Abstract

Objective

To evaluate role of molecular (endothelin-1, soluble Fas-L, NT-proBNP, TNF-α, interleukin-1β,) and genetic factors (NOS3 (rs1799983), EDNRA (C + 70G, rs5335), NADPH oxidase (C242T, rs4673), p53 protein (polymorphic marker-Arg72Pro exon 4, rs1042522), NOS3 (Glu298Asp, rs1799983), Caspase 8 (CASP8, rs3834129 and rs1045485), interleukin-1β gene (Il-1β, rs1143634), TNF-α gene (rs1800629), SOD2 (rs4880), GPX1 (rs1050450) in development of anthracycline-induced cardiotoxicity (AIC) in women without cardiovascular diseases.

Methods

A total of 176 women with breast cancer and without cardiovascular diseases who received anthracyclines were enrolled in the study. After the 12 months of chemotherapy (CT), all patients were divided into two groups: group 1 (n = 52) comprised patients with AIC, group 2 (n = 124) comprised those without it.

Results

Based on ROC-analysis, levels of endothelin-1 of ≥9.0 pg/mL (AUC of 0.699), sFas-L of ≥98.3 ng/mL (AUC of 0.990), and NT-proBNP of ≥71.5 pg/mL (AUC of 0.994;) were identified as a cut-off values predicting AIC during 12 months after CT. Whereas, NT-proBNP and sFas-L were more significant predictors than endothelin-1 (p < 0.001). The development of AIC was significantly related to Arg/Arg of p53 protein gene (OR = 2.972; p = 0.001), T/T of NOS3 gene (OR = 3.059, p = 0.018), T/T of NADPH oxidase gene (OR = 2.753, p = 0.008), and C/C of GPX1 (OR = 2.345; p = 0.007).

Conclusion

Evaluation of polymorphisms genes of p53 (rs1042522), NOS3 (rs1799983), GPX1 (rs1050450), and NADPH oxidase (rs4673) can be recommended before CT for the risk assessment of AIC development. The serum levels of NT-proBNP and soluble Fas-L after CT may be considered as non-invasive biomarkers for prediction of AIC development during the 12 months.

中文翻译：

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蒽环类药物对无心血管疾病女性的心脏毒性：分子和遗传预测因子

摘要

客观的

评估分子（内皮素-1、可溶性 Fas-L、NT-proBNP、TNF-α、白介素-1β）和遗传因素（NOS3 (rs1799983)、EDNRA (C + 70G、rs5335)、NADPH 氧化酶 (C242T) 的作用, rs4673), p53 蛋白 (多态性标记-Arg72Pro 外显子 4, rs1042522), NOS3 (Glu298Asp, rs1799983), Caspase 8 (CASP8, rs3834129 and rs1045485), interleukin-1β 基因 (Il-1β, rs1143634), TNF-α 基因(rs1800629)、SOD2 (rs4880)、GPX1 (rs1050450) 在没有心血管疾病的女性中发生蒽环类药物引起的心脏毒性 (AIC)。

方法

共有 176 名接受蒽环类药物治疗的患有乳腺癌但没有心血管疾病的女性参加了这项研究。在 12 个月的化疗 (CT) 后，所有患者被分为两组：第 1 组（n  = 52）包括患有 AIC 的患者，第 2 组（n  = 124）包括没有 AIC 的患者。

结果

基于 ROC 分析，内皮素-1 的水平≥9.0 pg/mL（AUC 为 0.699），sFas-L 的水平≥98.3 ng/mL（AUC 的 0.990），NT-proBNP 的水平≥71.5 pg/mL（AUC 0.994;) 被确定为预测 CT 后 12 个月内 AIC 的截止值。然而，NT-proBNP 和 sFas-L 是比内皮素-1 更重要的预测因子 ( p  < 0.001)。AIC的发生与p53蛋白基因Arg/Arg (OR = 2.972; p  = 0.001)、NOS3基因T/T (OR = 3.059, p  = 0.018)、NADPH氧化酶基因T/T (OR = 2.753，p  = 0.008）和 GPX1 的 C/C（OR = 2.345；p  = 0.007）。

结论

p53 (rs1042522)、NOS3 (rs1799983)、GPX1 (rs1050450) 和 NADPH 氧化酶 (rs4673) 的多态性基因评估可推荐在 CT 前评估 AIC 发展的风险。CT 后 NT-proBNP 和可溶性 Fas-L 的血清水平可被视为预测 12 个月期间 AIC 发展的非侵入性生物标志物。