Pharmacogenomic Prediction of Anthracycline-Induced Cardiotoxicity in Children by Visscher Henk, Ross Colin J D, Rassekh S Rod, Barhdadi Amina, Dubé Marie-Pierre, Al-Saloos Hesham, Sandor George S, Caron Huib N, van Dalen Elvira C, Kremer Leontien C, van der Pal Helena J, Brown Andrew M K, Rogers Paul C, Phillips Michael S, Rieder Michael J, Carleton Bruce C, Hayden Michael R, Canadian Pharmacogenomics Network for Drug Safety Consortium in Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2011). PubMed

Abstract

PURPOSEAnthracycline-induced cardiotoxicity (ACT) is a serious adverse drug reaction limiting anthracycline use and causing substantial morbidity and mortality. Our aim was to identify genetic variants associated with ACT in patients treated for childhood cancer. PATIENTS AND METHODSWe carried out a study of 2,977 single-nucleotide polymorphisms (SNPs) in 220 key drug biotransformation genes in a discovery cohort of 156 anthracycline-treated children from British Columbia, with replication in a second cohort of 188 children from across Canada and further replication of the top SNP in a third cohort of 96 patients from Amsterdam, the Netherlands.ResultsWe identified a highly significant association of a synonymous coding variant rs7853758 (L461L) within the SLC28A3 gene with ACT (odds ratio, 0.35; P = 1.8 × 10(-5) for all cohorts combined). Additional associations (P < .01) with risk and protective variants in other genes including SLC28A1 and several adenosine triphosphate-binding cassette transporters (ABCB1, ABCB4, and ABCC1) were present. We further explored combining multiple variants into a single-prediction model together with clinical risk factors and classification of patients into three risk groups. In the high-risk group, 75% of patients were accurately predicted to develop ACT, with 36% developing this within the first year alone, whereas in the low-risk group, 96% of patients were accurately predicted not to develop ACT. CONCLUSIONWe have identified multiple genetic variants in SLC28A3 and other genes associated with ACT. Combined with clinical risk factors, genetic risk profiling might be used to identify high-risk patients who can then be provided with safer treatment options.

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