血液肿瘤患儿MTHFR和ABCB1基因多态性与甲氨蝶呤骨髓抑制的相关性

Correlation between gene polymorphism of MTHFR and ABCB1 and methotrexate myelosuppression in children with hematologic malignancies

目的探究血液肿瘤患儿应用大剂量甲氨蝶呤(HD-MTX)化疗后骨髓抑制与MTHFR和ABCB1基因多态性的相关性,为临床个体化用药提供参考依据。方法选取徐州医科大学附属医院2019-2020年收治的94例接受HD-MTX化疗的患儿,收集外周血,用直接测序法测定MTHFR和ABCB1的基因型,统计患儿化疗前后血常规信息。参照世界卫生组织推荐的化疗药物毒副反应分级标准,将骨髓抑制严重程度分为轻度(0~Ⅱ级)和重度(Ⅲ级以上)。结果94例患儿中,MTHFR C677T位点TT型的构成比为26.60%,CT为44.68%,CC为28.72%,ABCB1 C3435T位点的CC、CT和TT基因型的构成比分别为45.74%,36.17%和18.09%。共有45例(47.87%)患儿发生了Ⅲ级以上甲氨蝶呤相关的骨髓抑制。MTHFR C677T位点为野生型CC的患儿发生Ⅲ级以上骨髓抑制比率低于杂合型CT携带者,差异具有统计学意义(P<0.05)。ABCB13435位点为CC的患儿率发生Ⅲ级以上骨髓抑制的比率显著低于TT型携带者和至少携带1个等位基因T(CT+TT基因型)的患者(P<0.05)。结论MTHFR C677T和ABCB1 C3435T位点的基因多态性与MTX骨髓抑制具有一定程度的相关性。

Objective To investigate the correlation between myelosuppression and MTHFR and ABCB1 gene polymorphism after high-dose methotrexate(HD-MTX)used in children with hematologic malignancies,and to provide a reference for clinical individualized medication.Methods Totally 94 children who received HD-MTX chemotherapy in the Affiliated Hospital of Xuzhou Medical University from 2019 to 2020 were selected.The genotypes of MTHFR and ABCB1 were determined by direct sequencing in peripheral blood,and the information such as blood-routine changes after chemotherapy was recorded.Patients were divided into mild myelosuppression group and severe myelosuppression group according to toxicity standards of the World Health Organization.Results Among 94 children,the frequency of MTHFR C677T polymorphisms was 26.60%for TT,44.68%for CT and 28.72%for CC;ABCB1 C3435T polymorphisms were 45.74%,36.17%and 18.09%for CC,CT and TT,respectively.There were 45 cases(47.87%)which had gradeⅢor higher MTX-myelosuppression.The rate of gradeⅢor higher myelosuppression in patients with wild-type CC of MTHFR C677T genotype was lower than that in heterozygous CT carriers,the difference being statistically significant(P<0.05).The rate of gradeⅢor higher myelosuppression in patients with ABCB13435CC genotype was significantly lower than that in TT and CT+TT(patients with at least one T allele)carriers(P<0.05).Conclusion The gene polymorphism of MTHFR C677T and ABCB1 C3435T is correlated with MTX-myelosuppression to some extent.