A Polymorphism in the Cytidine Deaminase Promoter Predicts Severe Capecitabine-Induced Hand-Foot Syndrome
A Polymorphism in the Cytidine Deaminase Promoter Predicts Severe Capecitabine-Induced Hand-Foot Syndrome
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DOI：
10.1158/1078-0432.ccr-10-1741
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发表时间：
2011-04-01
影响因子：
11.5
通讯作者：
Gonzalez-Neira, Anna
中科院分区：
文献类型：
--
作者：
Caronia, Daniela;Martin, Miguel;Gonzalez-Neira, Anna
目的：手足综合征（HFS）是卡培他滨最相关的剂量限制性不良反应之一，卡培他滨是一种用于乳腺癌和结直肠癌标准治疗的5-氟尿嘧啶口服前药。我们研究了3级HFS与卡培他滨代谢相关基因的遗传变异之间的关系。实验设计：对130例卡培他滨治疗患者的羧酸酯酶2 （CES2）基因、胞苷脱氨酶（CDD）基因、胸腺苷磷酸化酶（TP）基因、胸腺苷合酶（TS）基因和二氢嘧啶脱氢酶（DPD）基因共13个多态性进行基因分型。我们将这些多态性与HFS易感性联系起来。结果：我们发现HFS的出现与位于CDD启动子区的rs532545相关（OR = 2.02, 95% CI = 1.02-3.99, P = 0.039）。由于我们没有发现rs532545基因型与Epstein-Barr病毒淋巴母细胞样细胞中CDD mRNA表达之间的关联，因此我们探索了CDD启动子的其他遗传变异。我们发现插入位点rs3215400与rss532545连锁不平衡（D' = 0.92），更明显地与患者的HFS （OR = 0.51, 95% CI = 0.27-0.95, P = 0.028）和淋巴母细胞样细胞的CDD基因总表达（P = 0.004）相关。计算机分析表明，这一插入可能为转录调节因子E2F创造了一个结合位点。在淋巴母细胞样细胞中使用SNaPshot检测，我们观察到缺失等位基因的等位基因特异性mRNA表达增加了5.7倍。结论：缺失的rs3215400等位基因显示出等位基因特异性表达的增加，并与卡培他滨诱导HFS的风险增加显著相关。临床癌症研究；17 (7);2006 - 13所示。AACR (C) 2011。
Purpose: Hand-foot syndrome (HFS) is one of the most relevant dose-limiting adverse effects of capecitabine, an oral prodrug of 5-fluorouracil used in the standard treatment of breast and colorectal cancer. We investigated the association between grade 3 HFS and genetic variations in genes involved in capecitabine metabolism.Experimental Design: We genotyped a total of 13 polymorphisms in the carboxylesterase 2 (CES2) gene, the cytidine deaminase (CDD) gene, the thymidine phosphorylase (TP) gene, the thymidylate synthase (TS) gene, and the dihydropyrimidine dehydrogenase (DPD) gene in 130 patients treated with capecitabine. We correlated these polymorphisms with susceptibility to HFS.Results: We found an association of HFS appearance with rs532545 located in the promoter region of CDD (OR = 2.02, 95% CI = 1.02-3.99, P = 0.039). Because we found no association between the rs532545 genotype and CDD mRNA expression in Epstein-Barr virus lymphoblastoid cells, we explored additional genetic variations across the CDD promoter. We found an insertion, rs3215400, in linkage disequilibrium with rs532545 (D' = 0.92), which was more clearly associated with HFS (OR = 0.51, 95% CI = 0.27-0.95, P = 0.028) in patients and with total CDD gene expression (P = 0.004) in lymphoblastoid cells. In silico analysis suggested that this insertion might create a binding site for the transcriptional regulator E2F. Using a SNaPshot assay in lymphoblastoid cells, we observed a 5.7-fold increased allele-specific mRNA expression from the deleted allele.Conclusions: The deleted allele of rs3215400 shows an increased allele-specific expression and is significantly associated with an increased risk of capecitabine-induced HFS. Clin Cancer Res; 17(7); 2006-13. (C)2011 AACR.