Can we identify patients carrying targeted deleterious DPYD variants with plasma uracil and dihydrouracil? A GPCO-RNPGx retrospective analysis.
| Autor: | Launay M; Service de médecine intensive et réanimation médicale et Centre Régional de Pharmacovigilance, CHU de Saint-Etienne, Saint-Etienne, France.; French Clinical Oncopharmacology Group (GPCO)-UNICANCER, Paris, France., Raymond L; Département de génétique, Laboratoire Eurofins Biomnis, Lyon, France.; Francophone Network of Pharmacogenetics (RNPGx), Paris, France., Guitton J; Laboratoire de Biochimie et Toxicologie, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite, France.; Laboratoire de Toxicologie, ISPB, Faculté de Pharmacie, Université Lyon 1, Université de Lyon, Lyon, France.; French Clinical Oncopharmacology Group (GPCO)-UNICANCER, Paris, France., Loriot MA; Department of Clinical Chemistry, Hôpital européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-Centre, Paris, France.; INSERM UMR-S1138, Université of Paris Cité, Centre de recherches des Cordeliers, Paris, France.; Francophone Network of Pharmacogenetics (RNPGx), Paris, France., Chatelut E; Oncopole Claudius Regaud, Institut Universitaire du Cancer and CRCT, University of Toulouse, Inserm, Toulouse, France.; French Clinical Oncopharmacology Group (GPCO)-UNICANCER, Paris, France., Haufroid V; Louvain centre for Toxicology and Applied Pharmacology (LTAP), Institut de recherche expérimentale et clinique, UClouvain, Brussels and Clinical Chemistry Department, Cliniques Universitaires Saint-Luc, Brussels, Belgium.; Francophone Network of Pharmacogenetics (RNPGx), Paris, France., Thomas F; Oncopole Claudius Regaud, Institut Universitaire du Cancer and CRCT, University of Toulouse, Inserm, Toulouse, France.; French Clinical Oncopharmacology Group (GPCO)-UNICANCER, Paris, France.; Francophone Network of Pharmacogenetics (RNPGx), Paris, France., Etienne-Grimaldi MC; Oncopharmacology Laboratory, Centre Antoine Lacassagne, Nice, France.; French Clinical Oncopharmacology Group (GPCO)-UNICANCER, Paris, France.; Francophone Network of Pharmacogenetics (RNPGx), Paris, France. |
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| Jazyk: | angličtina |
| Zdroj: | Clinical chemistry and laboratory medicine [Clin Chem Lab Med] 2024 Jun 19; Vol. 62 (12), pp. 2415-2424. Date of Electronic Publication: 2024 Jun 19 (Print Publication: 2024). |
| DOI: | 10.1515/cclm-2024-0317 |
| Abstrakt: | Objectives: Dihydropyrimidine dehydrogenase (DPD) deficiency is the main cause of severe fluoropyrimidine-related toxicities. The best strategy for identifying DPD-deficient patients is still not defined. The EMA recommends targeted DPYD genotyping or uracilemia (U) testing. We analyzed the concordance between both approaches. Methods: This study included 19,376 consecutive French patients with pre-treatment plasma U, UH2 and targeted DPYD genotyping (*2A, *13, D949V, *7) analyzed at Eurofins Biomnis (2015-2022). Results: Mean U was 9.9 ± 10.1 ng/mL (median 8.7, range 1.6-856). According to French recommendations, 7.3 % of patients were partially deficient (U 16-150 ng/mL) and 0.02 % completely deficient (U≥150 ng/mL). DPYD variant frequencies were *2A: 0.83 %, *13: 0.17 %, D949V: 1.16 %, *7: 0.05 % (2 homozygous patients with U at 22 and 856 ng/mL). Variant carriers exhibited higher U (median 13.8 vs. 8.6 ng/mL), and lower UH2/U (median 7.2 vs. 11.8) and UH2/U 2 (median 0.54 vs. 1.37) relative to wild-type patients (p<0.00001). Sixty-six% of variant carriers exhibited uracilemia <16 ng/mL, challenging correct identification of DPD deficiency based on U. The sensitivity (% patients with a deficient phenotype among variant carriers) of U threshold at 16 ng/mL was 34 %. The best discriminant marker for identifying variant carriers was UH2/U 2 . UH2/U 2 <0.942 (29.7 % of patients) showed enhanced sensitivity (81 %) in identifying deleterious genotypes across different variants compared to 16 ng/mL U. Conclusions: These results reaffirm the poor concordance between DPD phenotyping and genotyping, suggesting that both approaches may be complementary and that targeted DPYD genotyping is not sufficiently reliable to identify all patients with complete deficiency. (© 2024 Walter de Gruyter GmbH, Berlin/Boston.) |
| Databáze: | MEDLINE |
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