Publications by authors named "Andrej Rosic"

2 Publications

  • Page 1 of 1

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

Science 2018 08;361(6405)

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, UK.

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.
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http://dx.doi.org/10.1126/science.aam8419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176908PMC
August 2018

Direct Transcriptional Consequences of Somatic Mutation in Breast Cancer.

Cell Rep 2016 08 4;16(7):2032-46. Epub 2016 Aug 4.

Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Disordered transcriptomes of cancer encompass direct effects of somatic mutation on transcription, coordinated secondary pathway alterations, and increased transcriptional noise. To catalog the rules governing how somatic mutation exerts direct transcriptional effects, we developed an exhaustive pipeline for analyzing RNA sequencing data, which we integrated with whole genomes from 23 breast cancers. Using X-inactivation analyses, we found that cancer cells are more transcriptionally active than intermixed stromal cells. This is especially true in estrogen receptor (ER)-negative tumors. Overall, 59% of substitutions were expressed. Nonsense mutations showed lower expression levels than expected, with patterns characteristic of nonsense-mediated decay. 14% of 4,234 rearrangements caused transcriptional abnormalities, including exon skips, exon reusage, fusions, and premature polyadenylation. We found productive, stable transcription from sense-to-antisense gene fusions and gene-to-intergenic rearrangements, suggesting that these mutation classes drive more transcriptional disruption than previously suspected. Systematic integration of transcriptome with genome data reveals the rules by which transcriptional machinery interprets somatic mutation.
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http://dx.doi.org/10.1016/j.celrep.2016.07.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4987284PMC
August 2016
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