scholarly journals Construction and validation of a novel eight-gene risk score to predict the progression and prognosis of bladder cancer

2021 ◽  
Author(s):  
Ruiliang Wang ◽  
Zongtai Zheng ◽  
Shiyu Mao ◽  
Wentao Zhang ◽  
Ji Liu ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Risk Score ◽  
Cox Regression ◽  
Cox Model ◽  
The Cancer Genome Atlas ◽  
Invasive Bladder Cancer ◽  
Training Dataset ◽  
Muscle Invasive Bladder Cancer ◽  
Risk Of Death ◽  
Muscle Invasive

Abstract Background: The progression from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) increases the risk of death. It is therefore important to find new relevant molecular models that will allow for effective prediction of the progression of bladder cancer (BC).Methods: Using RNA-Sequence data of 49 BC patients in our center and weighted gene co-expression network analysis methods, a co-expression network of genes was developed from which three key modules with prognostic value were selected using Univariate Cox regression in The Cancer Genome Atlas Program (TCGA). Subsequently, an eight-gene risk score was established using the Least absolute shrinkage and selection operator Cox model. Results: A novel eight-gene risk score was closely related to the malignant clinical features of BC and could predict the prognosis of patients in the training dataset (TCGA) and two validation sets (GSE3289 and GSE13507). Further, a nomogram for predicting the overall survival of patients was designed. The nomogram showed good calibration with clinical value through decision curve analysis. Lastly, we found that the mRNA and protein expression level of the eight genes were found to be differentially expressed in cell lines and tissue.Conclusions: In our study, we established a novel eight-gene risk score which could predict the progression and prognoses of BC patients.

scholarly journals Construction and Validation of a Novel Eight-Gene Risk Score to Predict the Malignant Progression and Prognoses in Bladder Cancer Patients

2020 ◽  
Author(s):  
Ruiliang Wang ◽  
Zongtai Zheng ◽  
Shiyu Mao ◽  
Wentao Zhang ◽  
Ji Liu ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Risk Score ◽  
Cox Regression ◽  
Cox Model ◽  
Malignant Progression ◽  
The Cancer Genome Atlas ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Normal Bladder ◽  
Muscle Invasive

Abstract The progression from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) largely predisposes a life-threatening risk. Owing to this, it is of paramount importance to find new relevant molecular models that will allow for effectively predict the malignant progression of BC. Based on the RNA-Sequence data of 49 BC patients in our center and weighted gene co-expression network analysis methods, a co-expression network was developed using these genes before selecting the three key modules. Univariate Cox regression was used to select the key module genes with prognostic value in The Cancer Genome Atlas Program (TCGA). Subsequently, we developed an eight-gene risk score using the Least absolute shrinkage and selection operator Cox model. Notably, the eight-gene risk score was observed to be closely related to the malignant clinical features and also showed a favorable predictive power of differentiation between NMIBC and MIBC in the training (TCGA) and the two validation sets (GSE3289 and GSE13507). Furthermore, we generated a nomogram for predicting the overall survival. Both the calibrations and decision curve analysis curves displayed predictive effectiveness of the nomogram. Lastly, the RT-qPCR results revealed that the majority of the eight genes were differentially expressed between BC cell lines and a normal bladder epithelial cell line. Hence, from our study, we established a model of eight-gene risk score, with the potential of predicting malignant progression and determine prognoses of BC patients.

scholarly journals Eight-gene risk score predicts progression and prognosis in bladder cancer

2021 ◽  
Author(s):  
Ruiliang Wang ◽  
Zongtai Zheng ◽  
Shiyu Mao ◽  
Wentao Zhang ◽  
Ji Liu ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Protein Expression ◽  
Cell Lines ◽  
Risk Score ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Risk Of Death ◽  
Mrna And Protein Expression ◽  
Muscle Invasive ◽  
Prognostic Prediction

