Identification of Potential Diagnostic Genes for Bladder Cancer by Bioinformatic Analysis

Abstract Background: Cytology and transurethral cystoscopy constitute the gold standard for the diagnosis of bladder cancer (BC). However, some minor lesions cannot be detected in time with these techniques, resulting in a high rate of missed diagnosis. Finding biomarkers that are economical, convenient, sensitive, and specific has become an urgent priority.Methods: Gene expression profile data from BC and normal bladder tissue were downloaded from the Gene Expression Omnibus (GEO) database and used as a training set to screen for differentially expressed genes (DEGs). The bladder gene expression and related clinical data derived from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases were used as a validation set. The effectiveness of the DEGs as diagnostic criteria was verified in terms of gene expression, gene mutation and diagnostic efficiency.Results: Two upregulated and eight downregulated hub genes were identified by screening. In terms of gene expression, the expression levels of these genes were significantly different between bladder cancer tissues and normal tissues. In terms of clinical diagnostic efficacy, TOP2A had the highest single diagnostic value, while the combinations of TOP2A/CNN1, TOP2A/ISG15/CNN1 and TOP2AISG15/ACTG2 had the largest area under the curve (AUC) among two- or three-indicator combinations.Conclusion: TOP2A, either alone or as part of a combination, has notable diagnostic advantages. However, this still needs to be confirmed in a larger sample with further biological experiments.

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A Transcriptional Signature of IL-2 Expanded Natural Killer Cells Predicts More Favorable Prognosis in Bladder Cancer

Frontiers in Immunology ◽

10.3389/fimmu.2021.724107 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yuhan Sun ◽

Alexander James Sedgwick ◽

Md Abdullah-Al-Kamran Khan ◽

Yaseelan Palarasah ◽

Stefano Mangiola ◽

...

Keyword(s):

Bladder Cancer ◽

Natural Killer ◽

Antitumor Immunity ◽

Cell Function ◽

Nk Cell ◽

The Cancer Genome Atlas ◽

Cell Phenotype ◽

Clinical Role ◽

Bladder Tissue ◽

Normal Bladder

Activation of natural killer (NK) cell function is regulated by cytokines, such as IL-2, and secreted factors upregulated in the tumor microenvironment, such as platelet-derived growth factor D (PDGF-DD). In order to elucidate a clinical role for these important regulators of NK cell function in antitumor immunity, we generated transcriptional signatures representing resting, IL-2-expanded, and PDGF-DD-activated, NK cell phenotypes and established their abundance in The Cancer Genome Atlas bladder cancer (BLCA) dataset using CIBERSORT. The IL-2-expanded NK cell phenotype was the most abundant in low and high grades of BLCA tumors and was associated with improved prognosis. In contrast, PDGFD expression was associated with numerous cancer hallmark pathways in BLCA tumors compared with normal bladder tissue, and a high tumor abundance of PDGFD transcripts and the PDGF-DD-activated NK cell phenotype were associated with a poor BLCA prognosis. Finally, high tumor expression of transcripts encoding the activating NK cell receptors, KLRK1 and the CD160–TNFRSF14 receptor–ligand pair, was strongly correlated with the IL-2-expanded NK cell phenotype and improved BLCA prognosis. The transcriptional parameters we describe may be optimized to improve BLCA patient prognosis and risk stratification in the clinic and potentially provide gene targets of therapeutic significance for enhancing NK cell antitumor immunity in BLCA.

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N6-Methylandenosine-Related lncRNAs are Potential Biomarkers for Predicting the Overall Survival Rate of Patients Bladder Cancer

10.21203/rs.3.rs-534193/v1 ◽

2021 ◽

Author(s):

Haihang Zhang ◽

Panpan Xie ◽

Kaijia Shi ◽

Danni Xu ◽

Xingrui Cai ◽

...

