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POLRMT as a Novel Susceptibility Gene for Cardiotoxicity in Epirubicin Treatment of Breast Cancer Patients

Authors :
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
Source :
Pharmaceutics, Vol 13, Iss 11, p 1942 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

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 POLRMT (OR = 5.76, P = 2.23 × 10−5). We replicated this association in a validation cohort of 123 patients (P = 0.021). This variant regulates the expression of POLRMT, 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 POLRMT 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.

Details

Language :
English
ISSN :
19994923
Volume :
13
Issue :
11
Database :
Directory of Open Access Journals
Journal :
Pharmaceutics
Publication Type :
Academic Journal
Accession number :
edsdoj.fc41170d71e949d6a10cde030ad32cba
Document Type :
article
Full Text :
https://doi.org/10.3390/pharmaceutics13111942