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The Landscape of Long Non-Coding RNA Dysregulation and Clinical Relevance in Muscle Invasive Bladder Urothelial Carcinoma

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The Landscape of Long Non-Coding RNA Dysregulation and Clinical Relevance in Muscle Invasive Bladder Urothelial Carcinoma

Haotian Shen et al. Cancers (Basel).

Abstract

Bladder cancer is one of the most common cancers in the United States, but few advancements in treatment options have occurred in the past few decades. This study aims to identify the most clinically relevant long non-coding RNAs (lncRNAs) to serve as potential biomarkers and treatment targets for muscle invasive bladder cancer (MIBC). Using RNA-sequencing data from 406 patients in The Cancer Genome Atlas (TCGA) database, we identified differentially expressed lncRNAs in MIBC vs. normal tissues. We then associated lncRNA expression with patient survival, clinical variables, oncogenic signatures, cancer- and immune-associated pathways, and genomic alterations. We identified a panel of 20 key lncRNAs that were most implicated in MIBC prognosis after differential expression analysis and prognostic correlations. Almost all lncRNAs we identified are correlated significantly with oncogenic processes. In conclusion, we discovered previously undescribed lncRNAs strongly implicated in the MIBC disease course that may be leveraged for diagnostic and treatment purposes in the future. Functional analysis of these lncRNAs may also reveal distinct mechanisms of bladder cancer carcinogenesis.

Keywords: TCGA; bladder carcinoma; lncRNA-protein interaction; lncRNAs.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Summary of differential expression and patient survival results. (A) Heat map of significant differentially expressed long non-coding RNAs (lncRNAs) (FDR < 1 × 10−5, |log(fold change)| > 1) when comparing bladder urothelial carcinoma (BLCA) samples to adjacent normal samples. (B) Clustering of patients based on lncRNA expression landscape. The top portion of the heat map represents the patient clinical parameter. The bottom heat map depicts lncRNAs most prominently expressed in each cluster. (C) Hazard ratio plots of significant differentially expressed lncRNAs for patients in a low expression group (below median expression) for each lncRNA. All lncRNAs presented also significantly correlate with patient survival and one or more clinical variables. (D) Receiver operating characteristic (ROC) curves illustrating the power of three different expression panels in discriminating muscle invasive bladder cancer (MIBC) samples from normal samples.
Figure 1
Figure 1
Summary of differential expression and patient survival results. (A) Heat map of significant differentially expressed long non-coding RNAs (lncRNAs) (FDR < 1 × 10−5, |log(fold change)| > 1) when comparing bladder urothelial carcinoma (BLCA) samples to adjacent normal samples. (B) Clustering of patients based on lncRNA expression landscape. The top portion of the heat map represents the patient clinical parameter. The bottom heat map depicts lncRNAs most prominently expressed in each cluster. (C) Hazard ratio plots of significant differentially expressed lncRNAs for patients in a low expression group (below median expression) for each lncRNA. All lncRNAs presented also significantly correlate with patient survival and one or more clinical variables. (D) Receiver operating characteristic (ROC) curves illustrating the power of three different expression panels in discriminating muscle invasive bladder cancer (MIBC) samples from normal samples.
Figure 2
Figure 2
Clinical variable correlation with expression of key lncRNAs. Boxplots depict significant correlations (Kruskal–Wallis tests; p < 0.05) with clinical variables for (A) significantly upregulated lncRNAs and (B) significantly downregulated lncRNAs that correlated with patient survival. The red crosses indicate non-significant correlations. An explanation for non-significance is given below the stated p-value if it is <0.05.
Figure 3
Figure 3
Canonical pathways filtered for cancer-associated pathways and immune-associated pathways (C2) from gene set enrichment analysis (GSEA) (nominal p < 0.05) for the significantly downregulated lncRNAs including (A) lnc-BOD1-1:7, 1:8, 1:9; (B) lnc-ACSBG2-1:1; and (C) lnc-ANKRD54-1:1. Significantly downregulated lncRNAs with fewer than 15 cancer- and immune-associated pathways are placed in the Supplementary Materials (Supplementary Figure S3A).
Figure 3
Figure 3
Canonical pathways filtered for cancer-associated pathways and immune-associated pathways (C2) from gene set enrichment analysis (GSEA) (nominal p < 0.05) for the significantly downregulated lncRNAs including (A) lnc-BOD1-1:7, 1:8, 1:9; (B) lnc-ACSBG2-1:1; and (C) lnc-ANKRD54-1:1. Significantly downregulated lncRNAs with fewer than 15 cancer- and immune-associated pathways are placed in the Supplementary Materials (Supplementary Figure S3A).
Figure 4
Figure 4
Canonical pathways filtered for cancer-associated and immune-associated pathways (C2) from gene set enrichment analysis (nominal p < 0.05) for significantly upregulated lncRNAs including (A) lnc-GCH1-2:1, 2:2, 2:3; and (B) lnc-CGRRF1-3:1. Significantly upregulated lncRNAs with fewer than 15 cancer- and immune-associated pathways are placed in the Supplementary Materials (Supplementary Figure S3B).
Figure 5
Figure 5
Significant oncogenic signatures (C6) from GSEA (nominal p < 0.05). Barplots showing (A) significantly downregulated lncRNAs and (B) significantly upregulated lncRNAs that correlate with patient survival and clinical variables. All bars extending towards the left indicate negative enrichment of pathway activity to lncRNA expression, such that higher pathway activity corresponds to lower lncRNA expression. Significantly upregulated or downregulated lncRNAs with fewer than 10 oncogenic signatures are placed in Supplementary Materials (Supplementary Figure S4).
Figure 5
Figure 5
Significant oncogenic signatures (C6) from GSEA (nominal p < 0.05). Barplots showing (A) significantly downregulated lncRNAs and (B) significantly upregulated lncRNAs that correlate with patient survival and clinical variables. All bars extending towards the left indicate negative enrichment of pathway activity to lncRNA expression, such that higher pathway activity corresponds to lower lncRNA expression. Significantly upregulated or downregulated lncRNAs with fewer than 10 oncogenic signatures are placed in Supplementary Materials (Supplementary Figure S4).
Figure 6
Figure 6
Association of genomic alterations with the expression of (A) significantly downregulated lncRNAs and (B) significantly upregulated lncRNAs that correlated with patient survival and clinical variables using repeated evaluation of variables’ conditional entropy and redundancy (REVEALER) (|CIC| > 0.3). The gradient bar visualizes the expression distribution of the lncRNA. The dark red extreme represents the highest expression, whereas the dark blue extreme represents the lowest expression.
Figure 6
Figure 6
Association of genomic alterations with the expression of (A) significantly downregulated lncRNAs and (B) significantly upregulated lncRNAs that correlated with patient survival and clinical variables using repeated evaluation of variables’ conditional entropy and redundancy (REVEALER) (|CIC| > 0.3). The gradient bar visualizes the expression distribution of the lncRNA. The dark red extreme represents the highest expression, whereas the dark blue extreme represents the lowest expression.

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