Dihydropyrimidine Dehydrogenase Genotype-Phenotype Correlations in Plasma and Peripheral Blood Mononuclear Cells.

DPYD

Deleterious DPYD variants reduce the activity of DPD, the rate-limiting enzyme of 5-fluorouracil catabolism; phenotypic assays measure either enzyme activity in peripheral blood mononuclear cells or plasma uracil and the dihydrouracil/uracil ratio.

In matched samples from 203 patients with available DPYD exome sequencing, the authors compared DPD activity measured in peripheral blood mononuclear cells with plasma metabolites (uracil, dihydrouracil, UH2:U ratio). Beyond established high-risk variants, three rare DPYD variants predicted to be deleterious were identified: c.274C>G, c.966C>A and c.1435G>A, associated with impaired DPD function with effect sizes comparable to well-studied toxicity-associated variants. Correlations between mononuclear cell DPD activity and either the UH2:U ratio or uracil level were significant but weak, both at population level and within genotypes. The authors conclude that phenotypic assays detect severe DPD deficiency but that their variability limits their use as standalone diagnostic tools, and argue for integration with genetic testing.

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

The question is the one every laboratory faces before a fluoropyrimidine: phenotype, genotype, or both. The answer here is clear and in proportion to the sample size: weak correlations between enzyme activity and plasma metabolites disqualify metabolite measurement alone as a substitute for genotyping. The three added rare variants still require clinical validation before being used to adjust a dose.

Analysis by Dr Thibaut Benquey