RARG S427L attenuates the DNA repair response to doxorubicin in induced pluripotent stem cell-derived cardiomyocytes

Huang, Haojun; Christidi, Effimia; Shafaattalab, Sanam; Davis, Margot K.; Tibbits, Glen F.; Brunham, Liam R.

doi:10.1016/j.stemcr.2022.03.002

Cited by 14 publications

(8 citation statements)

References 19 publications

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“…For instance, literature reported that a missense variant rs2229774 in the retinoic acid receptor- γ (RARG) gene is associated with increased susceptibility to ACT. 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 ].…”

Section: Discussionmentioning

confidence: 99%

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

Wang

Rao

Lin

et al. 2022

Oxidative Medicine and Cellular Longevity

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Anthracyclines constitute the cornerstone of numerous chemotherapy regimens for various cancers. However, the clinical application of anthracyclines is significantly limited to their dose-dependent cardiotoxicity. A comprehensive understanding of the current status of anthracycline-induced cardiotoxicity is necessary for in-depth research and optimal clinical protocols. Bibliometric analysis is widely applied in depicting development trends and tracking frontiers of a specific field. The present study is aimed at revealing the status and trends of anthracycline-induced cardiotoxicity during the past two decades by employing bibliometric software including R-bibliometric, VOSviewer, and CiteSpace. A total of 3504 publications concerning anthracycline-induced cardiotoxicity from 2002 to 2021 were collected from the Web of Science Core Collection database. Results showed significant growth in annual yields from 90 records in 2002 to 304 papers in 2021. The United States was the most productive country with the strongest collaboration worldwide in the field. Charles University in the Czech Republic was the institution that contributed the most papers, while 7 of the top 10 productive institutions were from the United States. The United States Department of Health and Human Services and the National Institutes of Health are the two agencies that provide financial support for more than 50% of sponsored publications. The research categories of included publications mainly belong to Oncology and Cardiac Cardiovascular Systems. The Journal of Clinical Oncology had a comprehensive impact on this research field with the highest IF value and many publications. Simunek Tomas from Charles University contributed the most publications, while Lipshultz Steven E. from the State University of New York possessed the highest H -index. In addition, the future research frontiers of anthracycline-induced cardiotoxicity might include early detection, pharmacogenomics, molecular mechanism, and cardiooncology. The present bibliometric analysis may provide a valuable reference for researchers and practitioners in future research directions.

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Section: Discussionmentioning

confidence: 99%

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

Wang

Rao

Lin

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…The effects of the SNP were recapitulated in an iPSC-CM model of DOX toxicity in these individuals (43). Independent genetic manipulation of this susceptibility variant decreases DOX-induced toxicity in iPSC-CMs (58), and does so through the DNA damage response (59). This SNP and gene have therefore been the best characterized cardiotoxicity-associated locus.…”

Section: Discussionmentioning

confidence: 99%

Anthracycline-induced cardiotoxicity associates with a shared gene expression response signature to TOP2-inhibiting breast cancer drugs in cardiomyocytes

Matthews,

Johnson,

Horn

et al. 2023

Preprint

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TOP2 inhibitors (TOP2i) are effective drugs for breast cancer treatment. However, they can cause cardiotoxicity in some women. The most widely used TOP2i include anthracyclines (AC) Doxorubicin (DOX), Daunorubicin (DNR), Epirubicin (EPI), and the anthraquinone Mitoxantrone (MTX). It is unclear whether women would experience the same adverse effects from all drugs in this class, or if specific drugs would be preferable for certain individuals based on their cardiotoxicity risk profile. To investigate this, we studied the effects of treatment of DOX, DNR, EPI, MTX, and an unrelated monoclonal antibody Trastuzumab (TRZ) on iPSC-derived cardiomyocytes (iPSC-CMs) from six healthy females. All TOP2i induce cell death at concentrations observed in cancer patient serum, while TRZ does not. A sub-lethal dose of all TOP2i induces limited cellular stress but affects calcium handling, a function critical for cardiomyocyte contraction. TOP2i induce thousands of gene expression changes over time, giving rise to four distinct gene expression response signatures, denoted as TOP2i early-acute, early-sustained, and late response genes, and non-response genes. TOP2i early response genes are enriched in chromatin regulators, which mediate AC sensitivity across breast cancer patients. However, there is increased transcriptional variability between individuals following AC treatments. To investigate potential genetic effects on response variability, we first identified a reported set of expression quantitative trait loci (eQTLs) uncovered following DOX treatment in iPSC-CMs. Indeed, DOX response eQTLs are enriched in genes that respond to all TOP2i. Next, we identified eight genes in loci associated with AC toxicity by GWAS or TWAS. All eight genes, includingRARGandSLC28A3,respond to at least two ACs, and their expression correlates with the release of cardiotoxicity markers. Our data demonstrate that TOP2i induce thousands of shared gene expression changes in cardiomyocytes, including genes near SNPs associated with inter-individual variation in response to DOX treatment and AC-induced cardiotoxicity.Author summaryAnthracycline drugs such as Doxorubicin are effective treatments for breast cancer; however, they can cause cardiotoxicity in some women. It is unclear whether women would experience the same toxicity for all drugs in this class, or whether specific drugs would be better tolerated in specific individuals. We used anin vitrosystem of induced pluripotent stem cell-derived cardiomyocytes from six healthy females to test the effects of five breast cancer drugs on cell heath and global gene expression. We identified a strong shared cellular and gene expression response to drugs from the same class. However, there is more variation in gene expression levels between individuals following treatment with each anthracycline compared to untreated cells. We found that genes in regions previously associated with Doxorubicin-induced cardiotoxicity in cancer patients, respond to at least two drugs in the class. This suggests that drugs in the same class induce similar effects on an individual’s heart. This work contributes to our understanding of how drug response, in the context of off-target effects, varies across individuals.

