title: Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes--a report from the Children's Oncology Group.
abstract: OBJECTIVE
  Carbonyl reductases (CBRs) catalyze reduction of anthracyclines to cardiotoxic alcohol metabolites. Polymorphisms in CBR1 and CBR3 influence synthesis of these metabolites. We examined whether single nucleotide polymorphisms in CBR1 (CBR1 1096G>A) and/or CBR3 (CBR3 V244M) modified the dose-dependent risk of anthracycline-related cardiomyopathy in childhood cancer survivors.
  
  
  METHODS
  One hundred seventy survivors with cardiomyopathy (patient cases) were compared with 317 survivors with no cardiomyopathy (controls; matched on cancer diagnosis, year of diagnosis, length of follow-up, and race/ethnicity) using conditional logistic regression techniques.
  
  
  RESULTS
  A dose-dependent association was observed between cumulative anthracycline exposure and cardiomyopathy risk (0 mg/m(2): reference; 1 to 100 mg/m(2): odds ratio [OR], 1.65; 101 to 150 mg/m(2): OR, 3.85; 151 to 200 mg/m(2): OR, 3.69; 201 to 250 mg/m(2): OR, 7.23; 251 to 300 mg/m(2): OR, 23.47; > 300 mg/m(2): OR, 27.59; P(trend) < .001). Among individuals carrying the variant A allele (CBR1:GA/AA and/or CBR3:GA/AA), exposure to low- to moderate-dose anthracyclines (1 to 250 mg/m(2)) did not increase the risk of cardiomyopathy. Among individuals with CBR3 V244M homozygous G genotypes (CBR3:GG), exposure to low- to moderate-dose anthracyclines increased cardiomyopathy risk when compared with individuals with CBR3:GA/AA genotypes unexposed to anthracyclines (OR, 5.48; P = .003), as well as exposed to low- to moderate-dose anthracyclines (OR, 3.30; P = .006). High-dose anthracyclines (> 250 mg/m(2)) were associated with increased cardiomyopathy risk, irrespective of CBR genotype status.
  
  
  CONCLUSIONS
  This study demonstrates increased anthracycline-related cardiomyopathy risk at doses as low as 101 to 150 mg/m(2). Homozygosis for G allele in CBR3 contributes to increased cardiomyopathy risk associated with low- to moderate-dose anthracyclines, such that there seems to be no safe dose for patients homozygous for the CBR3 V244M G allele. These results suggest a need for targeted intervention for those at increased risk of cardiomyopathy.
authors: The State University of New York at Buffalo, Buffalo, NY, USA.
authors: Javier G
authors: JG
authors: Blanco
authors: Can-Lan
authors: CL
authors: Sun
authors: Wendy
authors: W
authors: Landier
authors: Lu
authors: L
authors: Chen
authors: Diego
authors: D
authors: Esparza-Duran
authors: Wendy
authors: W
authors: Leisenring
authors: Allison
authors: A
authors: Mays
authors: Debra L
authors: DL
authors: Friedman
authors: Jill P
authors: JP
authors: Ginsberg
authors: Melissa M
authors: MM
authors: Hudson
authors: Joseph P
authors: JP
authors: Neglia
authors: Kevin C
authors: KC
authors: Oeffinger
authors: A Kim
authors: AK
authors: Ritchey
authors: Doojduen
authors: D
authors: Villaluna
authors: Mary V
authors: MV
authors: Relling
authors: Smita
authors: S
authors: Bhatia
mesh_terms: D000293:Adolescent; D000367:Age Factors; D000429:Alcohol Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D018943:Anthracyclines / Q000009:adverse effects* / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000378:metabolism; D001711:Biotransformation; D009202:Cardiomyopathies / Q000139:chemically induced / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016015:Logistic Models; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D016017:Odds Ratio; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors; D017741:Survivors; D013997:Time Factors; D014481:United States; D055815:Young Adult
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D000429:Alcohol Oxidoreductases; C531129:CBR1 protein, human; C531130:CBR3 protein, human