ArticleCancer chemotherapy and pharmacology2025
Potential clinical relevance of rare dihydropyrimidine dehydrogenase genetic variants identified using whole-exome NextGen sequencing in cancer patients with severe fluoropyrimidine toxicity.
Article in Cancer chemotherapy and pharmacology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Abstract
purposeAmong cancer patients treated with fluoropyrimidine chemotherapeutics, approximately 30% of individuals experience severe fluoropyrimidine-associated toxicity. Dihydropyrimidine dehydrogenase (DPD, gene DPYD) is the main enzyme responsible for fluoropyrimidine metabolism; genetic variation in the DPYD gene that reduce enzyme function may contribute to increased risk for fluoropyrimidine toxicity. Routine pre-emptive genotype testing and dose adjustments for c.1905 + 1G > A (rs3918290, DPYD*2A), c.2846 A > T (rs67376798, p.D949V), c.1679T > G (rs55886062, DPYD*13, p.I560S), and c.1129-5923 C > G (rs75017182, HapB3) according to the guidelines established by international consortia predicts 20-30% of toxicity cases. However, the majority of severe adverse events are not captured by the currently recommended panel of four variants. There is a paucity of data regarding novel and rare (minor allelic frequency < 1%) DPYD genetic variants associated with chemotherapy-related toxicity.
methodsWhole-exome next generation sequencing was carried out in a retrospective study of 334 fluoropyrimidine-treated cancer patients to identify DPYD variants and potential association with severe toxicity.
resultsWe identified 10 rare DPYD variants among 334 fluoropyrimidine-treated cancer patients that were wildtype for the pre-emptively tested variants. Four nonsynonymous rare DPYD variants, c.257 C > T (rs568132506, p.P86L), c.601 A > C (rs72549308, p.S201R), c.1850 C > T (rs753707032, p.T617M), and c.2324T > G (rs200643089, p.L775W), were found in patients that experienced severe toxicity.
conclusionsThe discovery of rare DPYD variants followed by functional characterization may aid in further optimization of fluoropyrimidine dosing.
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