Daniela Rojo-Serrato, Francisco Javier Flores-Murrieta, Haydeé Rosas-Vargas, Elva Jiménez-Hernández, Juan Carlos Núñez-Enríquez, Carolina González-Torres, Javier Gaytan-Cervantes, Deyanira Escalante-Bautista, María Luisa Pérez-Saldivar, Janet Flores-Lujano, América Mariana Jasso-Mata, Abimael Efraín Marquez-Águilar, José Ángel Sotelo Hernández, Omar Alejandro Sepúlveda-Robles, María de Los Ángeles Romero-Tlalolini, Carmen Alaez-Verson, Jorge Alfonso Martín-Trejo, Silvia Jiménez-Morales, José Luis Cruz-Jaramillo, Norma A Oviedo de Anda, Manuel A Castillo-Mendéz, José Refugio Torres-Nava, Luz Victoria Flores-Villegas, Laura Elizabeth Merino-Pasaye, María Raquel Miranda-Madrazo, María de Lourdes Gutiérrez-Rivera, Karina Anatasia Solís-Labastida, Gabriela Alicia Herández-Echaurregui, Jorge Melendez-Zajgla, Angélica Rangel-López, José Arellano-Galindo, Minerva Mata-Rocha, Juan Manuel Mejía-Aranguré
Mexico has one of the highest incidences of childhood acute lymphoblastic leukemia worldwide and also reports one of the lowest 5-year overall survival rates; one cause is elevated treatment-related mortality from severe hematologic toxicity, a critical side effect during chemotherapy. Although association studies have identified common genetic variants linked to toxicity, the Mexican population remains incompletely explored. We performed targeted next-generation sequencing of genes involved in methotrexate and mercaptopurine metabolism in 96 Mexican children with ALL, stratified by hematologic toxicity severity according to CTCAE v5.0. Logistic regression revealed nominally significant associations between the TSER*3/TSER*2 genotype (rs45445694) in the 5' UTR of TYMS severe hematologic toxicity (overdominant model: OR = 3.21; 95% CI = 1.23-8.38; p = 0.014 and codominant model: OR = 3.31; 95% CI = 1.17-9.34; p = 0.047). Additionally, the CCND1 LD block (rs678653/rs7177) also showed nominal associations (overdominant model: OR = 2.60; 95% CI = 1.01-6.71; p = 0.044). None of these associations remained statistically significant after Bonferroni correction for multiple testing (corrected α = 0.000588). Patients with severe toxicity had lower 5-year overall survival than those without severe toxicity (70.2% vs. 90.5%; p = 0.0609), although the difference was not statistically significant. Variants in 5' and 3' UTRs regions were markedly enriched compared to coding sequences, underscoring the importance of regulatory region analysis.