Deciphering the Genomics of Cardiotoxicity in Cardio-oncology

A new paper in Cardiovascular Research looks at genomic predisposition to oncology-drug-induced cardiotoxicity, which has been hinted at for decades but not rigorously explored.

It has only recently become possible to assess and validate the experimental hypothesis of potential genetic predisposition to cardiomyopathy from cancer drugs through the development of adequately powered genome-wide association studies (GWAS) and the use of human-inducted pluripotent stem cells (hsPSCs), according to the paper. The authors also said that the identification of single nucleotide polymorphisms (SNPs) that are specifically responsible for a susceptibility to toxicity from a specific drug is a difficult, but that “great strides” have also been made with the use of gene association studies, larger GWAS, and in vivo whole-organism studies.

The researchers also laid out a number of pharmacogenomic factors in chemotherapy-induced cardiac adverse events as uncovered through relevant gene association studies and GWAS, such as a discussion of variants associated with anthracycline-induced cardiotoxicity, HER2 inhibitor trastuzumab-induced cardiotoxicity, thalidomide-induced venous thromboembolysm, and vascular endothelial growth factor signalling pathway inhibitor-induced cardiotoxicity.

Harnessing hiPSC and CRISPR

They also made mention of the importance and relative power of new hiPSC technology, which they wrote “is uniquely suited to investigating the pharmacogenomics of chemotherapy-induced adverse cardiovascular effects by providing “a model with which to identify potential toxicities, examining the mechanism of toxicities, and identify and validate genetic determinants of susceptibility to toxicities.”

The authors also worked to define adverse effect phenotype in vitro, and investigation the mechanisms of cardiovascular adverse effects using hiPSCs. One area of interest getting recent attention in the area of genetic manipulation of hiPSCs is a widely-accepted genetic editing technique in basic science research known as clustered regularly interspaced short palindromic repeats (CRISPR), which “involves DNA cleavage CRISPR associated eneyme 9 (Cas9) and a guide RNA (gRNA) that directs Cas9 to the appropriate genome location,” the authors wrote. The noted that the CRISPR/Cas9 technique for genome editing has been “widely adopete due to its ease of use and high specificity.”

The researchers concluded by reiterating the concern for a need to address chemotherapy-induced cardiac adverse events, which they said are a “common and growing concern” for both cancer patients and their care providers.

“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,” they wrote in their conclusion.

human-induced pluripotent stem cells (hiPSCs) in cardio-oncology: deciphering the genomics https://t.co/dckzT6EcJz @ICOSociety @EuroCardioOnc

— R.R. Baliga, MD (@OSUCardioOnc) March 8, 2019

How can #hiPSC models inform #clinical recommendations and drug discovery in #CardioOncology? Identifying #genetic variants arising in #CAEs and mechanisms of drug-induced #toxicity
More: https://t.co/IeATBBG2qU@ESC_Journals @escardio @pwburridge #CRISPR #CardiovascularResearch pic.twitter.com/vNQZ1szCS8

— CVR Tomasz Guzik (@CVR_TomaszGuzik) April 23, 2019

How can #hiPSC models inform #clinical recommendations and drug discovery in #CardioOncology? Identifying #genetic variants arising in #CAEs and mechanisms of drug-induced #toxicity
More: https://t.co/IeATBBG2qU@ESC_Journals @escardio @pwburridge #CRISPR #CardiovascularResearch pic.twitter.com/vNQZ1szCS8

— CVR Tomasz Guzik (@CVR_TomaszGuzik) April 23, 2019