Abstract Background: The progression from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) increases the risk of death. It is therefore important to find new relevant molecular models that will allow for effective prediction of the progression and prognosis of bladder cancer (BC).Methods: Using RNA-Sequence data of 49 BC patients in our center and weighted gene co-expression network analysis methods, a co-expression network of genes was developed and three key modules associated with malignant progression were selected. Based on the genes in three key modules, an eight-gene risk score was established using univariate Cox regression and the Least absolute shrinkage and selection operator Cox model in The Cancer Genome Atlas Program (TCGA) and validated in validation sets. Subsequently, a nomogram based on the risk score was constructed for prognostic prediction. The mRNA and protein expression levels of eight genes in cell lines and tissues were further investigated.Results: A novel eight-gene risk score was closely related to the malignant clinical features of BC and could predict the prognosis of patients in the training dataset (TCGA) and three validation sets (GSE3289 , GSE13507 and IMvigor210 trial). The nomogram showed good prognostic prediction and calibration. The mRNA and protein expression level of the eight genes were differentially expressed in cell lines and tissues.Conclusions: In our study, we established a novel eight-gene risk score which could predict the progression and prognoses of BC patients.

scholarly journals Stromal LAG-3+cells infiltration defines poor prognosis subtype muscle-invasive bladder cancer with immunoevasive contexture

2020 ◽  
Vol 8 (1) ◽  
pp. e000651 ◽  
Author(s):  
Han Zeng ◽  
Quan Zhou ◽  
Zewei Wang ◽  
Hongyu Zhang ◽  
Zhaopei Liu ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Immune Checkpoint ◽  
Cox Regression ◽  
Mrna Level ◽  
Disease Free Survival ◽  
The Cancer Genome Atlas ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

BackgroundLymphocyte activation gene 3 (LAG-3) is a promising immune checkpoint therapeutic target being evaluated in clinical trials. We assessed the LAG-3+cells distribution, its association with clinical outcomes and immune contexture and its role in the landscape of muscle-invasive bladder cancer (MIBC) treatment.Methods141 patients with MIBC from Zhongshan Hospital were included for survival and adjuvant chemotherapy (ACT) benefit analyses. 32 fresh resected samples of MIBC were collected to detect CD8+T cells functional state. The molecular classification analyses were based on 391 patients with MIBC from The Cancer Genome Atlas. Immunohistochemistry and flow cytometry were performed to characterize various immune cells infiltration.ResultsIn Kaplan-Meier analyses and Cox regression models, stromal LAG-3+cells enrichment was consistently associated with inferior overall survival and disease-free survival, and indicated suboptimal responsiveness to ACT. Patents with high stromal LAG-3+cells possessed increased protumor cells, immunosuppressive cytokines and immune checkpoint expression. The phenotypic analyses of CD8+T cells correlated its dysfunctional state with LAG-3+cells. Besides, LAG-3 mRNA level was linked to luminal and basal subtypes of MIBC. LAG-3-high tumors exhibited limited FGFR3 mutation and signaling signature, and displayed activated immunotherapeutic and EGFR-associated pathway.ConclusionsStromal LAG-3+cells abundance indicated an immunoevasive contexture with dysfunctional CD8+T cells, and represented an independent predictor for adverse survival outcome and ACT resistance in MIBC. LAG-3 expression could potentially be a novel biomarker for FGFR3-targeted and EGFR-targeted therapies and immunotherapy. The crucial role of LAG-3+cells in the therapeutic landscape of MIBC needs further validation retrospectively and prospectively.

scholarly journals Identification of a Nuclear Mitochondrial-Related Multi-Genes Signature to Predict the Prognosis of Bladder Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Xuewen Jiang ◽  
Yangyang Xia ◽  
Hui Meng ◽  
Yaxiao Liu ◽  
Jianfeng Cui ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cox Regression ◽  
Checkpoint Inhibitors ◽  
Expression Profiles ◽  
The Cancer Genome Atlas ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Genome Database ◽  
Cox Regression Analysis ◽  
Muscle Invasive

