{"title":"我们能否通过血浆尿嘧啶和二氢尿嘧啶来识别携带定向有害 DPYD 变体的患者?GPCO-RNPGx 回顾性分析。","authors":"Manon Launay, Laure Raymond, Jérôme Guitton, Marie-Anne Loriot, Etienne Chatelut, Vincent Haufroid, Fabienne Thomas, Marie-Christine Etienne-Grimaldi","doi":"10.1515/cclm-2024-0317","DOIUrl":null,"url":null,"abstract":"<p><strong>Objectives: </strong>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 <i>DPYD</i> genotyping or uracilemia (U) testing. We analyzed the concordance between both approaches.</p><p><strong>Methods: </strong>This study included 19,376 consecutive French patients with pre-treatment plasma U, UH2 and targeted <i>DPYD</i> genotyping (*2A, *13, D949V, *7) analyzed at Eurofins Biomnis (2015-2022).</p><p><strong>Results: </strong>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). <i>DPYD</i> 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<sup>2</sup> (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<sup>2</sup>. UH2/U<sup>2</sup><0.942 (29.7 % of patients) showed enhanced sensitivity (81 %) in identifying deleterious genotypes across different variants compared to 16 ng/mL U.</p><p><strong>Conclusions: </strong>These results reaffirm the poor concordance between DPD phenotyping and genotyping, suggesting that both approaches may be complementary and that targeted <i>DPYD</i> genotyping is not sufficiently reliable to identify all patients with complete deficiency.</p>","PeriodicalId":10390,"journal":{"name":"Clinical chemistry and laboratory medicine","volume":null,"pages":null},"PeriodicalIF":3.8000,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Can we identify patients carrying targeted deleterious <i>DPYD</i> variants with plasma uracil and dihydrouracil? A GPCO-RNPGx retrospective analysis.\",\"authors\":\"Manon Launay, Laure Raymond, Jérôme Guitton, Marie-Anne Loriot, Etienne Chatelut, Vincent Haufroid, Fabienne Thomas, Marie-Christine Etienne-Grimaldi\",\"doi\":\"10.1515/cclm-2024-0317\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objectives: </strong>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 <i>DPYD</i> genotyping or uracilemia (U) testing. We analyzed the concordance between both approaches.</p><p><strong>Methods: </strong>This study included 19,376 consecutive French patients with pre-treatment plasma U, UH2 and targeted <i>DPYD</i> genotyping (*2A, *13, D949V, *7) analyzed at Eurofins Biomnis (2015-2022).</p><p><strong>Results: </strong>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). <i>DPYD</i> 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<sup>2</sup> (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<sup>2</sup>. UH2/U<sup>2</sup><0.942 (29.7 % of patients) showed enhanced sensitivity (81 %) in identifying deleterious genotypes across different variants compared to 16 ng/mL U.</p><p><strong>Conclusions: </strong>These results reaffirm the poor concordance between DPD phenotyping and genotyping, suggesting that both approaches may be complementary and that targeted <i>DPYD</i> genotyping is not sufficiently reliable to identify all patients with complete deficiency.</p>\",\"PeriodicalId\":10390,\"journal\":{\"name\":\"Clinical chemistry and laboratory medicine\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.8000,\"publicationDate\":\"2024-06-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical chemistry and laboratory medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1515/cclm-2024-0317\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICAL LABORATORY TECHNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical chemistry and laboratory medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1515/cclm-2024-0317","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICAL LABORATORY TECHNOLOGY","Score":null,"Total":0}
Can we identify patients carrying targeted deleterious DPYD variants with plasma uracil and dihydrouracil? A GPCO-RNPGx retrospective analysis.
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.
期刊介绍:
Clinical Chemistry and Laboratory Medicine (CCLM) publishes articles on novel teaching and training methods applicable to laboratory medicine. CCLM welcomes contributions on the progress in fundamental and applied research and cutting-edge clinical laboratory medicine. It is one of the leading journals in the field, with an impact factor over 3. CCLM is issued monthly, and it is published in print and electronically.
CCLM is the official journal of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) and publishes regularly EFLM recommendations and news. CCLM is the official journal of the National Societies from Austria (ÖGLMKC); Belgium (RBSLM); Germany (DGKL); Hungary (MLDT); Ireland (ACBI); Italy (SIBioC); Portugal (SPML); and Slovenia (SZKK); and it is affiliated to AACB (Australia) and SFBC (France).
Topics:
- clinical biochemistry
- clinical genomics and molecular biology
- clinical haematology and coagulation
- clinical immunology and autoimmunity
- clinical microbiology
- drug monitoring and analysis
- evaluation of diagnostic biomarkers
- disease-oriented topics (cardiovascular disease, cancer diagnostics, diabetes)
- new reagents, instrumentation and technologies
- new methodologies
- reference materials and methods
- reference values and decision limits
- quality and safety in laboratory medicine
- translational laboratory medicine
- clinical metrology
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