GSTP1和ERCC1基因多态性与食管癌患者放疗敏感性及预后的关系

Relationship between GSTP1 and ERCC1 Gene Polymorphisms and Radiation Sensitivity and Prognosis in Esophageal Cancer Patients

目的探讨谷胱甘肽硫转移酶P1基因(GSTP1)和切除修复交叉互补基因1(ERCC1)基因多态性与食管癌患者放疗敏感性及预后的关系。方法选取接受多西他赛单药化疗和同期放疗的食管癌患者200例,放疗1个疗程后根据完全缓解、部分缓解、稳定、进展情况将患者分为放疗敏感组(完全缓解、部分缓解)、放疗不敏感组(稳定、进展),进行3 a随访,记录患者生存情况。采集患者外周静脉血,提取基因组DNA并进行PCR扩增,分析GSTP1基因G28152A位点和ERCC1基因C118T位点的单核苷酸多态性(SNP)。取适量的患者食管癌组织,组织匀浆后应用酶联免疫吸附法测定髓磷脂碱性蛋白1(MBP-1)、磷酸酶张力蛋白同源物(PTEN)、G1/S-特异性周期蛋白-D1(Cyclin D1)、磷脂酶Cε1(PLCE1)基因蛋白浓度。结果GSTP1基因携带杂合型GA和突变型AA的食管癌患者放疗后完全缓解、部分缓解的比例明显高于野生型GG的患者,稳定、进展的比例明显低于野生型GG的患者(P<0.01)。ERCC1基因携带野生型CC的食管癌患者放疗后完全缓解、部分缓解的比例明显高于携带杂合型CT和突变型TT的患者(P<0.01)。GSTP1基因携带杂合型GA和突变型AA的食管癌患者放疗后生存率升高(P<0.05);ERCC1基因携带野生型CC的食管癌患者放疗后生存率明显升高(P<0.05)。放疗不敏感组凋亡相关基因MBP-1、PTEN表达水平明显降低,增殖相关基因Cyclin D1、PLCE1表达水平明显升高(P<0.05)。GSTP1基因携带杂合型GA和突变型AA的食管癌患者MBP-1、PTEN表达水平明显升高,Cyclin D1、PLCE1表达水平明显降低(P<0.01)。ERCC1基因携带野生型CC的食管癌患者MBP-1、PTEN表达水平明显升高,Cyclin D1、PLCE1表达水平明显降低(P<0.05)。结论GSTP1基因携带杂合型GA和突变型AA、ERCC1基因携带野生型CC的食管癌患者放疗预后较好,可能与上调凋亡相关基因MBP-1、PTEN表达,下调增殖相关基因Cyclin D1、PLCE1表达有关。

Objective To explore the relationship between glutathione S-transferase P1 gene(GSTP1)and excision repair cross-complementation group 1 gene(ERCC1)polymorphisms and the radiosensitivity and prognosis of patients with esophageal cancer.Method A total of 200 patients with esophageal cancer who received docetaxel monotherapy and concurrent radiotherapy were selected.After one course of radiotherapy,they were divided into radiotherapy sensitive group(complete remission,partial remission)and radiotherapy non-sensitive group(stable,progression)according to complete remission,partial remission,stable and progression.Follow-up was conducted for 3 years to record survival of patient.Peripheral venous blood samples were collected,genomic DNA was extracted and PCR amplification was performed to analyze the single nucleotide polymorphisms(SNP)of GSTP1 gene G28152A site and ERCC1 gene C118T site.Adequate amounts of esophageal cancer tissues were obtained,and after tissue homogenization,the concentrations of myelin basic protein 1(MBP-1),phosphatase and tensin homolog(PTEN),G1/S-specific Cyclin D1,and phospholipase Cε1(PLCE1)gene proteins were measured by using enzyme-linked immunosorbent assay.Results The proportion of patients with esophageal cancer carrying heterozygous GA and mutant AA genotypes of GSTP1 gene who achieved complete remission or partial remission after radiotherapy was significantly higher than that of patients with wild-type GG genotype,and the proportion of patients with stable or progression was significantly lower than that of patients with wild-type GG genotype(P<0.01).The proportion of patients with esophageal cancer carrying wild-type CC genotype of ERCC1 gene who achieved complete remission or partial remission after radiotherapy was significantly higher than that of patients carrying heterozygous CT and mutant TT genotypes(P<0.01).The survival rate of patients with esophageal cancer carrying heterozygous GA and mutant AA genotypes of GSTP1 gene after radiotherapy increased(P<0.05);The survival rate of patients with esophageal cancer carrying wild-type CC genotype of ERCC1 gene after radiotherapy significantly increased(P<0.05).The expression levels of apoptosis-related genes MBP-1 and PTEN significantly decreased,while the expression levels of proliferation-related genes Cyclin D1 and PLCE1 significantly increased in the radiotherapy non-sensitive group(P<0.05).The expression levels of MBP-1 and PTEN significantly increased,and the expression levels of Cyclin D1 and PLCE1 significantly decreased in patients with esophageal cancer carrying heterozygous GA and mutant AA genotypes of GSTP1 gene(P<0.01).The expression levels of MBP-1 and PTEN significantly increased,and the expression levels of Cyclin D1 and PLCE1 significantly decreased in patients with esophageal cancer carrying wild-type CC genotype of ERCC1 gene(P<0.05).Conclusion Patients with esophageal cancer carrying heterozygous GA and mutant AA genotypes of GSTP1 gene and wild-type CC genotype of ERCC1 gene have better prognosis after radiotherapy,which may be related to upregulation of apoptosis-related genes MBP-1 and PTEN expression and downregulation of proliferation-related genes Cyclin D1 and PLCE1 expression.