Impact of hemochromatosis gene mutations on cardiac status in doxorubicin-treated survivors of childhood high-risk leukemia

Steven E Lipshultz, Stuart R. Lipsitz, Jeffery L. Kutok, Tracie L Miller, Steven D. Colan, Donna S. Neuberg, Kristen E. Stevenson, Mark D. Fleming, Stephen E. Sallan, Vivian I. Franco, Jacqueline M. Henkel, Barbara L. Asselin, Uma H. Athale, Luis A. Clavell, Bruno Michon, Caroline Laverdiere, Eric Larsen, Kara M. Kelly, Lewis B. Silverman

Research output: Contribution to journalArticle

78 Citations (Scopus)

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. Cancer 2013;119:3555-3562. © 2013 American Cancer Society. Doxorubicin is associated with progressive cardiac dysfunction, possibly by forming doxorubicin-iron complexes leading to free-radical injury. In the current study, doxorubicin-associated myocardial injury was associated with carriers of the C282Y allele, a common allelic variant of hemochromatosis, among long-term survivors of childhood high-risk acute lymphoblastic leukemia.

Original languageEnglish
Pages (from-to)3555-3562
Number of pages8
JournalCancer
Volume119
Issue number19
DOIs
StatePublished - Oct 1 2013

Fingerprint

Hemochromatosis
Doxorubicin
Survivors
Leukemia
Mutation
Wounds and Injuries
Genes
Troponin T
Brain Natriuretic Peptide
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Left Ventricular Function
Free Radicals
Alleles
DNA
Cardiomyopathies
Echocardiography
Neoplasms
Biomarkers
Genotype
Serum

Keywords

  • cardiotoxicity
  • doxorubicin
  • hemochromatosis
  • leukemia
  • pediatrics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Lipshultz, S. E., Lipsitz, S. R., Kutok, J. L., Miller, T. L., Colan, S. D., Neuberg, D. S., ... Silverman, L. B. (2013). Impact of hemochromatosis gene mutations on cardiac status in doxorubicin-treated survivors of childhood high-risk leukemia. Cancer, 119(19), 3555-3562. https://doi.org/10.1002/cncr.28256

Impact of hemochromatosis gene mutations on cardiac status in doxorubicin-treated survivors of childhood high-risk leukemia. / Lipshultz, Steven E; Lipsitz, Stuart R.; Kutok, Jeffery L.; Miller, Tracie L; Colan, Steven D.; Neuberg, Donna S.; Stevenson, Kristen E.; Fleming, Mark D.; Sallan, Stephen E.; Franco, Vivian I.; Henkel, Jacqueline M.; Asselin, Barbara L.; Athale, Uma H.; Clavell, Luis A.; Michon, Bruno; Laverdiere, Caroline; Larsen, Eric; Kelly, Kara M.; Silverman, Lewis B.

In: Cancer, Vol. 119, No. 19, 01.10.2013, p. 3555-3562.

