ArticleGenome medicine2024
Discovering novel germline genetic variants linked to severe fluoropyrimidine-related toxicity in- and outside DPYD.
Article in Genome medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02324452 (Safety, Feasibility and Cost-effectiveness of Genotype-directed Individualized Dosing of Fluoropyrimidines), which is not on this map. Cited by 9 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Safety, Feasibility and Cost-effectiveness of Genotype-directed Individualized Dosing of Fluoropyrimidines
Who cites it
9 citing papers in PubMed.
- Trial
- A thymine-challenge test to prospectively evaluate dihydropyrimidine dehydrogenase activity for risk of severe 5-fluorouracil-induced gastrointestinal toxicity.Cancer chemotherapy and pharmacology · 2025Trial
- Dihydropyrimidine Dehydrogenase Genotype-Phenotype Correlations in Plasma and Peripheral Blood Mononuclear Cells.Clinical pharmacology and therapeutics · 2026Article
- Genetic Variants Associated with Fluoropyrimidine-Induced Toxicity in Real-World Patients After Pre-EmptivePharmaceuticals (Basel, Switzerland) · 2026Article
- The evolving landscape of pharmacogenomics: Current achievements and future directions.Pharmacological reviews · 2026Review
- Functional studies of human variants in C. elegans link iron metabolism to DPD deficiency and 5-FU sensitivity.Genetics · 2026Article
- Potential clinical relevance of rare dihydropyrimidine dehydrogenase genetic variants identified using whole-exome NextGen sequencing in cancer patients with severe fluoropyrimidine toxicity.Cancer chemotherapy and pharmacology · 2025Article
- Dihydropyrimidine Dehydrogenase Deficiency (DPYD) Genotyping-Guided Fluoropyrimidine-Based Adjuvant Chemotherapy for Breast Cancer. A Cost-Effectiveness Analysis.Clinical drug investigation · 2025Article
- Article
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Authors and funding
29 authors.
Funding
Abstract
backgroundThe Alpe-DPD study (NCT02324452) demonstrated that prospective genotyping and dose-individualization using four alleles in DPYD (DPYD*2A/rs3918290, c.1236G > A/rs75017182, c.2846A > T/rs67376798 and c.1679 T > G/rs56038477) can mitigate the risk of severe fluoropyrimidine toxicity. However, this could not prevent all toxicities. The goal of this study was to identify additional genetic variants, both inside and outside DPYD, that may contribute to fluoropyrimidine toxicity.
methodsBiospecimens and data from the Alpe-DPD study were used. Exon sequencing was performed to identify risk variants inside DPYD. In silico and in vitro analyses were used to classify DPYD variants. A genome-wide association study (GWAS) with severe fluoropyrimidine-related toxicity was performed to identify variants outside DPYD. Association with severe toxicity was assessed using matched-pair analyses for the exon sequencing and logistic, Cox, and ordinal regression analyses for GWAS.
resultsTwenty-four non-synonymous, frameshift, and splice site DPYD variants were detected in ten of 986 patients. Seven of these variants (c.1670C > T, c.1913 T > C, c.1925 T > C, c.506delC, c.731A > C, c.1740 + 1G > T, c.763 - 2A > G) were predicted to be deleterious. The carriers of either of these variants showed a trend towards a 2.14-fold (95% CI, 0.41-11.3, P = 0.388) increased risk of severe toxicity compared to matched controls (N = 30). After GWAS of 942 patients, no individual single nucleotide polymorphisms achieved genome-wide significance (P ≤ 5 × 10
conclusionsResults from DPYD exon sequencing and GWAS analysis did not identify additional genetic variants associated with severe toxicity, which suggests that testing for single markers at a population level currently has limited clinical value. Identifying additional variants on an individual level is still promising to explain fluoropyrimidine-related severe toxicity. In addition, studies with larger samples sizes, in more diverse cohorts are needed to identify potential clinically relevant genetic variants related to severe fluoropyrimidine toxicity.
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