A Gene Signature Derived from the Loss of CDKN1A (p21) Is Associated with CMS4 Colorectal Cancer

Abstract

The epithelial–mesenchymal transition (EMT) is associated with tumor aggressiveness and increased invasion, migration, metastasis, angiogenesis, and drug resistance. Although the HCT116 p21-/- cell line is well known for its EMT-associated phenotype, with high Vimentin and low E-cadherin protein levels, the gene signature of this rather intermediate EMT-like cell line has not been determined so far. In this work, we present a robust molecular and bioinformatics analysis, to reveal the associated gene expression profile and its correlation with different types of colorectal cancer tumors. We compared the quantitative signature obtained with the NanoString platform with the expression profiles of colorectal cancer (CRC) Consensus Molecular Subtypes (CMS) as identified, and validated the results in a large independent cohort of human tumor samples. The expression signature derived from the p21-/- cells showed consistent and reliable numbers of upregulated and downregulated genes, as evaluated with two machine learning methods against the four CRC subtypes (i.e., CMS1, 2, 3, and 4). High concordance was found between the upregulated gene signature of HCT116 p21-/- cells and the signature of the CMS4 mesenchymal subtype. At the same time, the upregulated gene signature of the native HCT116 cells was similar to that of CMS1. Using a multivariate Cox regression model to analyze the survival data in the CRC tumor cohort, we selected genes that have a predictive risk power (with a significant gene risk incidence score). A set of genes of the mesenchymal signature was proven to be significantly associated with poor survival, specifically in the CMS4 CRC human cohort. We suggest that the gene signature of HCT116 p21-/- cells could be a suitable metric for mechanistic studies regarding the CMS4 signature and its functional consequences in CRC. Moreover, this model could help to discover the molecular mechanisms of intermediate EMT, which is known to be associated with extraordinarily high stemness and drug resistance.

Stratification of Colorectal Patients Based on Survival Analysis Shows the Value of Consensus Molecular Subtypes and Reveals the CBLL1 Gene as a Biomarker of CMS2 Tumours

“…Guinney et al previously found different associations between CMS groups and clinical variables, including overall survival (OS) [3]. Although subsequent publications show controversial data regarding the OS between different CMS, in a recent study, we highlighted the differences in prognosis observed between CMSs (taking into account gene expression signatures), confirming the clinical relevance of the biological processes implicated in each CMS [34,35]. In light of this, we aimed to investigate the potential impact of CBLL1 as a prognostic marker (measuring OS).…”

Prognostic significance of p16, p21, and Ki67 expression at the invasive front of colorectal cancers

“…The p21-ZEB1 complex inhibits EMT in cultured cells. 28 The gene signature from the colon cancer tissues of p21 loss is associated with Consensus Molecular Subgroup 4 (CMS4), 29 which is characterized by wound response and EMT. 1 These results suggest the p16-high/p21-low cells in the EMT state.…”

CDKN1A/p21 in Breast Cancer: Part of the Problem, or Part of the Solution?

“…MiR-149-3p, a microRNA highly expressed in ovarian cancer patients, promotes EMT, in part by downregulating CDKN1A/p21 expression at both the RNA and protein levels [117]. In addition, loss of CDKN1A/p21 is associated with CMS4 colorectal cancer, an aggressive form of colorectal cancer characterised by the presence of mesenchymal-type cells [118].…”