Keyword(s):

Bladder Cancer ◽

Prognostic Value ◽

Immune Cell ◽

Cox Regression ◽

Pearson Correlation ◽

Prognostic Significance ◽

The Cancer Genome Atlas ◽

Bladder Tissue ◽

Cox Regression Analysis ◽

Normal Bladder

Abstract Background: The prognostic value of N6-methylandenosine-related long non-coding RNAs (m6A-related lncRNAs) was investigated in 414 bladder cancer (BLCA) and 19 normal bladder tissue samples from The Cancer Genome Atlas (TCGA) datasets. Methods: We implemented Pearson correlation analysis to explore the lncRNAs associated with m6A, and then performed univariate Cox regression analysis to identify nine m6A-associated lncRNAs with prognostic value. The patients with BLCA were divided into two subgroups by consistency clustering. Analysis of the two groups of immune cell infiltration, immune microenvironment and clinical results were significantly different. We identified the prognostic significance of m6A-related lncRNAs by bioinformatic and statistical analysis of data from patients with BLCA.Results: We constructed an m6A-related lncRNA prognostic signature (m6A-LPS, including AL136295.2, AC104564.3, ATP1B3-AS1, EHMT2-AS1 and AC116914.2) to predict the OS of BLCA patients. It is proved that m6A LPS has independent prognostic value.

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Prognostic value of CLIC3 mRNA overexpression in bladder cancer

PeerJ ◽

10.7717/peerj.8348 ◽

2020 ◽

Vol 8 ◽

pp. e8348

Author(s):

Mei Chen ◽

Shufang Zhang ◽

Xiaohong Wen ◽

Hui Cao ◽

Yuanhui Gao

Keyword(s):

Gene Expression ◽

Bladder Cancer ◽

Mrna Expression ◽

Prognostic Value ◽

Multivariate Analyses ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Functional Enrichment ◽

Receptor Interaction ◽

Normal Tissues

Background Human intracellular chloride channel 3 (CLIC3) is involved in the development of various cancers, but the expression and prognostic value of CLIC3 mRNA in bladder cancer (BC) remain unclear. Methods The gene expression data and clinical information of CLIC3 were obtained from the Gene Expression Omnibus (GEO) database and verified in the Oncomine and The Cancer Genome Atlas (TCGA) database. The expression of CLIC3 mRNA in BC tissues and adjacent normal tissues was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The Kaplan-Meier method was used to analyze the relationship between the expression of CLIC3 mRNA and the prognosis of BC. Cox univariate and multivariate analyses were performed on the overall survival and tumor-specific survival of BC patients. The genes coexpressed with CLIC3 were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). CLIC3-related signal transduction pathways in BC were explored with gene set enrichment analysis (GSEA). Results The expression of CLIC3 mRNA in BC tissues was higher than that in normal tissues (P < 0.01). High CLIC3 mRNA expression was associated with age (P = 0.021) and grade (P = 0.045) in BC patients. High CLIC3 mRNA expression predicted a poor prognosis in BC patients (P < 0.05). Cox univariate and multivariate analyses showed that high CLIC3 mRNA expression was associated with tumor-specific survival in BC patients (P < 0.05). Functional enrichment analyses indicated that CLIC3 may be significantly associated with the cell cycle, focal adhesion, the extracellular matrix (ECM) receptor interaction and the P53 signaling pathway. Conclusions CLIC3 mRNA is highly expressed in BC, and its high expression is related to the adverse clinicopathological factors and prognosis of BC patients. CLIC3 can be used as a biomarker for the prognosis of BC patients.

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Controversial T1G3 bladder cancer is the key to revealing the changes in the biological functions of bladder cancer cells

10.21203/rs.2.20498/v1 ◽

2020 ◽

Author(s):

Shen Pan ◽

Yunhong Zhan ◽

Xiaonan Chen ◽

Bin Wu ◽

Bitian Liu

Keyword(s):

Gene Expression ◽

Bladder Cancer ◽

Cancer Cells ◽

Interaction Analysis ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Functional Enrichment ◽

