Mao Xiaoyan, Yin Runxiu, Sun Gaoyuan, Zhou Yan, Yang Chunhui, Fang Chunlian, Wu Yuhong, Cui Tingting, Liu Li, Gan Jiaxin, Tian Xin
Department of Hematology, The Affiliated Children's Hospital of Kunming Medical University, Kunming Medical University, Kunming, China.
Department of Pediatrics, Sichuan Clinical Research Center for Birth Defects, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
Front Pediatr. 2021 Oct 1;9:719803. doi: 10.3389/fped.2021.719803. eCollection 2021.
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. , and 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- 3C (rs1142345), c.415C>T (rs116855232), and c.94C>A (rs1127354) variants-in our cohort of pediatric ALL patients. 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 3C (rs1142345), c.415C>T (rs116855232), and 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. The allele frequencies of 3C (rs1142345), c.415C>T (rs116855232), and c.94C>A (rs1127354) were 1.34%, 14.43%, and 18.79%, respectively. Only c.415C>T (rs116855232) was strongly associated with 6-MP toxicity and 6-MP tolerable dose. c.415C>T was related to leukopenia, = 0.008, OR = 2.743 (95% CI: 1.305-5.768). The T allele was significantly correlated with 6-MP tolerable dose, dose of c.415C>T wild genotype CC 39.80 ± 1.32 mg/m, heterozygotes CT 35.20 ± 2.29 mg/m, and homozygotes TT 18.95 ± 3.95 mg/m. 6-MP tolerable dose between CC and TT had a significant difference, = 0.009. Between CC and CT, and CT and TT, they had no significant difference. EFS showed no significant difference among c.415C>T genotypes. 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.
6-巯基嘌呤（6-MP）是当前抗白血病治疗方案的基石，对提高儿童急性淋巴细胞白血病（ALL）患者的生存率有很大贡献。然而，6-MP的剂量相关毒性限制了其应用。 、 和 是预测6-MP相关毒性的药物遗传学标志物，但它们的基因多态性在不同种族人群中有所不同。在中国的多民族地区云南省，我们没有可用于预测6-MP毒性的基因数据。在本研究中，我们评估了参与6-MP代谢的最常见变异—— 3C（rs1142345）、 c.415C>T（rs116855232）和 c.94C>A（rs1127354）变异——在我们的儿童ALL患者队列中的情况。2017年至2019年期间，昆明医科大学附属儿童医院（云南省儿童医学中心）的149例儿童ALL患者被纳入这项回顾性研究。我们评估了 3C（rs1142345）、 c.415C>T（rs116855232）和 c.94C>A（rs1127354）的频率，并评估了这些ALL患者的基因型与6-MP毒性、6-MP剂量及无事件生存期（EFS）之间的关联。 3C（rs1142345）、 c.415C>T（rs116855232）和 c.94C>A（rs1127354）的等位基因频率分别为1.34%、14.43%和18.79%。只有 c.415C>T（rs116855232）与6-MP毒性和6-MP可耐受剂量密切相关。c.415C>T与白细胞减少有关， = 0.008，OR = 2.743（95%CI：1.305 - 5.768）。T等位基因与6-MP可耐受剂量显著相关，c.415C>T野生基因型CC的剂量为39.80±1.32mg/m，杂合子CT为35.20±2.29mg/m，纯合子TT为18.95±3.95mg/m。CC和TT之间的6-MP可耐受剂量有显著差异， = 0.009。CC和CT之间以及CT和TT之间没有显著差异。EFS在c.415C>T基因型之间没有显著差异。c.415C>T（rs116855232）是中国多民族地区云南省儿童ALL患者6-MP毒性和可耐受剂量的最佳预测指标，将在ALL的精准治疗中发挥重要作用。
