Oncotarget

Research Papers:

Differentially expressed microRNAs in lung adenocarcinoma invert effects of copy number aberrations of prognostic genes

Tomas Tokar, Chiara Pastrello, Varune R. Ramnarine, Chang-Qi Zhu, Kenneth J. Craddock, Larrisa A. Pikor, Emily A. Vucic, Simon Vary, Frances A. Shepherd, Ming-Sound Tsao, Wan L. Lam and Igor Jurisica _

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Oncotarget. 2018; 9:9137-9155. https://doi.org/10.18632/oncotarget.24070

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Abstract

Tomas Tokar1, Chiara Pastrello1, Varune R. Ramnarine1,2, Chang-Qi Zhu1, Kenneth J. Craddock1, Larrisa A. Pikor3, Emily A. Vucic3, Simon Vary1,4,5, Frances A. Shepherd1, Ming-Sound Tsao1,6,7, Wan L. Lam3 and Igor Jurisica1,6,8,9

1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, Canada

3Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, Canada

4Mathematical Institute, University of Oxford, Oxford, United Kingdom

5Faculty of Mathematics, Physics and Informatics, Comenius University, Bratislava, Slovakia

6Department of Medical Biophysics, University of Toronto, Toronto, Canada

7Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

8Department of Computer Science, University of Toronto, Toronto, Canada

9Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia

Correspondence to:

Igor Jurisica, email: [email protected]

Keywords: lung adenocarcinoma; copy number aberrations; microRNA; gene regulatory network; prognostic signature

Received: August 25, 2017     Accepted: January 02, 2018     Published: January 08, 2018

ABSTRACT

In many cancers, significantly down- or upregulated genes are found within chromosomal regions with DNA copy number alteration opposite to the expression changes. Generally, this paradox has been overlooked as noise, but can potentially be a consequence of interference of epigenetic regulatory mechanisms, including microRNA-mediated control of mRNA levels.

To explore potential associations between microRNAs and paradoxes in non-small-cell lung cancer (NSCLC) we curated and analyzed lung adenocarcinoma (LUAD) data, comprising gene expressions, copy number aberrations (CNAs) and microRNA expressions. We integrated data from 1,062 tumor samples and 241 normal lung samples, including newly-generated array comparative genomic hybridization (aCGH) data from 63 LUAD samples.

We identified 85 “paradoxical” genes whose differential expression consistently contrasted with aberrations of their copy numbers. Paradoxical status of 70 out of 85 genes was validated on sample-wise basis using The Cancer Genome Atlas (TCGA) LUAD data. Of these, 41 genes are prognostic and form a clinically relevant signature, which we validated on three independent datasets. By meta-analysis of results from 9 LUAD microRNA expression studies we identified 24 consistently-deregulated microRNAs. Using TCGA-LUAD data we showed that deregulation of 19 of these microRNAs explains differential expression of the paradoxical genes.

Our results show that deregulation of paradoxical genes is crucial in LUAD and their expression pattern is maintained epigenetically, defying gene copy number status.


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