MTHFR多态性对晚期胃癌患者化疗作用的预测研究

目的:研究亚甲基四氢叶酸还原酶(MTHFR)基因C677T、A1298C多态与胃癌患者对5-FU为基础的化疗敏感性和毒性的关系。方法:晚期胃癌患者106例,用聚合酶链反应-限定性片段长度多态性(PCR-RFLP)技术检测白细胞DNAMTH-FR基因型。所有患者经5-FU为基础的化疗方案治疗。结果:1)在106例晚期胃癌患者中,MTHFRC677TCC、CT、TT基因型分别占31·1%、46·2%和22·6%;MTH-FRA1298CAA、AC、CC基因型者分别为69·8%、29·2%和0·9%;化疗总有效率35·8%。2)MTHFRC677TTT基因型携带者化疗有效率(83·3%)明显高于C677TCT(24·5%;P=0·000)和C677TCC(18·2%;P=0·000)。而MTHFRA1298CAA组有效率(43·2%)亦明显高于A1298CAC CC组(18·8%,P=0·009)。3)在CFL、CFH、LFP方案治疗的患者中,C677T变异子携带者对化疗敏感性更高。对A1298C多态性,患者接受CFL方案化疗时,1298AA纯合子携带者有效率高于1298CT/CC患者。4)MTHFRC677TTT、CT或A1298CAA多态性携带者化疗相关的恶心/呕吐发生率明显高于其他三种多态性者。结论:MTHFR基因多态性的检测可能是晚期胃癌患者接受5-FU为基础化疗疗效和毒副反应的良好预测指标。

Methylenetetrahydrofolate reductase polymorphism in advanced gastric cancer: a novel genomic predictor of clinical response to fluoropyrimidine-based chemotherapy

OBJECTIVE: To investigate the relationship between polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) C677T or A1298C and the response to fluoropyrimidine (5-FU)-based chemotherapy in advanced stomach cancer. METHODS: 106 patients were treated with 5-FU-based chemotherapy and DNA of peripheral blood leukocytes was obtained before therapy. MTHFR genotypes were detected by PCR-RFLP method. RESULTS: 1) Of all the cases, the frequencies of MTHFR C677T CC, CT and TT genotype were 31.1%, 46.2% and 22.6%, while the frequencies of MTHFR A1298C AA, AC and CC genotype were 69.8%, 29.2% and 0.9%, respectively. The overal response rate to 5-FU-based chemotherapy was 35.8%. 2) The response rate to therapy among MTHFR C677T TT genotype patients (83.3%) was significantly higher than the C677T CT genotype (24.5%,P=0.000) or the C677T CC genotype (18.2%,P=0.000). The response rate to therapy among patients with MTHFR A1298C AA genotype (43.2%) was significantly higher than patients with A1298C C allele (18.8%,P=0.009). 3) When treated with the regimens of CFL, CFH, or LFP, patients with C677T mutants are more sensitive to chemotherapy than the patients with wild type allele. For A1298C polymorphism, patients with 1298AA genotype achieved a significantly higher response rate than patients with 1298AC/CC genotype, when treated with the regimen of CFL. However, when treated with the other 4 regimens, no significant differences were found. 4) The incidence rates of nausea/vomiting in MTHFR C677T TT, CT or A1298C AA genotypes were significantly higher than other genotypes. CONCLUSIONS: The present study indicates that the polymorphisms of MTHFR may be an important factor to predict the efficacy and/or treatment-related toxicity in the 5-Fu based chemotherapy of gastric cancer.