Identification of a Ferroptosis-Related LncRNA Signature as a Novel Prognosis Model for Lung Adenocarcinoma

Abstract

Lung adenocarcinoma (LUAD) is a highly heterogeneous malignancy, which makes prognosis prediction of LUAD very challenging. Ferroptosis is an iron-dependent cell death mechanism that is important in the survival of tumor cells. Long non-coding RNAs (lncRNAs) are considered to be key regulators of LUAD development and are involved in ferroptosis of tumor cells, and ferroptosis-related lncRNAs have gradually emerged as new targets for LUAD treatment and prognosis. It is essential to determine the prognostic value of ferroptosis-related lncRNAs in LUAD. In this study, we obtained RNA sequencing (RNA-seq) data and corresponding clinical information of LUAD patients from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database and ferroptosis-related lncRNAs by co-expression analysis. The best predictors associated with LUAD prognosis, including C5orf64, LINC01800, LINC00968, LINC01352, PGM5-AS1, LINC02097, DEPDC1-AS1, WWC2-AS2, SATB2-AS1, LINC00628, LINC01537, LMO7DN, were identified by Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression analysis, and the LUAD risk prediction model was successfully constructed. Kaplan-Meier analysis, receiver operating characteristic (ROC) time curve analysis and univariate and multivariate Cox regression analysis and further demonstrated that the model has excellent robustness and predictive ability. Further, based on the risk prediction model, functional enrichment analysis revealed that 12 prognostic indicators involved a variety of cellular functions and signaling pathways, and the immune status was different in the high-risk and low-risk groups. In conclusion, a risk model of 12 ferroptosis related lncRNAs has important prognostic value for LUAD and may be ferroptosis-related therapeutic targets in the clinic.

Keywords: ferroptosis; lncRNAs; lung adenocarcinoma; prognosis; risk score.

Figure 1

Differentially expressed ferroptosis-related lncRNA between LUAD and normal samples (log2 fold change>2, adjusted p-value < 0.01). Compared with normal samples, 49 ferroptosis-related lncRNAs were upregulated and 43 ferroptosis-related lncRNA downregulated in LUAD samples. (A) is a volcano map for differentially expressed ferroptosis-related lncRNAs. Red dots represent significantly upregulated expressed genes and green dots represent significantly downregulated expressed genes. (B) indicates the HR (95% Cl) and p-value of selected lncRNAs by univariate Cox proportional hazards. Blue dots represent protective factors, and red dots represent risk factors.

Figure 2

Prognostic analysis of the risk score in the TCGA and three GEO cohorts. (A, B) Time-dependent receiver operating characteristic curves assess the prognostic performance of the risk score in TCGA and three GEO cohorts respectively. (C, D) Kaplan-Meier curves display the overall survival of patients in the high- and low-risk group in TCGA and three GEO cohorts respectively. (E, F) The univariate Cox regression analysis of the associations between the risk scores and clinical parameters and the overall survival (OS) of patients in TCGA and three GEO cohort. (G, H) The multivariate Cox regression analysis of the associations between the risk scores and clinical parameters and the OS of patients in TCGA and three GEO cohorts.

Figure 3

(A, C) Principal component analysis (PCA) plot in the TCGA and three GEO cohorts. (B, D) t-distributed stochastic neighbor embedding (tSNE) analysis in the TCGA and three GEO cohorts.

Figure 4

Further comparison between high- and low-risk groups of the TCGA cohort. (A) and (B) show the bar plot and cluster plot of significant GO functional items, respectively. (C) and (D) show the bar plot and cluster plot of significant KEGG pathways, respectively.

Figure 5

Comparison of the immunity analysis between different risk groups. (A–F) indicates the ESTIMATE, TIMER, MCP counter, CIBERSORTx, and single-sample gene set enrichment analysis (ssGSEA) algorithms to compare the cellular components or cell immune responses between two groups. CCR, cytokine-cytokine receptor. Adjusted P values were showed as: ns, not significant; *P < 0.05; **P < 0.01; ***P < 0.001.