亚甲基四氢叶酸还原酶基因C677T多态性与胃癌患者对5-FU化疗敏感性的关系

Relationship of Methylenetetrahydrofolate Reductase C677T Polymorphism and Chemosensitivity to 5-Fluorouracil in Gastric Carcinoma

背景和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5-FU的抗瘤活性。本研究旨在观察MTHFR基因C677T多态性对预测胃癌患者对5-FU的敏感性和化疗毒性的影响。方法收集经病理学确诊的晚期胃癌75例。所有病例化疗前抽外周静脉血2ml,用PCR-RFLP技术检测研究对象的MTHFR基因型。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)3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75例晚期胃癌患者中,MTHFRC/C基因型24例(32.0%),MTHFRC/T基因型33例(44.0%),MTHFRT/T基因型18例(24.0%)。其中22例PR,29例NC,24例PD,化疗总有效率29.3%。MTHFRT/T基因型患者的化疗有效率(20/24,83.3%)明显高于MTHFRC/C基因型患者(2/24,8.3%)(χ2=24.01,P<0.001),同样高于MTHFRC/T基因型患者(5/33,15.2%)(χ2=22.7,P<0.001)。MTHFRC/C基因型患者的化疗有效率与MTHFRC/T基因型患者之间无显著性差异(χ2=0.6,P=0.439)。非条件多元Logistic回归分析(调整性别、年龄、化疗方案、辅助化疗因素的影响)结果显示C/C+C/T基因型患者对化疗有效的可能性为T/T基因型患者的0.017倍(95%CI0.003～0.102,P<0.001)。

BACKGROUND &OBJECTIVE: Methylenetrahydrofolate reductase (MTHFR) C677T polymorphism modifies enzyme activity and thus effects the level of 5, 10 methylenetetrahydrofolate (5,10 MTHR), which correlates with the tumor response to 5 fluorouracil (5 FU). This study was to evaluate the effect of MTHFR C677T polymorphism on chemosensitivity and toxicity to 5 FU in patients with gastric carcinoma. METHODS: A total of 75 patients with histologically confirmed advanced gastric carcinoma were included. All patients received 5 fluoropyrimidine based chemotherapy. Two milliliters of peripheral blood was extracted from each patient before treatment. PCR RFLP was used to determine the genotypes of MTHFR, including wild type homozygotes (C/C), heterozygotes (C/T), and mutant homozygotes (T/T). RESULTS: C/C genotype presented in 24 patients (24/75, 32.0%),C/T genotype presented in 33 patients (33/75, 44.0%),and T/T genotype presented in 18 patients (18/75, 24.0%). Total response rate of chemotherapy was 29.3%, among which 22 with partial response, 29 with no change, and 24 with progressive disease. Response rate in patients with T/T genotype (20/24, 83.3%) was significantly greater than either that in patients with C/C genotype (2/24, 8.3%) (χ2=24.01, P< 0.001), or that in patients with C/T genotype (5/33, 15.2%) (χ2=22.7, P< 0.001). There was no difference of response rate between C/C and C/T genotypes (χ2=0.6, P=0.439). Multiple variances logistic regression analysis (adjusted for gender, age, chemotherapy regimens, and adjuvant chemotherapy factors) showed that the probability of chemotherapy work on patients with combination of C/C and C/T genotypes was 0.017 fold to that in patients with T/T genotype (95%CI ranging from 0.003 to 0.102, P< 0.001); incidence of treatment related side effects, vomiting and nausea, was significantly greater in latter patients than in former patients (χ2=12.264, P=0.002). CONCLUSIONS: MTHFR C677T polymorphism can predict the effects and toxicity of 5 fluoropyrimidine based chemotherapy in advanced gastric carcinoma.