Burgueño-Rodríguez Gabriela, Méndez Yessika, Olano Natalia, Schelotto Magdalena, Castillo Luis, Soler Ana María, da Luz Julio
Laboratorio de Genética Molecular Humana, Departamento de Ciencias Biológicas, CENUR Litoral Norte-Sede Salto, Universidad de la República, Salto, Uruguay.
Red Latinoamericana de Implementación y Validación de Guías Clínicas Farmacogenómicas (RELIVAF-CYTED), Santiago, Chile.
Front Pharmacol. 2023 Nov 17;14:1278769. doi: 10.3389/fphar.2023.1278769. eCollection 2023.
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 (, , , , and ) 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 (rs3832526; 3R/3R vs. 2R carriers; OR: = 6.88 [1.88-25.14], = ) and (non-expressors vs. expressors; OR: 4.55 [1.01-20.15], = ) genes. Regarding Cushing syndrome, patients with the TA genotype (rs1049674, ) had a higher risk of developing Cushing syndrome than those with the TT genotype (OR: 2.60 [1.23-5.51], = ). Neurotoxicity was significantly associated with (rs9282564; TC vs. TT; OR: 4.25 [1.47-12.29], = ). 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], = ). This study shows the importance of knowing individual genetics to improve the efficacy and safety of acute lymphoblastic leukemia.
在乌拉圭，小儿急性淋巴细胞白血病（ALL）的治愈率为82.2%，与发达国家报告的治愈率相似。然而，许多患者会出现不良反应，部分原因可能是基因变异。本研究旨在识别与诱导期使用药物相关的基因变异，并考虑个体遗传血统分析它们对不良反应的影响。对200名患者的五个基因（、、、和）中的十个与泼尼松、长春新碱和L-天冬酰胺酶相关的多态性进行了基因分型。使用45个祖先信息标记（AIMs）确定血统。样本血统为69.2%欧洲人、20.1%美洲原住民和10.7%非洲人，但具有高度异质性。粘膜炎、库欣综合征和神经毒性是仅与基因变异和血统相关的不良反应。粘膜炎与基因（rs3832526；3R/3R与2R携带者相比；OR：=6.88[1.88 - 25.14]，=）和基因（非表达者与表达者相比；OR：4.55[1.01 - 20.15]，=）显著相关。关于库欣综合征，TA基因型（rs1049674，）的患者患库欣综合征的风险高于TT基因型患者（OR：2.60[1.23 - 5.51]，=）。神经毒性与基因（rs9282(此处原文可能有误，推测为rs9282564)；TC与TT相比；OR：4.25[1.47 - 12.29]，=）显著相关。此外，美洲原住民血统低于20%的患者发生神经毒性的风险低于血统≥20%的患者（OR：0.312[0.120 - 0.812]，=）。本研究表明了解个体基因对于提高急性淋巴细胞白血病的疗效和安全性具有重要意义。