Specific Gene ◽

Gene Sets ◽

Bladder Cancer Cells

Abstract Background T1G3 shows a higher chance of recurrence and progression among early bladder cancer types and the available treatment option is controversial. High recurrence and progression are the problems that need to be explored and solved. Changes in the internal signals of bladder cancer cells and differential genes may be the root cause of these problems. Methods GSE120736, GSE19915, GSE19423, GSE32548 and GSE37815 datasets were obtained from Gene Expression Omnibus (GEO ) to identify differentially expressed genes (DEGs). Bladder cancer transcript data from The Cancer Genome Atlas (TCGA) were clustered into different cell-specific gene sets according to weighted gene co-expression network analysis (WGCNA). Multiple sets of databases were used for gene expression comparison, functional enrichment, and protein interaction analysis, including The Human Protein Atlas, Cancer Dependency Map, Metascape, Gene set enrichment analysis, and DisNor. Results DEGs were obtained through GEO data comparison and intersection. After WGCNA was proven to recognise cell-specific gene sets, candidate DEGs were selected and shown to be specifically expressed in cancer cells. Candidate DEGs were related to mitosis and cell cycle. Further, 12 functional candidate markers were identified from the sequencing data of 30 bladder cancer cell lines. These genes were all up-regulated and previously shown to be closely related to bladder cancer progression. Conclusions Twelve functional genes with specific differential expression in bladder cancer cells were identified. WGCNA can identify the relatively specific expression sets of different cells in bladder cancer with greater tumour heterogeneity, which provides new perspectives for future cancer research.

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SATB1 and Her2 as predictive molecular and immunohistochemical markers for urothelial cell carcinoma of the bladder

Cancer Biomarkers ◽

10.3233/cbm-200072 ◽

2020 ◽

pp. 1-11

Author(s):

Samia Hussein ◽

Anan Fathi ◽

Nehal S. Abouhashem ◽

Samar Amer ◽

Mohamed Hemida ◽

...

Keyword(s):

Bladder Cancer ◽

Prognostic Significance ◽

Immunohistochemical Analysis ◽

Lymph Node Involvement ◽

Genetic Alterations ◽

Response To Therapy ◽

Clinicopathological Parameters ◽

Bladder Tissue ◽

Normal Bladder ◽

Erbb2 Mrna

Studying bladder cancer molecular biology revealed the presence of genetic alterations. So, detection of molecular biomarkers that help in monitoring the disease, evaluating the prognosis of the patients, and their response to therapy is needed. In this study, we investigated the expression and the prognostic significance of SATB-1 and ERBB2 mRNA and protein by quantitative RT-PCR and immunohistochemical analysis in urothelial bladder cancer cases and the surrounding normal bladder tissue. The correlations between the expression of both markers and the clinicopathological parameters were performed with further analysis of the correlation between the expression of SATB-1 and ERBB2. Compared to control, the expression of SATB-1 and ERBB2 mRNA and protein in cancer tissues were significantly up-regulated (p< 0.05). Also, a positive correlation between both markers was found (r= 0.53, p< 0.001). Moreover, elevated levels of both markers were significantly associated with the stage, lymph node involvement at both mRNA and protein levels (p< 0.001). In conclusion, there is a clinical significance of SATB-1 and ERBB2 as potential biomarkers for predicting bladder cancer patients of aggressive behavior and poor prognosis.

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Novel oncogenic function of ATDC in bladder cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.4591 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 4591-4591

Author(s):

Phillip Lee Palmbos ◽

Lidong Wang ◽

Huibin Yang ◽

Taylor Detzler ◽

Gina Ney ◽

...

Keyword(s):

