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.
Highlights
Anthracyclines, especially doxorubicin (DOX) and epirubicin (EPI), are very effective and widely used chemotherapeutic drugs, alone or in combination regimens [1–3]
To identify novel genetic variants associated with Anthracycline-induced cardiotoxicity (AIC), we conducted a two-stage genome-wide association study (GWAS) in epirubicin-treated breast cancer (BC) patients and addressed the functional significance of our findings
Most of them have not been properly replicated [53–55]. This can be explained by the heterogeneity of the study designs, in which patients of different ages with different cancer types and/or treated with different anthracyclines were combined
Summary
Anthracyclines, especially doxorubicin (DOX) and epirubicin (EPI), are very effective and widely used chemotherapeutic drugs, alone or in combination regimens [1–3]. Ruiz-Pinto et al [11] identified and replicated the missense variant rs7933877 in ETFB, encoding a subunit of the mitochondrial flavoprotein beta, involved in the catabolism of fatty acids and amino acids via electron transfer to the electron transport chain It has been shown in rat models that doxorubicin exerts a downregulation of this gene, which subsequently resulted in a decreased energy production, especially in heart, where the oxidation of fatty acids is the main energy source [11]. These genetic variants are not sufficient to allow an accurate stratification of patients based on their individual genetic risk to develop AIC. To identify novel genetic variants associated with AIC, we conducted a two-stage genome-wide association study (GWAS) in epirubicin-treated BC patients and addressed the functional significance of our findings
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