Possible roles of genetic variations in chemotherapy related cardiotoxicity in pediatric acute lymphoblastic leukemia and osteosarcoma

Judit C. Sági, Bálint Egyed, Andrea Kelemen, Nóra Kutszegi, Márta Hegyi, András Gézsi, Martina Ayaka Herlitschke, Andrea Rzepiel, Lili E. Fodor, Gábor Ottóffy, Gábor T. Kovács, Dániel J. Erdélyi, C. Szalai, Ágnes F. Semsei

Research output: Contribution to journalArticle

Abstract

Background: The treatment of acute lymphoblastic leukemia (ALL) and osteosarcoma (OSC) is very effective: the vast majority of patients recover and survive for decades. However, they still need to face serious adverse effects of chemotherapy. One of these is cardiotoxicity which may lead to progressive heart failure in the long term. Cardiotoxicity is contributed mainly to the use of anthracyclines and might have genetic risk factors. Our goal was to test the association between left ventricular function and genetic variations of candidate genes. Methods: Echocardiography data from medical records of 622 pediatric ALL and 39 OSC patients were collected from the period 1989-2015. Fractional shortening (FS) and ejection fraction (EF) were determined, 70 single nucleotide polymorphisms (SNPs) in 26 genes were genotyped. Multivariate logistic regression and multi-adjusted general linear model were performed to investigate the influence of genetic polymorphisms on the left ventricular parameters. Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA) method was applied to test for the potential interaction of the studied cofactors and SNPs. Results: Our results indicate that variations in ABCC2, CYP3A5, NQO1, SLC22A6 and SLC28A3 genes might influence the left ventricular parameters. CYP3A5 rs4646450 TT was 17% among ALL cases with FS lower than 28, and 3% in ALL patients without pathological FS (p=5.60E-03; OR=6.94 (1.76-27.39)). SLC28A3 rs7853758 AA was 12% in ALL cases population, while only 1% among controls (p=6.50E-03; OR=11.56 (1.98-67.45)). Patients with ABCC2 rs3740066 GG genotype had lower FS during the acute phase of therapy and 5-10years after treatment (p=7.38E-03, p=7.11E-04, respectively). NQO1 rs1043470 rare T allele was associated with lower left ventricular function in the acute phase and 5-10years after the diagnosis (p=4.28E-03 and 5.82E-03, respectively), and SLC22A6 gene rs6591722 AA genotype was associated with lower mean FS (p=1.71E-03), 5-10years after the diagnosis. Conclusions: Genetic variants in transporters and metabolic enzymes might modulate the individual risk to cardiac toxicity after chemotherapy.

Original languageEnglish
Article number704
JournalBMC Cancer
Volume18
Issue number1
DOIs
Publication statusPublished - Jul 3 2018

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Osteosarcoma
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Pediatrics
Drug Therapy
Cytochrome P-450 CYP3A
Left Ventricular Function
Genes
Single Nucleotide Polymorphism
Genotype
Multilevel Analysis
Bayes Theorem
Anthracyclines
Genetic Polymorphisms
Medical Records
Echocardiography
Linear Models
Therapeutics
Heart Failure
Logistic Models
Alleles

Keywords

  • Anthracycline
  • Cancer
  • Cardiotoxicity
  • Childhood cancer
  • Genetic polymorphisms

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research

Cite this

Possible roles of genetic variations in chemotherapy related cardiotoxicity in pediatric acute lymphoblastic leukemia and osteosarcoma. / Sági, Judit C.; Egyed, Bálint; Kelemen, Andrea; Kutszegi, Nóra; Hegyi, Márta; Gézsi, András; Herlitschke, Martina Ayaka; Rzepiel, Andrea; Fodor, Lili E.; Ottóffy, Gábor; Kovács, Gábor T.; Erdélyi, Dániel J.; Szalai, C.; Semsei, Ágnes F.

In: BMC Cancer, Vol. 18, No. 1, 704, 03.07.2018.

