Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors

Abstract

Sarcomas are cancers of the bone and soft tissue often defined by gene fusions. Ewing sarcoma involves fusions between , a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) transcription factors. We explored how and when fusions arise by studying the whole genomes of Ewing sarcomas. In 52 of 124 (42%) of tumors, the fusion gene arises by a sudden burst of complex, loop-like rearrangements, a process called chromoplexy, rather than by simple reciprocal translocations. These loops always contained the disease-defining fusion at the center, but they disrupted multiple additional genes. The loops occurred preferentially in early replicating and transcriptionally active genomic regions. Similar loops forming canonical fusions were found in three other sarcoma types. Chromoplexy-generated fusions appear to be associated with an aggressive form of Ewing sarcoma. These loops arise early, giving rise to both primary and relapse Ewing sarcoma tumors, which can continue to evolve in parallel.

SOX2 expression identifies Ewing sarcoma patients with high risk for tumor relapse and poor survival

“…Genetically, the hallmark of EwS are chromosomal translocations generating chimeric proteins through fusion of the EWSR1 (Ewing sarcoma breakpoint region 1) gene to variable members of the ETS (E26 transformation specific) family of transcription factors, in 85% FLI1 (Friend leukemia virus integration 1) [3][4][5] . These EWSR1-ETS fusion oncoproteins act as aberrant transcription factors that promote tumor initiation and progression by massively rewiring the cellular transcriptome and spliceosome 1,6,7 .…”

Oncogenic hijacking of a developmental transcription factor evokes therapeutic vulnerability for ROS-induction in Ewing sarcoma

“…While great advances in treatment of localized disease have been achieved, established therapies still have limited success in advanced stages despite high toxicity 1 . Thus, more specific and in particular less toxic therapies are urgently required.As a genetic hallmark, EwS tumors express chimeric EWSR1-ETS (EwS breakpoint region 1 -E26 transformation specific) fusion oncoproteins generated through fusion of the EWSR1 gene and variable members of the ETS-family of transcription factors (TF), most commonly FLI1 (85% of all cases) 4,5 . Prior studies demonstrated that EWSR1-FLI1 acts as a pioneer transcription factor that massively rewires the tumor transcriptome ultimately promoting the malignant phenotype of EwS 6,7 .…”

A germline BARD1 mutation in a patient with Ewing Sarcoma: Implications for familial testing and counseling

“…Further, loss of CDKN2A and CDKN2B and a rare type 3 EWS‐FLI1 translocation were noted. The mutational burden of this tumor is higher than the average (∼0.5 mutations/Mb) for Ewing tumors, at 2 mutations/Mb.…”