognosis, and treatment outcome of pediatric Ewing sarcomas.
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