遗传变异在儿童急性淋巴细胞白血病和骨肉瘤化疗相关心脏毒性中的可能作用。
Possible roles of genetic variations in chemotherapy related cardiotoxicity in pediatric acute lymphoblastic leukemia and osteosarcoma.
机构信息
Department of Genetics, Cell- and Immunobiology, Semmelweis University, 1089 Nagyvárad tér 4., 6 em, Budapest, 611, Hungary.
Second Department of Pediatrics, Semmelweis University, Tűzoltó utca 7-9, Budapest, H-1094, Hungary.
出版信息
BMC Cancer. 2018 Jul 3;18(1):704. doi: 10.1186/s12885-018-4629-6.
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 5-10 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.
CONCLUSIONS
Genetic variants in transporters and metabolic enzymes might modulate the individual risk to cardiac toxicity after chemotherapy.
背景
急性淋巴细胞白血病（ALL）和骨肉瘤（OSC）的治疗非常有效：绝大多数患者都能康复并存活数十年。然而，他们仍需面对化疗的严重不良反应。其中之一是心脏毒性，长期可能导致进行性心力衰竭。心脏毒性主要与蒽环类药物的使用有关，可能存在遗传风险因素。我们的目标是检验候选基因的遗传变异与左心室功能之间的相关性。
方法
收集了 1989 年至 2015 年间 622 名儿科 ALL 和 39 名 OSC 患者的病历中的超声心动图数据。确定了分数缩短（FS）和射血分数（EF），对 26 个基因中的 70 个单核苷酸多态性（SNP）进行了基因分型。采用多元逻辑回归和多因素线性模型分析遗传多态性对左心室参数的影响。应用基于贝叶斯网络的贝叶斯多层分析（BN-BMLA）方法检验研究协变量和 SNP 之间的潜在相互作用。
结果
我们的结果表明，ABCC2、CYP3A5、NQO1、SLC22A6 和 SLC28A3 基因的变异可能影响左心室参数。ALL 患者中 CYP3A5 rs4646450 TT 基因型 FS 低于 28 的比例为 17%，而 FS 正常的 ALL 患者中该比例为 3%（p=5.60E-03；OR=6.94（1.76-27.39））。SLC28A3 rs7853758 AA 基因型在 ALL 患者中的比例为 12%，而对照组中的比例为 1%（p=6.50E-03；OR=11.56（1.98-67.45））。ABCC2 rs3740066 GG 基因型的患者在治疗急性期和治疗后 5-10 年内 FS 较低（p=7.38E-03，p=7.11E-04）。NQO1 rs1043470 罕见 T 等位基因与急性期和诊断后 5-10 年内的左心室功能降低相关（p=4.28E-03 和 5.82E-03），SLC22A6 基因 rs6591722 AA 基因型与平均 FS 降低相关（p=1.71E-03），发生在诊断后 5-10 年。
结论
转运体和代谢酶的遗传变异可能调节化疗后心脏毒性的个体风险。
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