Development and validation of a robust immune-related prognostic signature in early-stage lung adenocarcinoma

Abstract

Background: The incidence of stage I and stage II lung adenocarcinoma (LUAD) is likely to increase with the introduction of annual screening programs for high-risk individuals. We aimed to identify a reliable prognostic signature with immune-related genes that can predict prognosis and help making individualized management for patients with early-stage LUAD.

Methods: The public LUAD cohorts were obtained from the large-scale databases including 4 microarray data sets from the Gene Expression Omnibus (GEO) and 1 RNA-seq data set from The Cancer Genome Atlas (TCGA) LUAD cohort. Only early-stage patients with clinical information were included. Cox proportional hazards regression model was performed to identify the candidate prognostic genes in GSE30219, GSE31210 and GSE50081 (training set). The prognostic signature was developed using the overlapped prognostic genes based on a risk score method. Kaplan-Meier curve with log-rank test and time-dependent receiver operating characteristic (ROC) curve were used to evaluate the prognostic value and performance of this signature, respectively. Furthermore, the robustness of this prognostic signature was further validated in TCGA-LUAD and GSE72094 cohorts.

Results: A prognostic immune signature consisting of 21 immune-related genes was constructed using the training set. The prognostic signature significantly stratified patients into high- and low-risk groups in terms of overall survival (OS) in training data set, including GSE30219 (HR = 4.31, 95% CI 2.29-8.11; P = 6.16E-06), GSE31210 (HR = 11.91, 95% CI 4.15-34.19; P = 4.10E-06), GSE50081 (HR = 3.63, 95% CI 1.90-6.95; P = 9.95E-05), the combined data set (HR = 3.15, 95% CI 1.98-5.02; P = 1.26E-06) and the validation data set, including TCGA-LUAD (HR = 2.16, 95% CI 1.49-3.13; P = 4.54E-05) and GSE72094 (HR = 2.95, 95% CI 1.86-4.70; P = 4.79E-06). Multivariate cox regression analysis demonstrated that the 21-gene signature could serve as an independent prognostic factor for OS after adjusting for other clinical factors. ROC curves revealed that the immune signature achieved good performance in predicting OS for early-stage LUAD. Several biological processes, including regulation of immune effector process, were enriched in the immune signature. Moreover, the combination of the signature with tumor stage showed more precise classification for prognosis prediction and treatment design.

Conclusions: Our study proposed a robust immune-related prognostic signature for estimating overall survival in early-stage LUAD, which may be contributed to make more accurate survival risk stratification and individualized clinical management for patients with early-stage LUAD.

Keywords: Immune-related genes; Lung adenocarcinoma; Overall survival; Prognosis; Risk score.

Fig. 1

Flow chart of this study

Fig. 2

Correlation between the 21-gene signature and Overall survival in the training set (early-stage LUAD). a Kaplan–Meier survival curves between high- and low-risk groups, b ROC curves for 1-year, 3-year and 5-year survival prediction by the 21-gene signature

Fig. 3

Correlation between the 21-gene signature and Overall survival in the validation set (early-stage LUAD). a Kaplan–Meier survival curves between high- and low-risk groups in TCGA-LUAD and GSE72094 cohort, respectively. b ROC curves for 1-year, 3-year and 5-year survival prediction by the 21-gene signature in TCGA-LUAD and GSE72094 cohort, respectively

Fig. 4

Kaplan–Meier curves of overall survival for patients grouped by stage and 21-gene signature combination (early-stage LUAD)

Fig. 5

Functional enrichment analysis of the 21 prognostic genes. a Gene Ontology analysis, b Kyoto Encyclopedia of Genes and Genomes pathway analysis