Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China.
Shandong University, Jinan, 250100, Shandong Province, China.
Eur J Pediatr. 2024 Feb;183(2):581-590. doi: 10.1007/s00431-023-05267-8. Epub 2023 Oct 18.
This study aims to assess the role of methotrexate-related gene polymorphisms in children with acute lymphoblastic leukemia (ALL) during high-dose methotrexate (HD-MTX) therapy and to explore their effects on serum metabolites before and after HD-MTX treatment. The MTHFR 677C>T, MTHFR 1298A>C, ABCB1 3435C>T, and GSTP1 313A>G genotypes of 189 children with ALL who received chemotherapy with the CCCG-ALL-2020 regimen from January 2020 to April 2023 were analyzed, and toxic effects were reported according to the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). Fasting peripheral blood serum samples were collected from 27 children before and after HD-MTX treatment, and plasma metabolites were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS). The results of univariate and multivariate analyses showed that MTHFR 677C>T and ABCB1 3435 C>T gene polymorphisms were associated with the delayed MTX clearance (P < 0.05) and lower platelet count after treatment in children with MTHFR 677 mutation compared with wild-type ones (P < 0.05), and pure mutations in ABCB1 3435 were associated with higher serum creatinine levels (P < 0.05). No significant association was identified between MTHFR 677C>T, MTHFR 1298A>C, ABCB1 3435 C>T, and GSTP1 313A>G genes and hepatotoxicity or nephrotoxicity (P > 0.05). However, the serum metabolomic analysis indicated that the presence of the MTHFR 677C > T gene polymorphism could potentially contribute to delayed MTX clearance by influencing L-phenylalanine metabolism, leading to the occurrence of related toxic side effects.
MTHFR 677C>T and ABCB1 3435 C>T predicted the risk of delayed MTX clearance during HD-MTX treatment in children with ALL. Serum L-phenylalanine levels were significantly elevated after HD-MTX treatment in children with the MTHFR 677C>T mutation gene.
This study was registered at the Chinese Clinical Trial Registry (registration number: ChiCTR2000035264; registration: 2020/08/05; https://www.chictr.org.cn/ ).
• MTX-related genes play an important role in MTX pharmacokinetics and toxicity, but results from different studies are inconsistent and the mechanisms involved are not clear.
• Characteristics, prognosis, polymorphisms of MTX-related genes, and metabolite changes were comprehensively evaluated in children treated with HD-MTX chemotherapy. • Analysis revealed that both heterozygous and pure mutations in MTHFR 677C>T resulted in a significantly increased risk of delayed MTX clearance, and that L-phenylalanine has the potential to serve as a predictive marker for the metabolic effects of the MTHFR 677C>T polymorphism.
评估甲氨蝶呤相关基因多态性在儿童急性淋巴细胞白血病（ALL）接受大剂量甲氨蝶呤（HD-MTX）治疗期间的作用，并探讨其对 HD-MTX 治疗前后血清代谢物的影响。
分析了 2020 年 1 月至 2023 年 4 月期间采用 CCCG-ALL-2020 方案化疗的 189 例 ALL 患儿的 MTHFR 677C>T、MTHFR 1298A>C、ABCB1 3435C>T 和 GSTP1 313A>G 基因型，并根据不良事件通用术语标准（CTCAE，版本 5.0）报告毒性作用。在 HD-MTX 治疗前后采集 27 例儿童的空腹外周血血清样本，采用液相色谱-串联质谱法（LC-MS）分析血浆代谢物。单因素和多因素分析结果显示，与野生型相比，MTHFR 677C>T 和 ABCB1 3435C>T 基因突变与 MTHFR 677 突变患儿 MTX 清除延迟（P<0.05）和治疗后血小板计数降低有关（P<0.05），纯 ABCB1 3435 突变与血清肌酐水平升高有关（P<0.05）。未发现 MTHFR 677C>T、MTHFR 1298A>C、ABCB1 3435C>T 和 GSTP1 313A>G 基因与肝毒性或肾毒性之间存在显著相关性（P>0.05）。然而，血清代谢组学分析表明，MTHFR 677C>T 基因多态性可能通过影响 L-苯丙氨酸代谢导致 MTX 清除延迟，从而导致相关毒性副作用的发生。
MTHFR 677C>T 和 ABCB1 3435C>T 预测了 ALL 患儿接受 HD-MTX 治疗期间 MTX 清除延迟的风险。MTHFR 677C>T 基因突变患儿接受 HD-MTX 治疗后，血清 L-苯丙氨酸水平显著升高。
本研究在中国临床试验注册中心（注册号：ChiCTR2000035264；注册日期：2020/08/05；https://www.chictr.org.cn/ ）进行了注册。
• MTX 相关基因在 MTX 药代动力学和毒性中起重要作用，但来自不同研究的结果不一致，其涉及的机制尚不清楚。
• 全面评估了接受 HD-MTX 化疗的儿童的 MTX 相关基因特征、预后、多态性和代谢物变化。• 分析表明，MTHFR 677C>T 杂合和纯合突变均显著增加 MTX 清除延迟的风险，L-苯丙氨酸有可能成为 MTHFR 677C>T 多态性代谢影响的预测标志物。
