Gene Expression and Co-expression Networks Are Strongly Altered Through Stages in Clear Cell Renal Carcinoma

Abstract

Clear cell renal carcinoma (ccRC) is a highly heterogeneous and progressively malignant disease. Analyzing ccRC progression in terms of modifications at the molecular and genetic level may help us to develop a broader understanding of its patho-physiology and may give us a glimpse toward improved therapeutics. In this work, by using TCGA data, we studied the molecular progression of the four main ccRC stages (i, ii, iii, iv) in two different yet complementary approaches: (a) gene expression and (b) gene co-expression. For (a) we analyzed the differential gene expression between each stage and the control non-cancer group. We compared the progression molecular signature between stages, and observed those genes that change their expression patterns through progression stages. For (b) we constructed and analyzed co-expression networks for the four ccRC progression stages, as well as for the control phenotype, to observe whether and how the co-expression landscape changes with progression. We separated genomic interactions into intra-chromosome (cis-) and inter-chromosome (trans-). Finally, we intersected those networks and performed functional enrichment analysis. All calculations were made over different network sizes, from the top 100 edges to top 1,000,000. We show that differential expression is quite similar between ccRC progression stages. However, interestingly, two genes, namely SLC6A19 and PLG show a significant progressive decrease in their expression according to ccRC stage, meanwhile two other genes, SAA2-SAA4 and CXCL13 show progressive increase. Despite the high similarity between gene expression profiles, all networks are substantially different between them in terms of their topological features. Control network has a larger proportion of trans- interactions, meanwhile for any stage, the amount of cis- interactions is higher, independent of the network cut-off. The majority of interactions in any network are phenotype-specific. Only 189 interactions are shared between the five networks, and 533 edges are ccRC-specific, independent of the stage. The small resulting connected components in both cases are formed by genes with the same differential expression trend, and are associated with important biological processes, such as cell cycle or immune system, suggesting that activity of these categories follows the differential expression trend. With this approach we have shown that, even if the expression program is similar during ccRC progression, the co-expression programs strongly differ. More research is needed to understand the delicate interplay between expression and co-expression, but this is a first approach to enclose both approaches in an integrative view aimed at a deeper understanding in gene regulation in tumor evolution.

Keywords: CXCL13 progressive overexpression; PLG progressive underexpression; SAA2-SAA4 progressive overexpression; SLC6A19 progressive underexpression; cancer progression stages; clear cell renal carcinoma; gene co-expression networks; loss of long-range co-expression.