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. 2020 Aug 29;12(15):15624-15637.
doi: 10.18632/aging.103718.

An autophagy-related long non-coding RNA prognostic signature accurately predicts survival outcomes in bladder urothelial carcinoma patients

Zhuolun Sun  1   2 , Changying Jing  3   2 , Chutian Xiao  1 , Tengcheng Li  1
Affiliations

An autophagy-related long non-coding RNA prognostic signature accurately predicts survival outcomes in bladder urothelial carcinoma patients

Zhuolun Sun et al. Aging (Albany NY). .

Abstract

In this study, we analyzed the prediction accuracy of an autophagy-related long non-coding RNA (lncRNA) prognostic signature using bladder urothelial carcinoma (BLCA) patient data from The Cancer Genome Atlas (TCGA) database. Univariate and multivariate Cox regression analyses showed significant correlations between five autophagy-related lncRNAs, LINC02178, AC108449.2, Z83843.1, FAM13A-AS1 and USP30-AS1, and overall survival (OS) among BCLA patients. The risk scores based on the autophagy-related lncRNA prognostic signature accurately distinguished high- and low-risk BCLA patients that were stratified according to age; gender; grade; and AJCC, T, and N stages. The autophagy-related lncRNA signature was an independent prognostic predictor with an AUC value of 0.710. The clinical nomogram with the autophagy-related lncRNA prognostic signature showed a high concordance index of 0.73 and accurately predicted 1-, 3-, and 5-year survival times among BCLA patients in the high- and low-risk groups. The lncRNA-mRNA co-expression network contained 77 lncRNA-mRNA links among 5 lncRNAs and 49 related mRNAs. Gene set enrichment analysis showed that cancer- and autophagy-related pathways were significantly enriched in the high-risk group, and immunoregulatory pathways were enriched in the low-risk group. These findings demonstrate that an autophagy-related lncRNA signature accurately predicts the prognosis of BCLA patients.

Keywords: autophagy; bladder urothelial carcinoma; long non-coding RNA; prognostic signature; the cancer genome atlas.

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Conflict of interest statement

CONFLICTS OF INTEREST: The authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1
Construction and validation of the autophagy-related lncRNA prognostic signature in BCLA patients. (A) The univariate Cox regression analysis results show that 7 autophagy-related lncRNAs, AC002553.2, Z83843.1, LINC02178, FAM13A−AS1, USP30−AS1, AC108449.2 and AC243960.1, correlate with overall survival (OS) of BCLA patients from the TCGA database. (B) Kaplan–Meier survival curve analysis shows that survival time of patients with high-risk scores based on the autophagy-related lncRNA prognostic signature is significantly shorter than those with low-risk scores. (C) Principal components analysis (PCA) based on the confirmed five autophagy-related lncRNAs showed two significantly different distribution patterns between high-risk and low-risk groups. (D) Receiver operating characteristic (ROC) curve analysis shows the accuracy of the autophagy-related lncRNA prognostic signature in predicting survival times (prognosis) of BCLA patients from the TCGA database. (E) Distribution of risk scores of high- and low-risk BCLA patients based on the autophagy-related lncRNA prognostic signature. (F) Scatter plot shows the correlation between survival time and risk score of BCLA patients based on the autophagy-related lncRNA prognostic signature. (G) Heatmap shows that high-risk patients expressed higher levels of risk factors (AC108449.2 and LINC02178), while low-risk patients expressed higher levels of protective factors (Z83843.1, FAM13A−AS1 and USP30−AS1).
Figure 2
Figure 2
Correlation analyses of the autophagy-related lncRNA prognostic signature with various clinicopathological characteristics of the BCLA patients. The analysis compares the expression of the 5 prognostic lncRNAs in the BCLA patient cohort from the TCGA database stratified according to (A) age (< 65 y, n = 189; ≥ 65 y, n = 235); (B) gender (male, n = 291 vs. female, n = 102); (C) tumor grades (high grade, n = 372; low grade, n = 18); and (D) AJCC stages (stages I/II, n = 115; stages III/IV, n = 266).
Figure 3
Figure 3
The survival rates of high- and low-risk BCLA patients stratified by different clinicopathological characteristics. Kaplan Meier survival curve analysis shows overall survival (OS) rates of high- and low-risk BCLA patients from the TCGA database stratified by (A, B) age (≤ 65 y vs. > 65 y), (C, D) gender (male vs. female), (E, F) tumor grades (high grade vs. low grade), (G, H) AJCC stages (stages I and II vs. stages III and IV), (I, J) T stages (T1/T2 vs. T3/T4), and (K-L) N stages (N0 vs. N1/N2/N3).
Figure 4
Figure 4
Estimation of the prognostic accuracy of the autophagy-related lncRNA prognostic signature and other clinicopathological variables in the BCLA patients. (A) Univariate Cox regression analysis shows the correlation between overall survival and various clinicopathological parameters such as age, gender, AJCC stage, T stage, N stage and the autophagy-related lncRNA prognostic signature risk score. The remaining parameters (P < 0.001) are significantly associated with OS in addition to the gender. (B) Multivariate Cox regression analysis shows that age and risk score (P < 0.001) are independent prognostic indicators for overall survival rates of BCLA patients. (C) Receiver operating characteristic (ROC) curve analysis shows the prognostic accuracy of clinicopathological parameters such as age, AJCC stage, T stage, N stage and autophagy-related lncRNA prognostic risk score.
Figure 5
Figure 5
Construction and validation of the prognostic nomogram with autophagy-related lncRNA prognostic signature risk score as one of the parameters. (A) The predicted 1-, 3-, 5-year survival rates of BCLA patients based on the prognostic nomogram constructed using the risk score from autophagy-related lncRNA prognostic signature and clinicopathological parameters such as age, AJCC stage, T stage, N stage is shown. (B–D) Calibration curves show the concordance between predicted and observed (B) 1-year, (C) 3-year, and (D) 5-year survival rates of high- and low-risk BCLA patients based on the prognostic nomogram after bias correction.
Figure 6
Figure 6
Construction of the autophagy-related lncRNA–mRNA co-expression network and functional enrichment analyses. (A) Diagrammatic representation of the autophagy-related lncRNA–mRNA network shows 77 lncRNA-mRNA co-expression pairs formed between 5 autophagy-related lncRNAs and 49 mRNAs. The yellow circles correspond to autophagy-related lncRNAs, and the gray diamonds correspond to the mRNAs. Every edge represents a co-expression relationship between an lncRNA and an mRNA in the context of BCLA. (B) The Sankey diagram shows the connection degree between the 49 mRNAs and 5 autophagy-related lncRNAs (risk/protective). (C–E) Gene Ontology (GO) analysis results show the enriched (C) biological processes, (D) cell components and (E) molecular functions associated with the mRNAs that co-express with the 5 autophagy-related lncRNAs. (F) Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis results shows the enriched signaling pathways associated with the mRNAs that co-express with the 5 autophagy-related lncRNAs.
Figure 7
Figure 7
Gene set enrichment analysis (GSEA) of high-risk and low-risk BCLA patients based on the autophagy-related lncRNA prognostic signature. (A) GSEA results show significant enrichment of cancer- and autophagy-related signaling pathways in the high-risk BCLA patients. The black and blue boxes correspond to cancer-related and autophagy-related KEGG signaling pathways, respectively. (B) GSEA results show significant enrichment of immunoregulatory signaling pathways in the low-risk BCLA patients. (C, D) The top 10 KEGG signaling pathways in the (C) high-risk and (D) low-risk BCLA patients.
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