Analysis Of Postoperative Prognosis Factors And Establishment Of Immune-related Prognostic Model For StageⅠ-Ⅱ Lung Adenocarcinoma

ObjectiveLung Adenocarcinoma(LUAD)has high morbidity and mortality.Due to tumor heterogeneity,Stage Ⅰ-Ⅱ LUAD patients are also at risk of recurrence and metastasis after surgical resection of the lesion,leading to differences in prognosis.It is necessary to look for prognostic factors in clinical features to evaluate the prognosis of patients.First of all,the clinical data of 93 stage Ⅰ-ⅡLUAD patients who received surgical treatment in the First Affiliated Hospital of Guangxi Medical University in 2015 were retrospectively studied,and the independent prognostic factors were analyzed and summarized.Secondly,the gene expression data and clinical data of the stage Ⅰ-Ⅱ LUAD patients in The Cancer Genome Atlas(TCGA)database were downloaded to established an immune-related prognostic model that associated with oncogenic driver alteration.Methods1)The clinical data of 93 stage Ⅰ-Ⅱ LUAD patients who received surgical treatment in the First Affiliated Hospital of Guangxi Medical University in 2015 were retrospectively studied,and the independent prognostic factors of stage Ⅰ-ⅡLUAD patients were summarized after the survival analysis.2)The gene expression data and clinical data of stage Ⅰ-Ⅱ LUAD patients were downloaded from the TCGA database.Gene Set Enrichment Analysis(GSEA),univariate Cox regression analysis,the Cox-proportional Hazards Analysis based on the L1-penalized(LASSO)Analysis are used to identify immune-related genes with core roles associated with EGFR,ALK,ROS1,and BRAF mutation status.The "predict" function in R software was used to calculate the IPM risk score of each patient,and the optimal threshold of IPM risk score was determined by analyzing the curve of Receiver Operating Characteristic(ROC).Patients were divided into IPM-HR(high risk)group and IPM-LR(low risk)group.Area Under ROC(AUC)was used to evaluate the predicting ability of IPM.The predicting ability of the IPM was validated in GSE31210 and GSE26939 downloaded from the Gene Expression Omnibus(GEO)database.The Cell type Identification by Estimating Relative Subsets of RNA Transcripts(CIBERSORT)is used for estimate the composition of 22 immune cells in the IPM-HR and IPM-LR samples in the TCGA database.Immune cell composition and immune checkpoints(including CTLA-4,PDCD1,CD274,HAVCR2,LAG3,and TIGIT)were compared between the IPM-HR group and IPM-LR group by using the Mann-Whitney U test.Results1)The 1-year,3-year,and 5-year OS of stage Ⅰ-Ⅱ LUAD patients who received surgical treatment were 94.5%(95%CI: 86.0%-97.9%),76.2%(95%CI:64.5-84.5%),and 70.5%(95%CI: 58.4%-79.7%).The 5-year OS of stage ⅠA LUAD patients was 85.5%(95%CI: 70.5%-93.2%).2)Univariate survival analysis showed that,T stage,N stage,pathological stage,CEA,CA125,CYFRA21-1 and Ki-67 were prognostic factors in stageⅠ-Ⅱ LUAD patients.Multiariate analysis showed that CEA>3.06ng/ml,CA125>36.93U/ml and CYFRA21-1>2.91 ng/ml were the independent prognostic factors for OS in stage Ⅰ-Ⅱ LUAD patients.3)In the TCGA database,a total of 171 patients had available gene expression profile and mutation data,among which 164 patients had survival information.Three immune-related genes with core functions were found to be related to EGFR mutation,ALK translocation,ROS1 translocation and BRAF mutation,namely Phosphodiesterase 4B(PDE4B),Receptor-interacting protein kinase 2(RIPK2)and Interferon-inducible Transmembrane protein 1(IFITM1).IPM was established in the training cohort based on three core immune-related genes.IPM showed strong prognostic predicting ability in the training cohort,validation cohort and whole TCGA stage Ⅰ-Ⅱ LUAD cohort.Survival analysis showed that IPM-HR group was an independent adverse prognostic factor for OS of stage Ⅰ-Ⅱ LUAD patients.The prognostic predicting ability of IPM was verified in two GEO stage I-II LUAD cohorts.4)IPM-HR group had significantly higher proportions of macrophages M1 and activated mast cells but lower proportions of memory B cells,resting CD4 memory T cells and resting mast cells than IPM-LR group(all P<0.05).In addition,the IPM-HR group had a significantly lower expression of CTLA-4,PDCD1,HAVCR2,and TIGIT than the IPM-LR group(all P<0.05)Conclusion1)The prognosis of stage Ⅰ-Ⅱ LUAD patients after surgery was generally good,with 5-year overall survival of 70.5%,among which,the 5-year overall survival of stage ⅠA LUAD patients is 85.5%.2)Serum CEA,CA125 and CYFRA21-1 were independent prognostic factors of stage Ⅰ-Ⅱ LUAD patients after surgery.3)We established and validated an IPM based on 3 immune related genes associated with EGFR mutation,ALK translocation,ROS1 translocation,and BRAF mutation status,which independently predicted the overall survival of stage Ⅰ-Ⅱ LUAD patients.4)IPM-HR was related to lower proportion of resting CD4 memory T cells and lower expression of checkpoint molecules CTLA-4,PDCD1,HAVCR2,and TIGIT.