Abstract
BackgroundDue to the relatively insidious early symptoms of lung adenocarcinoma (LUAD), most LUAD patients are at an advanced stage at the time of diagnosis and lose the best chance of surgical resection. Mounting evidence suggested that the tumor microenvironment (TME) was highly correlated with tumor occurrence, progress, and prognosis. However, TME in advanced LUAD remained to be studied and reliable prognostic signatures based on TME in advanced LUAD also had not been well-established. This study aimed to understand the cell composition and function of TME and construct a gene signature associated with TME in advanced LUAD.MethodsThe immune, stromal, and ESTIMATE scores of each sample from The Cancer Genome Atlas (TCGA) database were, respectively, calculated using an ESTIMATE algorithm. The LASSO and Cox regression model were applied to select prognostic genes and to construct a gene signature associated with TME. Two independent datasets from the Gene Expression Omnibus (GEO) were used for external validation. Twenty-two subsets of tumor-infiltrating immune cells (Tiics) were analyzed using the CIBERSORT algorithm.ResultsFavorable overall survival (OS) and progression-free survival (PFS) were found in patients with high immune score (p = 0.048 and p = 0.028; respectively) and stromal score (p = 0.024 and p = 0.025; respectively). Based on the immune and stromal scores, 453 differentially expressed genes (DEGs) were identified. Using the LASSO and Cox regression model, a seven-gene signature containing AFAP1L2, CAMK1D, LOXL2, PIK3CG, PLEKHG1, RARRES2, and SPP1 was identified to construct a risk stratification model. The OS and PFS of the high-risk group were significantly worse than that of the low-risk group (p < 0.001 and p < 0.001; respectively). The receiver operating characteristic (ROC) curve analysis confirmed the good potency of the seven-gene signature. Similar findings were validated in two independent cohorts. In addition, the proportion of macrophages M2 and Tregs was higher in high-risk patients (p = 0.041 and p = 0.022, respectively).ConclusionOur study established and validated a seven-gene signature associated with TME, which might serve as a prognosis stratification tool to predict survival outcomes of advanced LUAD patients. In addition, macrophages M2 polarization may lead to worse prognosis in patients with advanced LUAD.
Highlights
Lung cancer ranks first in the incidence and mortality of all malignant tumors worldwide (Bray et al, 2018)
Significant progress has been made in the research of molecular genetics and immunotherapy of lung cancer, and molecular typing based on genetic characteristics has brought the treatment of advanced lung cancer into the era of personalized molecular targeted therapy (Subramanian and Govindan, 2008)
In order to explore the potential role of Differentially Expressed Gene (DEG) in survival outcome, a univariate Cox proportional hazards regression model was first conducted, and the results showed that 96 DEGs were selected by univariate analysis
Summary
Lung cancer ranks first in the incidence and mortality of all malignant tumors worldwide (Bray et al, 2018). The 5-year survival rate of lung cancer patients is less than 20% (Herbst et al, 2018). Clinical studies have shown that nearly 70% of LUAD patients are discovered in stage III–IV, and 57% of LUAD patients have already developed distant metastasis at the time of initial diagnosis, and have lost the best opportunity for surgical resection (Jemal et al, 2017). Looking for a new survival predictor for advanced LUAD patients is important for personalized treatment of clinical decision-making and prognostic health management. Due to the relatively insidious early symptoms of lung adenocarcinoma (LUAD), most LUAD patients are at an advanced stage at the time of diagnosis and lose the best chance of surgical resection.
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