Identification of A novel anoikis-related genes-based signature for non-small cell lung cancer

Abstract

The prognostic value of anoikis in NSCLC and its mechanism in tumorigenesis and progress have not been fully elucidated. This study aimed to reveal the correlation between anoikis-related genes (ARGs) and tumor prognosis, to reveal molecular and immune features, and to evaluate the anticancer drug sensitivity and the efficacy of immunotherapy of NSCLC. ARGs were selected from both the GeneCards and Harmonizome databases and then were intersected with the Cancer Genome Atlas (TCGA) database by differential expression analysis, followed by functional analysis of the target ARGs. An ARGs-based prognostic signature was constructed using LASSO (least absolute shrinkage and selection operator) Cox regression analysis; Kaplan-Meier analysis, univariant and multivariant Cox analysis were used to validate the value of this model in NSCLC prognosis. Differential analyses on molecular and immune landscapes were applied in the model. Anticancer drug sensitivity and efficacy in immune-checkpoint inhibitors (ICI) therapy were analyzed. A total of 509 ARGs and 168 differentially expressed ARGs in NSCLC were generated. Functional analysis revealed enrichment in extracolonic apoptotic signaling pathway, collagen-containing ECM, and integrin binding, and indicated an association with the PI3K-Akt signaling pathway. Subsequently, a 14-genes signature was generated. The high-risk group had a worse prognosis, with higherM0 and M2 macrophage infiltration, and fewer CD8 T-cells and T follicular helper (TFH) cells. The high-risk group had higher expression of immune checkpoint genes, HLA-I genes, and higher TIDE scores than the low-risk group, leading to less benefit of ICI therapy. Additionally, an Immunohistochemical staining comparison revealed that FADD was highly expressed in tumor tissue, compared to normal tissue, consistent with the previous results.