Bradford, J.R., Cox, A. orcid.org/0000-0002-5138-1099, Bernard, P. et al. (1 more author) (2016) Consensus Analysis of Whole Transcriptome Profiles from Two Breast Cancer Patient Cohorts Reveals Long Non-Coding RNAs Associated with Intrinsic Subtype and the Tumour Microenvironment. PLoS One, 11 (9). e0163238. ISSN 1932-6203
Abstract
Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of cellular processes and diseases such as cancer; however, their functions remain poorly characterised. Several studies have demonstrated that lncRNAs are typically disease and tumour subtype specific, particularly in breast cancer where lncRNA expression alone is sufficient to discriminate samples based on hormone status and molecular intrinsic subtype. However, little attempt has been made to assess the reproducibility of lncRNA signatures across more than one dataset. In this work, we derive consensus lncRNA signatures indicative of breast cancer subtype based on two clinical RNA-Seq datasets: the Utah Breast Cancer Study and The Cancer Genome Atlas, through integration of differential expression and hypothesis-free clustering analyses. The most consistent signature is associated with breast cancers of the basal-like subtype, leading us to generate a putative set of six lncRNA basal-like breast cancer markers, at least two of which may have a role in cis-regulation of known poor prognosis markers. Through in silico functional characterization of individual signatures and integration of expression data from pre-clinical cancer models, we discover that discordance between signatures derived from different clinical cohorts can arise from the strong influence of non-cancerous cells in tumour samples. As a consequence, we identify nine lncRNAs putatively associated with breast cancer associated fibroblasts, or the immune response. Overall, our study establishes the confounding effects of tumour purity on lncRNA signature derivation, and generates several novel hypotheses on the role of lncRNAs in basal-like breast cancers and the tumour microenvironment.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2016 Bradford et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 05 Oct 2016 14:35 |
Last Modified: | 05 Oct 2016 14:35 |
Published Version: | http://dx.doi.org/10.1371/journal.pone.0163238 |
Status: | Published |
Publisher: | Public Library of Science |
Refereed: | Yes |
Identification Number: | 10.1371/journal.pone.0163238 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:105450 |