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, Layeghifard M, Novokmet A, Kowalski PE, Anaka M, Davidson S, Zarrei M, Said BI, Schreiner LC, Marchand R, Sitter J, Gokgoz N, Brunga L, Graham GT, Fullam A, Pillay N, Toretsky JA, Yoshida A, Shibata T, Metzler M, Somers GR, Scherer SW, Flanagan AM, Campbell PJ, Schiffman JD, Shago M, Alexandrov LB, Wunder JS, Andrulis IL, Malkin D, Behjati S, Shlien A (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Science American Association for the Advancement of Science

Book Volume: 361

Journal Issue: 6405

DOI: 10.1126/science.aam8419

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.

Authors with CRIS profile

Markus Metzler Professur für Kinder- und Jugendmedizin mit dem Schwerpunkt Pädiatrische Onkologie und Hämatologie

Involved external institutions

The Hospital for Sick Children (SickKids) CA Canada (CA) Wellcome Trust Sanger Institute - Genome Research Limited GB United Kingdom (GB) Sinai Health System CA Canada (CA) Georgetown University US United States (USA) (US) University College London (UCL) GB United Kingdom (GB) National Cancer Centre Singapore (NCCS) SG Singapore (SG) University of Toronto CA Canada (CA) Royal National Orthopaedic Hospital Trust GB United Kingdom (GB) University of Utah US United States (USA) (US) University of California, San Diego US United States (USA) (US) Mount Sinai Hospital (MSH) CA Canada (CA)

How to cite

APA:

Anderson, N.D., De Borja, R., Young, M.D., Fuligni, F., Rosic, A., Roberts, N.D.,... Shlien, A. (2018). Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors. Science, 361(6405). https://dx.doi.org/10.1126/science.aam8419

MLA:

Anderson, Nathaniel D., et al. "Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors." Science 361.6405 (2018).

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