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

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

doi:10.18632/oncotarget.24070

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.

Highlights

Integration of array comparative genomic hybridization with mRNA microarray data has revealed significant associations between occurrence of copy number aberrations (CNAs) and differential gene expression in diverse cancers [1,2,3,4,5,6,7]
We identified multiple chromosomal regions with significantly (p < 0.05, randomization test) high frequency of gains or losses; frequencies and corresponding p-values are listed in Supplementary Data 1
To identify genes whose differential expression remained consistent across patient cohorts, we performed integrative analysis of 10 publicly available gene expression datasets, comprising 740 lung adenocarcinoma (LUAD) samples and 241 normal tissue samples

Summary

Introduction

Integration of array comparative genomic hybridization (aCGH) with mRNA microarray data has revealed significant associations between occurrence of copy number aberrations (CNAs) and differential gene expression in diverse cancers [1,2,3,4,5,6,7]. Phillips et al reported that 14% of the genes downregulated in prostate cancer reside within regions of DNA copy number gains, and approximately 9% of upregulated ones reside in regions of DNA copy number loss [1]. This paradox is ignored as a noise, but can potentially be a consequence of interference of other regulatory mechanisms controlling mRNA transcription [8]. Growing evidence implicates miRNAs as factors associated with major human pathologies, including cancer [13,14,15,16]

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