A genome-wide association study for doxorubicin-induced cardiomyopathy in childhood cancer survivors from the St. Jude lifetime cohort (SJLIFE) and the childhood cancer survivor (CCSS) studies.

Abstract

12088 Background: Treatment of childhood cancer using doxorubicin is associated with a well-established dose-related risk of cardiomyopathy, which can lead to heart failure and affects ~7-10% of exposed children and adolescents. Here, we identified a genetic variant associated with risk of doxorubicin-induced cardiomyopathy (diCM) in survivors of childhood cancer. Methods: A genome-wide association study using common variants (MAF≥5%; whole-genome sequencing data) was performed among 993 SJLIFE survivors of European ancestry (median age, 36.6 years; range, 8.7-62.2 years) treated with doxorubicin only (210 with diCM; defined as CTCAE grade ≥2 clinically assessed cardiomyopathy). Replication analyses were performed separately among 1,430 CCSS survivors of European ancestry (median age, 35.4 years; range, 15.8-60.7 years) and 159 SJLIFE survivors of African ancestry (median age, 32.6 years; range, 8.9-61.1 years) exposed to doxorubicin only. Analyses were adjusted for age at primary cancer diagnosis, sex, doxorubicin dose, age at last contact and top five principal components. Results: We identified a genome-wide significant association between a novel locus near HS3ST4 and diCM risk in SJLIFE survivors of European ancestry (rs112474856; OR = 2.78; P= 3.3×10-8). This association replicated in CCSS survivors of European ancestry (OR = 1.74, P= 0.036) but had an opposite effect among SJLIFE survivors of African ancestry (OR = 0.34, P= 0.028). SNP rs112474856 did not show significant association with diCM risk in two independent datasets including survivors of European ancestry in SJLIFE (OR = 1.20; P= 0.71) and CCSS (OR = 1.02; P= 0.98) who were not exposed to doxorubicin but were treated with daunorubicin or chest radiotherapy, suggesting doxorubicin specificity. No association was observed between rs112474856 and risks of cardiomyopathy (OR = 1.00; P= 0.88) or heart failure (OR = 1.00; P= 0.59) in 361,194 UK Biobank participants from the general population. HS3ST4 was significantly upregulated ( P= 4.7×10-6) in response to doxorubicin treatment in human induced pluripotent stem-cell-derived cardiomyocytes from patients with diCM. HS3ST4 encodes heparan sulfate, the latter was recently linked to immune activation, cardiac fibrosis, and heart failure. Conclusions: Leveraging the two largest cohorts of childhood cancer survivors in North America, we identified and replicated a novel locus for diCM which was associated with increased risk in survivors of European ancestry but decreased in their African counterpart.