Gene Expression ◽

Bladder Cancer ◽

Cancer Cell ◽

Pten Expression ◽

Cancer Tissue ◽

Bladder Tumors ◽

Human Bladder ◽

Urothelial Carcinomas ◽

Normal Bladder

4591 Background: Bladder cancer is a common and deadly disease, but the molecular events leading to its initiation and progression are incompletely understood. We recently identified Ataxia-Telangiectasia Group D Associated (ATDC) as a novel oncogene which drives tumor proliferation and invasion in pancreatic carcinoma (Cancer Cell, 2009). In this study, we describe the role of ATDC as an oncogene in bladder cancer. Methods: To further determine the oncogenic role of ATDC, we generated ATDC transgenic (tg) mice in which ATDC expression was driven by a CMV promoter and characterized the resulting tumors. Results: Interestingly, the dominant phenotype in these mice was the development of both non-invasive and invasive urothelial carcinomas (9% and 20% respectively, average age of onset 10-12 months of age). Histologically, these tumors were indistinguishable from human urothelial carcinomas. Gene expression profiling of invasive tumors derived from ATDC tg mice demonstrated a marked overlap with gene signatures of human invasive bladder cancers. ATDC was the 11th most highly up-regulated gene in bladder cancers represented in the Oncomine gene expression database. Analysis of a human bladder cancer tissue microarray (311 samples) by IHC showed elevated expression in 70% (173/252) of muscle-invasive carcinomas, 22% (5/23) of papillary tumors and little or no expression in normal bladder urothelium. ATDC tg mouse bladder tumors demonstrated loss of p53 signaling and down-regulation of PTEN expression, which correlated with ATDC induced methylation of the PTEN promoter by DNMT3A. Furthermore, ATDC knock-down in invasive cancer cell lines resulted in decreased proliferation, invasion and reactivation of p53-mediated signaling and PTEN expression. Conclusions: ATDC is a novel oncogene that is highly expressed in human bladder cancers and is sufficient to drive the development of invasive bladder tumors in tg mice. The mechanism by which ATDC drives bladder cancer formation involves alterations in p53 and PTEN pathways known to be important in bladder tumorigenesis.

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Molecular profiling of small cell bladder cancer (SCBC) to reveal gene expression determinants of an aggressive phenotype.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.4529 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 4529-4529 ◽

Cited By ~ 1

Author(s):

Vadim S. Koshkin ◽

Jordan Reynolds ◽

Paul Elson ◽

Cristina Magi-Galluzzi ◽

Jesse McKenney ◽

...

Keyword(s):

Gene Expression ◽

Protein Expression ◽

Expression Patterns ◽

Cleveland Clinic ◽

Molecular Profiling ◽

Small Cell ◽

Gene Expression Patterns ◽

Bladder Tissue ◽

Normal Bladder ◽

L1 Protein

4529 Background: SCBC is rare and its underlying biology poorly understood. Molecular profiling can shed light on the biology and identify treatment targets and biomarkers. Methods: A retrospective review of 63 patients (pts) with biopsy-confirmed SCBC at Cleveland Clinic (1994-2015) was performed. Percentage of small cell component (SC%) was defined by independent pathology review. DLL3 and PD-L1 protein expression were measured by IHC in 53 pts. Gene expression analysis was done in 38 primary SCBC tumor samples, 1 metastatic sample, and 5 normal bladder tissue samples (44 total) from the same cohort using HTG EdgeSeq OBP Assay with probes for 2568 genes. Analysis was performed via the RNAseq workflow (Partek Genomics Suite). Results: Among 63 identified pts, median age was 71 (39-90), 83% were men, median SC% was 100% (range 5-100%), median follow-up was 16.6 months and estimated median overall survival (OS) was 22.8 months. Unsupervised hierarchical clustering of gene expression patterns from 44 samples produced 4 distinct clusters. Pts with tumors in cluster 1 (that also included normal samples) did not have metastasis at diagnosis or distant recurrence, both of which were over-represented in the other 3 clusters. Kaplan-Meier analysis revealed a trend towards longer OS in cluster 1 patients (log rank p = 0.065). Higher gene expression of PRC1, NCAM1 (CD56) and DLL3 correlated with higher SC%, as did lower gene expression of ERBB2, PD-L1 and HPGD (p < 0.01). PD-L1 protein expression (≥1% cells) was noted in 30% of pts but did not correlate with outcome, SC%, DLL3 protein expression, or PD-L1 gene expression. DLL3 protein expression (≥1% cells) was noted in 68% of pts and DLL3 > 10% correlated with decreased OS (p = .03). Higher DLL3 protein expression correlated with DLL3 gene expression (Spearman r = 0.70, p < .01) and with SC% (r = .33, p = .01). Conclusions: This is the first study to reveal distinct gene expression patterns that define aggressive behavior, metastatic potential and outcomes in SCBC. The prognostic value of differential gene expression networks and the presence of underlying genomic and epigenetic alterations is the subject of ongoing prospective validation in a larger cohort.

