背景:6-巯基嘌呤(6-MP)是当前抗白血病方案的基石,并有助于改善小儿急性淋巴细胞白血病(ALL)患者的生存率。然而,6-MP剂量相关毒性限制了其应用。TPMT,NUDT15和ITPA是预测6-MP相关毒性的药物遗传学标志物,但是他们的遗传多态性与种族人群不同。在云南省,中国的多民族地区,我们没有预测6-MP毒性的遗传数据.在这项研究中,我们评估了参与6-MP代谢-TPMT*3C的最常见变体(rs1142345),NUDT15c.415C>T(rs116855232),和ITPAc.94C>A(rs1127354)变异-在我们的儿科ALL患者队列中。方法:回顾性研究昆明医科大学附属儿童医院(云南儿童医学中心)2017-2019年149例小儿ALL患者。我们评估了TPMT*3C(rs1142345),NUDT15c.415C>T(rs116855232),和ITPAc.94C>A(rs1127354)频率,并评估基因型和6-MP毒性之间的关联,6-MP剂量,所有患者的无事件生存率(EFS)。结果:TPMT*3C的等位基因频率(rs1142345),NUDT15c.415C>T(rs116855232),ITPAc.94C>A(rs1127354)为1.34%,14.43%,18.79%,分别。只有NUDT15c.415C>T(rs116855232)与6-MP毒性和6-MP耐受剂量密切相关。NUDT15c.415C>T与白细胞减少症有关,p=0.008,OR=2.743(95%CI:1.305-5.768)。T等位基因与6-MP耐受剂量显著相关,NUDT15c.415C>T野生型CC39.80±1.32mg/m2,杂合子CT35.20±2.29mg/m2,纯合子TT18.95±3.95mg/m2。6-MP耐受剂量在CC和TT之间有显著差异,p=0.009。在CC和CT之间,CT和TT,他们没有显着差异。在NUDT15c.415C>T基因型之间,EFS没有显着差异。结论:NUDT15c.415C>T(rs116855232)是云南省小儿ALL患者6-MP毒性和耐受剂量的最佳预测因子。中国的多民族地区,并将在ALL的精确治疗中发挥重要作用。
Background: 6-Mercaptopurine (6-MP) is the cornerstone of current antileukemia regimen and contributes greatly to improve the survival of pediatric acute lymphoblastic leukemia (ALL) patients. However, 6-MP dose-related toxicities limit its application.
TPMT, NUDT15, and ITPA are pharmacogenetic markers predicting 6-MP-related toxicities, but their genetic polymorphisms differ from those of ethnic populations. In Yunnan province, a multiethnic region of
China, we had no genetic data to predict 6-MP toxicities. In this study, we evaluated the most common variants involved in 6-MP metabolism-
TPMT *3C (rs1142345), NUDT15 c.415C>T (rs116855232), and ITPA c.94C>A (rs1127354) variants-in our cohort of pediatric ALL patients. Methods: A total of 149 pediatric ALL patients in the Affiliated Children\'s Hospital of Kunming Medical University (Yunnan Children\'s Medical Center) from 2017 to 2019 were enrolled in this retrospective study. We assessed the TPMT *3C (rs1142345), NUDT15 c.415C>T (rs116855232), and ITPA c.94C>A (rs1127354) frequencies and evaluated association between genotypes and 6-MP toxicities, 6-MP dose, and event-free survival (EFS) in these ALL patients. Results: The allele frequencies of
TPMT *3C (rs1142345), NUDT15 c.415C>T (rs116855232), and ITPA c.94C>A (rs1127354) were 1.34%, 14.43%, and 18.79%, respectively. Only NUDT15 c.415C>T (rs116855232) was strongly associated with 6-MP toxicity and 6-MP tolerable dose. NUDT15 c.415C>T was related to leukopenia, p = 0.008, OR = 2.743 (95% CI: 1.305-5.768). The T allele was significantly correlated with 6-MP tolerable dose, dose of NUDT15 c.415C>T wild genotype CC 39.80 ± 1.32 mg/m2, heterozygotes CT 35.20 ± 2.29 mg/m2, and homozygotes TT 18.95 ± 3.95 mg/m2. 6-MP tolerable dose between CC and TT had a significant difference, p = 0.009. Between CC and CT, and CT and TT, they had no significant difference. EFS showed no significant difference among NUDT15 c.415C>T genotypes. Conclusion: NUDT15 c.415C>T (rs116855232) was an optimal predictor for 6-MP toxicity and tolerable dose in pediatric ALL patients from Yunnan province, a multiethnic region in
China, and would play an important role in precise therapy for ALL.