Prevalence of TPMT and NUDT15 diplotypes in Mexican children with B-cell acute lymphoblastic leukemia.
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Garcia-Solorio Joaquin, Molina-Garay Carolina, Sánchez-Martínez Víctor Jesús, Villegas-Torres Beatriz Eugenia, Campos-Perez Irlanda, Jiménez-Olivares Marco, Flores-Espino Fernanda, Casique-Aguirre Diana, Núñez-Enriquez Juan Carlos, Flores-Lujano Janet, Mata-Rocha Minerva, Peñaloza-Gonzalez José Gabriel, Olivares-Villalpando Victor Hugo, Baños-Lara Ma Del Rocío, García-Soto Ángel, Galván-Díaz César Alejandro, Olaya-Vargas Alberto, Solano-Cardozo Moises, Garrido-Hernández Miguel Ángel, Luna-Silva Nuria Citlalli, Cano-Cuapio Lena Sarahi, Carrillo-Sanchez Karol, Flores-Lagunes Luis Leonardo, Mendoza-Caamal Elvia Cristina, González-Osnaya Vincent, Pelayo-Camacho Rosana, Mejía-Arangure Juan Manuel, Yang Jun J, Alaez-Verson Carmen
Аннотация
METHODS: Samples from 275 pediatric B-cell acute lymphoblastic leukemia patients were analyzed. Next-generation sequencing was used for TPMT and NUDT15 genotyping. Alleles and diplotypes were assessed according to the Clinical Pharmacogenetics Implementation Consortium guidelines. Their geographic distribution was compared across Mexican states and global populations. In-silico analyses were conducted to assess the structural and functional impact of TPMT variants not associated with star alleles.
RESULTS: The wild-type *1 allele, associated with normal enzymatic activity, was predominant in both genes: TPMT (94.15%) and NUDT15 (90.45%). TPMT showed greater allelic diversity compared with previous studies in Mexican populations. Alleles conferring absent or indeterminate enzymatic activity in TPMT were distributed across six diplotypes (11.62%), with *3A allele (4.73%) and *1 / *3A diplotype (9.45%) being the most frequent. Additionally, two unclassified TPMT variants, p.G126A and p.D137Y, were identified. For NUDT15 , three non-wild-type diplotypes were observed (19.09%), with the *2 allele (6.74%) and *1* / 2 diplotype (13.48%) being the most prevalent.
CONCLUSION: Approximately 28% of patients carried TPMT and/or NUDT15 variants associated with non-wild-type enzymatic activity, increasing the risk of mercaptopurine-induced myelotoxicity. Preemptive genotyping is essential to reduce toxicity, optimize treatment, and advance precision medicine in this population. Additionally, the two TPMT variants p.G126A and p.D137Y, currently not classified within Clinical Pharmacogenetics Implementation Consortium-defined star alleles, highlight the need for functional validation and potential clinical classification to improve pharmacogenetic interpretation in diverse populations.