Loss of Long Distance Co-Expression in Lung Cancer

Abstract

Lung cancer is one of the deadliest, most aggressive cancers. Abrupt changes in gene expression represent an important challenge to understand and fight the disease. Gene co-expression networks (GCNs) have been widely used to study the genomic regulatory landscape of human cancer. Here, based on 1,143 RNA-Seq experiments from the TCGA collaboration, we constructed GCN for the most common types of lung tumors: adenocarcinoma (TAD) and squamous cells (TSCs) as well as their respective control networks (NAD and NSC). We compared the number of intra-chromosome (cis-) and inter-chromosome (trans-) co-expression interactions in normal and cancer GCNs. We compared the number of shared interactions between TAD and TSC, as well as in NAD and NSC, to observe which phenotypes were more alike. By means of an over-representation analysis, we associated network topology features with biological functions. We found that TAD and TSC present mostly cis- small disconnected components, whereas in control GCNs, both types have a giant trans- component. In both cancer networks, we observed cis- components in which genes not only belong to the same chromosome but to the same cytoband or to neighboring cytobands. This supports the hypothesis that in lung cancer, gene co-expression is constrained to small neighboring regions. Despite this loss of distant co-expression observed in TAD and TSC, there are some remaining trans- clusters. These clusters seem to play relevant roles in the carcinogenic processes. For instance, some clusters in TAD and TSC are associated with the immune system, response to virus, or control of gene expression. Additionally, other non-enriched trans- clusters are composed of one gene and several associated pseudo-genes, as in the case of the FTH1 gene. The appearance of those common trans- clusters reflects that the gene co-expression program in lung cancer conserves some aspects for cell maintenance. Unexpectedly, 0.48% of the edges are shared between control networks; conversely, 35% is shared between lung cancer GCNs, a 73-fold larger intersection. This suggests that in lung cancer a process of de-differentiation may be occurring. To further investigate the implications of the loss of distant co-expression, it will become necessary to broaden the investigation with other omic-based approaches. However, the present approach provides a basis for future work toward an integrative perspective of abnormal transcriptional regulatory programs in lung cancer.

Keywords: differentiation processes in cancer; gene co-expression networks; loss of distant co-expression; lung adenocarcinoma; squamous lung cancer.