DataSheet1_v1_Ancestry and TPMT-VNTR Polymorphism: Relationship with Hematological Toxicity in Uruguayan Patients with Acute Lymphoblastic Leukemia.PDF

6-Mercaptopurine (6-MP) is a thiopurine drug widely used in childhood acute lymphoblastic leukemia (ALL) therapy. Genes such as TPMT and NUDT15 have an outstanding role in 6-MP metabolism. Mutations in both genes explain a significant portion of hematological toxicities suffered by ALL Uruguayan pediatric patients. A variable number tandem repeat in the TPMT promoter (TPMT-VNTR) has been associated with TPMT expression. This VNTR has a conservative architecture (AnBmC). To explore new causes of hematological toxicities related to ALL therapy, we genotyped the TPMT-VNTR of 130 Uruguayan pediatric patients. Additionally, individual genetic ancestry was estimated by 45 ancestry-informative markers (AIMs). Hematological toxicity was measured as the number of leukopenia events and 6-MP dose along the maintenance phase. As previously reported, we found TPMT*2 and TPMT*3C alleles were associated to TPMT-VNTR A2BC and AB2C, respectively. However, contrasting with other reports, TPMT*3A allele was found in a heterogeneous genetic background in linkage equilibrium. Patients carrying more than 5 A repeats present a significant higher number of leukopenia events among patients without TPMT and/or NUDT15 variants. Native American ancestry and the number of A repeats were significantly correlated with the number of leukopenia events. However, the correlation between Native American ancestry and the number of leukopenia events was lost when the number of A repeats was considered as covariate. This suggests that TPMT-VNTR alleles are more relevant than Native American ancestry in the hematological toxicity. Our results emphasize that TPMT-VNTR may be used as a pharmacogenetic biomarker to predict 6-MP-related hematological toxicity in ALL childhood therapy.

6-巯基嘌呤（6-Mercaptopurine, 6-MP）是一类广泛应用于儿童急性淋巴细胞白血病（acute lymphoblastic leukemia, ALL）治疗的硫嘌呤类药物。TPMT与NUDT15等基因在6-MP代谢过程中发挥关键作用。这两类基因的突变可解释乌拉圭儿童急性淋巴细胞白血病患者所经历的相当比例的血液学毒性事件。TPMT启动子区的可变数目串联重复序列（TPMT-VNTR）已被证实与TPMT的表达水平相关，该序列具有保守的（AnBmC）结构构型。为探究儿童急性淋巴细胞白血病治疗相关血液学毒性的新诱因，我们对130名乌拉圭儿科患者的TPMT-VNTR进行了基因分型。此外，通过45个祖先信息标记（ancestry-informative markers, AIMs）对个体的遗传祖先成分进行了评估。血液学毒性以维持治疗阶段的白细胞减少事件发生次数与6-MP给药剂量进行量化。正如既往研究所报道的那样，我们发现TPMT*2与TPMT*3C等位基因分别与TPMT-VNTR的A2BC及AB2C分型相关。但与其他研究结果不同的是，TPMT*3A等位基因在连锁平衡的异质遗传背景中被检出。在未携带TPMT和/或NUDT15变异的患者中，携带5个以上A重复序列的个体出现白细胞减少事件的次数显著更高。美洲原住民祖先成分与A重复序列数目均与白细胞减少事件次数呈显著正相关。但当将A重复序列数目作为协变量纳入分析后，美洲原住民祖先与白细胞减少事件次数之间的相关性便不复存在。这提示TPMT-VNTR等位基因在预测血液学毒性方面较美洲原住民祖先更为关键。本研究结果表明，TPMT-VNTR可作为药物基因组学生物标志物，用于预测儿童急性淋巴细胞白血病治疗中6-MP相关的血液学毒性。