TY - JOUR
T1 - Uncovering tumour heterogeneity through PKR and nc886 analysis in metastatic colon cancer patients treated with 5-FU-based chemotherapy
AU - Ortega-García, María Belén
AU - Mesa, Alberto
AU - Moya, Elisa L.J.
AU - Rueda, Beatriz
AU - Lopez-Ordoño, Gabriel
AU - García, Javier Ángel
AU - Conde, Verónica
AU - Redondo-Cerezo, Eduardo
AU - Lopez-Hidalgo, Javier Luis
AU - Jiménez, Gema
AU - Peran, Macarena
AU - Martínez-González, Luis J.
AU - Val, Coral Del
AU - Zwir, Igor
AU - Marchal, Juan Antonio
AU - García, María Ángel
N1 - Funding Information:
Funding: This research was funded by the Instituto de Salud Carlos III (DTS15/00174; PIE16-00045), by the Consejería de Economía, Conocimiento, Empresas y Universidad de la Junta de Andalucía and European Regional Development Fund (ERDF), references SOMM17/6109/UGR (UCE-PP2017-3) and (PI-0441-2014), and by the Chair “Doctors Galera-Requena in cancer stem cell research” (CMC-CTS963). This research was also funded partially by RTI2018-098983-B-I00.
Funding Information:
This research was funded by the Instituto de Salud Carlos III (DTS15/00174; PIE16-00045), by the Consejer?a de Econom?a, Conocimiento, Empresas y Universidad de la Junta de Andaluc?a and European Regional Development Fund (ERDF), references SOMM17/6109/UGR (UCE-PP2017-3) and (PI-0441-2014), and by the Chair ?Doctors Galera-Requena in cancer stem cell research? (CMC-CTS963). This research was also funded partially by RTI2018-098983-B-I00.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/2
Y1 - 2020/2
N2 - 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.
AB - 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.
KW - 5-fluorouracil-based chemotherapy
KW - Ambispective study
KW - Biomarkers
KW - Cluster of patients
KW - Colorectal cancer
KW - Non-coding nc886
KW - Protein kinase PKR
UR - http://www.scopus.com/inward/record.url?scp=85079173396&partnerID=8YFLogxK
U2 - 10.3390/cancers12020379
DO - 10.3390/cancers12020379
M3 - Article
C2 - 32045987
AN - SCOPUS:85079173396
VL - 12
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 2
M1 - 379
ER -