Ewing Sarcoma Gene Fusions Can Be Generated via Chromoplexy

Structural rearrangements that result in gene fusions occur commonly in cancer and can drive tumorigenesis. Sarcomas are often defined by characteristic gene fusions, such as the EWSR1–ETS fusions in Ewing sarcoma (where EWSR1 is fused to one of the ETS transcription factors, FLI1, ERG or ETV1). The downstream effects of EWS–FLI1 and other sarcoma fusion proteins have been widely studied, but the timing and mechanism by which they occur have not been determined. Anderson and colleagues investigated the genesis of EWSR1–ETS fusions through whole-exome or whole-genome sequencing data from 124 patients with Ewing sarcoma. As has been previously reported, the tumors were genetically quiet with few somatic mutations. However, analysis of structural rearrangements revealed that in 52 of 124 (42%) tumors, the EWSR1–ETS fusion arose by chromoplexy, a sudden burst of complex, loop-like rearrangements, in contrast to more the common mechanism of fusion gene generation by simple reciprocal translocation. Chromoplexy-generated fusions were enriched in patients with aggressive disease and poor outcomes. Chromoplexy-mediated generation of EWSR1–ETS fusions occurred preferentially in bursts in early replicating DNA and in transcriptionally active regions. The EWSR1–ETS fusion was always at the center of the loops but multiple other genes were simultaneously disrupted. Analysis of matched relapsed or metastatic tumors revealed that primary and relapsed tumors diverged after the generation of EWSR1–ETS in the ancestral clone, with primary and relapsed tumors evolving independently. Further, recurrent chromoplexy-generated fusions were detected in chondromyxoid fibroma, synovial sarcoma, and phosphaturic mesenchymal tumor, exhibiting a similar looped formation. In addition to elucidating the mechanisms by which Ewing sarcoma and other tumor-associated fusion genes are generated, these findings provide insight into the mutational processes underpinning Ewing sarcoma.

Anderson ND, de Borja R, Young MD, Fuligni F, Rosic A, Roberts ND, et al. Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors. Science 2018;361:eaam8419.

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