ArticleBiomedicine & pharmacotherapy = Biomedecine & pharmacotherapie2022
Rare genetic variant burden in DPYD predicts severe fluoropyrimidine-related toxicity risk.
Article in Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers, 1 of them a synthesis that pooled it.
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Who cites it
23 citing papers in PubMed, 1 synthesis or guideline pooled it, 39 citations in OpenAlex.
- Dihydropyrimidine dehydrogenase gene variants for predicting grade 4-5 fluoropyrimidine-induced toxicity: FUSAFE individual patient data meta-analysis.British journal of cancer · 2024Pooled it
- Trial
- Allelic Variants of theGenes · 2026Observational
- Pharmacogenetic testing in Italy: results of a nationwide survey by the Joint Working Group for the pharmacogenetics implementation in Italy.European journal of human genetics : EJHG · 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
- Identification of a largeFrontiers in pharmacology · 2026Article
- Suspected capecitabine-induced fatal toxicity in the context of a new DPYD variant.BMJ case reports · 2025Article
- Implementation of pre-emptive testing of a pharmacogenomic panel in clinical practice: Where do we stand?British journal of clinical pharmacology · 2025Review
- Dihydropyrimidine Dehydrogenase Polymorphism c.2194G>A Screening Is a Useful Tool for Decreasing Gastrointestinal and Hematological Adverse Drug Reaction Risk in Fluoropyrimidine-Treated Patients.Current issues in molecular biology · 2024Article
- Discovering novel germline genetic variants linked to severe fluoropyrimidine-related toxicity in- and outside DPYD.Genome medicine · 2024Article
- Article
- Approach for Phased Sequence-Based Genotyping of the Critical Pharmacogene Dihydropyrimidine Dehydrogenase (International journal of molecular sciences · 2024Article
- Rare variants in pharmacogenes influence clozapine metabolism in individuals with schizophrenia.European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology · 2024Article
- Integrating rare genetic variants into DPYD pharmacogenetic testing may help preventing fluoropyrimidine-induced toxicity.The pharmacogenomics journal · 2024Article
- Case report: A case of severe capecitabine toxicity due to confirmed in trans compound heterozygosity of a common and rare DPYD variant.Frontiers in pharmacology · 2024Article
- Clinical implications of a gain-of-function genetic polymorphism in DPYD (rs4294451) in colorectal cancer patients treated with fluoropyrimidines.Frontiers in pharmacology · 2024Article
- Clinical Implementation of Rare and NovelInternational journal of biological sciences · 2024Review
- The burden of rare variants in DPYS gene is a novel predictor of the risk of developing severe fluoropyrimidine-related toxicity.Human genomics · 2023Article
- Characterization of pharmacogenomic variants in a Brazilian admixed cohort of elderly individuals based on whole-genome sequencing data.Frontiers in pharmacology · 2023Article
Corrections and comments
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Authors and funding
14 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Preemptive targeted pharmacogenetic testing of candidate variations in DPYD is currently being used to limit toxicity associated with fluoropyrimidines. The use of innovative next generation sequencing (NGS) approaches could unveil additional rare (minor allele frequency <1%) genetic risk variants. However, their predictive value and management in clinical practice are still controversial, at least partly due to the challenges associated with functional analyses of rare variants. The aim of this study was to define the predictive power of rare DPYD variants burden on the risk of severe fluoropyrimidine-related toxicity. The DPYD coding sequence and untranslated regions were analyzed by NGS in 120 patients developing grade 3-5 (NCI-CTC vs3.0) fluoropyrimidine-related toxicity and 104 matched controls (no-toxicity). The functional impact of rare variants was assessed using two different in silico predictive tools (i.e., Predict2SNP and ADME Prediction Framework) and structural modeling. Plasma concentrations of uracil (U) and dihydrouracil (UH2) were quantified in carriers of the novel variants. Here, we demonstrate that the burden of rare variants was significantly higher in patients with toxicity compared to controls (p = 0.007, Mann-Whitney test). Carriers of at least one rare missense DPYD variant had a 16-fold increased risk in the first cycle and an 11-fold increased risk during the entire course of chemotherapy of developing a severe adverse event compared to controls (p = 0.013 and p = 0.0250, respectively by multinomial regression model). Quantification of plasmatic U/UH2 metabolites and in silico visualization of the encoded protein were consistent with the predicted functional effect for the novel variations. Analysis and consideration of rare variants by DPYD-sequencing could improve prevention of severe toxicity of fluoropyrimidines and improve patients' quality of life.
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