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

Abstract

BackgroundThe 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.MethodsEchocardiography 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.ResultsOur 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 5–10 years 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 5–10 years 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), 5–10 years after the diagnosis.ConclusionsGenetic variants in transporters and metabolic enzymes might modulate the individual risk to cardiac toxicity after chemotherapy.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4629-6) contains supplementary material, which is available to authorized users.

Possible Susceptibility Genes for Intervention against Chemotherapy-Induced Cardiotoxicity

“…The results of multivariate analysis showed that the incidence of congestive heart failure (CHF) was higher in patients with pre-HCT chest radiation and with gene variants coding for the NOX subunit RAC2 (rs13058338), HFE (rs1799945), or the DOX efflux transporter ATP-binding cassette subfamily C member 2 (ABCC2, rs8187710) [ 35 , 39 ]. In addition, the polymorphisms of NOX subunits and transporters ABCC1, ABCC2, and SLC28A3 were genotyped in patients with aggressive CD20 B-cell lymphoma [ 40 , 41 ]. The RAC2 subunit genotypes were found to have statistical significance in the multivariate logistic regression analysis.…”

Using Network Pharmacology to Explore Potential Treatment Mechanism for Coronary Heart Disease Using Chuanxiong and Jiangxiang Essential Oils in Jingzhi Guanxin Prescriptions

“…Ko and Shin [65] demonstrated that cardio-sulfa caused aberrant heart development in zebrafish and was activated through the AhR signaling pathway in a CYP1A -independent manner. Research results indicate that variations in the ABCC2 gene might influence the left ventricular parameters [66]. Additionally, AHR is highly correlated with heart defects.…”

Promising genes and variants to reduce chemotherapy adverse effects in acute lymphoblastic leukemia

“…Moreover, it has been observed that SLC28A3 can transport several anthracyclines drugs including doxorubicin into cells, providing a potential mechanism by which these variants could affect ACT. Studies have provided evidence for the association among of rs7853758 (p.Leu461Leu) and rs885004 (Leu248Leu) with ACT [ 40 , 44 ]. The most consistent results were found between the minor allele rs7853758 461Leu with ACT [44] , [45] , [46] , which is also associated and with reduced SLC28A3 mRNA expression in monocytes [47] .…”

“…Studies have provided evidence for the association among of rs7853758 (p.Leu461Leu) and rs885004 (Leu248Leu) with ACT [ 40 , 44 ]. The most consistent results were found between the minor allele rs7853758 461Leu with ACT [44] , [45] , [46] , which is also associated and with reduced SLC28A3 mRNA expression in monocytes [47] . Although scarce evidences regarding the role of this SNP in ALL, there is a recommendation for genetic testing to all patients under anthracyclines treatment to reduce the incidence of ACT [ 40 , 46 ].…”