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

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.

Profiling the heterogeneity of colorectal cancer consensus molecular subtypes using spatial transcriptomics

“…2k, l, Methods), such as the correlation between CMS1 tumor cell abundance and activity of the immune-related pathways JAK-STAT 19 (Fig. 2m, n), TNFα 20 and NFkB. Additionally, activation of the MAPK pathway (Fig.…”

Charting the Heterogeneity of Colorectal Cancer Consensus Molecular Subtypes using Spatial Transcriptomics

“…For the CMS1 tumor cells, we captured the expected correlation with JAK-STAT 29 (Fig. 2m) and immune-related pathways, such as the TNF⍺ 30 and NFkB. In addition, a correlation with the EGFR and MAPK pathway was identified.…”