Tufts Medical Center, Tufts University School of Medicine, Division of Hematology/Oncology, Department of Medicine, Director, GI Oncology Program, 800 Washington Street, Box 245, Boston, MA 02111, USA.
Cancer Genomics Proteomics. 2013 Mar-Apr;10(2):89-92.
Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme of the degradation of pyrimidine base, and plays a pivotal role in the pharmacogenetic syndrome of 5-fluorouracil (5-FU). Deficiency of DPD activity leads to severe toxicities, even death, following administration of 5-FU. Several studies have demonstrated that molecular defects of the dihydropyrimidine dehydrogenase gene (DPYD) lead to the deficiency of DPD activity and cause this pharmacogenetic syndrome. We present the analysis of DPYD genotyping in untreated Caucasian patients (control group) and Caucasian patients with 5-FU/CAP-related grade 3/4 toxicities (toxicity group) who underwent a capecitabine TheraGuide 5-FU testing.
Full sequencing of DPYD was performed in the Myriad Genetic Laboratories, Inc. as part of TheraGuide 5-FU test.
Among 227 patients from the toxicity group, 27 (12%) had deleterious mutations in DPYD: twelve (5%) had IVS14 +1 G>A, eleven (5%) had D949V and four (2%) had other mutations. Only 7/192 (4%) patients from the control group had DPYD genotype abnormalities: two (1%) had IVS14 +1 G>A, four (2%) had D949V and one (1%) had other mutation. Genotype abnormalities were observed more frequently in the toxicity group (p=0.001). Among 65 patients with toxicities due to capecitabine, nine (14%) had mutated DPYD, which was more frequent than in the control group (p=0.006).
Mutated DPYD is frequently observed in Caucasian patients who experience toxicities while receiving 5-FU/capecitabine. Screening of patients for DPYD mutations prior to administration of 5-FU/capecitabine using new pharmacogenetic testing methods, may help for identify those patients who are at greatest risk for adverse effects, allowing a more individualized approach to their chemotherapy management.
二氢嘧啶脱氢酶（DPD）是嘧啶碱基降解的限速酶，在 5-氟尿嘧啶（5-FU）的药物遗传综合征中起着关键作用。DPD 活性缺乏会导致使用 5-FU 后出现严重的毒性反应，甚至死亡。多项研究表明，二氢嘧啶脱氢酶基因（DPYD）的分子缺陷导致 DPD 活性缺乏，并导致这种药物遗传综合征。我们分析了未经治疗的高加索患者（对照组）和接受卡培他滨 TheraGuide 5-FU 检测的出现 5-FU/CAP 相关 3/4 级毒性的高加索患者（毒性组）的 DPYD 基因分型。
在 Myriad Genetic Laboratories, Inc. 进行 DPYD 的全序列测序，作为 TheraGuide 5-FU 检测的一部分。
在毒性组的 227 例患者中，27 例（12%）存在 DPYD 的有害突变：12 例（5%）存在 IVS14+1 G>A，11 例（5%）存在 D949V，4 例（2%）存在其他突变。对照组的 192 例患者中只有 7 例（4%）存在 DPYD 基因型异常：2 例（1%）存在 IVS14+1 G>A，4 例（2%）存在 D949V，1 例（1%）存在其他突变。毒性组中观察到基因型异常更为频繁（p=0.001）。在 65 例因卡培他滨而出现毒性的患者中，9 例（14%）存在突变 DPYD，这比对照组更为常见（p=0.006）。
在接受 5-FU/卡培他滨治疗时出现毒性的高加索患者中，经常观察到突变的 DPYD。使用新的药物遗传学检测方法在给予 5-FU/卡培他滨之前对患者进行 DPYD 突变筛查，可能有助于识别那些发生不良反应风险最高的患者，从而对其化疗管理采用更个体化的方法。
