胞苷脱氨酶基因遗传变异对结直肠癌患者术后辅助卡培他滨为基础化疗方案疗效的影响

Effect of Cytidine Deaminase Gene Polymorphism on Clinical Outcomes of Colorectal Cancer Patients Receiving Capecitabine-based Adjuvant Chemotherapy

[目的]探讨胸苷脱氨酶(CDA)基因遗传变异对结直肠癌患者术后辅助卡培他滨为基础的化疗方案疗效及安全性的影响。[方法]纳入215例术后接受辅助化疗的结直肠癌患者。收集患者外周血提取DNA用来进行CDA多态性位点基因分型。另外,收集85例结直肠癌患者的化疗前外周血单核细胞(PBMC)提取RNA对CDA mRNA表达水平进行测定。对基因型和基线临床资料进行相关性分析。基因型和预后的单变量分析用Kaplan-Meier生存分析方法,并通过Cox风险比例模型对其他变量进行校正。[结果] CDA基因启动子区域的多态性位点rs532545和疗效相关。rs532545位点在结直肠癌患者中的分布频率为:GG型157例(73.02%),GA型53例(24.65%),AA型5例(2.33%),最小等位基因频率为0.15,三种基因型分布频率符合哈迪温伯格平衡(P=0.834)。预后比较将GA和AA型患者合并,对不同基因型患者进行预后分析发现,GA/AA和GG基因型患者的3年无疾病生存(DFS)率分别为81.03%和62.42%,差异具有统计学意义(P=0.002)。两种基因型患者的5年总生存(OS)率分别为72.41%和53.50%,差异具有统计学意义(P=0.016)。对DFS构建多变量的Cox模型校正之后GA/AA基因型对DFS的影响仍然具有统计学意义(OR=0.55,P=0.011)。另外,进一步在85例外周血单核细胞的mRNA表达分析中发现,携带A等位基因的患者相对于野生型GG型患者,外周血单核细胞中CDA的mRNA表达明显较高,并具有统计学意义(P<0.001)。[结论] CDA基因rs532545位点可能通过影响该基因mRNA的表达进而使结直肠癌患者从卡培他滨的治疗当中获益。

[Purpose ]To investigate the association between CDA gene polymorphism and clinical outcomes of colorectal cancer(CRC)patients receiving capecitabine-based adjuvant chemotherapy.[Methods] Two hundred and fifteen patients with colorectal cancer receiving adjuvant chemotherapy were included in this study.Peripheral blood samples were collected for DNA extraction and the genotyping of CDA gene.Additionally,pretreatment peripheral blood mononuclear cells (PBMCs)of 85CRC patients were collected for CDA mRNA expression analysis.The survival of patients was analyzed by Kaplan-Meier method.The association of CDA genotypes with clinical features and the survival of patients was examined with univariate and multivariate Cox regression analysis.[Results ]The distribution of GG,GA,AA genotypes of CDA rs532545 was 73.02%(157/215),24.65%(53/215)and 2.33%(5/215),the minor allele frequency of 5633C>T was 0.15.The distribution of three genotypes was in accordance with Hardy- Weinberg equilibrium (P=0.834).The 3-year disease-free survivals (DFS)of GA/AA genotype and GG genotype were 81.03% and 62.42% (P=0.002);and the 5-year overall survivals (OS)were 72.41% and 53.50%(P=0.016).Multivariate Cox regression analysis showed that GA/AA genotype was an independent factor for favorable DFS (OR=0.55,P=-0.011).The mRNA expression of CDA in PBMCs of patients with GA or AA genotypes was significantly higher than that of GG genotype patients (P<0.001). [Conclusion]CRC patients with higher CDA mRNA expression are likely to benefit from capecitabine based adjuvant chemotherapy,which may be associated with rs532545 polymorphism of CDA gene.