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Integrated Bioinformatic Analysis of Key Biomarkers and Signaling Pathways in Psoriasis

10.21203/rs.3.rs-421570/v1 ◽

2021 ◽

Author(s):

Suwei Tang ◽

Ping Xu ◽

Shaoqiong Xie ◽

Wencheng Jiang ◽

Jiajing Lu ◽

...

Keyword(s):

Gene Expression ◽

Signaling Pathways ◽

Immune Cell ◽

Cell Types ◽

Bioinformatic Analysis ◽

Receptor Interaction ◽

Ppi Network ◽

Hub Genes ◽

Diagnostic Efficacy ◽

Network Analyses

Abstract Background: Psoriasis is a relatively common autoimmune inflammatory skin disease with a chronic etiology. The present study was designed to detect novel biomarkers and pathways associated with psoriasis incidence. Methods: Differentially expressed genes (DEGs) associated with psoriasis in the Gene Expression Omnibus (GEO) database were identified, and their functional roles and interactions were then annotated and evaluated through GO, KEGG, and gene set variation (GSVA) analyses. In addition, the STRING database was leveraged to construct a protein-protein interaction (PPI) network, and key hub genes from this network were validated as being relevant through receiver operating characteristic (ROC) curve analyses of three additional GEO datasets. The CIBERSORT database was additionally used to assess the relationship between these gene expression-related findings and immune cell infiltration. Results: In total 197 psoriasis-related DEGs were identified and found to primarily be associated with the NOD-like receptor, IL-17, and cytokine-cytokine receptor interaction signaling pathways. GSVA revealed significant differences between normal and lesional groups (P < 0.05), while PPI network analyses identified CXCL10 as the hub gene with the highest degree value, whereas IRF7, IFIT3, OAS1, GBP1, and ISG15 were promising candidate genes for the therapeutic treatment of psoriasis. ROC analyses confirmed that these 6 hub genes exhibited good diagnostic efficacy (AUC > 70%), and were predicted to be associated with increased sensitivity to 10 drugs (P < 0.01). The CIBERSORT database further predicted that these hub genes were associated with infiltration by 22 different immune cell types. Conclusion: These results offer a robust foundation for future studies of the molecular basis for psoriasis, potentially guiding efforts to treat this common and disruptive disease.

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Global Analysis of miRNA-mRNA Regulation Pair in Bladder Cancer

10.21203/rs.3.rs-1039601/v1 ◽

2021 ◽

Author(s):

Xingchen Fan ◽

Xuan Zou ◽

Cheng Liu ◽

Shuang Peng ◽

Shiyu Zhang ◽

...

Keyword(s):

