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

Anderson, ND; de Borja, R; Young, MD; Fuligni, F; Rosic, A; Roberts, ND; Hajjar, S; ... Shlien, A; + view all (2018) Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors. Science , 361 (6405) 10.1126/science.aam8419. Green open access

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Abstract

Sarcomas are cancers of the bone and soft tissue often defined by gene fusions. Ewing sarcoma involves fusions between EWSR1, a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) transcription factors. We explored how and when EWSR1-ETS 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.

Type: Article
Title: Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors
Open access status: An open access version is available from UCL Discovery
DOI: 10.1126/science.aam8419
Publisher version: https://doi.org/10.1126/science.aam8419
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, DIFFERENTIAL EXPRESSION ANALYSIS, MUTATIONAL PROCESSES, GENOMIC LANDSCAPE, EWING SARCOMA, CANCER, SIGNATURES, METASTASIS, COMPLEXITY, EVOLUTION, IMPACT
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Pathology
URI: https://discovery.ucl.ac.uk/id/eprint/10073155
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