IntroductionBladder cancer (BC) is one of the most prevalent urinary cancers, and its management is still a problem causing recurrence and progression, elevating mortality.Materials and MethodsWe aimed at the nuclear mitochondria-related genes (MTRGs), collected from the MITOMAP: A Human Mitochondrial Genome Database. Meanwhile, the expression profiles and clinical information of BC were downloaded from the Cancer Genome Atlas (TCGA) as a training group. The univariate, multivariate, and the least absolute shrinkage and selection operator (LASSO) Cox regression analyses were used to construct a nuclear mitochondrial-related multi-genes signature and the prognostic nomogram.ResultsA total of 17 nuclear MTRGs were identified to be correlated with the overall survival (OS) of BC patients, and a nuclear MTRGs signature based on 16 genes expression was further determined by the LASSO Cox regression analysis. Based on a nuclear MTRGs scoring system, BC patients from the TCGA cohort were divided into high- and low- nuclear MTRGs score groups. Patients with a high nuclear MTRGs score exhibited a significantly poorer outcome (median OS: 92.90 vs 20.20 months, p<0.0001). The nuclear MTRGs signature was further verified in three independent datasets, namely, GSE13507, GSE31684, and GSE32548, from the Gene Expression Omnibus (GEO). The BC patients with a high nuclear MTRGs score had significantly worse survival (median OS in GSE13507: 31.52 vs 98.00 months, p<0.05; GSE31684: 32.85 months vs unreached, p<0.05; GSE32548: unreached vs unreached, p<0.05). Furthermore, muscle-invasive bladder cancer (MIBC) patients had a significantly higher nuclear MTRGs score (p<0.05) than non-muscle-invasive bladder cancer (NMIBC) patients. The integrated signature outperformed each involved MTRG. In addition, a nuclear MTRGs-based nomogram was constructed as a novel prediction prognosis model, whose AUC values for OS at 1, 3, 5 years were 0.76, 0.75, and 0.75, respectively, showing the prognostic nomogram had good and stable predicting ability. Enrichment analyses of the hallmark gene set and KEGG pathway revealed that the E2F targets, G2M checkpoint pathways, and cell cycle had influences on the survival of BC patients. Furthermore, the analysis of tumor microenvironment indicated more CD8+ T cells and higher immune score in patients with high nuclear MTRGs score, which might confer sensitivity to immune checkpoint inhibitors.ConclusionsNot only could the signature and prognostic nomogram predict the prognosis of BC, but it also had potential therapeutic guidance.

scholarly journals A stemness-related seven-gene signature for predicting prognosis and treatment response in muscle invasive bladder cancer

2020 ◽  
Author(s):  
Maolang Tian ◽  
Jinlan He ◽  
Jiaqi Han ◽  
Hong Zhu
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Clinical Outcome ◽  
Treatment Response ◽  
Risk Score ◽  
Gene Signature ◽  
Invasive Bladder Cancer ◽  
Cancer Stemness ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

Abstract Background: Muscle invasive bladder cancer (MIBC) is an aggressive cancer characterized by therapeutic resistance and poor prognosis, which are possibly due to the existence of cancer stem cells (CSCs). In this study, we aimed to characterize the expression of cancer stemness-related genes and develop a multi-gene risk signature to predict clinical outcome and treatment response in MIBC.Methods: The mRNA expression data and clinical data of MIBC patients were collected from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database, which included the TCGA training cohort (n = 333) and three GEO validation cohorts, GSE13507 (n = 165), GSE32548 (n = 127), and GSE48075 (n = 72). A list of 166 stemness-related genes were obtained from the Cancer Single Cell State Atlas (CancerSEA) database and prognostic genes for overall survival (OS) were identified by univariate Cox analysis. Then, the least absolute shrinkage and selection operator (LASSO) regression and stepwise multivariate Cox regression were performed to generate a multi-gene risk signature. Kaplan-Meier curve, time-dependent receiver operating characteristic (ROC) curve, multivariate analysis, and stratification analysis were used to evaluate the performance of the gene signature. We also explored the relationship between risk score and response to chemotherapy and radiotherapy in MIBC patients. Moreover, independent prognostic factors for OS were combined together into a nomogram to improve predictive performance.Results: Firstly, a total of 25 prognostic genes were identified. Then, a seven-gene risk signature (EGFR, FOXA2, HES1, MME, RBM6, SMOC2, and TFRC) was constructed and it could robustly classify MIBC patients into high -risk and low-risk groups with different clinical outcomes. ROC curves showed that the seven-gene signature had a robust predictive accuracy in four cohorts. Besides, high risk score was significantly associated with advanced clinical stage and treatment failure. As an independent risk factor for OS, the stemness-related seven-gene signature could achieve better prognostic accuracy when integrated with clinical factors. Conclusions: We developed and validated a robust stemness-related gene signature which could robustly predicate clinical outcome and shed light on the cancer stemness in bladder cancer.