Gene Expression ◽

Bladder Cancer ◽

Correlation Analysis ◽

Global Analysis ◽

Characteristic Curve ◽

External Validation ◽

Regulation Of Gene Expression ◽

The Cancer Genome Atlas ◽

Mrna Regulation ◽

Qrt Pcr

Abstract Purpose: MicroRNA (miRNA) is a class of short non-coding RNA molecules that functions in RNA silencing and post-transcriptional regulation of gene expression. This study aims to identify critical miRNA-mRNA regulation pairs contributing to bladder cancer (BLCA) pathogenesis. Patients and methods: MiRNA and mRNA microarray and RNA-sequencing datasets were downloaded from gene expression omnibus (GEO) and the cancer genome atlas (TCGA) databases. The tool of GEO2R and R packages were used to screen differential miRNAs (DE-miRNAs) and mRNAs (DE-mRNAs) and DAVID, DIANA, and Hiplot tools were used to perform gene enrichment analysis. The miRNA-mRNA regulation pair were screened from the experimentally validated miRNA-target interactions databases (miRTarBase and TarBase). Twenty-eight pairs of BLCA tissues were used to further verify the screened DE-miRNAs and DE-mRNAs by quantitative reverse transcription and polymerase chain reaction (qRT-PCR). The diagnostic value of the miRNA-mRNA regulation pairs was evaluated by receiver operating characteristic curve (ROC) and decision curve analysis (DCA). The correlation analysis between the selected miRNA-mRNAs regulation pair and clinical, survival and tumor-related phenotypes was performed in this study.Results: After the analysis of 2 miRNA datasets, 6 mRNA datasets and TCGA-BLCA dataset, a total of 13 miRNAs (5 down-regulated and 8 up-regulated in BLCA tissues) and 181 mRNAs (72 up-regulated and 109 down-regulated in BLCA tissues) were screened out. The pairs of miR-17-5p (up-regulated in BLCA tissues) and TGFBR2 (down-regulated in BLCA tissues) were verified in the external validation cohort (28 BLCA vs. 28 NC) using qRT-PCR. Areas under the ROC curve of the miRNA-mRNA regulation pair panel were 0.929 (95% CI: 0.885-0.972, p<0.0001) in TCGA-BLCA and 0.767 (95% CI: 0.643-0.891, p=0.001) in the external validation. The DCA also showed that the miRNA-mRNA regulation pairs had an excellent diagnostic performance distinguishing BLCA from normal controls. Correlation analysis showed that miR-17-5p and TGFBR2 correlated with tumor immunity.Conclusions: The research identified potential miRNA-mRNA regulation pairs, providing a new idea for exploring the genesis and development of BLCA.

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ATDC as a novel oncogene in bladder cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.269 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 269-269

Author(s):

Phillip Lee Palmbos ◽

Lidong Wang ◽

Huibin Yang ◽

Taylor Detzler ◽

Gina Ney ◽

...

Keyword(s):

Gene Expression ◽

Bladder Cancer ◽

Cancer Cell ◽

Pten Expression ◽

Cancer Tissue ◽

Bladder Tumors ◽

Human Bladder ◽

Urothelial Carcinomas ◽

Normal Bladder

269 Background: Bladder cancer is a common and deadly disease, but the molecular events leading to its initiation and progression are incompletely understood. We recently identified Ataxia-Telangiectasia Group D Associated (ATDC) as a novel oncogene which drives tumor proliferation and invasion in pancreatic carcinoma (Cancer Cell, 2009). In this study, we describe the role of ATDC as an oncogene in bladder cancer. Methods: To further determine the oncogenic role of ATDC, we generated ATDC transgenic (tg) mice in which ATDC expression was driven by a CMV promoter and characterized the resulting tumors. Results: The dominant phenotype in these mice was the development of both papillary and invasive urothelial carcinomas (9% and 20% respectively, average age of onset 10-12 months of age). Histologically, these tumors were indistinguishable from human urothelial carcinomas. Gene expression profiling of invasive tumors derived from ATDC tg mice demonstrated a marked overlap with gene signatures of human invasive bladder cancers. Analysis of a human bladder cancer tissue microarray (311 samples) showed elevated expression in 70% (173/252) of muscle-invasive carcinomas, whereas normal bladder had no expression. 22% (5/23) of papillary tumors also expressed elevated levels of ATDC. ATDC was the 11th most highly up-regulated gene in bladder cancers represented in the Oncomine gene expression database. ATDC tg mouse bladder tumors demonstrated loss of p53 signaling and down-regulation of PTEN expression, which was determined to be due to ATDC abrogation of p53 function by cytoplasmic sequestration and ATDC-mediated methylation of the PTEN promoter. Furthermore, ATDC knock-down in invasive cancer cell lines resulted in decreased proliferation, invasion and reactivation of p53-mediated signaling and PTEN expression. Conclusions: ATDC is a novel oncogene that is highly expressed in human bladder cancers and is sufficient to drive the development of invasive bladder tumors in tg mice. The mechanism by which ATDC drives bladder cancer formation involves alterations in p53 and PTEN pathways known to be important in bladder tumorigenesis.

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