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Dysregulated Expression of Three Genes in Colorectal Cancer Stratifies Patients into Three Risk Groups

SIMPLE SUMMARY: The main prognostic factor of sporadic colorectal cancer (sCRC) is marked by the metastatic spread of the primary tumour. Although notable progress has been made in the study of the molecular processes involved, the genomic profile responsible for the aggressiveness of the tumour pro...

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Autores principales: Rodriguez, Alba, Corchete, Luís Antonio, Alcazar, José Antonio, Montero, Juan Carlos, Rodriguez, Marta, Chinchilla-Tábora, Luis Miguel, Vidal Tocino, Rosario, Moyano, Carlos, Muñoz-Bravo, Saray, Sayagués, José María, Abad, Mar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9454483/
https://www.ncbi.nlm.nih.gov/pubmed/36077612
http://dx.doi.org/10.3390/cancers14174076
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author Rodriguez, Alba
Corchete, Luís Antonio
Alcazar, José Antonio
Montero, Juan Carlos
Rodriguez, Marta
Chinchilla-Tábora, Luis Miguel
Vidal Tocino, Rosario
Moyano, Carlos
Muñoz-Bravo, Saray
Sayagués, José María
Abad, Mar
author_facet Rodriguez, Alba
Corchete, Luís Antonio
Alcazar, José Antonio
Montero, Juan Carlos
Rodriguez, Marta
Chinchilla-Tábora, Luis Miguel
Vidal Tocino, Rosario
Moyano, Carlos
Muñoz-Bravo, Saray
Sayagués, José María
Abad, Mar
author_sort Rodriguez, Alba
collection PubMed
description SIMPLE SUMMARY: The main prognostic factor of sporadic colorectal cancer (sCRC) is marked by the metastatic spread of the primary tumour. Although notable progress has been made in the study of the molecular processes involved, the genomic profile responsible for the aggressiveness of the tumour process has not yet been precisely defined. Based on previous gene expression studies, we simultaneously analysed the expression profile of 28 genes, previously associated with tumour aggressiveness and/or metastatic processes, together with a variety of clinical–biological and histopathological characteristics of the disease. This study was carried out with a total of 66 consecutive patients with sCRC with the objective of establishing a prognostic scoring system based on the altered expression of those transcripts that influence overall survival (OS). Here, we show how the altered expression of the ADH1B, BST2, and FER1L4 genes allows patients to be stratified into three risk groups that are directly associated with different 5-year survival rates. ABSTRACT: Despite advances in recent years in the study of the molecular profile of sporadic colorectal cancer (sCRC), the specific genetic events that lead to increased aggressiveness or the development of the metastatic process of tumours are not yet clear. In previous studies of the gene expression profile (GEP) using a high-density array (50,000 genes and 6000 miRNAs in a single assay) in sCRC tumours, we identified a 28-gene signature that was found to be associated with an adverse prognostic value for predicting patient survival. Here, we analyse the differential expression of these 28 genes for their possible association with tumour local aggressiveness and metastatic processes in 66 consecutive sCRC patients, followed for >5 years, using the NanoString nCounter platform. The global transcription profile (expression levels of the 28 genes studied simultaneously) allowed us to discriminate between sCRC tumours and nontumoral colonic tissues. Analysis of the biological and functional significance of the dysregulated GEPs observed in our sCRC tumours revealed 31 significantly altered canonical pathways. Among the most commonly altered pathways, we observed the increased expression of genes involved in signalling pathways and cellular processes, such as the PI3K-Akt pathway, the interaction with the extracellular matrix (ECM), and other functions related to cell signalling processes (SRPX2). From a prognostic viewpoint, the altered expression of BST2 and SRPX2 genes were the only independent variables predicting for disease-free survival (DFS). In addition to the pT stage at diagnosis, dysregulated transcripts of ADH1B, BST2, and FER1L4 genes showed a prognostic impact on OS in the multivariate analysis. Based on the altered expression of these three genes, a scoring system was built to stratify patients into low-, intermediate-, and high-risk groups with significantly different 5-year OS rates: 91%, 83%, and 52%, respectively. The prognostic impact was validated in two independent series of sCRC patients from the public GEO database (n = 562 patients). In summary, we show a strong association between the altered expression of three genes and the clinical outcome of sCRC patients, making them potential markers of suitability for adjuvant therapy after complete tumour resection. Additional prospective studies in larger series of patients are required to confirm the clinical utility of the newly identified biomarkers because the number of patients analysed remains small.
