亚甲基四氢叶酸还原酶和胸苷酸合成酶基因多态与乳腺癌化疗敏感性关系的研究

Relationship between genetic polymorphisms of methylene tetrahydrofolate reductase and thymidylate synthetase and chemosensitivity of breast cancer

目的:观察亚甲基四氢叶酸还原酶(MTHFR)基因C677T、A1298C多态和胸苷酸合成酶(TS)基因5′-UTR(28bp)、3′-UTR(6bp)多态与乳腺癌患者对化疗敏感性的关系。方法:乳腺癌患者87例,其中新辅助化疗61例,晚期姑息化疗26例。分别接受CAF、AT方案化疗。所有病例化疗前抽静脉血,提取白细胞DNA,用PCR-RFLP技术检测分析MTHFR和TS基因型。结果:87例乳腺癌患者化疗总有效率为69.0%。39例接受CAF方案化疗患者有效率为61.5%,48例接受AT方案化疗患者的有效率为75.0%。MTHFRC677TT/T基因型患者的化疗有效率(87.5%)显著高于C/C基因型患者(52.4%),χ2=6.24,P=0.01。CAF方案化疗组患者中,MTHFRC677TT/T、T/C基因型患者的化疗有效率(90.0%、68.8%)显著高于C/C基因型患者(30.8%),χ2=8.74,P=0.011。61例新辅助化疗患者,MTHFRC677TT/T基因型患者的化疗病理反应率(83.3%)显著高于C/C基因患者(35.7%),χ2=7.619,P=0.006。TS6bp-6/-6基因型患者的化疗病理反应率(80.8%)显著高于-6/+6基因患者(46.7%),χ2=6.911,P=0.009。接受AT方案化疗的患者中TS-6/-6基因型患者的化疗病理反应率(92.9%)显著高于-6/+6基因型患者(45.5%),χ2=6.866,P=0.009。结论:MTH-FRC677T和TS6bp基因多态性对指导乳腺癌临床个体化治疗具有较高的应用价值。

OBJECTIVE： To evaluate the relationship between the genetic polymorphisms of MTHFR （C677T and A1298C） and TS [5′-UTR（28 bp）and 3′-UTR（6 bp）] and chemosensitivity of breast cancer. METHODS： Eighty-seven cases of advanced breast cancer were investigated, and 61 of which were treated with neoadjuvant chemotherapy. Thirty nine cases were administrated with CAF chemotherapy, while 48 cases were AT. The blood of all the patients was collected before the chemotherapy, DNA of blood leukocytes was extracted and MTHFR genotypes and TS genotypes were detected by PCR-RFLP. RESULTS： The overall clinical response rate （cRR） to chemotherapy was 69.0%. The cRR（s） of the regimens of CAF and AT were 61.5% and 75.0%. The cRR of TT genotype in MTHFR C677T （87.5 %） cases was significantly higher than that of the C/C genotype （52. 4 %）, χ^2 = 6. 24, P = 0. 01. Among the cases administrated with CAF regimens, the cRR（s） of T/T and C/T genotypes （90. 0%, 68. 8%） in MTHFR C677T cases were significantly higher than those of the C/C genotype （30. 8%） ,χ^2=8. 74,P=0. 011. In the 61 cases treated with neoadjuvant chemotherapy, the cPR（s） of T/T genotype （83. 3%） in MTHFR C677T cases was significantly higher than that of the C/C genotype （35.7）χ^2 =7.619, P=0.006. The cPR of 6 bp -6/-6 genotype （80. 8%） in TS cases was significantly higher than that of the -6/＋6 genotype （46.7%）,7,2 =6.911,P= 0. 009. Among the cases administrated with AT regimens, the cPR of -6/-6 genotype （92. 9%） in TS cases was significantly higher than that of the - 6/＋ 6 genotype （45.5%）, χ^2 = 6. 866, P = 0. 009. CONCLUSION： The polyrnorphisms of MTHFR C677T and TS 6 bp may be an important factor to predict the efficacy of the chemotherapy in breast cancer.