hiPSCs in cardio-oncology: deciphering the genomics

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.