Unraveling UCA1 lncRNA prognostic utility in urothelial bladder cancer

2019 ◽  
Vol 40 (8) ◽  
pp. 965-974 ◽  
Author(s):  
Margaritis Avgeris ◽  
Anastasia Tsilimantou ◽  
Panagiotis K Levis ◽  
Theodoros Rampias ◽  
Maria-Alexandra Papadimitriou ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Clinical Benefit ◽  
Prediction Models ◽  
Cox Regression ◽  
Invasive Bladder Cancer ◽  
Precision Oncology ◽  
Muscle Invasive Bladder Cancer ◽  
Bootstrap Analysis ◽  
Cox Regression Analysis ◽  
Muscle Invasive

AbstractIn the era of precision oncology, bladder cancer (BlCa) is characterized by generic patient management and lack of personalized prognosis and surveillance. Herein, we have studied the clinical significance of urothelial cancer associated 1 (UCA1) lncRNA in improving patients’ risk stratification and prognosis. A screening cohort of 176 BlCa patients was used for UCA1 quantification. The Hedegaard et al. (n = 476) and The Cancer Genome Atlas (TCGA) provisional (n = 413) were analyzed as validation cohorts for non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC), respectively. Patients’ survival outcome was assessed using recurrence and progression for NMIBC or death for MIBC as clinical endpoint events. Bootstrap analysis was performed for internal validation of Cox regression analysis, whereas the clinical benefit of disease prognosis was assessed by decision curve analysis. UCA1 was significantly overexpressed in bladder tumors compared with normal urothelium, which was confirmed only in the case of NMIBC. Interestingly, reduced expression of UCA1 was correlated with muscle-invasive disease as well as with tumors of higher stage and grade. UCA1 loss was strongly associated with higher risk of short-term relapse [hazard ratio (HR) = 1.974; P = 0.032] and progression to invasive stages (HR = 3.476; P = 0.023) in NMIBC. In this regard, Hedegaard et al. and TCGA validation cohorts confirmed the unfavorable prognostic nature of UCA1 loss in BlCa. Finally, prognosis prediction models integrating UCA1 underexpression and established clinical disease markers contributed to improved stratification specificity and superior clinical benefit for NMIBC prognosis. Underexpression of UCA1 correlates with worse disease outcome in NMIBC and contributes to superior prediction of disease early relapse and progression as well as improved patient stratification specificity.

scholarly journals Chemoradiotherapy in octogenarians as primary treatment for muscle-invasive bladder cancer

2017 ◽  
Vol 11 (1-2) ◽  
pp. 24 ◽  
Author(s):  
Victor A. McPherson ◽  
George Rodrigues ◽  
Glenn Bauman ◽  
Eric Winquist ◽  
Joseph Chin ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Local Recurrence ◽  
Cox Regression ◽  
Bladder Tumour ◽  
Invasive Bladder Cancer ◽  
High Dose ◽  
Muscle Invasive Bladder Cancer ◽  
Trimodality Therapy ◽  
Muscle Invasive ◽  
Salvage Cystectomy