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spelling pubmed-94544832022-09-09 Dysregulated Expression of Three Genes in Colorectal Cancer Stratifies Patients into Three Risk Groups Rodriguez, Alba Corchete, Luís Antonio Alcazar, José Antonio Montero, Juan Carlos Rodriguez, Marta Chinchilla-Tábora, Luis Miguel Vidal Tocino, Rosario Moyano, Carlos Muñoz-Bravo, Saray Sayagués, José María Abad, Mar Cancers (Basel) Article SIMPLE SUMMARY: The main prognostic factor of sporadic colorectal cancer (sCRC) is marked by the metastatic spread of the primary tumour. Although notable progress has been made in the study of the molecular processes involved, the genomic profile responsible for the aggressiveness of the tumour process has not yet been precisely defined. Based on previous gene expression studies, we simultaneously analysed the expression profile of 28 genes, previously associated with tumour aggressiveness and/or metastatic processes, together with a variety of clinical–biological and histopathological characteristics of the disease. This study was carried out with a total of 66 consecutive patients with sCRC with the objective of establishing a prognostic scoring system based on the altered expression of those transcripts that influence overall survival (OS). Here, we show how the altered expression of the ADH1B, BST2, and FER1L4 genes allows patients to be stratified into three risk groups that are directly associated with different 5-year survival rates. ABSTRACT: Despite advances in recent years in the study of the molecular profile of sporadic colorectal cancer (sCRC), the specific genetic events that lead to increased aggressiveness or the development of the metastatic process of tumours are not yet clear. In previous studies of the gene expression profile (GEP) using a high-density array (50,000 genes and 6000 miRNAs in a single assay) in sCRC tumours, we identified a 28-gene signature that was found to be associated with an adverse prognostic value for predicting patient survival. Here, we analyse the differential expression of these 28 genes for their possible association with tumour local aggressiveness and metastatic processes in 66 consecutive sCRC patients, followed for >5 years, using the NanoString nCounter platform. The global transcription profile (expression levels of the 28 genes studied simultaneously) allowed us to discriminate between sCRC tumours and nontumoral colonic tissues. Analysis of the biological and functional significance of the dysregulated GEPs observed in our sCRC tumours revealed 31 significantly altered canonical pathways. Among the most commonly altered pathways, we observed the increased expression of genes involved in signalling pathways and cellular processes, such as the PI3K-Akt pathway, the interaction with the extracellular matrix (ECM), and other functions related to cell signalling processes (SRPX2). From a prognostic viewpoint, the altered expression of BST2 and SRPX2 genes were the only independent variables predicting for disease-free survival (DFS). In addition to the pT stage at diagnosis, dysregulated transcripts of ADH1B, BST2, and FER1L4 genes showed a prognostic impact on OS in the multivariate analysis. Based on the altered expression of these three genes, a scoring system was built to stratify patients into low-, intermediate-, and high-risk groups with significantly different 5-year OS rates: 91%, 83%, and 52%, respectively. The prognostic impact was validated in two independent series of sCRC patients from the public GEO database (n = 562 patients). In summary, we show a strong association between the altered expression of three genes and the clinical outcome of sCRC patients, making them potential markers of suitability for adjuvant therapy after complete tumour resection. Additional prospective studies in larger series of patients are required to confirm the clinical utility of the newly identified biomarkers because the number of patients analysed remains small. MDPI 2022-08-23 /pmc/articles/PMC9454483/ /pubmed/36077612 http://dx.doi.org/10.3390/cancers14174076 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Rodriguez, Alba
Corchete, Luís Antonio
Alcazar, José Antonio
Montero, Juan Carlos
Rodriguez, Marta
Chinchilla-Tábora, Luis Miguel
Vidal Tocino, Rosario
Moyano, Carlos
Muñoz-Bravo, Saray
Sayagués, José María
Abad, Mar
Dysregulated Expression of Three Genes in Colorectal Cancer Stratifies Patients into Three Risk Groups
title Dysregulated Expression of Three Genes in Colorectal Cancer Stratifies Patients into Three Risk Groups
title_full Dysregulated Expression of Three Genes in Colorectal Cancer Stratifies Patients into Three Risk Groups
title_fullStr Dysregulated Expression of Three Genes in Colorectal Cancer Stratifies Patients into Three Risk Groups
title_full_unstemmed Dysregulated Expression of Three Genes in Colorectal Cancer Stratifies Patients into Three Risk Groups
title_short Dysregulated Expression of Three Genes in Colorectal Cancer Stratifies Patients into Three Risk Groups
title_sort dysregulated expression of three genes in colorectal cancer stratifies patients into three risk groups
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9454483/
https://www.ncbi.nlm.nih.gov/pubmed/36077612
http://dx.doi.org/10.3390/cancers14174076
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