Can we identify patients carrying targeted deleterious DPYD variants with plasma uracil and dihydrouracil? A GPCO-RNPGx retrospective analysis.
Clin Chem Lab Med
; 2024 Jun 19.
Article
en En
| MEDLINE
| ID: mdl-38896022
ABSTRACT
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 ± 10.1â¯ng/mL (median 8.7, range 1.6-856). According to French recommendations, 7.3â¯% of patients were partially deficient (U 16-150â¯ng/mL) and 0.02â¯% completely deficient (U≥150â¯ng/mL). DPYD variant frequencies were *2A 0.83â¯%, *13 0.17â¯%, D949V 1.16â¯%, *7 0.05â¯% (2 homozygous patients with U at 22 and 856â¯ng/mL). Variant carriers exhibited higher U (median 13.8 vs. 8.6â¯ng/mL), and lower UH2/U (median 7.2 vs. 11.8) and UH2/U2 (median 0.54 vs. 1.37) relative to wild-type patients (p<0.00001). Sixty-six% of variant carriers exhibited uracilemia <16â¯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 16â¯ng/mL was 34â¯%. The best discriminant marker for identifying variant carriers was UH2/U2. UH2/U2<0.942 (29.7â¯% of patients) showed enhanced sensitivity (81â¯%) in identifying deleterious genotypes across different variants compared to 16â¯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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Clin Chem Lab Med
Asunto de la revista:
QUIMICA CLINICA
/
TECNICAS E PROCEDIMENTOS DE LABORATORIO
Año:
2024
Tipo del documento:
Article
País de afiliación:
Francia
Pais de publicación:
Alemania