Research output: Contribution to journalArticle

Lipshultz, SE, Lipsitz, SR, Kutok, JL, Miller, TL, Colan, SD, Neuberg, DS, Stevenson, KE, Fleming, MD, Sallan, SE, Franco, VI, Henkel, JM, Asselin, BL, Athale, UH, Clavell, LA, Michon, B, Laverdiere, C, Larsen, E, Kelly, KM & Silverman, LB 2013, 'Impact of hemochromatosis gene mutations on cardiac status in doxorubicin-treated survivors of childhood high-risk leukemia', Cancer, vol. 119, no. 19, pp. 3555-3562. https://doi.org/10.1002/cncr.28256
Lipshultz SE, Lipsitz SR, Kutok JL, Miller TL, Colan SD, Neuberg DS et al. Impact of hemochromatosis gene mutations on cardiac status in doxorubicin-treated survivors of childhood high-risk leukemia. Cancer. 2013 Oct 1;119(19):3555-3562. https://doi.org/10.1002/cncr.28256
Lipshultz, Steven E ; Lipsitz, Stuart R. ; Kutok, Jeffery L. ; Miller, Tracie L ; Colan, Steven D. ; Neuberg, Donna S. ; Stevenson, Kristen E. ; Fleming, Mark D. ; Sallan, Stephen E. ; Franco, Vivian I. ; Henkel, Jacqueline M. ; Asselin, Barbara L. ; Athale, Uma H. ; Clavell, Luis A. ; Michon, Bruno ; Laverdiere, Caroline ; Larsen, Eric ; Kelly, Kara M. ; Silverman, Lewis B. / Impact of hemochromatosis gene mutations on cardiac status in doxorubicin-treated survivors of childhood high-risk leukemia. In: Cancer. 2013 ; Vol. 119, No. 19. pp. 3555-3562.
@article{d43688b7c2a94dfcbd1fe0f00e4fcdc9,
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. Cancer 2013;119:3555-3562. {\circledC} 2013 American Cancer Society. Doxorubicin is associated with progressive cardiac dysfunction, possibly by forming doxorubicin-iron complexes leading to free-radical injury. In the current study, doxorubicin-associated myocardial injury was associated with carriers of the C282Y allele, a common allelic variant of hemochromatosis, among long-term survivors of childhood high-risk acute lymphoblastic leukemia.",
keywords = "cardiotoxicity, doxorubicin, hemochromatosis, leukemia, pediatrics",
author = "Lipshultz, {Steven E} and Lipsitz, {Stuart R.} and Kutok, {Jeffery L.} and Miller, {Tracie L} and Colan, {Steven D.} and Neuberg, {Donna S.} and Stevenson, {Kristen E.} and Fleming, {Mark D.} and Sallan, {Stephen E.} and Franco, {Vivian I.} and Henkel, {Jacqueline M.} and Asselin, {Barbara L.} and Athale, {Uma H.} and Clavell, {Luis A.} and Bruno Michon and Caroline Laverdiere and Eric Larsen and Kelly, {Kara M.} and Silverman, {Lewis B.}",
year = "2013",
month = "10",
day = "1",
doi = "10.1002/cncr.28256",
language = "English",
volume = "119",
pages = "3555--3562",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",
number = "19",

}

TY - JOUR

T1 - Impact of hemochromatosis gene mutations on cardiac status in doxorubicin-treated survivors of childhood high-risk leukemia

AU - Lipshultz, Steven E

AU - Lipsitz, Stuart R.

AU - Kutok, Jeffery L.

AU - Miller, Tracie L

AU - Colan, Steven D.

AU - Neuberg, Donna S.

AU - Stevenson, Kristen E.

AU - Fleming, Mark D.

AU - Sallan, Stephen E.

AU - Franco, Vivian I.

AU - Henkel, Jacqueline M.

AU - Asselin, Barbara L.

AU - Athale, Uma H.

AU - Clavell, Luis A.

AU - Michon, Bruno

AU - Laverdiere, Caroline

AU - Larsen, Eric

AU - Kelly, Kara M.

AU - Silverman, Lewis B.

PY - 2013/10/1

Y1 - 2013/10/1

N2 - 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. Cancer 2013;119:3555-3562. © 2013 American Cancer Society. Doxorubicin is associated with progressive cardiac dysfunction, possibly by forming doxorubicin-iron complexes leading to free-radical injury. In the current study, doxorubicin-associated myocardial injury was associated with carriers of the C282Y allele, a common allelic variant of hemochromatosis, among long-term survivors of childhood high-risk acute lymphoblastic leukemia.

AB - 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. Cancer 2013;119:3555-3562. © 2013 American Cancer Society. Doxorubicin is associated with progressive cardiac dysfunction, possibly by forming doxorubicin-iron complexes leading to free-radical injury. In the current study, doxorubicin-associated myocardial injury was associated with carriers of the C282Y allele, a common allelic variant of hemochromatosis, among long-term survivors of childhood high-risk acute lymphoblastic leukemia.

KW - cardiotoxicity

KW - doxorubicin

KW - hemochromatosis

KW - leukemia

KW - pediatrics

UR - http://www.scopus.com/inward/record.url?scp=84884908105&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84884908105&partnerID=8YFLogxK

U2 - 10.1002/cncr.28256

DO - 10.1002/cncr.28256

M3 - Article

VL - 119

SP - 3555

EP - 3562

JO - Cancer

JF - Cancer

SN - 0008-543X

IS - 19

ER -