Abstract：
OBJECTIVE: 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.
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.
摘要：
目的：二氢嘧啶脱氢酶（DPD）缺乏是导致氟嘧啶相关毒性严重的主要原因。识别DPD缺陷患者的最佳策略仍未确定。EMA建议进行有针对性的DPYD基因分型或尿毒症（U）检测。我们分析了两种方法之间的一致性。
方法：这项研究包括19,376名连续的法国患者，治疗前血浆U，UH2和靶向DPYD基因分型(*2A，*13,D949V,*7）在EurofinsBiomnis（2015-2022）进行分析。
结果：平均U为9.9±10.1ng/mL（中位数8.7，范围1.6-856）。根据法国的建议，7.3％的患者部分缺乏（U16-150ng/mL）和0.02％的患者完全缺乏（U≥150ng/mL）。DPYD变异频率为*2A：0.83%，*13：0.17%，D949V:1.16%,*7:0.05%(2名纯合患者,U在22和856ng/mL)。变体携带者表现出更高的U（中位数13.8与8.6ng/mL)，和较低的UH2/U（中位数7.2vs.11.8）和UH2/U2（中位数0.54与1.37)相对于野生型患者(p<0.00001)。66％的变异携带者表现出尿毒症<16ng/mL，基于U的DPD缺乏症的正确鉴定具有挑战性。U阈值在16ng/mL时的敏感性（变异携带者中具有缺陷表型的患者百分比）为34％。鉴别变异携带者的最佳判别标记是UH2/U2。与16ng/mL相比，UH2/U2<0.942（29.7％的患者）在识别不同变异体的有害基因型方面显示出增强的敏感性（81％）。
结论：这些结果重申了DPD表型和基因分型之间的不良一致性，这表明这两种方法可能是互补的，并且靶向DPYD基因分型对于识别所有完全缺陷患者不够可靠。
方法：这项研究包括19,376名连续的法国患者，治疗前血浆U，UH2和靶向DPYD基因分型(*2A，*13,D949V,*7）在EurofinsBiomnis（2015-2022）进行分析。
结果：平均U为9.9±10.1ng/mL（中位数8.7，范围1.6-856）。根据法国的建议，7.3％的患者部分缺乏（U16-150ng/mL）和0.02％的患者完全缺乏（U≥150ng/mL）。DPYD变异频率为*2A：0.83%，*13：0.17%，D949V:1.16%,*7:0.05%(2名纯合患者,U在22和856ng/mL)。变体携带者表现出更高的U（中位数13.8与8.6ng/mL)，和较低的UH2/U（中位数7.2vs.11.8）和UH2/U2（中位数0.54与1.37)相对于野生型患者(p<0.00001)。66％的变异携带者表现出尿毒症<16ng/mL，基于U的DPD缺乏症的正确鉴定具有挑战性。U阈值在16ng/mL时的敏感性（变异携带者中具有缺陷表型的患者百分比）为34％。鉴别变异携带者的最佳判别标记是UH2/U2。与16ng/mL相比，UH2/U2<0.942（29.7％的患者）在识别不同变异体的有害基因型方面显示出增强的敏感性（81％）。
结论：这些结果重申了DPD表型和基因分型之间的不良一致性，这表明这两种方法可能是互补的，并且靶向DPYD基因分型对于识别所有完全缺陷患者不够可靠。
