DPYD c.85 T > C, DPYD c.496 A>G, and DPYD c.2194 G>A and severe toxicity to fluoropyrimidines in PREPARE and Alpe-DPD trials. An original study and meta-analysis.

DPYD

Partial dihydropyrimidine dehydrogenase deficiency linked to DPYD variants absent from current genotyping panels, reducing 5-fluorouracil catabolism.

Current DPYD genotyping panels explain only a limited share of severe fluoropyrimidine toxicity. The authors combined patients from the PREPARE (Italian cohort) and Alpe-DPD trials with 31 published studies, yielding a meta-analysis of 33 studies and 17,485 patients, then ran three-locus haplotype analyses in the 1,296 trial participants. Taken individually, c.2194 G>A (OR 1.70; 95% CI 1.48-1.95) and c.496 A>G (OR 1.55; 95% CI 1.19-2.02) were associated with toxicity, whereas c.85 T > C was not associated overall. The haplotype combining the minor c.496 G allele with the major c.85 T allele was consistently associated with severe overall toxicity (PREPARE: OR 2.62; Alpe-DPD: OR 2.09) and gastrointestinal toxicity (OR 5.65 and 2.71), with a significant incremental gain in ROC discrimination. Pre-treatment plasma uracil and dihydrouracil confirmed reduced DPD function in these carriers.

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

This is the strongest paper of the week on a CPIC level A gene-drug pair: the size of the meta-analysis and the phenotypic confirmation by plasma uracil support the view that the four consensus variants are not enough. The practical message is not to add c.85 T > C to the panel on its own — alone it is associated with nothing — but to read DPYD loci as haplotypes, which most laboratory reports do not currently do. Still, the haplotype analysis rests on only 1,296 patients with wide confidence intervals: prospective replication is needed before dose-reduction thresholds are changed.

Analysis by Dr Thibaut Benquey