Functional characterization of rare DPYD variants identified in 8,380 Japanese individuals: implications for 5-fluorouracil metabolism.

DPYD

DPYD variants impair DPD activity through various mechanisms, including loss of homodimer formation, shown here for Gly194Asp and Glu386Ter.

Twenty-six rare DPYD variants, identified by whole-genome sequencing of 8,380 Japanese individuals, were functionally characterised in vitro. Recombinant DPD proteins were expressed in 293FT cells, enzyme activity was measured by liquid chromatography-tandem mass spectrometry (Km, Vmax, intrinsic clearance), and expression and quaternary structure were assessed by immunoblotting and blue native PAGE. Five variants showed markedly reduced or abolished activity compared with wild-type DPD, including three loss-of-function variants. Loss of homodimer formation was observed for Gly194Asp and Glu386Ter, whereas other functionally impaired variants retained dimerisation, indicating that altered dimerisation is only one of several mechanisms. The authors stress that the clinical significance of these variants and their use for fluoropyrimidine dose individualisation remain to be confirmed in patients receiving such chemotherapy.

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

The value lies in annotating a gene in a population where the risk variants established in Europeans are uncommon, a setting in which an imported panel detects few carriers. The work is entirely in vitro: no patient toxicity data link these five variants to a clinical event, as the authors explicitly state. This is a prioritisation step, not an argument for changing a dose today.

Analysis by Dr Thibaut Benquey