Oncotarget

Research Papers:

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

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

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Oncotarget. 2015; 6:42197-42221. https://doi.org/10.18632/oncotarget.6255

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Abstract

Oleg V. Grinchuk1, Efthymios Motakis1,3, Surya Pavan Yenamandra1, Ghim Siong Ow1, Piroon Jenjaroenpun1, Zhiqun Tang1, Aliaksandr A. Yarmishyn1, Anna V. Ivshina1 and Vladimir A. Kuznetsov1,2

1 Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), Singapore

2 School of Computing Engineering, Nanyang Technological University, Singapore

3 currently EM is working in RIKEN, Japan

Correspondence to:

Vladimir A. Kuznetsov, email:

Keywords: sense-antisense, breast cancer, prognostic, meta-analysis, GABPA

Received: May 16, 2015 Accepted: September 30, 2015 Published: October 28, 2015

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.


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