Evolution of Dihydropyrimidine Dehydrogenase Diagnostic Testing in a Single Center during an 8-Year Period of Time
Evolution of Dihydropyrimidine Dehydrogenase Diagnostic Testing in a Single Center during an 8-Year Period of Time
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DOI：
10.1016/j.curtheres.2018.10.001
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发表时间：
2019-01-01
影响因子：
1.9
通讯作者：
van den Bosch, Bianca J. C.
中科院分区：
文献类型：
--
作者：
Coenen, Marieke J. H.;Paulussen, Aimee D. C.;van den Bosch, Bianca J. C.
目的：根据二氢嘧啶脱氢酶（DPD）活性优化氟嘧啶处理。DPD功能障碍导致活性代谢物暴露增加，这可能导致严重甚至致命的毒性。方法：我们提供了8年的DPD诊断测试的概述（n=1194）。结果：在研究期间，我们的诊断测试从首先使用放射化学的单酶测量发展而来，然后通过超HPLC-MS对外周血单核细胞和尿嘧啶进行非放射化学测定，进行酶和遗传学联合检测（即聚合酶链反应），然后对DPYD基因的4种变体（即DPYD*2A、DPYD*13、c.2846A>T和1129- 5923 C>G;等位基因频率分别为0.58%、0.03%、0.29%和1.35%）进行桑格序列分析。具有检测的4种变体之一的患者（n=814）的酶活性低于总体患者组。大多数DPYD*2A变异患者（83%）始终显示酶活性降低。在95例低酶活性患者（检测4种变体）中，仅24例（25.3%）携带变体。在具有低酶活性且没有DPYD*2A变体的亚组（n= 47）中的完整DPYD测序揭示了10种遗传变体，其中4种先前未描述。我们没有观察到DPYD基因型和酶activity.Conclusions之间有很强的联系：以前的研究表明，DPD状态应确定治疗前与氟嘧啶类药物，以防止不必要的副作用，可能致命的后果。我们的研究结合文献表明，DPD酶活性和临床相关的单核苷酸多态性的存在之间存在差异。在这个时候，基因和酶测试的组合是最好的诊断测试。(Curr Ther Res Clin Exp. 2018; 79：XXX-XXX）。(C)2018作者爱思唯尔公司出版
Objective: Fluoropyrimidine treatment can be optimized based on dihydropyrimidine dehydrogenase (DPD) activity. DPD dysfunction leads to increased exposure to active metabolites, which can result in severe or even fatal toxicity.Methods: We provide an overview of 8 years of DPD diagnostic testing (n=1194).Results: Within the study period, our diagnostic test evolved from a single-enzyme measurement using first a radiochemical and then a nonradiochemical assay by ultra HPLC-MS in peripheral blood mononuclear cells with uracil, to a combined enzymatic and genetic test (ie, polymerase chain reaction) followed by Sanger sequence analysis of 4 variants of the DPYD gene (ie, DPYD*2A, DPYD*13, c.2846A>T, and 1129-5923C>G; allele frequencies 0.58%, 0.03%, 0.29%, and 1.35%, respectively). Patients who have 1 of the 4 variants tested (n=814) have lower enzyme activity than the overall patient group. The majority of patients with the DPYD*2A variant (83%) consistently showed decreased enzyme activity. Only 24 (25.3%) of 95 patients (tested for 4 variants) with low enzyme activity carried a variant. Complete DPYD sequencing in a subgroup with low enzyme activity and without DPYD*2A variant (n= 47) revealed 10 genetic variants, of which 4 have not been described previously. We did not observe a strong link between DPYD genotype and enzyme activity.Conclusions: Previous studies have shown that DPD status should be determined before treatment with fluoropyrimidine agents to prevent unnecessary side effects with possible fatal consequences. Our study in combination with literature shows that there is a discrepancy between the DPD enzyme activity and the presence of clinically relevant single nucleotide polymorphisms. At this moment, a combination of a genetic and enzyme test is preferable for diagnostic testing. (Curr Ther Res Clin Exp. 2018; 79:XXX-XXX). (C) 2018 The Authors. Published by Elsevier Inc.