PO.ET07.02 · 实验与分子治疗
作为5-FU毒性生物标志物的DPD活性表型标志物的比较分析
Comparative analysis of phenotypic markers of DPD activity as biomarkers of 5-FU toxicity
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
在美国，每年有近30万癌症患者接受氟嘧啶类化疗。约三分之一的患者经历严重且危及生命的毒性，可能导致死亡。DPYD基因编码氟嘧啶分解代谢的限速酶（二氢嘧啶脱氢酶，DPD），其有害基因变异在临床研究中已被证实与严重毒性相关。然而，这些变异仅能解释10-30%的毒性病例。DPD功能的表型测定是氟嘧啶毒性风险的具吸引力的生物标志物，有可能识别DPD缺乏的未知病因。在本研究中，我们利用204例具有全面DPYD基因型数据的受试者，比较了两种DPD酶活性测定方法：血浆二氢尿嘧啶与尿嘧啶比值（UH2:U）以及在外周血单个核细胞（PBMC）中直接测定DPD活性。与UH2:U比值相比，DPD PBMC测定显示出更高的总体个体间变异。对来自同一受试者的匹配样本，注意到UH2:U与PBMC测定之间相关性较低。正如预期，DPD代谢物（U和UH2）与UH2:U比值相关；然而，U或UH2水平与PBMC DPD活性之间未见相关性。此外，当按基因型分析数据时，UH2:U与PBMC DPD活性之间未见相关性。我们观察到四种经临床检测的DPYD变异携带者的UH2:U比值出现预期的下降，并识别出两个与UH2:U比值显著降低相关的新变异。为进一步研究罕见基因型和先前识别的DPYD单倍型对UH2:U比值的影响，我们利用了另外1994例和500例受试者的队列，这些队列针对特定基因型进行了富集。我们的结果提示，在个体水平上预测DPD缺乏时，表型分型作为单一检测的效度可能有限，并对经常报道的、认为PBMC DPD活性代表识别DPD缺乏"金标准"的观点提出质疑。尚需更多研究来探讨表型测定与患者5-FU毒性之间的相关性，可能作为与基因检测联合使用的次级生物标志物。
查看英文原文 English abstract
Nearly 300,000 cancer patients are treated with fluoropyrimidine chemotherapy in the U.S. annually. Approximately one-third of patients experience severe and life-threatening toxicities, which can result in death. Deleterious genetic variants in DPYD , which encodes the rate-limiting enzyme of fluoropyrimidine catabolism (dihydropyrimidine dehydrogenase, DPD), have been correlated with severe toxicity in clinical studies. However, these variants explain only 10-30% of toxicity cases. Phenotypic measures of DPD function are attractive biomarkers of fluoropyrimidine toxicity risk with the potential to identify unknown causes of DPD deficiency. In this study, we compared two measures of DPD enzyme activity, blood plasma dihydrouracil to uracil ratio (UH 2 :U) and direct measurement of DPD activity in peripheral blood mononuclear cells (PBMCs) using 204 subjects with comprehensive DPYD genotype data. DPD PBMC measurements showed higher overall inter-individual variation compared to UH 2 :U ratios. Low correlation between UH 2 :U and PBMC measurements were noted for matched samples taken from the same subject. As expected, DPD metabolites (U and UH 2 ) correlated with UH 2 :U ratio; however, no correlation was noted between U or UH 2 levels and the PBMC DPD activity. Furthermore, when data were analyzed by genotype, no correlations were noted between UH 2 :U and PBMC DPD activity. We observed the expected decrease in UH 2 :U ratio for carriers of the four clinically tested DPYD variants and identified two novel variants associated with a significantly decreased UH 2 :U ratio. To further investigate the impact of rare genotypes and previously identified DPYD haplotypes on the UH 2 :U ratio, additional cohorts of 1994 and 500 subjects, enriched for specific genotypes, were utilized. Our results suggest that phenotyping may have limited validity as a single test when predicting DPD deficiency at an individual level and call into question the often-reported belief that PBMC DPD activity represents the "gold standard" for identifying DPD deficiency. Additional studies are needed to investigate correlations between phenotypic measures and 5-FU toxicity in patients, potentially as secondary biomarkers in conjunction with genetic tests.
利益披露 Disclosure
B. Bembenek, None..
K. Bouchonville, None..
C. Largiadèr, None..
S. M. Offer, None.