Research output: Contribution to journalArticle

Sági, JC, Egyed, B, Kelemen, A, Kutszegi, N, Hegyi, M, Gézsi, A, Herlitschke, MA, Rzepiel, A, Fodor, LE, Ottóffy, G, Kovács, GT, Erdélyi, DJ, Szalai, C & Semsei, ÁF 2018, 'Possible roles of genetic variations in chemotherapy related cardiotoxicity in pediatric acute lymphoblastic leukemia and osteosarcoma', BMC Cancer, vol. 18, no. 1, 704. https://doi.org/10.1186/s12885-018-4629-6
Sági, Judit C. ; Egyed, Bálint ; Kelemen, Andrea ; Kutszegi, Nóra ; Hegyi, Márta ; Gézsi, András ; Herlitschke, Martina Ayaka ; Rzepiel, Andrea ; Fodor, Lili E. ; Ottóffy, Gábor ; Kovács, Gábor T. ; Erdélyi, Dániel J. ; Szalai, C. ; Semsei, Ágnes F. / Possible roles of genetic variations in chemotherapy related cardiotoxicity in pediatric acute lymphoblastic leukemia and osteosarcoma. In: BMC Cancer. 2018 ; Vol. 18, No. 1.
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abstract = "Background: The treatment of acute lymphoblastic leukemia (ALL) and osteosarcoma (OSC) is very effective: the vast majority of patients recover and survive for decades. However, they still need to face serious adverse effects of chemotherapy. One of these is cardiotoxicity which may lead to progressive heart failure in the long term. Cardiotoxicity is contributed mainly to the use of anthracyclines and might have genetic risk factors. Our goal was to test the association between left ventricular function and genetic variations of candidate genes. Methods: Echocardiography data from medical records of 622 pediatric ALL and 39 OSC patients were collected from the period 1989-2015. Fractional shortening (FS) and ejection fraction (EF) were determined, 70 single nucleotide polymorphisms (SNPs) in 26 genes were genotyped. Multivariate logistic regression and multi-adjusted general linear model were performed to investigate the influence of genetic polymorphisms on the left ventricular parameters. Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA) method was applied to test for the potential interaction of the studied cofactors and SNPs. Results: Our results indicate that variations in ABCC2, CYP3A5, NQO1, SLC22A6 and SLC28A3 genes might influence the left ventricular parameters. CYP3A5 rs4646450 TT was 17{\%} among ALL cases with FS lower than 28, and 3{\%} in ALL patients without pathological FS (p=5.60E-03; OR=6.94 (1.76-27.39)). SLC28A3 rs7853758 AA was 12{\%} in ALL cases population, while only 1{\%} among controls (p=6.50E-03; OR=11.56 (1.98-67.45)). Patients with ABCC2 rs3740066 GG genotype had lower FS during the acute phase of therapy and 5-10years after treatment (p=7.38E-03, p=7.11E-04, respectively). NQO1 rs1043470 rare T allele was associated with lower left ventricular function in the acute phase and 5-10years after the diagnosis (p=4.28E-03 and 5.82E-03, respectively), and SLC22A6 gene rs6591722 AA genotype was associated with lower mean FS (p=1.71E-03), 5-10years after the diagnosis. Conclusions: Genetic variants in transporters and metabolic enzymes might modulate the individual risk to cardiac toxicity after chemotherapy.",
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T1 - Possible roles of genetic variations in chemotherapy related cardiotoxicity in pediatric acute lymphoblastic leukemia and osteosarcoma

AU - Sági, Judit C.

AU - Egyed, Bálint

AU - Kelemen, Andrea

AU - Kutszegi, Nóra

AU - Hegyi, Márta

AU - Gézsi, András

AU - Herlitschke, Martina Ayaka

AU - Rzepiel, Andrea

AU - Fodor, Lili E.

AU - Ottóffy, Gábor

AU - Kovács, Gábor T.

AU - Erdélyi, Dániel J.

AU - Szalai, C.

AU - Semsei, Ágnes F.

