Cho Hyun-Jung, Park Young Suk, Kang Won Ki, Kim Jong-Won, Lee Soo-Youn
Departments of Laboratory Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Ther Drug Monit. 2007 Apr;29(2):190-6. doi: 10.1097/FTD.0b013e318040b1fe.
The important cellular proteins for 5-fluorouracil (5-FU) metabolism are the major target enzymes, thymidylate synthase, and the rate-limiting enzyme in the degradation pathway, dihydropyrimidine dehydrogenase. Adverse drug reactions to 5-FU-based chemotherapy have been reported to be in part the result of polymorphisms in the thymidylate synthase (TYMS) and dihydropyrimidine dehydrogenase (DPYD) genes. Therefore, we examined the type and frequency of polymorphisms in the TYMS and DPYD genes in 100 healthy Korean individuals and compared these findings with 21 patients with colorectal cancer who had a grade 3 or greater toxic response to 5-FU treatment. Genotyping analysis of the promotor enhancer region (TSER) and the 3'-untranslated region (3'-UTR) of the TYMS gene as well as haplotype analysis were conducted in all 121 study participants. For the TSER and the 3'-UTR of the TYMS gene, similar genotypes and allele frequencies were observed in control subjects and patients. For the haplotype analysis of the single nucleotide polymorphism G > C at the 12th nucleotide of the second repeat of the 3R allele of the TSER, different haplotype frequencies were noted in comparisons between the two groups; in addition, we found that the 3RC-del 6bp was significantly associated with severe toxicity with 5-FU treatment. Extensive polymorphisms in the DPYD gene were observed; in addition, four polymorphisms were related to the known DPYD allelic variants or to allelic variants that alter protein structure, among which the most common polymorphism was 1627A > G, observed in 20.5% of all alleles. The 496A > G allele and a novel 1774C > T allele were identified in two patients. The DPYD*2A allele, causing exon 14 skipping, was not identified in the study group. The findings, from Korean patients with colon cancer, suggest that polymorphisms of the DPYD gene are not associated with an increased risk for toxic response to 5-FU. These findings suggest that there may be an important relationship between the TYMS haplotypes examined and 5-FU toxicity. The novel variant in the DPYD gene, identified in this study, should be further investigated to confirm its functional significance. A large sample is required before DPYD or TYMS genotyping could be used as markers for individualized treatment of patients with colorectal cancer.
参与5-氟尿嘧啶（5-FU）代谢的重要细胞蛋白是主要靶酶胸苷酸合成酶，以及降解途径中的限速酶二氢嘧啶脱氢酶。据报道，基于5-FU的化疗药物不良反应部分是胸苷酸合成酶（TYMS）和二氢嘧啶脱氢酶（DPYD）基因多态性的结果。因此，我们检测了100名健康韩国人的TYMS和DPYD基因多态性类型及频率，并将这些结果与21名对5-FU治疗有3级或更严重毒性反应的结直肠癌患者进行比较。对所有121名研究参与者进行了TYMS基因启动子增强子区域（TSER）和3'非翻译区（3'-UTR）的基因分型分析以及单倍型分析。对于TYMS基因的TSER和3'-UTR，在对照组和患者中观察到相似的基因型和等位基因频率。对于TSER 3R等位基因第二个重复序列第12个核苷酸处单核苷酸多态性G>C的单倍型分析，两组比较时观察到不同的单倍型频率；此外，我们发现3RC-del 6bp与5-FU治疗的严重毒性显著相关。观察到DPYD基因存在广泛的多态性；此外，有4种多态性与已知的DPYD等位基因变体或改变蛋白质结构的等位基因变体相关，其中最常见的多态性是1627A>G，在所有等位基因中占20.5%。在两名患者中鉴定出496A>G等位基因和一个新的1774C>T等位基因。在研究组中未鉴定出导致外显子14跳跃的DPYD*2A等位基因。来自韩国结肠癌患者的这些发现表明，DPYD基因多态性与5-FU毒性反应风险增加无关。这些发现表明，所检测的TYMS单倍型与5-FU毒性之间可能存在重要关系。本研究中鉴定出的DPYD基因新变体，应进一步研究以确认其功能意义。在DPYD或TYMS基因分型可作为结直肠癌患者个体化治疗的标志物之前，需要大量样本。
