title: Impact of hemochromatosis gene mutations on cardiac status in doxorubicin-treated survivors of childhood high-risk leukemia.
abstract: BACKGROUND
  Doxorubicin is associated with progressive cardiac dysfunction, possibly through the formation of doxorubicin-iron complexes leading to free-radical injury. The authors determined the frequency of hemochromatosis (HFE) gene mutations associated with hereditary hemochromatosis and their relationship with doxorubicin-associated cardiotoxicity in survivors of childhood high-risk acute lymphoblastic leukemia.
  
  
  METHODS
  Peripheral blood was tested for 2 common HFE allelic variants: C282Y and H63D. Serum cardiac troponin-T (cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP), which are biomarkers of cardiac injury and cardiomyopathy, respectively, were assayed during therapy. Left ventricular (LV) structure and function were assessed with echocardiography.
  
  
  RESULTS
  A total of 184 patients had DNA results for at least 1 variant, and 167 had DNA results for both: 24% carried H63D and 10% carried C282Y. Heterozygous C282Y genotype was associated with multiple elevations in cTnT concentrations (P = .039), but not NT-proBNP. At a median of 2.2 years (range, 1.0 years-3.6 years) after diagnosis, the mean Z-scores for LV fractional shortening (-0.71 [standard error (SE), 0.25]; P = .008), mass (-0.84 [SE, 0.17]; P < .001), and end-systolic (-4.36 [SE, 0.26], P < .001) and end-diastolic (-0.68 [SE, 0.25]; P = .01) posterior wall thickness were found to be abnormal in children with either allele (n = 32). Noncarriers (n = 63) also were found to have below-normal LV mass (-0.45 [SE, 0.15]; P = .006) and end-systolic posterior wall thickness (-4.06 [SE, 0.17]; P < .001). Later follow-up demonstrated similar results.
  
  
  CONCLUSIONS
  Doxorubicin-associated myocardial injury was associated with C282Y HFE carriers. Although LV mass and wall thickness were found to be abnormally low overall, they were even lower in HFE carriers, who also had reduced LV function. Screening newly diagnosed cancer patients for HFE mutations may identify those at risk for doxorubicin-induced cardiotoxicity.
authors.affiliation: Department of Pediatrics, University of Miami Miller School of Medicine, Miami, Florida; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Lipshultz
authors.forename: Stuart R
authors.initials: SR
authors.lastname: Lipsitz
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Tracie L
authors.initials: TL
authors.lastname: Miller
authors.forename: Steven D
authors.initials: SD
authors.lastname: Colan
authors.forename: Donna S
authors.initials: DS
authors.lastname: Neuberg
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Stevenson
authors.forename: Mark D
authors.initials: MD
authors.lastname: Fleming
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sallan
authors.forename: Vivian I
authors.initials: VI
authors.lastname: Franco
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Henkel
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Asselin
authors.forename: Uma H
authors.initials: UH
authors.lastname: Athale
authors.forename: Luis A
authors.initials: LA
authors.lastname: Clavell
authors.forename: Bruno
authors.initials: B
authors.lastname: Michon
authors.forename: Caroline
authors.initials: C
authors.lastname: Laverdiere
authors.forename: Eric
authors.initials: E
authors.lastname: Larsen
authors.forename: Kara M
authors.initials: KM
authors.lastname: Kelly
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Silverman
mesh_terms: D000293:Adolescent; D054715:Cardiotoxins / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects*; D004452:Echocardiography / Q000379:methods; D005260:Female; D005817:Genetic Counseling; D005838:Genotype; D006331:Heart Diseases / Q000139:chemically induced* / Q000235:genetics*; D006432:Hemochromatosis / Q000235:genetics*; D006801:Humans; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D017741:Survivors
chemical_list: D054715:Cardiotoxins; D004317:Doxorubicin
keywords: cardiotoxicity; doxorubicin; hemochromatosis; leukemia; pediatrics