Identification of Gene Co-Expression Networks Associated with Consensus Molecular Subtype-1 of Colorectal Cancer

SIMPLE SUMMARY: Colorectal cancer (CRC) is a frequently lethal disease with heterogenous outcomes. Alterations in the Wnt signaling pathways have been shown to promote activation of signaling pathways such as MAPK and PI3K-Akt. Consensus molecular subtyping (CMS) provides a cohesive structure to classify the heterogeneity of CRC using gene expression analysis. CMS is categorized into four subtypes: CMS1, immune; CMS2, canonical; CMS3, metabolic; and CMS4, mesenchymal. Here, we identify co-expressed gene networks associated with CMS1. Our findings distinguish co-expressed gene networks that play a pivotal role in key features specific for CMS1, such as immune infiltration and activation. The co-expressed gene networks for CMS1 were significantly and positively correlated with the TNF, WNT, and ERK1 and ERK2 signaling pathways. This study highlights the relevance of CMS1 gene networks relating to oncogenic signaling cascades, cell activation, and positive regulation of immune responses, promoting CRC progressiveness. ABSTRACT: Colorectal cancer (CRC) is driven in part by dysregulated Wnt, Ras-Raf-MAPK, TGF-β, and PI3K-Akt signaling. The progression of CRC is also promoted by molecular alterations and heterogeneous—yet interconnected—gene mutations, chromosomal instability, transcriptomic subtypes, and immune signatures. Genomic alterations of CRC progression lead to changes in RNA expression, which support CRC metastasis. An RNA-based classification system used for CRC, known as consensus molecular subtyping (CMS), has four classes. CMS1 has the lowest survival after relapse of the four CRC CMS phenotypes. Here, we identify gene signatures and associated coding mRNAs that are co-expressed during CMS1 CRC progression. Using RNA-seq data from CRC primary tumor samples, acquired from The Cancer Genome Atlas (TCGA), we identified co-expression gene networks significantly correlated with CMS1 CRC progression. CXCL13, CXCR5, IL10, PIK3R5, PIK3AP1, CCL19, and other co-expressed genes were identified to be positively correlated with CMS1. The co-expressed eigengene networks for CMS1 were significantly and positively correlated with the TNF, WNT, and ERK1 and ERK2 signaling pathways, which together promote cell proliferation and survival. This network was also aligned with biological characteristics of CMS1 CRC, being positively correlated to right-sided tumors, microsatellite instability, chemokine-mediated signaling pathways, and immune responses. CMS1 also differentially expressed genes involved in PI3K-Akt signaling. Our findings reveal CRC gene networks related to oncogenic signaling cascades, cell activation, and positive regulation of immune responses distinguishing CMS1 from other CRC subtypes.