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Review
. 2019 Apr 15;115(5):935-948.
doi: 10.1093/cvr/cvz018.

hiPSCs in cardio-oncology: deciphering the genomics

Emily A Pinheiro  1   2 , K Ashley Fetterman  1   2 , Paul W Burridge  1   2
Affiliations
Review

hiPSCs in cardio-oncology: deciphering the genomics

Emily A Pinheiro et al. Cardiovasc Res. .

Abstract

The genomic predisposition to oncology-drug-induced cardiovascular toxicity has been postulated for many decades. Only recently has it become possible to experimentally validate this hypothesis via the use of patient-specific human-induced pluripotent stem cells (hiPSCs) and suitably powered genome-wide association studies (GWAS). Identifying the individual single nucleotide polymorphisms (SNPs) responsible for the susceptibility to toxicity from a specific drug is a daunting task as this precludes the use of one of the most powerful tools in genomics: comparing phenotypes to close relatives, as these are highly unlikely to have been treated with the same drug. Great strides have been made through the use of candidate gene association studies (CGAS) and increasingly large GWAS studies, as well as in vivo whole-organism studies to further our mechanistic understanding of this toxicity. The hiPSC model is a powerful technology to build on this work and identify and validate causal variants in mechanistic pathways through directed genomic editing such as CRISPR. The causative variants identified through these studies can then be implemented clinically to identify those likely to experience cardiovascular toxicity and guide treatment options. Additionally, targets identified through hiPSC studies can inform future drug development. Through careful phenotypic characterization, identification of genomic variants that contribute to gene function and expression, and genomic editing to verify mechanistic pathways, hiPSC technology is a critical tool for drug discovery and the realization of precision medicine in cardio-oncology.

Keywords: Cardiotoxicity; Chemotherapy; Pharmacogenomics; Prediction; hiPSC.

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Figures

Figure 1
Figure 1
The role of hiPSCs in genetic biomarker and drug discovery. Blood samples collected from patients of interest can be differentiated into hiPSCs and subsequently differentiated into cardiovascular cell types of interest, such as CMs and ECs. The phenotypic response of these hiPSC derivatives to the drug of interest can be assessed through a variety of assays. Changes in gene expression pre- and post-drug exposure can be analysed with RNA-seq. WGS of DNA extracted from hiPSCs can then be used in combination with the differential transcriptomic data to conduct a differential eQTL analysis. Candidate variants from these studies can then be validated through genomic editing in hiPSCs and re-phenotyping. Validated eQTL variants will establish a foundation for both target identification and genetic biomarker discovery. Genetic biomarkers can be used clinically to screen for patients with a susceptibility to drug-induced CAEs. Identified targets can support drug discovery efforts through drug repurposing, small molecule screens, and in silico screens. Candidate drugs can be tested in vitro to verify that they do not cause CAEs and successful drugs can then be brought to patients through clinical trials.
Figure 2
Figure 2
Workflow for validation of candidate chemotherapy-induced CAE variants. Blood samples from patients treated with a specific chemotherapeutic who did and did not experience a specific CAE are collected. These samples can be used with a SNP chip for CGAS or GWAS studies and differentiated to hiPSCs and hiPSC derivatives to define the CAE phenotype in vitro. Assays can be developed before acquisition of patient samples using generic hiPSC derivatives to define the dose-response curve. Genes with variants identified in GWAS or CGAS should undergo fine mapping, either through sequencing of the gene or imputation, to identify nonsynonymous SNPs that were not assessed by the SNP chip but have potential to be the causal variant. The candidate variants identified through the GWAS/CGAS and subsequent fine mapping can then be tested in vitro. CRISPR/Cas9 technology can be used to knockout and overexpress the entire gene. A phenotypic change at this level validates the involvement of some variant within that gene in the CAE phenotype. If no phenotypic change is observed, it may be necessary to re-evaluate the phenotypic assays to ensure the assay captures the impact of the gene of interest in the mechanism. In some cases, a CRISPR/Cas9 knockout will render cells inviable, in which case an inducible knockout that is activated later in differentiation can be used. The final step is CRISPR/Cas9 editing at the SNP level to identify which SNP in a gene is causal.
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