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“…The GSE157282 dataset [14] [doxorubicin samples vs. 3 controls samples], which describes the differences in the hiPSC-CMs, was also used as the training set. GSE181517 [15] was used as the validation set to explore the dynamic changes in the critical signature, which included 3 doxorubicin samples and 3 control samples. The scale function in R version 4.2.0 software was used to combine GSE76314 and GSE157282 into one dataset and calibrate the batch using the SVA package [16].…”

Section: Data Acquisition and Homogenizationmentioning

confidence: 99%

Analysis and validation of critical signatures and immune cell infiltration characteristics in doxorubicin-induced cardiotoxicity by integrating bioinformatics and machine learning

Huang,

Pei,

et al. 2023

Preprint

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Doxorubicin-induced cardiotoxicity (DIC) is a severe side reaction in cancer chemotherapy that greatly impacts the well-being of cancer patients. Currently, there is still an insufficiency of effective and reliable biomarkers in the field of clinical practice for the early detection of doxorubicin-induced cardiotoxicity. We obtained high-throughput sequencing data from the Gene Expression Omnibus (GEO) database and performed data analysis and visualization using R software, GO, KEGG and Cytoscape. Machine learning methods and weighted gene coexpression network (WGCNA) were used to identify key genes for diagnostic model construction. Receiver operating characteristic (ROC) analysis and a nomogram were used to assess their diagnostic values. A multiregulatory network was built to reveal the possible regulatory relationships of critical signatures. Cell-cype identification by estimating relative subsets of RNA transcript (CIBERSORT) analysis was used to investigate differential immune cell infiltration. Additionally, a doxorubicin-induced cardiotoxicity cell model was constructed to investigate the relationship between the identified genes and doxorubicin-induced cardiotoxicity. Finally, among the 3713 differentially expressed genes, three hub genes ( CSGALNACT1, ZNF296 and FANCB) were identified. A nomogram and ROC curves based on three hub genes showed excellent diagnostic predictive performance. The regulatory network analysis showed that the TFs CREB1, EP300, FLI1, FOXA1, MAX, and MAZ modulated CSGALNACT1, ZNF296 and FANCB. An analysis of immune cell infiltration indicated that many immune cells (activated NK cells, M0 macrophages, activated dendritic cells and neutrophils) might be related to the progression of DOX-induced cardiotoxicity. Furthermore, there may be various degrees of correlation between the three critical signatures and immune cells. RT‒qPCR in vitro demonstrated that the mRNA expression of CSGALNACT1 and ZNF296 was significantly upregulated, while FANCB was significantly downregulated in doxorubicin-treated cardiomyocytes. Our results suggested that the differential expression of CSGALNACT1, ZNF296 and FANCB is associated with cardiotoxicity and is involved in immune cell infiltration in doxorubicin-induced cardiotoxicity. They might be potential biomarkers for the early occurrence of doxorubicin-induced cardiotoxicity.

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RARG S427L attenuates the DNA repair response to doxorubicin in induced pluripotent stem cell-derived cardiomyocytes

Cited by 14 publications

References 19 publications

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

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

Anthracycline-induced cardiotoxicity associates with a shared gene expression response signature to TOP2-inhibiting breast cancer drugs in cardiomyocytes

Analysis and validation of critical signatures and immune cell infiltration characteristics in doxorubicin-induced cardiotoxicity by integrating bioinformatics and machine learning

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