Identification of Biomarkers Correlated with the TNM Staging and Overall Survival of Patients with Bladder Cancer.

Yue Cao,Xiantao Zeng,Sheng Li,Hong Weng,Xiaohong Yin,Cheng Fang,Di Huang,Xinghuan Wang,Xiangyu Meng,Tongzu Liu,Xiaoping Liu

doi:10.3389/fphys.2017.00947

Abstract

Objective: To identify candidate biomarkers correlated with clinical prognosis of patients with bladder cancer (BC).Methods: Weighted gene co-expression network analysis was applied to build a co-expression network to identify hub genes correlated with tumor node metastasis (TNM) staging of BC patients. Functional enrichment analysis was conducted to functionally annotate the hub genes. Protein-protein interaction network analysis of hub genes was performed to identify the interactions among the hub genes. Survival analyses were conducted to characterize the role of hub genes on the survival of BC patients. Gene set enrichment analyses were conducted to find the potential mechanisms involved in the tumor proliferation promoted by hub genes.Results: Based on the results of topological overlap measure based clustering and the inclusion criteria, top 50 hub genes were identified. Hub genes were enriched in cell proliferation associated gene ontology terms (mitotic sister chromatid segregation, mitotic cell cycle and, cell cycle, etc.) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways (cell cycle, Oocyte meiosis, etc.). 17 hub genes were found to interact with ≥5 of the hub genes. Survival analysis of hub genes suggested that lower expression of MMP11, COL5A2, CDC25B, TOP2A, CENPF, CDCA3, TK1, TPX2, CDCA8, AEBP1, and FOXM1were associated with better overall survival of BC patients. BC samples with higher expression of hub genes were enriched in gene sets associated with P53 pathway, apical junction, mitotic spindle, G2M checkpoint, and myogenesis, etc.Conclusions: We identified several candidate biomarkers correlated with the TNM staging and overall survival of BC patients. Accordingly, they might be used as potential diagnostic biomarkers and therapeutic targets with clinical utility.

Highlights

Bladder cancer (BC) is the second most frequent genitourinary malignancy and the sixth most common malignancy in men
Preprocessed gene expression profile of GSE13507 was obtained from Gene Expression Omnibus (GEO) database for our Weighted gene co-expression network analysis (WGCNA) analysis
Gene expression profile of GSE13507 was obtained from GEO database, and probes with variances ranked in top 10,000 were used in the subsequent analyses

Summary

Introduction

Bladder cancer (BC) is the second most frequent genitourinary malignancy and the sixth most common malignancy in men. For patients with superficial BC, telescopic removal of the cancer (transurethral resection of bladder tumor, TURBT) followed by instillation of chemotherapy or vaccine-based therapy into the bladder with prolonged telescopic checking of the bladder are usually recommended, and the 5-year overall survival for these patients reaches 90%, while about 40–80% of these patients will develop disease recurrence or progression (Malmström et al, 2017). For patients with invasive BC, radical cystectomy plus pelvic lymph node dissection (PLND) followed by neo-adjuvant chemotherapy is recommended as a standard of care, and once it becomes metastatic cancer, the 5-year overall survival for patients with invasive BC is a dismal 6% (Salama et al, 2016; Sargos et al, 2016). Identification of biomarkers that are associated with clinical outcomes of patients with BC might be of clinical significance (Giunchi et al, 2017)

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Results

Conclusion