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Uncovering Tumour Heterogeneity through PKR and nc886 Analysis in Metastatic Colon Cancer Patients Treated with 5-FU-Based Chemotherapy

Colorectal cancer treatment has advanced over the past decade. The drug 5-fluorouracil is still used with a wide percentage of patients who do not respond. Therefore, a challenge is the identification of predictive biomarkers. The protein kinase R (PKR also called EIF2AK2) and its regulator, the non...

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Autores principales: Ortega-García, María Belén, Mesa, Alberto, Moya, Elisa L.J., Rueda, Beatriz, Lopez-Ordoño, Gabriel, García, Javier Ángel, Conde, Verónica, Redondo-Cerezo, Eduardo, Lopez-Hidalgo, Javier Luis, Jiménez, Gema, Peran, Macarena, Martínez-González, Luis J., del Val, Coral, Zwir, Igor, Marchal, Juan Antonio, García, María Ángel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072376/
https://www.ncbi.nlm.nih.gov/pubmed/32045987
http://dx.doi.org/10.3390/cancers12020379
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author Ortega-García, María Belén
Mesa, Alberto
Moya, Elisa L.J.
Rueda, Beatriz
Lopez-Ordoño, Gabriel
García, Javier Ángel
Conde, Verónica
Redondo-Cerezo, Eduardo
Lopez-Hidalgo, Javier Luis
Jiménez, Gema
Peran, Macarena
Martínez-González, Luis J.
del Val, Coral
Zwir, Igor
Marchal, Juan Antonio
García, María Ángel
author_facet Ortega-García, María Belén
Mesa, Alberto
Moya, Elisa L.J.
Rueda, Beatriz
Lopez-Ordoño, Gabriel
García, Javier Ángel
Conde, Verónica
Redondo-Cerezo, Eduardo
Lopez-Hidalgo, Javier Luis
Jiménez, Gema
Peran, Macarena
Martínez-González, Luis J.
del Val, Coral
Zwir, Igor
Marchal, Juan Antonio
García, María Ángel
author_sort Ortega-García, María Belén
collection PubMed
description Colorectal cancer treatment has advanced over the past decade. The drug 5-fluorouracil is still used with a wide percentage of patients who do not respond. Therefore, a challenge is the identification of predictive biomarkers. The protein kinase R (PKR also called EIF2AK2) and its regulator, the non-coding pre-mir-nc886, have multiple effects on cells in response to numerous types of stress, including chemotherapy. In this work, we performed an ambispective study with 197 metastatic colon cancer patients with unresectable metastases to determine the relative expression levels of both nc886 and PKR by qPCR, as well as the location of PKR by immunohistochemistry in tumour samples and healthy tissues (plasma and colon epithelium). As primary end point, the expression levels were related to the objective response to first-line chemotherapy following the response evaluation criteria in solid tumours (RECIST) and, as the second end point, with survival at 18 and 36 months. Hierarchical agglomerative clustering was performed to accommodate the heterogeneity and complexity of oncological patients’ data. High expression levels of nc886 were related to the response to treatment and allowed to identify clusters of patients. Although the PKR mRNA expression was not associated with chemotherapy response, the absence of PKR location in the nucleolus was correlated with first-line chemotherapy response. Moreover, a relationship between survival and the expression of both PKR and nc886 in healthy tissues was found. Therefore, this work evaluated the best way to analyse the potential biomarkers PKR and nc886 in order to establish clusters of patients depending on the cancer outcomes using algorithms for complex and heterogeneous data.
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spelling pubmed-70723762020-03-19 Uncovering Tumour Heterogeneity through PKR and nc886 Analysis in Metastatic Colon Cancer Patients Treated with 5-FU-Based Chemotherapy Ortega-García, María Belén Mesa, Alberto Moya, Elisa L.J. Rueda, Beatriz Lopez-Ordoño, Gabriel García, Javier Ángel Conde, Verónica Redondo-Cerezo, Eduardo Lopez-Hidalgo, Javier Luis Jiménez, Gema Peran, Macarena Martínez-González, Luis J. del Val, Coral Zwir, Igor Marchal, Juan Antonio García, María Ángel Cancers (Basel) Article Colorectal cancer treatment has advanced over the past decade. The drug 5-fluorouracil is still used with a wide percentage of patients who do not respond. Therefore, a challenge is the identification of predictive biomarkers. The protein kinase R (PKR also called EIF2AK2) and its regulator, the non-coding pre-mir-nc886, have multiple effects on cells in response to numerous types of stress, including chemotherapy. In this work, we performed an ambispective study with 197 metastatic colon cancer patients with unresectable metastases to determine the relative expression levels of both nc886 and PKR by qPCR, as well as the location of PKR by immunohistochemistry in tumour samples and healthy tissues (plasma and colon epithelium). As primary end point, the expression levels were related to the objective response to first-line chemotherapy following the response evaluation criteria in solid tumours (RECIST) and, as the second end point, with survival at 18 and 36 months. Hierarchical agglomerative clustering was performed to accommodate the heterogeneity and complexity of oncological patients’ data. High expression levels of nc886 were related to the response to treatment and allowed to identify clusters of patients. Although the PKR mRNA expression was not associated with chemotherapy response, the absence of PKR location in the nucleolus was correlated with first-line chemotherapy response. Moreover, a relationship between survival and the expression of both PKR and nc886 in healthy tissues was found. Therefore, this work evaluated the best way to analyse the potential biomarkers PKR and nc886 in order to establish clusters of patients depending on the cancer outcomes using algorithms for complex and heterogeneous data. MDPI 2020-02-07 /pmc/articles/PMC7072376/ /pubmed/32045987 http://dx.doi.org/10.3390/cancers12020379 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ortega-García, María Belén
Mesa, Alberto
Moya, Elisa L.J.
Rueda, Beatriz
Lopez-Ordoño, Gabriel
García, Javier Ángel
Conde, Verónica
Redondo-Cerezo, Eduardo
Lopez-Hidalgo, Javier Luis
Jiménez, Gema
Peran, Macarena
Martínez-González, Luis J.
del Val, Coral
Zwir, Igor
Marchal, Juan Antonio
García, María Ángel
Uncovering Tumour Heterogeneity through PKR and nc886 Analysis in Metastatic Colon Cancer Patients Treated with 5-FU-Based Chemotherapy
title Uncovering Tumour Heterogeneity through PKR and nc886 Analysis in Metastatic Colon Cancer Patients Treated with 5-FU-Based Chemotherapy
title_full Uncovering Tumour Heterogeneity through PKR and nc886 Analysis in Metastatic Colon Cancer Patients Treated with 5-FU-Based Chemotherapy
title_fullStr Uncovering Tumour Heterogeneity through PKR and nc886 Analysis in Metastatic Colon Cancer Patients Treated with 5-FU-Based Chemotherapy
title_full_unstemmed Uncovering Tumour Heterogeneity through PKR and nc886 Analysis in Metastatic Colon Cancer Patients Treated with 5-FU-Based Chemotherapy
title_short Uncovering Tumour Heterogeneity through PKR and nc886 Analysis in Metastatic Colon Cancer Patients Treated with 5-FU-Based Chemotherapy
title_sort uncovering tumour heterogeneity through pkr and nc886 analysis in metastatic colon cancer patients treated with 5-fu-based chemotherapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072376/
https://www.ncbi.nlm.nih.gov/pubmed/32045987
http://dx.doi.org/10.3390/cancers12020379
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