Sense-antisense gene-pairs in breast cancer and associated pathological pathways.

Oleg V Grinchuk,Aliaksandr A Yarmishyn,Surya Pavan Yenamandra,Anna V Ivshina,Ghim Siong Ow,Efthymios Motakis,Piroon Jenjaroenpun,Zhiqun Tang,Vladimir A Kuznetsov

doi:10.18632/oncotarget.6255

Abstract

More than 30% of human protein-coding genes form hereditary complex genome architectures composed of sense-antisense (SA) gene pairs (SAGPs) transcribing their RNAs from both strands of a given locus. Such architectures represent important novel components of genome complexity contributing to gene expression deregulation in cancer cells. Therefore, the architectures might be involved in cancer pathways and, in turn, be used for novel drug targets discovery. However, the global roles of SAGPs in cancer pathways has not been studied. Here we investigated SAGPs associated with breast cancer (BC)-related pathways using systems biology, prognostic survival and experimental methods. Gene expression analysis identified 73 BC-relevant SAGPs that are highly correlated in BC. Survival modelling and metadata analysis of the 1161 BC patients allowed us to develop a novel patient prognostic grouping method selecting the 12 survival-significant SAGPs. The qRT-PCR-validated 12-SAGP prognostic signature reproducibly stratified BC patients into low- and high-risk prognostic subgroups. The 1381 SAGP-defined differentially expressed genes common across three studied cohorts were identified. The functional enrichment analysis of these genes revealed the GABPA gene network, including BC-relevant SAGPs, specific gene sets involved in cell cycle, spliceosomal and proteasomal pathways. The co-regulatory function of GABPA in BC cells was supported using siRNA knockdown studies. Thus, we demonstrated SAGPs as the synergistically functional genome architectures interconnected with cancer-related pathways and associated with BC patient clinical outcomes. Taken together, SAGPs represent an important component of genome complexity which can be used to identify novel aspects of coordinated pathological gene networks in cancers.

Highlights

RNA transcripts of sense-antisense (SA) gene pairs (SAGPs) represent a large subset of the human transcriptome varying from 30 to 50 % at all loci [1,2,3]
We selected the 73 breast cancer (BC)-relevant sense-antisense gene pair (SAGP) set (73-SAGPs), for which: i) the expression values of gene partners in a given SAGP were significantly correlated in the histologic grade 3 breast tumor datasets and ii) the differences of the distributions of correlation coefficients between gene partners of the SAGPs were significantly associated with the differences in the pathobiological status of breast tissue samples and clinical outcomes of BC patients
Among the 73-SAGPs, we identified the most significant prognostic paired gene sub-set, termed SA gene signature (SAGS), which reliably dichotomized the patients into low-risk (LR) and high-risk (HR) cancer development subgroups

Summary

Introduction

RNA transcripts of sense-antisense (SA) gene pairs (SAGPs) represent a large subset of the human transcriptome varying from 30 to 50 % at all loci [1,2,3]. Global deregulated patterns of SA transcripts and gene pairs in cancers have been well documented [5, 13,14,15,16]. In this context, a comprehensive approach to localize “hotspots” of deregulated antisense transcription [17], clarification of their global regulatory mechanisms and their involvement in pathobiological pathways in cancer could be clinically relevant

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