卡培他滨为基础的辅助化疗在结直肠癌中的疗效及相关药物基因组学分析

The Clinical Outcomes of CRC Patients Received Capecitabine Based on Adjuvant Chemotherapy and the Corresponding Pharmacogenomics Analysis

[目的]探讨卡培他滨为基础的辅助化疗在结直肠癌患者中的疗效及相关药物基因组学分析。[方法]纳入176例术后接受卡培他滨为基础辅助化疗的结直肠癌患者,收集患者外周血及术后癌组织标本分别进行基因分型及表达测定。多态性位点的基因型和其他变量的相关性通过Logistic回归模型进行分析。不同基因型的激酶插入区受体(kinase insert domain receptor,KDR)表达通过非参检验分析,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] 176例患者的中位无疾病生存期(median disease free survival,mDFS)为4.1年,中位总生存期(median overall survival,mOS)为5.2年。药物基因组学分析方面,在KDR的多态性位点中,只发现了4397T>C位点的临床意义。4397T>C位点的分布频率为:TT型95例(53.98%),TC型70例(39.77%),CC型11例(6.25%),最小等位基因频率为0.26,三种基因型分布频率符合哈迪温伯格平衡(P=0.690)。不同基因型在患者基线临床资料中分布均衡。携带C等位基因的TC/CC型患者和野生型TT型患者的mDFS分别为4.4和3.2年,差异有统计学意义(P=0.012)。TC/CC型和TT基因型患者的mOS分别为5.2年和4.0年,差异有统计学意义(P=0.007)。对OS构建多变量的Cox模型校正后TC/CC基因型对OS的影响仍具有统计学意义(HR=0.55,P=0.011)。另外,进一步在79例术后癌组织标本的mRNA表达分析中发现,4397T>C位点TC/CC基因型患者相对于野生型TT型患者,癌组织标本中KDR mRNA表达水平显著降低(P<0.001)。[结论] KDR基因4397T>C位点可能通过影响KDR mRNA的表达影响结直肠癌患者的预后。

[Objective] To investigate the clinical outcomes of CRC patients received Capecitabine based adjuvant chemotherapy and the corresponding pharmacogenomics analysis.[Methods] 176 patients with colorectal cancer who underwent surgical treatment and received capecitabine based adjuvant chemotherapy were included in this study. Peripheral blood and the postoperative tissue specimen of the CRC patients were collected for the genotyping of polymorphism and mRNA expression of kinase insert domain receptor(KDR),respectively. The correlation of the polymorphism genotypes and other variables was analyzed by logistic regression model. The univariate analysis of genotypes and prognosis was carried out by Kaplan-Meier survival analysis,and multivariate were adjusted by Cox regression analysis. [Results] The median disease-free survival(mDFS)of the 176 CRC patients was 4.1 years,and the median overall survival(mOS) was 5.2 years. In terms of the pharmacogenomics analysis,the prevalence of 4397 T>C in KDR among the study population were as follows:TT genotype 95 cases(53.98%),TC genotype 70 cases(39.77%),CC genotype 11 cases(6.25%),minor allele frequency of 4397 T>C was 0.26. The distribution of three genotypes in accordance with Hardy-Weinberg Equilibrium(P=0.690). There were no statistical differences in the distribution of the genotypes in baseline clinical data. The survival analysis of patients with different genotypes found that the mDFS of patients with C allele carriers and wild type TT genotype was 4.4 and 3.2 years(P=0.012). The mOS of the two genotypes were 5.2 and 4.0 years(P=0.007).Adjusted in multivariate Cox regression analysis for OS,TC/CC genotype was an independent factor for OS(HR =0.55,P =0.011). Additionally,of the 79 postoperative tissue specimens,gene expression analysis was conducted. And the results show that the expression of KDR in cancer tissues of the patients with TC/CC genotypes were significantly lower than those of the wild type TT genotype patients(P <0.001).[Conclusion] The polymorphism 4397 T>C of KDR may influence the prognosis of CRC patients by affecting the mRNA expression of KDR.