The Role of Copy Number Variants in Gene Co-Expression Patterns for Luminal B Breast Tumors

Abstract

Gene co-expression networks have become a usual approach to integrate the vast amounts of information coming from gene expression studies in cancer cohorts. The reprogramming of the gene regulatory control and the molecular pathways depending on such control are central to the characterization of the disease, aiming to unveil the consequences for cancer prognosis and therapeutics. There is, however, a multitude of factors which have been associated with anomalous control of gene expression in cancer. In the particular case of co-expression patterns, we have previously documented a phenomenon of loss of long distance co-expression in several cancer types, including breast cancer. Of the many potential factors that may contribute to this phenomenology, copy number variants (CNVs) have been often discussed. However, no systematic assessment of the role that CNVs may play in shaping gene co-expression patterns in breast cancer has been performed to date. For this reason we have decided to develop such analysis. In this study, we focus on using probabilistic modeling techniques to evaluate to what extent CNVs affect the phenomenon of long/short range co-expression in Luminal B breast tumors. We analyzed the co-expression patterns in chromosome 8, since it is known to be affected by amplifications/deletions during cancer development. We found that the CNVs pattern in chromosome 8 of Luminal B network does not alter the co-expression patterns significantly, which means that the co-expression program in this cancer phenotype is not determined by CNV structure. Additionally, we found that region 8q24.3 is highly dense in interactions, as well as region p21.3. The most connected genes in this network belong to those cytobands and are associated with several manifestations of cancer in different tissues. Interestingly, among the most connected genes, we found MAF1 and POLR3D, which may constitute an axis of regulation of gene transcription, in particular for non-coding RNA species. We believe that by advancing on our knowledge of the molecular mechanisms behind gene regulation in cancer, we will be better equipped, not only to understand tumor biology, but also to broaden the scope of diagnostic, prognostic and therapeutic interventions to ultimately benefit oncologic patients.

Keywords: breast cancer; co-expression networks; conditional mutual information; copy number variants; luminal B breast cancer.