Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Searle 8-525, 320 East Superior Street, Chicago, IL, USA.
Cardiovasc Res. 2019 Apr 15;115(5):935-948. doi: 10.1093/cvr/cvz018.
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.
几十年来，人们一直推测肿瘤药物引起的心血管毒性存在基因组倾向。直到最近，通过使用患者特异性人诱导多能干细胞（hiPSC）和适当的全基因组关联研究（GWAS），才有可能验证这一假设。确定导致特定药物毒性易感性的个体单核苷酸多态性（SNP）是一项艰巨的任务，因为这排除了使用基因组学中最强大的工具之一：将表型与近亲进行比较，因为这些近亲极不可能使用相同的药物进行治疗。通过使用候选基因关联研究（CGAS）和越来越大的 GWAS 研究，以及体内全器官研究，我们在进一步了解这种毒性的机制方面取得了巨大进展。hiPSC 模型是在此基础上进一步发展的强大技术，可以通过定向基因组编辑（如 CRISPR）识别和验证机制途径中的因果变体。通过这些研究确定的因果变体随后可用于临床，以识别可能经历心血管毒性并指导治疗选择的个体。此外，通过 hiPSC 研究确定的靶点可以为未来的药物开发提供信息。通过仔细的表型特征分析、确定导致基因功能和表达的基因组变体，以及基因组编辑来验证机制途径，hiPSC 技术是药物发现和实现精准医疗的关键工具。
