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Review
. 2021 Jan;22(1):41-54.
doi: 10.2217/pgs-2020-0104. Epub 2021 Jan 15.

Use of hiPSC to explicate genomic predisposition to anthracycline-induced cardiotoxicity

Tarek Magdy  1   2 , Paul W Burridge  1   2
Affiliations
Review

Use of hiPSC to explicate genomic predisposition to anthracycline-induced cardiotoxicity

Tarek Magdy et al. Pharmacogenomics. 2021 Jan.

Abstract

The anticancer agents of the anthracycline family are commonly associated with the potential to cause severe toxicity to the heart. To solve the question of why particular a patient is predisposed to anthracycline-induced cardiotoxicity (AIC), researchers have conducted numerous pharmacogenomic studies and identified more than 60 loci associated with AIC. To date, none of these identified loci have been developed into US FDA-approved biomarkers for use in routine clinical practice. With advances in the application of human-induced pluripotent stem cell-derived cardiomyocytes, sequencing technologies and genomic editing techniques, variants associated with AIC can now be validated in a human model. Here, we provide a comprehensive overview of known genetic variants associated with AIC from the perspective of how human-induced pluripotent stem cell-derived cardiomyocytes can be used to help better explain the genomic predilection to AIC.

Keywords: cardiomyocyte; cardiotoxicity; genomic editing; human-induced pluripotent stem cells; pharmacogenomics.

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Conflict of interest statement

Financial & competing interests disclosure

This work is funded by Fondation Leducq (http://dx.doi.org/10.13039/501100001674) and the National Cancer Institute (http://dx.doi.org/10.13039/100000054, R01-CA220002). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1.
Figure 1.. Genetic susceptibility of anthracycline-induced cardiotoxicity pharmacokinetic pathway.
Forest plot showing the top significant AIC-associated loci located in anthracyclines pharmacokinetic pathway. AIC: Anthracycline-induced cardiotoxicity; AML: Acute myeloid leukemia; B: Benign; CHOP: Cyclophosphamide, doxorubicin, vincristine and prednisone; D: Damaging; DAN: Daunorubicin; DBA: Doxorubicin-based anthracyclines; DLBCL: Diffuse large B-cell lymphoma; DOX: Doxorubicin; FES: 5-Fluorouracil, epirubicin and cyclophosphamide; HCT: Hematopoietic cell transplantation; MAF: Minor allele frequency; OR: Odds ratio; PP: Polyphen prediction; SP: Sift prediction; T: Tolerable; TFBS: Transcription factor-binding site; SAS: Splice acceptor site.
Figure 2.
Figure 2.. Genetic susceptibility of anthracycline-induced cardiotoxicity pharmacodynamic pathway.
Forest plot showing the top significant AIC-associated loci located in anthracyclines pharmacodynamic pathway. AIC: Anthracycline-induced cardiotoxicity; ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia; B: Benign; CHOP: Cyclophosphamide, doxorubicin, vincristine and prednisone; D: Damaging; DAN: Daunorubicin; DBA: Doxorubicin-based anthracyclines; DLBCL: Diffuse large B-cell lymphoma; DOX: Doxorubicin; FES: 5-Fluorouracil, epirubicin and cyclophosphamide; HCT: Hematopoietic cell transplantation; MAF: Minor allele frequency; MAP: Methotrexate, doxorubicin and cisplatin; NHL: Non-Hodgkin lymphoma; OR: Odds ratio; PP: Polyphen prediction; SP: Sift prediction; T: Tolerable; TFBS: Transcription factor-binding site; SAS: Splice acceptor site.
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