GSTP1基因遗传变异对结直肠癌患者术后接受辅助化疗的复发风险及预后的影响

Effect of GSTP1 genetic variation on the recurrence risk and prognosis of colorectal cancer patients received postoperative adjuvant chemotherapy

目的:探讨谷胱甘肽S-转移酶P-1(glutathione S-transferase P-1,GSTP1)基因遗传变异对结直肠癌(colorectal cancer,CRC)患者术后接受辅助化疗的复发风险及预后的影响。方法:收集2010年1月到2018年12月在郑州大学第一附属医院消化内科术后接受辅助化疗的195例CRC患者的临床资料。患者术后给予5-氟尿嘧啶(5-FU)为基础的辅助化疗,治疗期间在医院评估患者的复发情况,完成固定周期的辅助化疗后通过电话随访获取患者的长期生存数据。采集患者的外周血标本提取DNA进行GSTP1基因分型,并分析其与患者临床病例特征的相关性。另外,收集部分患者接受化疗前的外周血单个核细胞(peripheral blood mononuclear cell,PBMC)提取RNA,进行GSTP1 m RNA表达分析。Kaplan-Meier生存分析方法进行基因型和预后的单变量分析,并通过多变量Cox风险比例模型进行校正。结果:195例患者的中位无疾病生存期(DFS)为4.8年,中位总生存期(OS)为6.2年。基因多态性分析显示,位于GSTP-1基因编码区域的I105V位点和预后相关。I105V位点在研究人群中的分布频率:AA型135例(69.23%)、AG型56例(28.72%)、GG型4例(2.05%),最小等位基因频率为0.16,该位点基因型分布频率符合HardyWeinberg平衡(P>0.05)。对基因型患者进行复发风险和预后的分析发现,AA基因型和AG/GG基因型患者的中位DFS分别为5.7年和3.9年(P<0.01),中位OS分别为7.0年和4.5年(P<0.01)。AG/GG基因型对患者的OS具有独立的影响(OR=1.54,P<0.05)。与AA基因型患者比较,I105V位点AG/GG基因型患者PBMC中GSTP1 mRNA表达水平较高(P<0.01)。结论:GSTP1基因I105V位点可能通过介导GSTP1 mRNA表达,进而影响CRC患者术后接受辅助化疗的复发风险及预后。

Objective: To investigate the influence of glutathione S-transferase P-1(GSTP1) genetic variation on the recurrence risk and prognosis of colorectal cancer(CRC) patients received postoperative adjuvant chemotherapy. Methods: The clinical data of 195 CRC patients, who received postoperative adjuvant chemotherapy in the Department of Gastroenterology of the First Affiliated Hospital of Zhengzhou University from January 2010 to December 2018, were collected for this study. 5-fluorouracil(5-FU) based adjuvant chemotherapy was given after surgical resection. The recurrence status of the patients was assessed during hospitalization period, and the long-term survival data of patients were obtained by telephone follow-up after finishing the scheduled adjuvant chemotherapy.GSTP1 genotyping was performed with the DNA extracted from peripheral blood specimens, and its correlation with patients’ clinical characteristics was analyzed. Additionally, RNA was extracted from peripheral blood mononuclear cell(PBMC) specimens of some CRC patients that prior to chemotherapy for GSTP1 mRNA expression analysis. The univariate analysis of genotypes and prognosis was carried out by Kaplan-Meier survival analysis, and adjusted by multivariate Cox regression model. Results: The median disease-free survival(DFS) of the 195 CRC patients was 4.8 years, and the median overall survival(OS) was 6.2 years. Polymorphism analysis indicated that the I105V locus of GSTP-1 coding region was correlated with prognosis. The prevalence of I105V in the study population:AA genotype of 135 cases(69.23%), AG genotype of 56 cases(28.72%) and GG genotype of 4 cases(2.05%), the minor allele frequency of I105V was 0.16. The genotype distribution was in accordance with Hardy-Weinberg equilibrium(P>0.05). The analysis of recurrence risk and prognosis found that the median DFS of patients with AA genotype and AG/GG genotype was 5.7 and 3.9 years respectively(P<0.01), while the median OS of two groups of patients was 7.0 and 4.5 years respectively(P<0.01). The multivariate Cox regression results indicated that AG/GG genotype was an independent factor for OS(OR=1.54, P<0.05). The m RNA expression of GSTP1 in PBMC of the patients with AG/GG genotypes were significantly higher than those patients with AA genotype(P<0.01).Conclusion: GSTP1 I105 V genetic variation influences the recurrence risk and prognosis of CRC patients received postoperative adjuvant chemotherapy possibly via mediating the m RNA expression of GSTP1.