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

DPYD

Dihydropyrimidine dehydrogenase deficiency, encoded by DPYD, whose currently actionable variants were characterised in European populations.

The DPYD variants retained by current guidelines were described almost exclusively in European populations, raising the question of their yield in admixed groups. This study enrolled 208 Mexican patients with gastrointestinal cancers, of whom 192 samples passed genotyping quality control (Illumina Global Screening Array) and 156 patients received a fluoropyrimidine, with adverse events collected prospectively using CTCAE v5.0. Only three patients (1.5%) carried an actionable DPYD variant (rs3918290, rs67376798, rs75017182), an allele frequency of 0.26%, roughly ten-fold lower than reported in European cohorts. Genome-wide analysis showed no significant genotype-phenotype association, with only suggestive signals in SDK1, ZPBP and FGF12, while the pharmacodynamic variants TYMS rs2847153 and MTHFR rs1801133, already associated with fluoropyrimidine toxicity, were frequent. The predominantly Native Mexican ancestry (56.5%) most likely explains the scarcity of actionable alleles.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The message is uncomfortable for pre-emptive genotyping programmes: at a 0.26% allele frequency, screening the consensus DPYD variants in this population means testing several hundred patients to protect one. That is not an argument for dropping the test, since the toxicities avoided can be lethal, but for seriously considering phenotyping by plasma uracil, which is ancestry-independent, where a panel calibrated on European populations loses its yield. The limitation is sample size: 156 exposed patients support no genome-wide conclusion, and the signals in SDK1, ZPBP and FGF12 should be treated as noise until replicated.

Analysis by Dr Thibaut Benquey