Can we identify patients carrying targeted deleterious variants with plasma uracil and dihydrouracil? A GPCO-RNPGx retrospective analysis.

Launay, Manon;Raymond, Laure;Guitton, Jérôme;Loriot, Marie-Anne;Etienne-Grimaldi, Marie-Christine;et.al.
(2024) Clinical Chemistry and Laboratory Medicine : Associated with FESCC and IFCC — Vol. 62, n° 12, p. 2415-2424 (2024)

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Authors
  • Launay, Manon
    Author
  • Raymond, Laure
    Author
  • Guitton, Jérôme
    Author
  • Loriot, Marie-Anne
    Author
  • Haufroid, Vincentorcid-logoUCLouvain
    Author
  • Etienne-Grimaldi, Marie-Christine
    Author
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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 ± 10.1 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/U2 (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/U2. UH2/U2<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.
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Launay, M., Raymond, L., Guitton, J., Loriot, M.-A., Chatelut, E., Haufroid, V., Thomas, F., & Etienne-Grimaldi, M.-C. (2024). Can we identify patients carrying targeted deleterious variants with plasma uracil and dihydrouracil? A GPCO-RNPGx retrospective analysis. Clinical Chemistry and Laboratory Medicine : Associated with FESCC and IFCC, 62(12), 2415-2424. https://doi.org/10.1515/cclm-2024-0317 (Original work published 2024)