程序性死亡配体1基因遗传变异对术后结直肠癌患者接受5-FU为基础辅助化疗预后的影响

doi:10.12092/j.issn.1009-2501.2019.02.010

摘要/Abstract

摘要：

目的: 探讨程序性死亡配体1（programmed death-ligand 1,PD-L1）基因遗传变异对术后结直肠癌（colorectal cancer,CRC）患者接受5-氟尿嘧啶（5-FU）为基础辅助化疗预后的影响。方法: 本研究为回顾性分析，纳入213例术后接受5-FU为基础辅助化疗的结直肠癌患者。整理患者的基线及接受治疗的预后资料。另外，收集患者外周血及术后部分癌组织标本分别用来进行PD-L1基因标记多态性位点的基因分型及PD-L1基因mRNA的表达测定。PD-L1基因的多态性位点的基因型和其他变量的相关性通过卡方检验或非参检验进行分析。不同基因型患者的PD-L1基因mRNA表达通过非参检验分析，和预后的单变量分析用Kaplan-Meier生存分析方法，并通过Cox模型对其他变量进行校正。结果: 纳入研究的PD-L1的多态性位点均是经过NCBI数据库查阅在中国人群中突变频率大于10%的三个标记多态性位点（901T>A，-1813G>C和-1349T>A位点）。其中，在预后分析上只发现901T>A位点显著的临床意义。PD-L1基因901T>A位点位于该基因内含子区域，在纳入研究的CRC患者中的分布频率为：TT型148例（69.48%），TC型59例（27.70%），CC型6例（2.82%），最小等位基因频率为0.17，三种基因型分布频率符合哈迪温伯格平衡（P=0.967）。各个基因型在患者基线临床资料中分布均衡。在预后比较上，由于CC基因型患者相对较少，将TC和CC型患者合并，在无疾病生存期（DFS）方面：TT基因型和TC/CC基因型患者的中位无疾病生存期（mDFS）分别为4.7年和3.3年，差异具有显著的统计学意义（P=0.001）。在总生存期（OS）方面，两种基因型患者的中位总生存期（mOS）分别为6.5年和4.7年，差异具有显著统计学意义（P<0.001）。经过Cox模型校正OS之后，TC/CC基因型对OS具有独立的影响意义（OR=1.89，P=0.006）。另外，在79例癌组织标本的PD-L1 mRNA表达分析中发现，TC/CC型患者相对于TT基因型患者，癌组织中PD-L1的mRNA表达明显较高，并具有显著的统计学意义（P<0.001）。结论: PD-L1基因901T>A位点可能通过介导了PD-L1基因mRNA的表达从而影响了接受5-FU为基础辅助化疗的CRC患者的预后。

关键词: 结直肠癌, 程序性死亡配体1, 多态性, 预后

Abstract:

AIM: To investigate the association between PD-L1 genetic variation and clinical outcomes of postoperative CRC patients received 5-FU based adjuvant chemotherapy. METHODS: Designed as a retrospective analysis, a total of 213 CRC patients who underwent surgical treatment and received 5-FU based adjuvant chemotherapy were included in this study. Baseline characteristics and the clinical outcomes data of the patients included in this study were managed. Peripheral blood and the postoperative tissue specimen of the CRC patients were collected for the genotyping of the genetic variation and PD-L1 mRNA expression, respectively. The correlation between genetic variation and other baseline characteristics was analyzed by chi square test and non-parametric test. The mRNA expression of PD-L1 in different genotypes was analyzed by non-parametric test. The univariate analysis of genotypes and prognosis was carried out by Kaplan-Meier survival analysis, and multivariate was adjusted by Cox regression analysis. RESULTS:The single nucleotide polymorphism included in this this study were collected in the NCBI database with the minor allele frequency >10% in Chinese population (901T>A, -1813G>C and -1349T>A). Of the polymorphisms analyzed, only 901T>A was of clinical significance. Located in the Intron region, the prevalence of 901T>A among the CRC patients were as follows: TT genotype 148 cases (69.48%), TC genotype 59 cases (27.70%), CC genotype 6 cases (2.82%), the minor allele frequency was 0.17.The distribution of three genotypes was in accordance with Hardy-Weinberg Equilibrium (P=0.967). TC genotype and CC genotype patients were merged in the comparison of prognosis. The survival analysis of patients with different genotypes found that the median Disease-free survival (mDFS) of patients with TT and TC/CC genotypes was 4.7 and 3.3 years, which was statistically significant (P=0.001). In terms of overall survival (OS), the median OS (mOS) of the two genotypes were 6.5 and 4.7 years respectively, which was statistically significant as well (P<0.001). Adjusted in multivariate Cox regression analysis for OS, TC/CC genotype was an independent factor for OS (OR=1.89, P=0.006). Additionally, of the 79 postoperative tissue specimens, the results showed that the mRNA expression of PD-L1 in cancer tissues of the patients with TC/CC genotypes were significantly higher than those of the TT genotype patients (P<0.001). CONCLUSION: The clinical outcomes of CRC patients receiving 5-FU based adjuvant chemotherapy may be influenced by PD-L1 901T>A through mediating the mRNA expression of PD-L1.

Key words: colorectal cancer, programmed death-ligand 1, polymorphism, prognosis

中图分类号:

R735.3

白艳，郑晓永，杨雅阁，方立峰. 程序性死亡配体1基因遗传变异对术后结直肠癌患者接受5-FU为基础辅助化疗预后的影响[J]. 中国临床药理学与治疗学, 2019, 24(2): 180-187.

BAI Yan, ZHENG Xiaoyong, YANG Yage, FANG Lifeng. Influence of programmed death-ligand 1 genetic variation on the clinical outcomes of postoperative CRC patients received 5-FU based adjuvant chemotherapy[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2019, 24(2): 180-187.

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