Determining the genetic basis of anthracycline-cardiotoxicity by molecular response QTL mapping in induced cardiomyocytes.

David A Knowles,Nadine Norton,Yoav Gilad,Courtney K Burrows,Kristen M Patterson,Daniel J Serie,Jonathan K Pritchard,Carole Ober,John D Blischak

doi:10.7554/elife.33480

Abstract

Anthracycline-induced cardiotoxicity (ACT) is a key limiting factor in setting optimal chemotherapy regimes, with almost half of patients expected to develop congestive heart failure given high doses. However, the genetic basis of sensitivity to anthracyclines remains unclear. We created a panel of iPSC-derived cardiomyocytes from 45 individuals and performed RNA-seq after 24 hr exposure to varying doxorubicin dosages. The transcriptomic response is substantial: the majority of genes are differentially expressed and over 6000 genes show evidence of differential splicing, the later driven by reduced splicing fidelity in the presence of doxorubicin. We show that inter-individual variation in transcriptional response is predictive of in vitro cell damage, which in turn is associated with in vivo ACT risk. We detect 447 response-expression quantitative trait loci (QTLs) and 42 response-splicing QTLs, which are enriched in lower ACT GWAS [Formula: see text]-values, supporting the in vivo relevance of our map of genetic regulation of cellular response to anthracyclines.

Highlights

Anthracyclines, including the prototypical doxorubicin, continue to be used as chemotherapeutic agents treating a wide range of cancers, leukemia, lymphoma, multiple myeloma, breast cancer, and sarcoma
For some individuals the expression data following doxorubicin treatment with 1:25M is closer to the data from treatment with 0:625M, whereas for others it is closer to data from treatment with 2:5M
Targets of p53, a transcription factor that responds to DNA damage, are overrepresented in clusters 2 and 5; these clusters involve up-regulation at low concentrations (0:625M) but down-regulation at higher concentrations

Summary

Introduction

Anthracyclines, including the prototypical doxorubicin, continue to be used as chemotherapeutic agents treating a wide range of cancers, leukemia, lymphoma, multiple myeloma, breast cancer, and sarcoma. A well-known side-effect of doxorubicin treatment is anthracycline-induced cardiotoxicity (ACT). For some patients ACT manifests as an asymptomatic reduction in cardiac function, as measured by left ventricular ejection fraction (LVEF), but in more extreme cases ACT can lead to congestive heart failure (CHF). The risk of CHF is dosage-dependent: an early study (Von Hoff et al, 1979) estimated 3% of patients at 400 mg/m2, 7% of patients at 550 mg/m2, and 18% of patients at 700 mg/m2 develop CHF, where a more recent study puts these numbers at 5%, 26% and 48% respectively (Swain et al, 2003). Reduced LVEF shows a similar dosage-dependent pattern, but is not fully predictive of CHF

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