Complex Rearrangement Patterns in Undifferentiated Small Round Cell Sarcomas Associated with Poor Clinical Outcome

Undifferentiated small round cell sarcomas (USRCS) are highly aggressive neoplasms that predominantly affect children and young adults. Recent molecular findings allowed reclassification of these tumors that were formerly included in a wastebasket for different entities. Tumor types within this category comprises Ewing sarcoma (ES) and other neoplasms formerly designated “Ewing-like” sarcomas (ELS). USRCS are characterized by chromosomal translocations that generate oncogenic gene fusions, which constitute the driver alteration of the disease. However, secondary alterations at diagnosis are rare, as USRCS present a very low mutation rate. Therefore, little is known about the biological factors determining the risk of relapse or progression, thus precluding accurate patient stratification and risk-adapted therapeutic approaches. Despite USRCS were thought to be silent at genomic level, several studies have revealed that they can present genomic structural variations (SVs) such as copy number alteration in specific chromosomal regions, with an impact in disease progression. Besides, translocations themselves could represent a source of SV. Herein, we profiled SVs with optical genome mapping in a series of USRCS comprising 8 cases of ES (EWSR1-FLI1), and 2 cases of ELS (BCOR-CCNB3 and EWSR1-NFATC2). We detected the pathognomonic translocation in all the cases. The reciprocal translocation FL1-EWSR1 was detected in all ES samples excepting one. Additional chromoplectic translocation events were found in several ES samples that were obtained from patients with poor clinical outcome. Interestingly, two pairs of matched ES samples -primary and lung metastatic tumors-showed a similar SV profile, suggesting a common clonal origin for both lesions. Finally, the case with EWSR1-NFATC2 translocation showed amplification of the two loci reflecting the generation of a ring chromosome, along with clustered rearrangements that could correspond to a chromotriptic event.