Moradveisi Borhan, Muwakkit Samar, Zamani Fatemeh, Ghaderi Ebrahim, Mohammadi Ebrahim, Zgheib Nathalie K
Cancer and Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran.
Department of Pediatrics and Adolescent Medicine and Children's Cancer Center of Lebanon, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
Front Pharmacol. 2019 Aug 27;10:916. doi: 10.3389/fphar.2019.00916. eCollection 2019.
Acute lymphoblastic leukemia (ALL) is the most common cancer seen in children worldwide and in the Middle East. Although there have been major advances in treatment approaches for childhood ALL, serious toxicities do occur but with significant inter-individual variability. The aim of this study is to measure the frequency of polymorphisms in candidate genes involved in 6-Mercaptopurine (6-MP) disposition in a combined cohort of Middle Eastern Children with ALL, and evaluate whether these polymorphisms predict 6-MP intolerance and toxicity during ALL maintenance therapy. The study includes children treated for ALL on two treatment protocols from two cohorts; one from Lebanon (N = 136) and another from Kurdistan province of Iran (N = 74). Genotyping for the following six candidate genetic polymorphisms: (rs1127354) and (rs7270101), (rs1800462), (rs1800460) and (rs1142345), and (rs116855232) was performed and analyzed in association with 6-MP dose intensity and toxicity. As expected, and variants were uncommon. As for , both polymorphisms were more common in the Lebanese as compared to the Kurdish cohort with a minor allele frequency of 0.05 for and 0.14 for in the Lebanese only (N = 121), and of 0.01 for either polymorphism in Kurds. The most significant toxic effects were depicted with the polymorphism with a median 6-MP dose intensity of 33.33%, followed by 46.65% for polymorphism, followed by 65.33% for two risk allele carriers and 74% for one risk allele carriers, in comparison to a median of 100% for the homozygous wild type in the combined cohort (P < 0.001). In addition, the onset of febrile neutropenia was significantly higher in variant allele carriers in the combined cohorts. These data confirm the predictive role of , , and in 6-MP intolerance in Middle Eastern children with ALL. Given the relatively high frequency of variants in our study and their significant association with 6-MP dose intensity, we recommend that physicians consider genotyping for variants in conjunction with and prior to 6-MP therapy in these children.
急性淋巴细胞白血病（ALL）是全球及中东地区儿童中最常见的癌症。尽管儿童ALL的治疗方法取得了重大进展，但严重的毒性反应确实会发生，且个体间存在显著差异。本研究的目的是测量中东地区ALL儿童联合队列中参与6-巯基嘌呤（6-MP）代谢的候选基因多态性的频率，并评估这些多态性是否能预测ALL维持治疗期间的6-MP不耐受性和毒性。该研究纳入了两个队列中按照两种治疗方案接受ALL治疗的儿童；一个来自黎巴嫩（N = 136），另一个来自伊朗库尔德斯坦省（N = 74）。对以下六种候选基因多态性进行基因分型：（rs1127354）和（rs7270101）、（rs1800462）、（rs1800460）和（rs1142345）、（rs116855232），并分析其与6-MP剂量强度和毒性的关系。正如预期的那样，和变异并不常见。至于，与库尔德队列相比，这两种多态性在黎巴嫩队列中更为常见，仅在黎巴嫩队列中（N = 121），的次要等位基因频率为0.05，的次要等位基因频率为0.14，而在库尔德人中，两种多态性的次要等位基因频率均为0.01。最显著的毒性效应出现在多态性中，6-MP剂量强度中位数为33.33%，其次是多态性为46.65%，两个风险等位基因携带者为65.33%，一个风险等位基因携带者为74%，而联合队列中纯合野生型的中位数为100%（P < 0.001）。此外，联合队列中变异等位基因携带者发热性中性粒细胞减少症的发生率显著更高。这些数据证实了、和在中东地区ALL儿童6-MP不耐受性中的预测作用。鉴于我们研究中变异的频率相对较高，且它们与6-MP剂量强度显著相关，我们建议医生在这些儿童接受6-MP治疗前，考虑对变异以及和进行基因分型。
Zotero 插件