谷胱甘肽转硫酶P1(rs1695)基因多态性与Ⅳ期乳腺癌紫杉类和(或)蒽环类药物化疗疗效的关系

Association of polymorphisms of GSTP1(rs1695)with the efficacy of paclitaxel/anthracycline-based chemotherapy in stageⅣ breast cancer

目的检测乳腺癌患者外周血谷胱甘肽转硫酶P1(glutathione S-transferase P1,GSTP1)单核苷酸多态性位点rs1695[GSTP1(rs1695)]的基因分型,分析其与Ⅳ期乳腺癌患者采用紫杉类和(或)蒽环类药物化疗疗效的关系。方法应用聚合酶链式反应(PCR)-高分辨率熔解曲线技术(high resolution melting,HRM)检测128例Ⅳ期女性乳腺癌患者外周血中GSTP1(rs1695)基因分型,并根据PCR-HRM检测的不同基因型随机抽取10%的样本进行测序验证。应用SPSS11.5软件进行统计学分析,采用Hardy-Weinberg遗传平衡检验方法进行基因型分布遗传平衡吻合度检验,采用χ2检验及Fisher确切概率法分析不同基因型与乳腺癌患者化疗疗效的关系,用非条件logistic回归模型计算比值比(OR)和95%可信区间(CI)。结果 128例Ⅳ期乳腺癌患者中,GSTP1(rs1695)AA基因型占57.8%(74/128)、AG基因型占39.8%(51/128)、GG基因型占2.3%(3/128),经Hardy-Weinberg遗传平衡检验,证实本研究入组病例GSTP1(rs1695)基因具有群体代表性(P>0.05)。128例患者均接受以紫杉类和(或)蒽环类药物为基础的化疗方案,化疗有效率为57.03%(73/128),化疗无效率为42.97%(55/128),化疗无效病例中病情稳定占18.75%(24/128),AG/GG基因型患者的化疗疗效优于AA基因型(OR=4.139,95%CI:1.907～8.975,P<0.01),携带G基因患者的化疗有效率高于携带A基因的患者(χ2=12.163,P<0.01);其中70例紫杉类联合蒽环类药物化疗的患者中,AG/GG基因型患者的化疗疗效优于AA基因型(OR=4.016,95%CI:1.404～11.483,P<0.01),携带G基因患者的化疗有效率高于携带A基因的患者(χ2=5.943,P<0.05)。结论 GSTP1(rs1695)的基因多态性可作为乳腺癌患者采用紫杉类和(或)蒽环类药物化疗疗效预测的遗传标记物,值得进一步大样本量的研究。

Objective To detect the single nucleotide polymorphisms of rs1695 of glutathione transferase PI[GSTP1 （rs1695）] in the peripheral blood of breast cancer patients, and to analyze its association with the efficacy of paclitaxel/ anthracycline-based chemotherapy in stage IV breast cancer patients. Methods The genotypes of GSTP1 （rs1695） gene polymorphisms were determined by polymerase chain reaction （PCR）-high resolution melting （HRM） method in 128 cases of female stage IV breast cancer, and 10% samples were tested by gene sequencing technique according to the PCR-HRM results. The SPSS 11.5 software was used for statistical analysis, the Hardy-Weinberg equilibrium test was used for genetic equilibrium distribution of genotypes, the correlation of different genotypes with chemotherapy responses was analyzed by the X2 test and Fishers exact test, and non-conditional logistic regression model was used to calculate odds ratio （OR） and 95% confidenceinterval （CI）. Results Of the 128 cases of stage IV breast cancer, GSTPl（rs1695） AA genotype accounted for 57.8% （74/ 128）, AG genotype for 39. 8% （51/128）, and GG genotype for 2. 30% （3/128）. Hardy-Weinberg test suggested that our research had a group representation （P〈0. 05）. Chemotherapy with paclitaxel/anthracycline yielded an efficiency rate of 57.03% （73/128） and an inefficiency rate of 42.97% （55/128）, and in the latter the stable disease accounted for 18.75% （24/ 128）. Patients carrying GSTP1 （rs1695） AG/GG genotype had a better response to chemotherapy than those carrying AA genotype （OR=4. 139, 95CI： 1. 907-8. 975,P〈0.01）, and GSTPl（rs1695） G gene carriers had a better response than A gene carriers （2：2： 12. 163, P〈0.01）. Among the 70 cases receiving combined treatment with anthracycline, those carrying GSTP1 （rs1695） AG/GG genotype had a better response than those carrying,AA genotype （OR- 4. 016, 95 CI：I. 404 11. 483, P〈0.01）, and GSTPl（rs1695） G gene carriers had a better response than A gene carriers （7/2：5. 943,P〈0.05）. Conclusion Genetic polymorphisms in GSTPI （rs1695） can serve as a genetic marker to forecast the chemotherapy response of stage IV breast cancer patients to paclitaxel/anthracycline-based chemotherapy, which is worthy of further large sample study.