PD-L1基因遗传变异对接受铂类药物为基础辅助化疗的非小细胞肺癌患者的预后影响

Influence of genetic variation of programmed death-ligand 1(PD-L1)on the prognosis of patients with non-small cell lung cancer who received platinum-based adjuvant chemotherapy

目的探讨PD-L1基因遗传变异对接受铂类药物为基础辅助化疗的非小细胞肺癌患者的预后影响。方法纳入278例2012年1月至2018年12月在郑州大学第一附属医院呼吸科术后接受铂类药物为基础辅助化疗的非小细胞肺癌患者。入院接受治疗期间收集患者的生物学样本,辅助化疗期间评估患者的复发情况以及不良反应发生情况,完成固定周期的辅助化疗后通过电话随访获取患者的长期生存数据。通过收集的血液学样本提取的DNA进行PD-L1基因分型。进一步收集68例患者术后的癌组织标本,提取RNA进行PD-L1基因mRNA表达分析。基因型和预后的单变量分析用Kaplan-Meier生存分析方法。结果278例患者的中位无疾病生存期(DFS)为3.2年,中位总生存期(OS)为4.9年。-1813G>C位点的分布频率为:GG型173例(62.23%),GC型92例(33.09%),CC型13例(4.68%),最小等位基因频率为0.21,三种基因型分布频率符合哈迪温伯格平衡(P=0.864)。后期分析将GC和CC基因型合并;GG基因型和GC/CC基因型患者的中位DFS分别为2.7年和4.0年(P=0.013),中位OS分别为4.0年和5.4年(P=0.009)。未发现该位点不同基因型和2级以上不良反应发生率的存在关联(P>0.05);相对于GC/CC基因型患者,-1813G>C位点GG基因型患者癌组织标本中PD-L1基因的mRNA表达相对较高(3.67±0.65比2.69±0.78,P<0.001)。结论PD-L1基因-1813G>C位点可以影响术后接受铂类药物为基础辅助化疗的非小细胞肺癌患者的预后。

Objective The aim of present study was to investigate the influence of genetic variation of programmed death-ligand 1(PD-L1)on the prognosis of patients with non-small cell lung cancer(NSCLC)who received platinum-based adjuvant chemotherapy.Methods This study was designed as a retrospective analysis,and a total of 278 patients with postoperative NSCLC who received platinum-based adjuvant chemotherapy from January 2012 to December 2018 in the Department of Respiratory Medicine of the First affiliated Hospital of Zhengzhou University were included in this study.Biological specimens of the patients were collected during hospitalization.Recurrence status and adverse reactions were evaluated in the hospital during adjuvant chemotherapy.Survival data of the patients were obtained through telephone follow-up after completing the fixed cycle of adjuvant chemotherapy.DNA extracted from the collected hematological specimens was genotyped for PD-L1 gene polymorphism.Additionally,postoperative cancer tissue specimens from 68 patients were collected for RNA extraction in order to perform the PD-L1 mRNA expression analysis.The univariate analysis of genotypes and prognosis was carried out by Kaplan-Meier survival analysis.Results Prognostic results indicated that the median disease-free survival(DFS)of the 278 patients with NSCLC was 3.2 years and the median overall survival(OS)was 4.9 years.The prevalence of-1813G>C polymorphism were:GG genotype 173 cases(62.23%),GC genotype 92 cases(33.09%),CC genotype 13 cases(4.68%),the minor allele frequency was 0.21,the distribution of the three genotypes was in accordance with Hardy-Weinberg Equilibrium(P=0.864).In view of the rare frequency of CC genotype,GC and CC genotype were merged in the following analysis.The survival analysis results of the two genotype groups suggested that the median DFS of patients with GG and GC/CC genotype was 2.7 and 4.0 years,which was statistically significant(P=0.013).Furthermore,the median OS of patients with GG and GC/CC was 4.0 and 5.4 years respectively,which was statistically significant as well(P=0.009).However,the safety analysis failed to find the significant association between the polymorphism and adverse events(P>0.05).Interestingly,expression analysis of RNA extracted from cancer tissues specimens indicated that the PD-L1 mRNA expression of the patients with GG genotype were significantly higher than those of the GC/CC genotype(3.67±0.65 vs 2.69±0.78,P<0.001).Conclusion The prognosis of patients with postoperative non-small cell lung cancer who received platinum-based adjuvant chemotherapy is influenced by-1813G>C polymorphism of PD-L1 gene.