TPMT and NUDT15 Pharmacogenomic Profiles in Peruvian Patients With Pediatric Hematologic Malignancies.
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BACKGROUND: Thiopurines remain a cornerstone of treatment for pediatric acute lymphoblastic leukemia (ALL); however, interindividual variability in drug metabolism, largely driven by polymorphisms in the thiopurine S-methyltransferase (TPMT) and nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) genes, can predispose patients to severe, dose-dependent toxicities. Latin American populations have been underrepresented in several global pharmacogenomic (PGx) datasets, limiting the applicability of current dosing recommendations. METHODS: Thus, this study aimed to analyze TPMT and NUDT15 variants in 302 pediatric patients diagnosed with hematological malignancies at the Instituto Nacional de Salud del Niño-San Borja (INSN-SB). Targeted sequencing of the coding regions was performed using custom AmpliSeq™ panels and Illumina platforms, followed by variant annotation and star allele classification based on the Clinical Pharmacogenetics Implementation Consortium (CPIC) and PharmGKB guidelines. RESULTS: Among the TPMT alleles, *3A (8.97%) was the most prevalent actionable variant, followed by *2 (0.32%) and *3C (0.32%). For NUDT15, the most frequent reduced-function allele was *2 (9.29%), with additional findings of *4 (0.64%), *6 (0.32%), *3 (0.16%), and *15 (0.16%). A substantial proportion of the cohort was classified as intermediate or poor metabolizer categories, indicating an increased risk of thiopurine-related toxicity. The observed allele distribution suggests potential geographic variation, although these patterns should be interpreted as exploratory given the limited regional sample size. CONCLUSIONS: This study provides one of the first comprehensive characterizations of clinically relevant TPMT and NUDT15 variants in a Peruvian pediatric population. The findings highlight a substantial burden of actionable pharmacogenetic variants and support the implementation of preemptive genotyping to guide thiopurine dosing. These results help addressing the underrepresentation of Latin American populations in PGx research and provide a foundation for advancing precision medicine in the region.