The Prognostic Value Of Ki-67 In Patients With Non-small Cell Lung Cancer

Objectives:The prognostic value of Ki-67 in patients with lung adenocarcinoma and lung squamous cell carcinoma was analyzed by clinical data and verified by published articles,TCGA data and GEO data.Using bioinformatics to explain the possible mechanism of how Ki-67 affects prognosis,determine the prognostic value of Ki-67 in patients with lung adenocarcinoma and lung squamous cell carcinoma.Methods:Systematically reviewed patients who were admitted to the Department of Oncology,the First Hospital of China Medical University from August 2013 to January2019,and whose pathological diagnosis was lung adenocarcinoma(LUAD)or lung squamous cell carcinoma(LUSC)and the expression data of Ki-67 can be obtained,explored the relationship between Ki-67 expression and overall survival(OS)in LUAD or LUSC patients.Chi-square test was used to compare the differences between groups,kaplan-meier method was used to calculate the median survival time of Ki-67 high expression group and Ki-67 high expression group.Log-rank method was used to compare the median survival time.Cox regression analysis model was used to identify independent risk/protect factors that could affect the prognosis of LUAD or LUSC patients.A systematic search was performed on articles evaluating the relationship between Ki-67overexpression and OS/DFS in patients with LUAD or LUSC from the PubMed,EMbase,and Cochrane databases before January 4,2020,and supplemented with references from related articles,investigating the effect of Ki-67 overexpression on the prognosis of patients with LUAD and LUSC and their different subgroups.After determining the articles that meet the inclusion and exclusion criteria,use the NOS scale to evaluate the article quality and extract the relevant information of the article.The selected effect model is determined according to the heterogeneity test results,and the evaluation index is the hazard ratio(HR).funnel plots and Egger’s tests were used to investigate publication bias.Sensitivity analysis was used to explore sources of heterogeneity.Gene set enrichment analysis(GSEA)was used to explore the potential mechanism of Ki-67 and proliferation pathways.Pearson’s correlation coefficient was used to determine Ki-67related genes.Gene Set Variation Analysis(GSVA)is used to assess the activity of proliferation pathways.Statistical analysis was performed by R 3.6.1 software.Results:A total of 1249 patients diagnosed with LUAD were included.The results of Chi-square test showed that Ki-67 expression was related to gender(P<0.001),smoking history(P<0.001),histological differentiation degree(P<0.001),and TNM stage(P=0.026).Kaplan-Meier analysis showed that in patients with LUAD,the median OS of the Ki-67high expression group was 32.97 months,the median OS of the Ki-67 low expression group was 64.10 months,the Ki-67 high expression group had significantly lower OS than the Ki-67 low expression group(P<0.001).Cox regression multivariate analysis showed that the patient had a history of smoking(HR:1.496,P=0.001),the degree of histological differentiation was poorly differentiated or undifferentiated(HR:1.729,P=0.006),the TNM stage was stage IIIB-IV(HR:3.328,P<0.001),and Ki-67 high expression(≥25%)(HR:1.613,P<0.001)were independent risk factors affecting the prognosis of patients with LUAD.Meta-analysis included a total of 27 articles examining the relationship between Ki-67 overexpression and prognosis in patients with LUAD.The results showed that high expression group of Ki-67 in patients with LUAD was associated with an increased risk of death(I~2=81%,HR:1.137,P<0.0001).TCGA data show that high-expression group of Ki-67 suggests a poor prognosis in all but digestive system adenocarcinoma.A total of 402patients with pathological diagnosis of LUSC were included.Chi-square test results showed that Ki-67 expression was related to gender(P=0.020)and smoking history(P=0.048).Kaplan-Meier analysis showed that in patients with LUSC,the median OS of the Ki-67 high expression group was 41.13 months,while the median OS of the Ki-67 low expression group was 21.47 months,and Ki-67 was highly expressed.The median OS of the group was significantly higher than that of the Ki-67 low expression group(P=0.015).Cox regression multivariate analysis showed that age,TNM stage and Ki-67 high expression were independent factors affecting the prognosis of squamous cell carcinoma.Among them,over 60 years old(HR:1.408,P=0.034),stage IIIB-IV(HR:4.159,P<0.001)were risk factors affecting the prognosis of LUSC,and Ki-67 over-expression(≥25%)(HR:0.648,P=0.022)was a protective factor affecting the prognosis of patients with LUSC.The meta-analysis included a total of 7 articles examining the relationship between Ki-67 overexpression and prognosis in patients with LUSC.Among patients with LUSC,overexpression of Ki-67 was a protective factor(I~2=74%,HR:0.78,P=0.0253).TCGA data showed that in patients with squamous cell carcinoma,high expression of Ki-67tended to be a protective factor.Bioinformatics analysis found that Ki-67 has basically the same molecular function in LUAD and LUSC,mainly involved in cell pathways and mitosis.Only in patients with LUSC,the inactive proliferation pathway induced epithelial-mesenchymal transition(EMT)pathway.Conclusions:The high expression of Ki-67 has clinical significance in suggesting the prognosis of patients with LUAD and LUSC.In LUAD,high expression of Ki-67 indicates patients have an increased risk of disease progression and death.In patients with LUSC,high Ki-67 expression may be a slight protective factor.In patients with LUSC,the high expression of Ki-67 indicates that the patient has a good prognosis,which may be related to the different roles played by the proliferation pathway in patients with LUAD and LUSC.In patients with LUSC,the inactive group may be more prone to metastasis.In the future,more high-quality forward-looking articles will be needed for analysis and verification.