AUTHOR=Burgueño-Rodríguez Gabriela , Méndez Yessika , Olano Natalia , Schelotto Magdalena , Castillo Luis , Soler Ana María , da Luz Julio 

TITLE=Pharmacogenetics of pediatric acute lymphoblastic leukemia in Uruguay: adverse events related to induction phase drugs

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1278769

DOI=10.3389/fphar.2023.1278769

ISSN=1663-9812

ABSTRACT=<p>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 (<italic>ABCB1</italic>, <italic>CYP3A5</italic>, <italic>CEP72</italic>, <italic>ASNS</italic>, and <italic>GRIA1</italic>) 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 <italic>ASNS</italic> (rs3832526; 3R/3R vs. 2R carriers; OR: = 6.88 [1.88–25.14], <italic>p</italic> = <italic>0.004</italic>) and <italic>CYP3A5</italic> (non-expressors vs. expressors; OR: 4.55 [1.01–20.15], <italic>p</italic> = <italic>0.049</italic>) genes. Regarding Cushing syndrome, patients with the TA genotype (rs1049674, <italic>ASNS</italic>) had a higher risk of developing Cushing syndrome than those with the TT genotype (OR: 2.60 [1.23–5.51], <italic>p</italic> = <italic>0.012</italic>). Neurotoxicity was significantly associated with <italic>ABCB1</italic> (rs9282564; TC vs. TT; OR: 4.25 [1.47–12.29], <italic>p</italic> = <italic>0.007</italic>). Moreover, patients with &lt;20% Native American ancestry had a lower risk of developing neurotoxicity than those with ≥20% (OR: 0.312 [0.120–0.812], <italic>p</italic> = <italic>0.017</italic>). This study shows the importance of knowing individual genetics to improve the efficacy and safety of acute lymphoblastic leukemia.</p>