Introduction: While radical cystectomy is the gold standard for muscle-invasive bladder cancer (MIBC), in octogenarians cystectomy results in a higher perioperative mortality rate (6.8‒11.1%) than in younger patients (2.2%). Trimodality therapy is a bladdersparing regimen composed of transurethral resection of bladder tumour (TURBT) and chemoradiotherapy, with intent for salvage cystectomy, and has a 62.5‒90% initial complete response rate. In this study, we evaluate TURBT and chemoradiotherapy without salvage cystectomy in medically inoperable octogenarian patients.Methods: We identified a retrospective cohort of patients aged 80‒89 years with invasive urothelial carcinoma who received combination chemoradiotherapy between 2008 and June 2014. Outcomes were evaluated by Kaplan-Meier (KM) and Cox regression.Results: In 40 patients, the mean age was 84.5 years (interquartile range [IQR] 83‒86). Seventeen patients received hypofractionated, low-dose radiotherapy (LD) (37.5‒40 Gy), while 23 received conventionally fractionated radiotherapy (high-dose [HD]) (50‒65 Gy). Mean overall survival (OS) was 20.7 months (IQR 12.75‒23.25), while mean recurrence-free survival (RFS) was 13.75 months (IQR 3.75‒16.5). Patients receiving HD radiotherapy showed improved OS and local RFS (LRFS) without significant differences in Grade 3‒4 toxicities. Univariate Cox regression identified hydronephrosis as a predictor of worse OS and local recurrence and HD radiotherapy as a predictor of improved OS and local recurrence rates. Multivariate Cox regression identified hydronephrosis to be a significant predictor of LRFS.Conclusions: Primary chemoradiotherapy for inoperable patients with MIBC resulted in a three-year OS of 54.9% (comparable to cystectomy) and three-year RFS of 42.3%. Superior outcomes were associated with more aggressive chemoradiotherapy treatment. The results of the local control subanalyses in this study are hypothesisgenerating due to the limited patient numbers in the cohort.

scholarly journals Post-Bacille Calmette–Guerin surveillance for non-muscle invasive bladder cancer: do random biopsies offer an advantage?

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Nassib Abou Heidar ◽  
Muhieddine Saadeddine Labban ◽  
Alexandre Khalil Armache ◽  
Muhammad Ahmad Bulbul ◽  
Albert Elias El-Hajj ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Carcinoma In Situ ◽  
Cox Regression ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Flexible Cystoscopy ◽  
Time To Recurrence ◽  
Surveillance Method ◽  
Muscle Invasive

Abstract Background The optimal surveillance method for recurrence of non-muscle invasive bladder cancer (NMIBC) after intravesical BCG treatment is unknown. The aim of this study is to assess the difference between two surveillance methods: cystoscopy with bladder biopsies and office-based flexible cystoscopy in detecting NMIBC recurrence and time to recurrence. Methods Charts of patients who underwent transurethral resection of bladder tumor with subsequent intravesical Bacillus Calmette–Guerin (BCG) treatment were reviewed between January 2015 and December 2018. Baseline demographics and oncological parameters were compared between the two methods of surveillance. Then, the role of the surveillance method for NMIBC recurrence and time to recurrence were evaluated in backward logistic regression and hazard ratios estimated in Cox regression models, respectively. Results Fifty-one patients (50.5%) underwent office-based flexible cystoscopy and 50 patients (49.5%) had bladder biopsies. The patients undergoing either surveillance methods were comparable for baseline demographic and oncological parameter. The predictors of recurrence and earlier BCG relapse were increased body mass index, the presence of multifocal tumors, the presence of concurrent carcinoma in situ, and tumor size at presentation. Bladder cancer recurrence was mostly affected by multifocality of the disease [OR 3.61 95%CI (1.17–11.15)] and the presence of concomitant carcinoma in situ [4.35 (1.29–14.68)]. Yet, the surveillance method neither predicted a higher recurrence yield nor earlier diagnosis. Conclusion In our cohort, there is neither difference in recurrence yield nor earlier diagnosis of recurrence between office-based flexible cystoscopy and bladder biopsies. Larger prospective studies are needed to assess the generalizability of these findings.

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