Known variant DPYD alleles do not explain DPD deficiency in cancer patients
Known variant DPYD alleles do not explain DPD deficiency in cancer patients
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DOI：
10.1097/00008571-200004000-00002
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发表时间：
2000-04-01
期刊：
影响因子：
--
通讯作者：
McLeod, HL
中科院分区：
文献类型：
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作者：
Collie-Duguid, ESR;Etienne, MC;McLeod, HL
二氢嘧啶脱氢酶（DPD）降解了80%以上的5-氟尿嘧啶（5FU），从而调节了这种常用抗癌药物的疗效。DPD活性变化很大（8-21倍），活性降低的个体具有较高的5FU毒性风险。DPYD编码DPD蛋白，在DPD缺乏的受试者中已经报道了13种不同的突变。然而，这些变异基因型对体内多态DPD活性的贡献尚不清楚。前面描述的DPYD突变包含在10个外显子中。这10个外显子在DPD活性降低（n = 23）或正常（n = 14）的癌症患者队列中测序，以确定每个变异等位基因对体内低DPD活性的贡献。先前定义的13种DPYD突变中有8种（G62A、Delta TCAT295-298、C703T、G1003T、G1156T、Delta C1897、G2657A和G2983T）未被检测到。在三个DPD活性降低的个体中检测到先前定义的外显子13突变（G1601A）。在正常DPD活性个体中检测到外显子14剪接供体位点突变（内含子14 G1A）。结果表明，T85C、A1627G和G2194A为常见多态性。在DPD活性降低和5FU毒性的患者中检测到一种新的外显子突变（T1679G）。此外，在内含子10和13中检测到3个新的共同多态性。只有3名患者没有任何突变，30名患者在检查的区域有多个DPYD突变。然而，只有17%（4/23）的低DPD表型患者具有活性降低的分子基础。虽然在这项研究中发现了新的DPYD变异，但现在描述的17个DPYD突变并不能完全解释DPD的多态性活性和对5FU的毒性反应。这些数据强调了控制体内多态DPD活性的分子机制的复杂性。中国生物医学工程学报（英文版），2010,(3)。
Dihydropyrimidine dehydrogenase (DPD) degrades over 80% of administered 5-fluorouracil (5FU), thereby regulating the efficacy of this commonly used anticancer agent. DPD activity is highly variable (8-21-fold) and individuals with reduced activity have a high risk of 5FU toxicity. DPYD encodes DPD protein and 13 different mutations have been reported in DPD-deficient subjects. However, the contribution of these variant genotypes to polymorphic DPD activity in vivo is not clear. The previously described DPYD mutations are contained in 10 exons. These 10 exons were sequenced in a cohort of cancer patients with reduced (n = 23) or normal (n = 14) DPD activity to determine the contribution of each variant allele to low DPD activity in vivo. Eight of the 13 previously defined DPYD mutations (G62A, Delta TCAT295-298, C703T, G1003T, G1156T, Delta C1897, G2657A, and G2983T) were not detected. A previously defined exon 13 mutation (G1601A) was detected in three individuals with reduced DPD activity. An exon 14 splice donor site mutation (intron14 G1A) was detected in a normal DPD activity individual. It was demonstrated that T85C, A1627G and G2194A are common polymorphisms. A novel exonic mutation (T1679G) was detected in a patient with reduced DPD activity and 5FU toxicity. In addition, three novel common polymorphisms were detected in introns 10 and 13. Only three patients did not have any mutations and 30 had multiple DPYD mutations in the regions examined. However, only 17% (4/23) of the patients with a low DPD phenotype have a molecular basis for reduced activity. Although novel DPYD) variants have been identified in this study, the 17 DPYD mutations now described do not entirely explain polymorphic DPD activity and toxic response to 5FU. These data emphasize the complex nature of the molecular mechanisms controlling polymorphic DPD activity in vivo. Pharmacogenetics 10:217-223 (C) 2000 Lippincott Williams & Wilkins.