<i>POLRMT</i> as a Novel Susceptibility Gene for Cardiotoxicity in Epirubicin Treatment of Breast Cancer Patients

Anthracyclines are among the most used chemotherapeutic agents in breast cancer (BC). However their use is hampered by anthracycline-induced cardiotoxicity (AIC). The currently known clinical and genetic risk factors do not fully explain the observed inter-individual variability and only have a limi...

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Autores principales:	Alejandro Velasco-Ruiz, Rocio Nuñez-Torres, Guillermo Pita, Hans Wildiers, Diether Lambrechts, Sigrid Hatse, Danielle Delombaerde, Thomas Van Brussel, M. Rosario Alonso, Nuria Alvarez, Belen Herraez, Christof Vulsteke, Pilar Zamora, Teresa Lopez-Fernandez, Anna Gonzalez-Neira
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	anthracyclines cardiotoxicity epirubicin breast cancer adverse drug reaction <i>POLRMT</i> Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/fc41170d71e949d6a10cde030ad32cba
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spelling	oai:doaj.org-article:fc41170d71e949d6a10cde030ad32cba2021-11-25T18:42:13Z<i>POLRMT</i> as a Novel Susceptibility Gene for Cardiotoxicity in Epirubicin Treatment of Breast Cancer Patients10.3390/pharmaceutics131119421999-4923https://doaj.org/article/fc41170d71e949d6a10cde030ad32cba2021-11-01T00:00:00Zhttps://www.mdpi.com/1999-4923/13/11/1942https://doaj.org/toc/1999-4923Anthracyclines are among the most used chemotherapeutic agents in breast cancer (BC). However their use is hampered by anthracycline-induced cardiotoxicity (AIC). The currently known clinical and genetic risk factors do not fully explain the observed inter-individual variability and only have a limited ability to predict which patients are more likely to develop this severe toxicity. To identify novel predictive genes, we conducted a two-stage genome-wide association study in epirubicin-treated BC patients. In the discovery phase, we genotyped over 700,000 single nucleotide variants in a cohort of 227 patients. The most interesting finding was rs62134260, located 4kb upstream of <i>POLRMT</i> (OR = 5.76, P = 2.23 × 10<sup>−5</sup>). We replicated this association in a validation cohort of 123 patients (P = 0.021). This variant regulates the expression of <i>POLRMT</i>, a gene that encodes a mitochondrial DNA-directed RNA polymerase, responsible for mitochondrial gene expression. Individuals harbouring the risk allele had a decreased expression of <i>POLRMT</i> in heart tissue that may cause an impaired capacity to maintain a healthy mitochondrial population in cardiomyocytes under stressful conditions, as is treatment with epirubicin. This finding suggests a novel molecular mechanism involved in the development of AIC and may improve our ability to predict patients who are at risk.Alejandro Velasco-RuizRocio Nuñez-TorresGuillermo PitaHans WildiersDiether LambrechtsSigrid HatseDanielle DelombaerdeThomas Van BrusselM. Rosario AlonsoNuria AlvarezBelen HerraezChristof VulstekePilar ZamoraTeresa Lopez-FernandezAnna Gonzalez-NeiraMDPI AGarticleanthracyclinescardiotoxicityepirubicinbreast canceradverse drug reaction<i>POLRMT</i>Pharmacy and materia medicaRS1-441ENPharmaceutics, Vol 13, Iss 1942, p 1942 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	anthracyclines cardiotoxicity epirubicin breast cancer adverse drug reaction <i>POLRMT</i> Pharmacy and materia medica RS1-441
spellingShingle	anthracyclines cardiotoxicity epirubicin breast cancer adverse drug reaction <i>POLRMT</i> Pharmacy and materia medica RS1-441 Alejandro Velasco-Ruiz Rocio Nuñez-Torres Guillermo Pita Hans Wildiers Diether Lambrechts Sigrid Hatse Danielle Delombaerde Thomas Van Brussel M. Rosario Alonso Nuria Alvarez Belen Herraez Christof Vulsteke Pilar Zamora Teresa Lopez-Fernandez Anna Gonzalez-Neira <i>POLRMT</i> as a Novel Susceptibility Gene for Cardiotoxicity in Epirubicin Treatment of Breast Cancer Patients
description	Anthracyclines are among the most used chemotherapeutic agents in breast cancer (BC). However their use is hampered by anthracycline-induced cardiotoxicity (AIC). The currently known clinical and genetic risk factors do not fully explain the observed inter-individual variability and only have a limited ability to predict which patients are more likely to develop this severe toxicity. To identify novel predictive genes, we conducted a two-stage genome-wide association study in epirubicin-treated BC patients. In the discovery phase, we genotyped over 700,000 single nucleotide variants in a cohort of 227 patients. The most interesting finding was rs62134260, located 4kb upstream of <i>POLRMT</i> (OR = 5.76, P = 2.23 × 10<sup>−5</sup>). We replicated this association in a validation cohort of 123 patients (P = 0.021). This variant regulates the expression of <i>POLRMT</i>, a gene that encodes a mitochondrial DNA-directed RNA polymerase, responsible for mitochondrial gene expression. Individuals harbouring the risk allele had a decreased expression of <i>POLRMT</i> in heart tissue that may cause an impaired capacity to maintain a healthy mitochondrial population in cardiomyocytes under stressful conditions, as is treatment with epirubicin. This finding suggests a novel molecular mechanism involved in the development of AIC and may improve our ability to predict patients who are at risk.
format	article
author	Alejandro Velasco-Ruiz Rocio Nuñez-Torres Guillermo Pita Hans Wildiers Diether Lambrechts Sigrid Hatse Danielle Delombaerde Thomas Van Brussel M. Rosario Alonso Nuria Alvarez Belen Herraez Christof Vulsteke Pilar Zamora Teresa Lopez-Fernandez Anna Gonzalez-Neira
author_facet	Alejandro Velasco-Ruiz Rocio Nuñez-Torres Guillermo Pita Hans Wildiers Diether Lambrechts Sigrid Hatse Danielle Delombaerde Thomas Van Brussel M. Rosario Alonso Nuria Alvarez Belen Herraez Christof Vulsteke Pilar Zamora Teresa Lopez-Fernandez Anna Gonzalez-Neira
author_sort	Alejandro Velasco-Ruiz
title	<i>POLRMT</i> as a Novel Susceptibility Gene for Cardiotoxicity in Epirubicin Treatment of Breast Cancer Patients
title_short	<i>POLRMT</i> as a Novel Susceptibility Gene for Cardiotoxicity in Epirubicin Treatment of Breast Cancer Patients
title_full	<i>POLRMT</i> as a Novel Susceptibility Gene for Cardiotoxicity in Epirubicin Treatment of Breast Cancer Patients
title_fullStr	<i>POLRMT</i> as a Novel Susceptibility Gene for Cardiotoxicity in Epirubicin Treatment of Breast Cancer Patients
title_full_unstemmed	<i>POLRMT</i> as a Novel Susceptibility Gene for Cardiotoxicity in Epirubicin Treatment of Breast Cancer Patients
title_sort	<i>polrmt</i> as a novel susceptibility gene for cardiotoxicity in epirubicin treatment of breast cancer patients
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/fc41170d71e949d6a10cde030ad32cba
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<i>POLRMT</i> as a Novel Susceptibility Gene for Cardiotoxicity in Epirubicin Treatment of Breast Cancer Patients

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