ABCG2基因多态性与小儿急性淋巴细胞白血病大剂量甲氨蝶呤化疗效果及毒性反应的关系

Relationship between ABCG2 gene polymorphism and therapeutic effect of high-dose methotrexate in children with acute lymphoblastic leukemia

目的探讨ABC亚家族G成员2(ABCG2)基因多态性与小儿急性淋巴细胞白血病(ALL)大剂量甲氨蝶呤(MTX)化疗效果及毒性反应的关系。方法选取2012年1月至2018年12月嘉兴市第二医院新诊断的167例ALL患儿为研究对象。采用限制性片段长度多态性PCR法检测患儿ABCG2的2个单核苷酸多态性rs2231137、rs2231142位点的基因分型,比较不同基因型患儿MTX血药浓度、大剂量MTX化疗毒性反应、用药延迟时间、无事件生存率(EFS)等。结果在rs2231137位点,GG基因型87例,AG基因型52例,AA基因型28例;在rs2231142位点,CC基因型115例,CT基因型38例,TT基因型14例。GG与AG+AA基因型患儿巩固治疗期间第48、72 h时MTX血药浓度比较,差异均无统计学意义(均P>0.05);CT+TT基因型患儿巩固治疗期间第48、72 h时MTX血药浓度均高于CC基因型患儿(均P<0.05)。GG、AG、AA基因型患儿大剂量MTX化疗毒性反应比较,差异均无统计学意义(均P>0.05);CT、TT基因型患儿肾功能损伤发生率较CC基因型患儿明显升高(P<0.05),其余大剂量MTX化疗毒性反应各基因型患儿比较,差异均无统计学意义(均P>0.05)。各基因型患儿用药延迟情况比较,差异均无统计学意义(均P>0.05)。GG与AG+AA基因型、CC与CT+TT基因型患儿72个月EFS比较,差异均无统计学意义(均P>0.05)。结论ALL患儿ABCG2的rs2231142位点基因多态性与大剂量MTX化疗毒性反应肾功能损伤相关,但与预后关系不大。

Objective To investigate the relationship of ABCG2 gene polymorphism with therapeutic effect of high-dose methotrexate(MTX)in pediatric patients with acute lymphoblastic leukemia(ALL).Methods A total of 167 children with ALL receiving high-dose MTX chemotherapy in Pediatrics Department of Jiaxing Second Hospital from January 2012 to December 2018 were enrolled.Restriction fragment length polymorphism PCR was used to detect the polymorphisms of ABCG2 gene rs2231137 and rs2231142.The plasma concentration of MTX,toxicity of high-dose MTX,medication delay,and events-free survival(EFS)were compared among patients with different genotypes of ABCG2.Results At rs2231137 locus,there were 87 cases of GG genotype,52 cases of AG genotype and 28 cases of AA genotype.At rs2231142 locus,there were 115 cases of CC genotype,38 cases of CT genotype and 14 cases of TT genotype.There was no statistically significant difference in the blood concentration of MTX in children with rs2231137 GG,AG and AA genotypes at 48 and 72 h during consolidation treatment(both P>0.05).The blood concentration of MTX in children with rs2231142 CT and TT genotypes was higher than that of children with CC genotype at 48 and 72 h during consolidation treatment(all P>0.05).There was no significant difference in high-dose MTX toxicity in children with different rs2231137 genotypes(all P>0.05),while the incidence of renal impairment in children with rs2231142 CT and TT genotypes was significantly higher than that of CC genotypes(P>0.05).There was no significant difference in other toxicity reactions of high-dose MTX among children with different genotypes(all P>0.05).There was no significant difference in the medication delay among children with different rs2231137 and rs2231142 genotypes(all P>0.05).There was no significant difference in the 72-month EFS between rs2231137 GG and AG+AA genotypes and between rs2231142 CC and CT+TT genotypes(all P>0.05).Conclusion The rs2231142 gene polymorphism of ABCG2 in ALL children is associated with the renal function impairment of high-dose MTX chemotherapy,but not associated with prognosis of patients.