亚甲基四氢叶酸还原酶基因C677T和A1298C多态性与消化道癌化疗敏感性关系的研究  

Polymorphism of methylenetetrahydrofolate reductase and chemosensitivity of digestive tract carcinoma to 5-fluorouracil-based chemotherapy

作　　者：陆建伟[1] 高长明[2] 吴建中[2] 周兆飞[1] 尹必俭[1] 刘德林[1] 史美琪[1] 孙小峰[1] 冯继锋[1] Tajima Kazuo 

机构地区：[1]南京江苏省肿瘤防治研究所内科,210009 [2]江苏省肿瘤防治研究所流行病室,210009 [3]日本爱知县がんセソタ一研究所免疫,预防部

出　　处：《临床肿瘤学杂志》2005年第6期601-605,609,共6页Chinese Clinical Oncology

基　　金：江苏省科技厅社会发展科学基金资助项目(BS2003048);日本文科省国际学术研究癌症特别研究经费资助项目(08042015)

摘　　要：目的:亚甲基四氢叶酸还原酶(methylenetetrahydrofolatereductase,MTHFR)基因变异影响MTHFR的活性,以致影响体内5,10-MTHF的浓度,从而影响氟尿嘧啶(5-FU)的抗瘤活性。本研究旨在观察MTHFR基因C677T、A1298C多态性对预测消化道癌患者对5-FU的敏感性和化疗毒性的临床价值。方法:收集经病理学检查确诊的晚期消化道癌122例。所有病例化疗前抽外周静脉血2毫升,用PCR-RFLP技术检测研究对象的MTHFR基因型。C677T基因型分为野生型纯合子(C/C)、杂合子(C/T)、变异型纯合子(T/T)三种类型,A1298C基因型分为纯合子A/A、杂合子A/C和纯合子C/C三种类型。所有患者经含5-FU为基础的联合化疗方案化疗。结果:122例晚期消化道癌患者中,化疗总有效率为38.5%,其中C677TT/T基因型患者的化疗有效率为82·1%,显著高于C/C基因型患者的21·6%(χ2=23·402;P=0.000),C/T基因型患者的28.1%(χ2=22·110;P=0.000),C/C基因型与C/T基因型之间无差异(χ2=0·491;P=0·481)。A1298CA/A基因型患者的化疗有效率为45.3%,显著高于A/C基因型患者的22.9%(χ2=5.297;P=0.021)。在不同化疗方案亚组分析中,经CFL方案、CFH方案和L-FP方案化疗的C677TT/T基因型患者有效率显著高于C/T、C/C基因型患者(χ2=8.156,df=2,P=0·017;χ2=15.297,df=2,P=0.000;χ2=6.685,df=2,P=0.036);A1298CA/A基因型患者的疗效均高于A/C+C/C基因型患者,但仅CFL方案组取得统计学差异(χ2=5.400;df=1,P=0.020)。C677TT/T基因型患者的恶心呕吐和口腔炎副反应均显著高于C/C、C/T基因型。A1298CA/A基因型患者的毒副反应均显著高于C/C+A/C基因患者。结论:MTHFR基因C677T、A1298C基因型多态性对于预测以5-FU为基础化疗方案治疗晚期消化道癌的疗效和毒性具有较好的临床意义。Objective：To investigate the effect of the MTHFR C677T polymorphism on the prediction of chemosensitivity and toxicity to 5-FU-based chemotherapy in patients with digestive tract carcinoma. Methods： 122 patients with histological confirmed advanced digestive tract carcinoma were analyzed. All patients were treated with 5-fluoropyrimidine-based chemotherapy. Two milliliters of peripheral blood was extracted from each of them. PCR-RFLP was employed to determine the genotypes of MTHFR,i. e. C677T wildtype homozygotes （ C/C ） , heterozygotes （C/T） and mutant homozygotes （T/T） ; A 1298 C wild-type homozygotes （ A/A ） , heterozygotes （ A/ C） and mutant homozygotes（C/C） Results： Of all the patients, the frequencies of MTHFR C/C, C/T and T/T genotype were 30.3% , 46.7%and 23.0% ,while the frequencies of MTHFR A1298C A/A,A/Cand C/C gentype were 70.5% ,28.7% and 0.8% ,respectively. Total response rate of chemotherapy was 38.5% ,among which 47 with PR,39 with NC and 36 with PD. Response rate in patients with MTHFR C677T T/T genotype（ 82.1% ） was significantly greater than either that of C/C genotype （21.6%） （X^2=23. 402;P=0. 000） ,or that of C/T genotype （28.1% ） （X^2=22.110 ;P=0. 000）. There was no difference of response rate between C/C and C/T genotypes（X^2= 0.491 ;P=0. 484 ）. Response rate in patients with MTHFR A1298C A/A genotype （45.3%）was significantly greater than either that of A/C genotype（ 22.9% ） （X^2=5. 297 ;P = 0. 021 ）. The response rate to CFL,CFH and L-FP chemotherapy among patients with C677T T/T genotype was sigificantly greater than either that of C/C genotype and C/T genotypes （X^2=8. 156;df=2,P= 0. 017 ;X^2=15. 297, df=2, P=0. 000 ;X^2=6. 685, df=2, P=0. 036 ） ; The response rate to CFL chemotherapy among patients with A1298C A/A genotype was significantly greater than either that of A/C ＋ C/C genotypes（X^2=5.400,dr=1 ,P =0.020） ,but no difference among other chemotherapy. The incidence rate of vomiting/nausea and stomatitis i

关 键 词：晚期消化道癌 亚甲基四氢叶酸还原酶 C677T A1298C多态性 氟尿嘧啶 化疗 

分 类 号：R730.53[医药卫生—肿瘤]