Direct transcriptional consequences of somatic mutation in breast cancer

Shlien, A. et al. (2016) Direct transcriptional consequences of somatic mutation in breast cancer. Cell Reports, 16(7), pp. 2032-2046. (doi: 10.1016/j.celrep.2016.07.028) (PMID:27498871) (PMCID:PMC4987284)

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 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cooke, Dr Susie
• Authors: Shlien, A., Raine, K., Fuligni, F., Arnold, R., Nik-Zainal, S., Dronov, S., Mamanova, L., Rosic, A., Ju, Y. S., Cooke, S. L., Ramakrishna, M., Papaemmanuil, E., Davies, H. R., Tarpey, P. S., Van Loo, P., Wedge, D. C., Jones, D. R., Martin, S., Marshall, J., Anderson, E., Hardy, C., Barbashina, V., Aparicio, S. A.J.R., Sauer, T., Garred, Ø., Vincent-Salomon, A., Mariani, O., Boyault, S., Fatima, A., Langerød, A., Borg, Å., Thomas, G., Richardson, A. L., Børresen-Dale, A.-L., Polyak, K., Stratton, M. R., and Campbell, P. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cell Reports
• Publisher: Elsevier (Cell Press)
• ISSN: 2211-1247
• ISSN (Online): 2211-1247
• Published Online: 04 August 2016
• Copyright Holders: Copyright © 2016 The Authors
• First Published: First published in Cell Reports 16(7):2032-2046
• Publisher Policy: Reproduced under a Creative Commons License