[摘要] 目的：探讨激酶插入区受体（kinase insert domain receptor,KDR）基因遗传变异与接受5-FU 为基础辅助化疗的结直肠癌（colorectal cancer, CRC）患者预后的关系。方法：回顾性分析2012 年1 月至2017 年12 月在郑州人民医院肛肠外科接受手术切除治疗的CRC 患者共176 例的临床资料，并收集93 例术后癌组织标本。采用聚合酶链式反应-限制性片段长度多态性(PCRRFLP)技术检测KDR基因多态性位点基因型，采用qPCR检测癌组织中KDR基因mRNA的表达水平。通过logistic 回归模型分析多态性位点的基因型与其他变量的相关性，非参数检验分析KDR不同基因型的表达，采用Kaplan-Meier 生存分析单变量KDR基因型与患者预后的关系，并通过Cox 风险比例模型对其他变量进行校正。结果：在KDR 的多态性位点中，仅发现了rs2071559 位点具有临床意义。该位点在176 例CRC患者中的分布频率：TT基因型95 例（53.98%），TC基因型70 例（39.77%），CC基因型11 例（6.25%）；最小等位基因频率为0.26；3 种基因型分布符合Hardy-Weinberg 遗传平衡定律（P=0.690）。携带C等位基因的TC/CC基因型患者与野生型TT基因型患者的中位无复发生存期（mDFS）分别为4.4 和3.2 年（P< 0.05）；TC/CC基因型和TT基因型患者的中位总生存期（mOS）分别为5.2 和4.0 年（P<0.05）。对OS构建多变量的Cox模型校正后，TC/CC基因型对mOS具有明显影响（OR=0.55，P<0.05）。rs2071559 位点TC/CC基因型患者相对于野生型TT 基因型患者KDR mRNA 表达水平显著降低（P<0.01）。结论：KDR基因rs2071559 位点多态性与CRC患者临床治疗效果相关，其机制是可能通过影响KDR mRNA表达水平进而影响CRC患者的预后。

[Abstract] Objective: To investigate the association between genetic variation of kinase insert domain receptor (KDR) and the prognosis in colorectal cancer (CRC) patients received 5-FU based adjuvant chemotherapy. Methods: The clinical data of 176 CRC patients,who underwent surgical treatment at the Department of Anus and Intestine Surgery, People’s Hospital of Zhengzhou during January 2012 and December 2017, were retrospectively analyzed, and 93 cases of tumor tissues were collected for this study. The genotype of KDR polymorphism locus was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). qPCR was used to detect the expression of KDR mRNA in colorectal cancer tissues. The correlation between the polymorphism genotypes and other variables was analyzed by logistic regression model. The expression of different genotypes of KDR was analyzed by nonparametric test. The relationship between KDR genotype and prognosis of patients was analyzed by Kaplan-Meier survival analysis, and the other variables were adjusted by Cox risk scale model. Results: Of the polymorphisms analyzed, only rs2071559 was of clinical significance.The distribution frequency of KDR rs2071559 in 176 CRC patients was as follows: TT genotype in 95 cases (53.98%), TC genotype in 70 cases (39.77%) and CC genotype in 11 cases (6.25%); the minor allele frequency was 0.26; and the distribution of three genotypes was in accordance with Hardy-Weinberg's Equilibrium (P=0.690). The median disease free survival (mDFS) of patients carrying C allele and wild type TT genotype was 4.4 and 3.2 years, respectively (P<0.05); The median overall survival (mOS) of patients with TC/CC genotype and TT genotype was 5.2 and 4.0 years, respectively (P<0.05). After COX model modification, the effect of TC/CC genotype on mOS was still statistically significant (OR=0.55, P<0.05). The mRNA expression of KDR in cancer tissues of the patients with TC/CC genotypes were significantly lower than those of the wild type TT genotype (P<0.01). Conclusion: The polymorphism of KDR rs2071559 is associated with clinical outcomes in patients with colorectal cancer. KDR rs2071559 may affect the prognosis of colorectal cancer patients by affecting the mRNA expression of KDR.

河南省郑州市科技发展计划资助项目（No.20150061）