摘要
背景与目的:程序性死亡配体1(programmed death-ligand 1,PD-L1)在结直肠癌细胞的免疫逃逸过程中发挥关键作用。探讨PD-L1基因遗传变异对术后结直肠癌患者接受卡培他滨为基础辅助化疗预后的影响。方法:回顾性分析在河南省肿瘤医院普外科和河南中医药大学第三附属医院肛肠外科收治的213例术后接受卡培他滨为基础辅助化疗的结直肠癌患者的预后状况,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χ2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:预后数据方面,纳入研究的213例患者均可评价预后,整体人群的中位无病生存期(disease-free survival,DFS)为4.6年,中位总生存期(overall survival,OS)为6.5年。纳入研究的PD-L1的多态性位点均是经过数据库查阅在中国人群中突变频率大于10%的3个标记多态性位点(rs2297136、rs822336和rs822337位点)。其中,在预后分析上只发现了rs2297136位点显著的临床意义。PD-L1基因rs2297136位点位于该基因内含子区域,在纳入研究的结直肠癌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0.17,3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DFS方面,TT基因型和TC/CC基因型患者的中位DFS分别为4.7和3.3年,差异有统计学意义(P=0.001)。在OS方面,两种基因型患者的中位OS分别为6.5和4.7年,差异有统计学意义(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,差异有统计学意义(P<0.001)。结论:PD-L1基因rs2297136位点可能通过介导PD-L1基因mRNA的表达从而影响接受卡培他滨为基础辅助化疗的结直肠癌患者的预后。
Background and purpose:Programmed death-ligand 1(PD-L1)is of great importance in the process of colorectal cancer cell escaping from immune system.Therefore,the association between PD-L1 genetic variation and clinical outcomes of postoperative colorectal cancer patients receiving capecitabine-based adjuvant chemotherapy was investigated in this study.Methods:Designed as a retrospective analysis,a total of 213 colorectal cancer patients from Department of General Surgery,Tumor Hospital of Henan Province and Department of Anus and Intestine Surgery,the Third Affiliated Hospital of Henan University of Traditional Chinese Medicine underwent surgical treatment and received capecitabine-based adjuvant chemotherapy 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 specimens of the colorectal cancer 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 Chisquare test and nonparametric test.The mRNA expression levels of PD-L1 in different genotypes were analyzed by nonparametric test.The univariate analyses of genotypes and prognosis were carried out by Kaplan-Meier survival analysis,and multivariate analyses were adjusted by Cox regression analysis.Results:In terms of the clinical outcomes,all of the 213 colorectal cancer patients were available for efficacy evaluation.The median disease-free survival(DFS)of the 213 colorectal cancer patients was 4.6 years,and the median overall survival(OS)was 6.5 years.The single nucleotide polymorphisms included in this study were collected in the database with the minor allele frequency>10%in Chinese population(rs2297136,rs822336 and rs822337).Of the polymorphisms analyzed,only rs2297136 was of clinical significance.The following was the prevalence of rs2297136 in the intron region among the colorectal cancer patients:TT genotype 148 cases(69.48%),TC genotype 59 cases(27.70%)and CC genotype 6 cases(2.82%).The minor allele frequency was 0.17.The distributions of three genotypes were in accordance with Hardy-Weinberg Equilibrium(P=0.967).Patients with TC and CC genotypes were merged in the comparison of prognosis.The survival analysis of patients with different genotypes showed that the median DFS of patients with TT genotype or TC/CC genotype was 4.7 and 3.3 years,respectively(P=0.001).The median OS was 6.5 and 4.7 years for the two genotypes 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 DFS(OR=1.89,P=0.006).Additionally,of the 79 postoperative tissue specimens,the results showed that the mRNA expression levels of PD-L1 in cancer tissues of the patients with TC/CC genotype were significantly higher compared with patients with TT genotype(P<0.001).Conclusion:The clinical outcomes of colorectal cancer patients receiving capecitabine-based adjuvant chemotherapy may be influenced by PD-L1 rs2297136 through mediating the mRNA expression of PD-L1.
作者
张慧俭
刘佃温
周晓丽
刘永刚
李敏
刘世举
ZHANG Huijian;LIU Dianwen;ZHOU Xiaoli;LIU Yonggang;LI Min;LIU Shiju(School of Acupuncture,Moxibustion and Tuina,Henan University of Traditional Chinese Medicine,Zhengzhou 450000,Henan Province,China;Department of Anus and Intestine Surgery,the Third Affiliated Hospital of Henan University of Traditional Chinese Medicine,Zhengzhou 450000,Henan Province,China;Department of General Surgery,Tumor Hospital of Henan Province,Zhengzhou 450000,Henan Province,China)
出处
《中国癌症杂志》
CAS
CSCD
北大核心
2019年第10期795-802,共8页
China Oncology
基金
河南省科技厅科技攻关项目（162102310109）
关键词
结直肠癌
程序性死亡配体1
多态性
预后
Colorectal cancer
Programmed death-ligand 1
Polymorphism
Prognosis
