title: Pharmacogenomic prediction of anthracycline-induced cardiotoxicity in children.
abstract: OBJECTIVE
  Anthracycline-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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  We 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.
authors: University of British Columbia, Vancouver, British Columbia.
authors: Henk
authors: H
authors: Visscher
authors: Colin J D
authors: CJ
authors: Ross
authors: S Rod
authors: SR
authors: Rassekh
authors: Amina
authors: A
authors: Barhdadi
authors: Marie-Pierre
authors: MP
authors: Dubé
authors: Hesham
authors: H
authors: Al-Saloos
authors: George S
authors: GS
authors: Sandor
authors: Huib N
authors: HN
authors: Caron
authors: Elvira C
authors: EC
authors: van Dalen
authors: Leontien C
authors: LC
authors: Kremer
authors: Helena J
authors: HJ
authors: van der Pal
authors: Andrew M K
authors: AM
authors: Brown
authors: Paul C
authors: PC
authors: Rogers
authors: Michael S
authors: MS
authors: Phillips
authors: Michael J
authors: MJ
authors: Rieder
authors: Bruce C
authors: BC
authors: Carleton
authors: Michael R
authors: MR
authors: Hayden
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000367:Age Factors; D018943:Anthracyclines / Q000009:adverse effects* / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000378:metabolism; D001711:Biotransformation; D002170:Canada; D002648:Child; D002675:Child, Preschool; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006331:Heart Diseases / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy*; D009426:Netherlands; D016017:Odds Ratio; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D018528:ATP-Binding Cassette Transporters; D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D026901:Membrane Transport Proteins; C065171:cif nucleoside transporter