PY - 2018/7/3

Y1 - 2018/7/3

N2 - Background: The treatment of acute lymphoblastic leukemia (ALL) and osteosarcoma (OSC) is very effective: the vast majority of patients recover and survive for decades. However, they still need to face serious adverse effects of chemotherapy. One of these is cardiotoxicity which may lead to progressive heart failure in the long term. Cardiotoxicity is contributed mainly to the use of anthracyclines and might have genetic risk factors. Our goal was to test the association between left ventricular function and genetic variations of candidate genes. Methods: Echocardiography data from medical records of 622 pediatric ALL and 39 OSC patients were collected from the period 1989-2015. Fractional shortening (FS) and ejection fraction (EF) were determined, 70 single nucleotide polymorphisms (SNPs) in 26 genes were genotyped. Multivariate logistic regression and multi-adjusted general linear model were performed to investigate the influence of genetic polymorphisms on the left ventricular parameters. Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA) method was applied to test for the potential interaction of the studied cofactors and SNPs. Results: Our results indicate that variations in ABCC2, CYP3A5, NQO1, SLC22A6 and SLC28A3 genes might influence the left ventricular parameters. CYP3A5 rs4646450 TT was 17% among ALL cases with FS lower than 28, and 3% in ALL patients without pathological FS (p=5.60E-03; OR=6.94 (1.76-27.39)). SLC28A3 rs7853758 AA was 12% in ALL cases population, while only 1% among controls (p=6.50E-03; OR=11.56 (1.98-67.45)). Patients with ABCC2 rs3740066 GG genotype had lower FS during the acute phase of therapy and 5-10years after treatment (p=7.38E-03, p=7.11E-04, respectively). NQO1 rs1043470 rare T allele was associated with lower left ventricular function in the acute phase and 5-10years after the diagnosis (p=4.28E-03 and 5.82E-03, respectively), and SLC22A6 gene rs6591722 AA genotype was associated with lower mean FS (p=1.71E-03), 5-10years after the diagnosis. Conclusions: Genetic variants in transporters and metabolic enzymes might modulate the individual risk to cardiac toxicity after chemotherapy.

AB - Background: The treatment of acute lymphoblastic leukemia (ALL) and osteosarcoma (OSC) is very effective: the vast majority of patients recover and survive for decades. However, they still need to face serious adverse effects of chemotherapy. One of these is cardiotoxicity which may lead to progressive heart failure in the long term. Cardiotoxicity is contributed mainly to the use of anthracyclines and might have genetic risk factors. Our goal was to test the association between left ventricular function and genetic variations of candidate genes. Methods: Echocardiography data from medical records of 622 pediatric ALL and 39 OSC patients were collected from the period 1989-2015. Fractional shortening (FS) and ejection fraction (EF) were determined, 70 single nucleotide polymorphisms (SNPs) in 26 genes were genotyped. Multivariate logistic regression and multi-adjusted general linear model were performed to investigate the influence of genetic polymorphisms on the left ventricular parameters. Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA) method was applied to test for the potential interaction of the studied cofactors and SNPs. Results: Our results indicate that variations in ABCC2, CYP3A5, NQO1, SLC22A6 and SLC28A3 genes might influence the left ventricular parameters. CYP3A5 rs4646450 TT was 17% among ALL cases with FS lower than 28, and 3% in ALL patients without pathological FS (p=5.60E-03; OR=6.94 (1.76-27.39)). SLC28A3 rs7853758 AA was 12% in ALL cases population, while only 1% among controls (p=6.50E-03; OR=11.56 (1.98-67.45)). Patients with ABCC2 rs3740066 GG genotype had lower FS during the acute phase of therapy and 5-10years after treatment (p=7.38E-03, p=7.11E-04, respectively). NQO1 rs1043470 rare T allele was associated with lower left ventricular function in the acute phase and 5-10years after the diagnosis (p=4.28E-03 and 5.82E-03, respectively), and SLC22A6 gene rs6591722 AA genotype was associated with lower mean FS (p=1.71E-03), 5-10years after the diagnosis. Conclusions: Genetic variants in transporters and metabolic enzymes might modulate the individual risk to cardiac toxicity after chemotherapy.

KW - Anthracycline

KW - Cancer

KW - Cardiotoxicity

KW - Childhood cancer

KW - Genetic polymorphisms

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U2 - 10.1186/s12885-018-4629-6

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M3 - Article

VL - 18

JO - BMC Cancer

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