Abstract
Anthracycline-based chemotherapy is associated with dose-dependent, irreversible damage to the heart. Childhood cancer survivors with hypertension after anthracycline exposure are at increased risk of cardiotoxicity, leading to the hypothesis that genetic susceptibility loci for hypertension may serve as predictors for development of late cardiotoxicity. Therefore, we determined the association between 12 GWAS-identified hypertension-susceptibility loci and cardiotoxicity in a cohort of long-term childhood cancer survivors (N = 108) who received anthracyclines and were screened for cardiac function via echocardiograms. Hypertension-susceptibility alleles of PLCE1:rs9327264 and ATP2B1:rs17249754 were significantly associated with cardiotoxicity risk conferring a protective effect with a 64% (95% CI: 0.18–0.76, P = 0.0068) and 74% (95% CI: 0.07–0.96, P = 0.040) reduction in risk, respectively. In RNAseq experiments of human induced pluripotent stem cell (iPSC) derived cardiomyocytes treated with doxorubicin, both PLCE1 and ATP2B1 displayed anthracycline-dependent gene expression profiles. In silico functional assessment further supported this relationship - rs9327264 in PLCE1 (P = 0.0080) and ATP2B1 expression (P = 0.0079) were both significantly associated with daunorubicin IC50 values in a panel of lymphoblastoid cell lines. Our findings demonstrate that the hypertension-susceptibility variants in PLCE1 and ATP2B1 confer a protective effect on risk of developing anthracycline-related cardiotoxicity, and functional analyses suggest that these genes are influenced by exposure to anthracyclines.
Highlights
There has been tremendous success over the past 40 years in the treatment of childhood cancers that has resulted in a dramatic shift in the 5-year survival rate for these patients, from less than 60% in the 1970s to over 80% in more recent reports[1]
More of the cases were diagnosed with hypertension during follow-up compared to controls (59% vs. 35%, P = 0.017) and a diagnosis of hypertension was associated with a 2.58-fold increased risk of cardiotoxicity
This increased risk of cardiotoxicity underscores the importance of increased understanding of the predictors of late-effects and the underlying mechanisms
Summary
There has been tremendous success over the past 40 years in the treatment of childhood cancers that has resulted in a dramatic shift in the 5-year survival rate for these patients, from less than 60% in the 1970s to over 80% in more recent reports[1]. It is clear that a number of survivors develop clinical cardiovascular side effects at current recommended dosing, with a much higher proportion exhibiting subclinical cardiotoxicity[3, 4] This underscores the need for predictive biomarkers to enable identification of those at high risk who would be candidates for alternative therapeutic regimens and/or cardioprotective interventions, as well as to guide the design of risk-stratified, cost-effective follow-up surveillance programs to reduce the adverse effects of anthracyclines on the heart. To identify predictors of anthracycline-induced cardiotoxicity, we genotyped a cohort of long-term childhood cancer survivors for these loci They had all been treated with anthracyclines and were followed for a median of 15.8 years with echocardiogram-based screening according to COG guidelines. The genetic association findings were followed up with analysis of gene expression in iPSC-cardiomyocytes exposed to anthracyclines and in silico functional assessment
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