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Article

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

1
Bioinformatics and Functional Genomics Group, Cancer Research Center (CiC-IMBCC, CSIC/USAL/IBSAL), Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca (USAL), 37007 Salamanca, Spain
2
Experimental Tumor Pathology, University Hospital of the Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany
3
Institute of Pathology, University Hospital of the Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany
4
Preclinical Imaging Platform Erlangen (PIPE), Institute of Radiology, University Hospital Erlangen-Nuremberg, 91054 Erlangen, Germany
5
Department of Statistics, University of Salamanca (USAL), 37008 Salamanca, Spain
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Comprehensive Cancer Center-EMN (CCC), University Hospital, Friedrich-Alexander-University of Erlangen-Nüremberg (FAU), 91054 Erlangen, Germany.
§
These authors contributed equally to this work.
Academic Editors: John Souglakos and Serge Roche
Cancers 2022, 14(1), 136; https://doi.org/10.3390/cancers14010136
Received: 22 November 2021 / Revised: 14 December 2021 / Accepted: 20 December 2021 / Published: 28 December 2021
(This article belongs to the Special Issue Molecular Biomarkers in Colorectal Cancer)
A gene signature derived from the loss of CDKN1A (p21) gene, obtained in HCT116 p21-/- colorectal cancer cells, is identified in a large cohort of primary colorectal (CRC) tumors and is associated with the Consensus Molecular Subtype (CMS) of colon cancer that has a worse relapse-free and overall survival, that is, CMS4 (also called mesenchymal subtype). The presented gene signature can help to uncover the early molecular mechanisms of epithelial–mesenchymal transition (EMT), which is known to be associated with high stemness and drug resistance.
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. View Full-Text
Keywords: CDKN1A; consensus molecular subtypes (CMS); colorectal cancer; HCT116 cells; epithelial–mesenchymal transition (EMT); SNAI2; intermediate EMT; CAM model CDKN1A; consensus molecular subtypes (CMS); colorectal cancer; HCT116 cells; epithelial–mesenchymal transition (EMT); SNAI2; intermediate EMT; CAM model
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MDPI and ACS Style

Bueno-Fortes, S.; Muenzner, J.K.; Berral-Gonzalez, A.; Hampel, C.; Lindner, P.; Berninger, A.; Huebner, K.; Kunze, P.; Bäuerle, T.; Erlenbach-Wuensch, K.; Sánchez-Santos, J.M.; Hartmann, A.; De Las Rivas, J.; Schneider-Stock, R. A Gene Signature Derived from the Loss of CDKN1A (p21) Is Associated with CMS4 Colorectal Cancer. Cancers 2022, 14, 136. https://doi.org/10.3390/cancers14010136

AMA Style

Bueno-Fortes S, Muenzner JK, Berral-Gonzalez A, Hampel C, Lindner P, Berninger A, Huebner K, Kunze P, Bäuerle T, Erlenbach-Wuensch K, Sánchez-Santos JM, Hartmann A, De Las Rivas J, Schneider-Stock R. A Gene Signature Derived from the Loss of CDKN1A (p21) Is Associated with CMS4 Colorectal Cancer. Cancers. 2022; 14(1):136. https://doi.org/10.3390/cancers14010136

Chicago/Turabian Style

Bueno-Fortes, Santiago, Julienne K. Muenzner, Alberto Berral-Gonzalez, Chuanpit Hampel, Pablo Lindner, Alexandra Berninger, Kerstin Huebner, Philipp Kunze, Tobias Bäuerle, Katharina Erlenbach-Wuensch, José M. Sánchez-Santos, Arndt Hartmann, Javier De Las Rivas, and Regine Schneider-Stock. 2022. "A Gene Signature Derived from the Loss of CDKN1A (p21) Is Associated with CMS4 Colorectal Cancer" Cancers 14, no. 1: 136. https://doi.org/10.3390/cancers14010136

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