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

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.

Current Status and Trends of Research on Anthracycline-Induced Cardiotoxicity from 2002 to 2021: A Twenty-Year Bibliometric and Visualization Analysis

“…At the same time, RARG agonist treatment has the potential to further protect patients with or without the rs2229774 variant from cardiotoxicity [ 108 , 109 ]. POLRMT, a gene that encodes a mitochondrial DNA-directed RNA polymerase, was discovered as a novel susceptibility gene for the act of breast cancer patients in a genome-wide association study [ 110 ]. Similarly, the multiple genetic variants in the solute carrier family 28 member 3 (SLC28A3) could distinguish child patients with high or low risk for the ACT, and researchers identified the solute carrier (SLC) competitive inhibitor can effectively against ACT [ 111 , 112 ].…”

New Insights in the Era of Clinical Biomarkers as Potential Predictors of Systemic Therapy-Induced Cardiotoxicity in Women with Breast Cancer: A Systematic Review

“…With respect to the genetic factors, the following are currently under investigation with potentially promising outcomes: polymorphisms in p53 (rs1042522) [ 313 , 314 ], NOS3 (rs1799983), NADPH oxidase (rs4673), GPX1 (rs1050450) [ 313 ], RARG [ 37 , 315 ], POLRMT [ 316 ] DPYD [ 317 ] and ABCC1 [ 318 ]. Interestingly, Varkoly et al, 2022 [ 319 ], demonstrated for the first time that circulating RNA virus gene sequences (e.g., influenza orthomyxovirus) were detected in the blood samples of patients with hematological malignancies or breast cancer and were associated with myocarditis and lower LVEF in response to chemotherapy.…”

LINA: A Linearizing Neural Network Architecture for Accurate First-Order and Second-Order Interpretations

“…Model interpretation is important for making biological discoveries from predictive models, because first-order interpretation can identify individual genes involved in a disease [22], [23] and second-order interpretation can uncover epistatic interactions among genes for a disease [24], [25]. These discoveries may provide new drug targets [26]- [28] and enable personalized formulation of treatment plans [29]- [31] for breast cancer.…”