Prevalence and clinical impact of the uncommon DPYD c.257C>T (Pro86Leu) variant in a multiethnic cohort receiving fluoropyrimidine therapy.

The rare missense c.257C>T variant (Pro86Leu, rs568132506) is a hypofunctional DPYD variant missed by targeted genotyping of the seven polymorphisms usually tested before fluoropyrimidine therapy.

A centre replaced targeted DPYD genotyping with comprehensive DPYD exome sequencing in 2021, and reports here 762 consecutive patients pre-emptively genotyped between 2021 and 2025. Among the seven established risk variants, only DPYD 2A and HapB3 were identified, at their expected minor allele frequencies, with no carrier of the five others. Four patients were heterozygous for the rare missense c.257C>T variant (Pro86Leu, rs568132506), with a minor allele frequency of 2.62 × 10⁻³ — similar to that reported in Middle Eastern populations but 26-fold higher than in the gnomAD global population. Three of the four carriers (75%) developed grade 3-4 fluoropyrimidine toxicity after one or two cycles, a relative risk of 14.5 (95% CI: 5.0-30.4; P = 0.0009) compared with a control cohort without hypofunctional DPYD variants.

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

Four carriers and three toxicities: the relative risk of 14.5 rests on tiny numbers, and its confidence interval says so. The genuinely useful result lies elsewhere — in this multiethnic population, a variant absent from the list of seven tested was more frequent than most of them, five of which had no carrier at all. That is a concrete argument for sequencing DPYD in full rather than querying a fixed list, at least where recruitment is not of European ancestry.

Analysis by Dr Thibaut Benquey