Characterization of DPYD pharmacogenetic variation in Mexican patients with gastrointestinal malignancies.

PURPOSE: Fluoropyrimidines are among the most widely used chemotherapeutic agents for gastrointestinal malignancies, but interindividual variability in dihydropyrimidine dehydrogenase (DPD) activity, encoded by DPYD, can lead to severe or lethal toxicities. Most pharmacogenetic data on DPYD originates from European populations, limiting the applicability of current guidelines in admixed groups. METHODS: We evaluated DPYD pharmacogenetic variation and its association with fluoropyrimidine-related adverse events in Mexican patients with gastrointestinal cancers. Adverse events were prospectively assessed using CTCAE v5.0. Genotyping was performed with the Illumina Global Screening Array and analyzed using PLINK and R. RESULTS: A total of 208 patients were enrolled, and 192 samples passed genotyping quality control; 156 patients received fluoropyrimidines. Only three patients (1.5%) carried actionable DPYD variants (rs3918290, rs67376798 and rs75017182), yielding allele frequencies of 0.26%, approximately ten-fold lower than those reported in European cohorts. Genome-wide analyses did not reveal significant genotype-phenotype associations, though suggestive variants in SDK1, ZPBP, and FGF12 were observed. Pharmacodynamic analyses identified frequent variation in TYMS rs2847153 and MTHFR rs1801133, both previously associated with fluoropyrimidine toxicity. Overall, patients exhibited a predominantly Native Mexican ancestry (56.5%), which may explain the markedly low frequency of actionable DPYD alleles commonly found in European populations. CONCLUSIONS: These findings highlight the limited representation of admixed populations in pharmacogenetic research and underscore the need for population-specific data to inform safe and equitable fluoropyrimidine dosing.