谷胱甘肽-S-转移酶P1基因多态性与晚期胃癌患者对顺铂化疗疗效的相关性研究

Relationship between glutathione S-transferase P1 polymorphism and clinical outcomes of advanced gastric cancer patients treated with DDP-based chemotherapy

目的基因多态性通过影响药物的代谢、转运和作用靶点从而导致药物疗效和毒性的个体差异,寻找明确的生物学标记来识别获益人群已成为最大的挑战。本研究旨在观察谷胱甘肽-S-转移酶P1(GSTP1)基因多态性与以顺铂(DDP)为基础的化疗方案治疗晚期胃癌疗效间的关系。方法收集经病理学确诊的晚期胃癌患者59例。所有病例化疗前抽取外周静脉血,提取脱氧核糖核酸(DNA),用连接酶检测反应技术(PCR-LDR)检测研究对象的GSTP1基因型。所有患者经多西他赛(DOCETAXEL)/DDP/5-氟尿嘧啶(5-FU)联合方案化疗,化疗结束后观察疗效及其与GSTP1基因多态性的关系。结果 59例晚期胃癌患者中,15例(25.4%)为GSTP1G/G基因型,21例(35.6%)为GSTP1G/A基因型,23例(39.0%)为GSTP1A/A基因型。其中4例完全缓解,14例部分缓解,19例稳定,22例进展,总有效率为30.5%(18/59)。GSTP1G/G基因型患者的化疗有效率(73.3%)明显高于G/A基因型患者(19.0%)(χ2=10.616,P=0.005),同样明显高于A/A基因型患者(13.0%)(χ2=14.202,P=0.001)。G/A基因型患者的化疗有效率与A/A基因型患者之间差异无统计学意义(χ2=0.31,P=0.856)。突变基因型(G/G+G/A)对化疗较敏感,其化疗有效率是野生基因型(A/A)的3.2倍(95%CI1.442～7.302,P=0.004)。结论 GSTP1基因型对预测以DDP为基础化疗方案治疗晚期胃癌的疗效具有较好的临床意义。

Objective The main challenge is the development of predictive marker profiles to identify patients who will derive both minimal toxicity and maximum benefit from certain chemotherapy.The aim of this study was to assess whether genetic polymorphisms of the glutathione S-transferase P1（GSTP1）,are associated with the clinical outcome of advanced gastric cancer patients treated with DOCETAXEL/DDP/5-FU-based chemotherapy.Methods DNAs of peripheral blood leukocytes from 59 patients with advanced gastric cancer were obtained before chemotherapy and were analyzed for GSTP1 genotypes by polymerase chain reaction ligation detection reaction（PCR-LDR）method.Then all of the patients were treated with DOCETAXEL/DDP/5-FU-based chemotherapy.Results The frequencies of GSTP1 genotype,G/G were 25.4%,G/A were 35.6% and A/A were 39.0%.Total response rate of chemotherapy was 30.5%,including 4 patients with complete response,14 with partial response,19 with stable disease and 22 with progressive disease.However,the response rate in patients with G/G genotype（73.3%）was significantly higher than either patients with G/A genotype（19.0%）（χ2=10.616,P=0.005）or patients with A/A genotype（13.0%）（χ2=14.202,P=0.001）.There was no difference of response rate between G/A and A/A genotype（χ2=0.31,P=0.856）.The response rate in patients with mutation genotype（G/G＋G/A）significantly（3.2-fold）higher than either patients with wild genotype（A/A）（95% CI ranging from 1.442 to 7.302,P=0.004）.Conclusions GSTP1 polymorphism can predict the effects of DOCETAXEL/5-FU/DDP-based chemotherapy in advanced gastric carcinoma.