Table2_Pharmacogenetics of pediatric acute lymphoblastic leukemia in Uruguay: adverse events related to induction phase drugs.DOCX

In Uruguay, the pediatric acute lymphoblastic leukemia (ALL) cure rate is 82.2%, similar to those reported in developed countries. However, many patients suffer adverse effects that could be attributed, in part, to genetic variability. This study aims to identify genetic variants related to drugs administered during the induction phase and analyze their contribution to adverse effects, considering individual genetic ancestry. Ten polymorphisms in five genes (ABCB1, CYP3A5, CEP72, ASNS, and GRIA1) related to prednisone, vincristine, and L-asparaginase were genotyped in 200 patients. Ancestry was determined using 45 ancestry informative markers (AIMs). The sample ancestry was 69.2% European, 20.1% Native American, and 10.7% African, but with high heterogeneity. Mucositis, Cushing syndrome, and neurotoxicity were the only adverse effects linked with genetic variants and ancestry. Mucositis was significantly associated with ASNS (rs3832526; 3R/3R vs. 2R carriers; OR: = 6.88 [1.88–25.14], p = 0.004) and CYP3A5 (non-expressors vs. expressors; OR: 4.55 [1.01–20.15], p = 0.049) genes. Regarding Cushing syndrome, patients with the TA genotype (rs1049674, ASNS) had a higher risk of developing Cushing syndrome than those with the TT genotype (OR: 2.60 [1.23–5.51], p = 0.012). Neurotoxicity was significantly associated with ABCB1 (rs9282564; TC vs. TT; OR: 4.25 [1.47–12.29], p = 0.007). Moreover, patients with <20% Native American ancestry had a lower risk of developing neurotoxicity than those with ≥20% (OR: 0.312 [0.120–0.812], p = 0.017). This study shows the importance of knowing individual genetics to improve the efficacy and safety of acute lymphoblastic leukemia.

乌拉圭儿科急性淋巴细胞白血病（Acute Lymphoblastic Leukemia, ALL）的治愈率达82.2%，与发达国家报道的水平相当。然而，诸多患者会出现不良反应，此类反应在一定程度上可归因于遗传变异。本研究旨在识别诱导治疗阶段所用药物相关的遗传变异，并结合个体遗传血统，分析这些变异对不良反应的影响。研究对200例患者的5个基因（ABCB1、CYP3A5、CEP72、ASNS及GRIA1）上的10个多态位点进行了基因分型，这些位点与泼尼松、长春新碱及L-天冬酰胺酶相关。本研究采用45个血统信息标记（Ancestry Informative Markers, AIMs）确定患者的遗传血统，样本的遗传血统构成分别为欧洲血统69.2%、美洲原住民血统20.1%、非洲血统10.7%，但存在较高异质性。研究发现，黏膜炎、库欣综合征及神经毒性是仅有的与遗传变异及遗传血统相关的不良反应。其中，黏膜炎与ASNS基因（rs3832526；3R/3R基因型 vs 2R等位基因携带者；比值比（Odds Ratio, OR）=6.88，95%置信区间（Confidence Interval, CI）：1.88~25.14，p=0.004）及CYP3A5基因（非表达型 vs 表达型；OR=4.55，95%CI：1.01~20.15，p=0.049）显著相关。针对库欣综合征，携带TA基因型（rs1049674，位于ASNS基因）的患者发生库欣综合征的风险显著高于TT基因型携带者（OR=2.60，95%CI：1.23~5.51，p=0.012）。神经毒性与ABCB1基因（rs9282564；TC基因型 vs TT基因型；OR=4.25，95%CI：1.47~12.29，p=0.007）显著相关。此外，美洲原住民血统占比<20%的患者发生神经毒性的风险显著低于血统占比≥20%的患者（OR=0.312，95%CI：0.120~0.812，p=0.017）。本研究证实，明确个体遗传特征有助于提升急性淋巴细胞白血病治疗的有效性与安全性。