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Direct Transcriptional Consequences of Somatic Mutation in Breast Cancer

Shlien, Adam; Raine, Keiran; Fuligni, Fabio; Arnold, Roland; Nik-Zainal, Serena; Dronov, Serge; Mamanova, Lira; Rosic, Andrej; Ju, Young Seok and Cooke, Susanna L., et al. (2016) In Cell Reports 16(7). p.2032-2046
Abstract

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... (More)

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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@article{79f2cada-6cc2-4680-85c7-d0f995e56dc1,
  abstract     = {<p>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.</p>},
  author       = {Shlien, Adam and Raine, Keiran and Fuligni, Fabio and Arnold, Roland and Nik-Zainal, Serena and Dronov, Serge and Mamanova, Lira and Rosic, Andrej and Ju, Young Seok and Cooke, Susanna L. and Ramakrishna, Manasa and Papaemmanuil, Elli and Davies, Helen R. and Tarpey, Patrick S. and Van Loo, Peter and Wedge, David C. and Jones, David R. and Martin, Sancha and Marshall, John and Anderson, Elizabeth and Hardy, Claire and Barbashina, Violetta and Aparicio, Samuel A J R and Sauer, Torill and Garred, Øystein and Vincent-Salomon, Anne and Mariani, Odette and Boyault, Sandrine and Fatima, Aquila and Langerød, Anita and Borg, Åke and Thomas, Gilles and Richardson, Andrea L. and Børresen-Dale, Anne Lise and Polyak, Kornelia and Stratton, Michael R. and Campbell, Peter J.},
  issn         = {2211-1247},
  language     = {eng},
  month        = {08},
  number       = {7},
  pages        = {2032--2046},
  publisher    = {Cell Press},
  series       = {Cell Reports},
  title        = {Direct Transcriptional Consequences of Somatic Mutation in Breast Cancer},
  url          = {http://dx.doi.org/10.1016/j.celrep.2016.07.028},
  volume       = {16},
  year         = {2016},
}