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Article

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

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Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
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Department of Oncology, Virgen de las Nieves University Hospital, 18014 Granada, Spain
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Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research, (CIBM) University of Granada, 18100 Granada, Spain
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Excellence Research Unit “Modelling Nature” (MNat), University of Granada, 18071 Granada, Spain
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Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI Institute), 18014 Granada, Spain
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Department of Pathology, San Cecilio University Hospital, 18016 Granada, Spain
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Department of Gastroenterology, Torrecardenas Hospital, 04009 Almería, Spain
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Department of Gastroenterology, Virgen de las Nieves University Hospital, 18014 Granada, Spain
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Department of Health Sciences, University of Jaén, 23071 Jaen, Spain
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GENYO: Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18007 Granada, Spain
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Department of Computer Science and Artificial Intelligence, University of Granada, 18071 Granada, Spain
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Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, USA
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Department of Human Anatomy and Embryology, University of Granada, 18016 Granada, Spain
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Department of Biochemistry and Molecular Biology III, University of Granada, 18016 Granada, Spain
*
Authors to whom correspondence should be addressed.
Cancers 2020, 12(2), 379; https://doi.org/10.3390/cancers12020379
Received: 15 January 2020 / Revised: 3 February 2020 / Accepted: 4 February 2020 / Published: 7 February 2020
(This article belongs to the Special Issue Non-canonical Kinases and Substrates in Cancer Progression)
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. View Full-Text
Keywords: colorectal cancer; 5-fluorouracil-based chemotherapy; protein kinase PKR; non-coding nc886; ambispective study; cluster of patients; biomarkers colorectal cancer; 5-fluorouracil-based chemotherapy; protein kinase PKR; non-coding nc886; ambispective study; cluster of patients; biomarkers
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MDPI and ACS Style

Ortega-García, M.B.; Mesa, A.; Moya, E.L.J.; Rueda, B.; Lopez-Ordoño, G.; García, J.Á.; Conde, V.; Redondo-Cerezo, E.; Lopez-Hidalgo, J.L.; Jiménez, G.; Peran, M.; Martínez-González, L.J.; del Val, C.; Zwir, I.; Marchal, J.A.; García, M.Á. Uncovering Tumour Heterogeneity through PKR and nc886 Analysis in Metastatic Colon Cancer Patients Treated with 5-FU-Based Chemotherapy. Cancers 2020, 12, 379. https://doi.org/10.3390/cancers12020379

AMA Style

Ortega-García MB, Mesa A, Moya ELJ, Rueda B, Lopez-Ordoño G, García JÁ, Conde V, Redondo-Cerezo E, Lopez-Hidalgo JL, Jiménez G, Peran M, Martínez-González LJ, del Val C, Zwir I, Marchal JA, García MÁ. Uncovering Tumour Heterogeneity through PKR and nc886 Analysis in Metastatic Colon Cancer Patients Treated with 5-FU-Based Chemotherapy. Cancers. 2020; 12(2):379. https://doi.org/10.3390/cancers12020379

Chicago/Turabian Style

Ortega-García, María B., Alberto Mesa, Elisa L.J. Moya, Beatriz Rueda, Gabriel Lopez-Ordoño, Javier Á. García, Verónica Conde, Eduardo Redondo-Cerezo, Javier L. Lopez-Hidalgo, Gema Jiménez, Macarena Peran, Luis J. Martínez-González, Coral del Val, Igor Zwir, Juan A. Marchal, and María Á. García. 2020. "Uncovering Tumour Heterogeneity through PKR and nc886 Analysis in Metastatic Colon Cancer Patients Treated with 5-FU-Based Chemotherapy" Cancers 12, no. 2: 379. https://doi.org/10.3390/cancers12020379

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