Development of a prognostic index and screening of prognosis related genes based on an immunogenomic landscape analysis of bladder cancer

Abstract

Background: Bladder cancer (BLCA) is one of the most common urinary tract malignant tumors. It is associated with poor outcomes, and its etiology and pathogenesis are not fully understood. There is great hope for immunotherapy in treating many malignant tumors; therefore, it is worthwhile to explore the use of immunotherapy for BLCA.

Methods: Gene expression profiles and clinical information were obtained from The Cancer Genome Atlas (TCGA), and immune-related genes (IRGs) were downloaded from the Immunology Database and Analysis Portal. Differentially-expressed and survival-associated IRGs in patients with BLCA were identified using computational algorithms and Cox regression analysis. We also performed functional enrichment analysis. Based on IRGs, we employed multivariate Cox analysis to develop a new prognostic index.

Results: We identified 261 IRGs that were differentially expressed between BLCA tissue and adjacent tissue, 30 of which were significantly associated with the overall survival (all P<0.01). According to multivariate Cox analysis, nine survival-related IRGs (MMP9, PDGFRA, AHNAK, OAS1, OLR1, RAC3, IGF1, PGF, and SH3BP2) were high-risk genes. We developed a prognostic index based on these IRGs and found it accurately predicted BLCA outcomes associated with the TNM stage. Intriguingly, the IRG-based prognostic index reflected infiltration of macrophages.

Conclusions: An independent IRG-based prognostic index provides a practical approach for assessing patients' immune status and prognosis with BLCA. This index independently predicted outcomes of BLCA.

Keywords: The Cancer Genome Atlas; bladder cancer; immune-related genes; immunogenomic landscape; prognostic index.

Figure 1

Differentially expressed IRGs. (A) Heatmap demonstrating DEGs between BLCA and normal samples, with red representing high expression and green representing low expression. (B) Heatmap demonstrating differentially expressed IRGs between BLCA and normal samples, with red representing high expression and green representing low expression. (C) Volcano plot of 4893 DEGs, with red representing up-regulated DEGs and green representing down-regulated DEGs. (D) volcano plot of 261 differentially expressed IRGs, with red representing up-regulated IRGs and green representing down-regulated IRGs.

Figure 2

Forest plot of the hazard ratios showing the prognostic values of survival-associated IRGs, red dots represent high-risk genes (HR > 1), and green dots represent low-risk genes (HR < 1).

Figure 3

Transcription factor (TF) regulatory network. Differentially expressed TFs in the DEGs between BLCA samples and normal samples. (A) The heatmap and (B) volcano plot of differentially expressed TFs. (C) In the-mediated regulatory network, triangles represent TFs; circles represent IRGs.

Figure 4

Development of the IRGPI. (A) Distribution of patients with high-risk scores (red color) and low-risk scores (green color); (B) survival status of patients with BLCA (red dots stand for the deceased patients and the green dots stand for the survivors); (C) heatmap of the nine survival-associated IRGs expression profiles.

Figure 5

The evaluation of the IRGPI. (A) The Kaplan-Meier curves of OS for patients with high-risk scores (red line) and low-risk scores (blue line); (B) Verification of the accuracy of the IRGPI based on analysis of the AUC of the survival-dependent ROC curve.

Figure 6

Univariate (A) and multivariate (B) Cox regression analysis in terms of OS for patients with BLCA.

Figure 7

The relationships between the immune-based prognostic index and clinicopathological factors. (A) age; (B) gender; (C) pathological stage; (D) T stage; (E) N stage and (F) M stage in the high-risk (red) and low-risk (blue) groups of the BLCA.

Figure 8

Relationships between the abundances of six types of immune cells and the immune-based prognostic index in patients with BLCA. (A) B cells; (B) CD4 T cells; (C) CD8 T cells; (D) dendritic cells; (E) macrophages; (F) neutrophils.