Polymorphisms of ABCC5 and NOS3 genes influence doxorubicin cardiotoxicity in survivors of childhood acute lymphoblastic leukemia.
Anthracyclines are efficient chemotherapy agents. However, their use is limited by anthracycline-induced cardiotoxicity (CT). We investigated the influence of polymorphisms in doxorubicin metabolic and functional pathways on late-onset CT as estimated by echocardiography in 251 childhood acute lymphoblastic leukemia (cALL) patients. Association analyses revealed a modulating effect of two variants: A-1629 T in ABCC5, an ATP-binding cassette transporter, and G894T in the NOS3 endothelial nitric oxide synthase gene. Individuals with the ABCC5 TT-1629 genotype had an average of 8-12% reduction of ejection (EF) and shortening fractions (SF; EF: P<0.0001, and SF: P=0.001, respectively). A protective effect of the NOS3 TT894 genotype on EF was seen in high-risk patients (P=0.02), especially in those who did not receive dexrazoxane (P=0.002). Analysis of an additional cohort of 44 cALL patients replicated the ABCC5 association but was underpowered for NOS3. In summary, we identified two biomarkers that may contribute to cALL anthracycline CT risk stratification.
CHU Sainte-Justine Research Center, Montreal, QC, Canada.|Department of Pediatrics, University of Montreal, QC, Canada.|Department of Pharmacology, University of Montreal, QC, Canada.
M
M
Krajinovic
CHU Sainte-Justine Research Center, Montreal, QC, Canada.
J
J
Elbared
CHU Sainte-Justine Research Center, Montreal, QC, Canada.
S
S
Drouin
CHU Sainte-Justine Research Center, Montreal, QC, Canada.
L
L
Bertout
CHU Sainte-Justine Research Center, Montreal, QC, Canada.
A
A
Rezgui
CHU Sainte-Justine Research Center, Montreal, QC, Canada.|CANSEARCH Laboratories, Department of Paediatrics, Geneva University Hospital, Geneva, Switzerland.
M
M
Ansari
CHU Sainte-Justine Research Center, Montreal, QC, Canada.
M-J
MJ
Raboisson
Department of Pediatrics, Children's Hospital of Michigan, Wayne State University School of Medicine, Detroit, MI, USA.
S E
SE
Lipshultz
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital, Boston, MA, USA.
L B
LB
Silverman
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
S E
SE
Sallan
Molecular Pathology, Infinity Pharmaceuticals, Cambridge, MA, USA.
D S
DS
Neuberg
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
J L
JL
Kutok
CHU Sainte-Justine Research Center, Montreal, QC, Canada.|Department of Pediatrics, University of Montreal, QC, Canada.
C
C
Laverdière
CHU Sainte-Justine Research Center, Montreal, QC, Canada.|Department of Pediatrics, University of Montreal, QC, Canada.
D
D
Sinnett
CHU Sainte-Justine Research Center, Montreal, QC, Canada.|Department of Pediatrics, University of Montreal, QC, Canada.|Department of Pharmacology, University of Montreal, QC, Canada.
G
G
Andelfinger
D000293:Adolescent; D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D002316:Cardiotonic Agents / Q000627:therapeutic use; D066126:Cardiotoxicity; D002648:Child; D002675:Child, Preschool; D064730:Dexrazoxane / Q000627:therapeutic use; D004317:Doxorubicin / Q000009:adverse effects*; D005260:Female; D020022:Genetic Predisposition to Disease; D006331:Heart Diseases / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics* / Q000517:prevention & control; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D009200:Myocardial Contraction; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000378:metabolism; D010597:Pharmacogenetics; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D065840:Protective Factors; D018570:Risk Assessment; D012307:Risk Factors; D013318:Stroke Volume; D013997:Time Factors; D016896:Treatment Outcome; D016277:Ventricular Function, Left; D055815:Young Adult
D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D064730:Dexrazoxane; D004317:Doxorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D052250:Nitric Oxide Synthase Type III; C120809:ABCC5 protein, human; C496314:NOS3 protein, human