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A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer

Abstract

Anthracyclines are used in over 50% of childhood cancer treatment protocols1, but their clinical usefulness is limited by anthracycline-induced cardiotoxicity (ACT) manifesting as asymptomatic cardiac dysfunction and congestive heart failure in up to 57% and 16% of patients, respectively2,3. Candidate gene studies have reported genetic associations with ACT4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22, but these studies have in general lacked robust patient numbers, independent replication or functional validation. Thus, the individual variability in ACT susceptibility remains largely unexplained12,13. We performed a genome-wide association study in 280 patients of European ancestry treated for childhood cancer, with independent replication in similarly treated cohorts of 96 European and 80 non-European patients. We identified a nonsynonymous variant (rs2229774, p.Ser427Leu) in RARG highly associated with ACT (P = 5.9 × 10−8, odds ratio (95% confidence interval) = 4.7 (2.7–8.3)). This variant alters RARG function, leading to derepression of the key ACT genetic determinant Top2b, and provides new insight into the pathophysiology of this severe adverse drug reaction.

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Figure 1: A pharmacogenetic association with susceptibility to ACT is situated in RARG.
Figure 2: Functional characterization of RARG Ser427Leu identifies impaired transcriptional regulation.

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Acknowledgements

We acknowledge the participation of all the patients and families who took part in this study across Canada, the Netherlands and the United States. This work was supported by the Canadian Institutes of Health Research (CIHR; FRN-88362 to B.C.C., M.R.H. and C.J.D.R.), the CIHR Drug Safety and Effectiveness Network (FRN-117588 to B.C.C. and C.J.D.R.), the US National Institutes of Health (1R21HL123655-01 and HL123655 to D.B., B.C.C. and C.J.D.R.), a Stanford Comprehensive Cancer Center Translation Research Grant (to D.B.), the Child & Family Research Institute (Vancouver, British Columbia, Canada; Bertram Hoffmeister Postdoctoral Fellowship Award for F.A.), the Michael Smith Foundation for Health Research (Postdoctoral Fellowship Award for F.A.), the CIHR Training Program in Bridging Scientific Domains for Drug Safety and Effectiveness–DSECT program (Postdoctoral Fellowship Award for F.A.), the Canada Foundation for Innovation, Genome British Columbia and the Provincial Health Service Authority. Additional funding was provided by the Child & Family Research Institute (Vancouver, British Columbia, Canada), the Faculty of Medicine of the University of British Columbia, the Canadian Gene Cure Foundation, the C17 Research Network and the Childhood Cancer Foundation–Candlelighters Canada.

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B.C.C., M.R.H. and C.J.D.R. conceived and supervised the study. F.A., H.V., S.R.R., H.N.C., E.C.v.D., L.C.K., H.J.v.d.P., D.B., C.J.D.R., B.C.C. and the CPNDS Consortium enrolled the patients and collected and interpreted clinical data. F.A. conceived the statistical analyses, and F.A., H.V., J.W.L., A.P.B. and C.J.D.R. performed the statistical analyses. A.P.B. conceived the experiments, and A.P.B. and Y.L. performed the experiments. F.A., A.P.B., H.V., S.R.R., J.W.L., L.R.B., U.A., H.N.C., L.C.K., E.C.v.D., H.J.v.d.P., M.J.R., D.B., B.C.C., M.R.H. and C.J.D.R. analyzed and interpreted the data. All authors contributed to the writing, review and approval of the manuscript.

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Correspondence to Colin J D Ross.

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M.R.H., B.C.C., C.J.D.R., F.A., H.V. and A.P.B. have filed provisional patents based on the results of this work (US provisional patents 62/077,702 and 62/135,351).

Integrated supplementary information

Supplementary Figure 1 Study design.

Supplementary Figure 2 GWAS of anthracycline-induced cardiotoxicity in childhood cancer.

(a) Manhattan plot showing the observed distribution of –log10 (P values) against SNP chromosomal localization (GRCH37.p13). P values are for logistic regression analysis (additive model) with adjustment for age, cumulative dose, tumor type (ALL, Ewing’s sarcoma or rhabdomyosarcoma) and radiotherapy. Red line, P = 1.0 × 10–5 (ref.1). (b) Quantile-quantile plot. Quantile-quantile plot showing the distributions of observed –log10 (P values) plotted against expected –log10 (P values) (λGC = 1.021). Smaller P values than would be expected by chance were observed at the tail of the plot. λGC = 1.021 indicates no obvious population stratification.

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Supplementary Figures 1 and 2, and Supplementary Tables 1–7. (PDF 645 kb)

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Aminkeng, F., Bhavsar, A., Visscher, H. et al. A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer. Nat Genet 47, 1079–1084 (2015). https://doi.org/10.1038/ng.3374

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