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.

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 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 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 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 Long non-coding RNAs identify a subset of luminal muscle-invasive bladder cancer patients with favorable prognosis

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Joep J. de Jong ◽  
Yang Liu ◽  
A. Gordon Robertson ◽  
Roland Seiler ◽  
Clarice S. Groeneveld ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Expression Profiles ◽  
The Cancer Genome Atlas ◽  
Invasive Bladder Cancer ◽  
Cluster Solution ◽  
Muscle Invasive Bladder Cancer ◽  
Lncrna Expression ◽  
Favorable Prognosis ◽  
Non Coding Rnas ◽  
Muscle Invasive

Abstract Background Muscle-invasive bladder cancer (MIBC) is a heterogeneous disease, and gene expression profiling has identified several molecular subtypes with distinct biological and clinicopathological characteristics. While MIBC subtyping has primarily been based on messenger RNA (mRNA), long non-coding RNAs (lncRNAs) may provide additional resolution. Methods LncRNA expression was quantified from microarray data of a MIBC cohort treated with neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) (n = 223). Unsupervised consensus clustering of highly variant lncRNAs identified a four-cluster solution, which was characterized using a panel of MIBC biomarkers, regulon activity profiles, gene signatures, and survival analysis. The four-cluster solution was confirmed in The Cancer Genome Atlas (TCGA) cohort (n = 405). A single-sample genomic classifier (GC) was trained using ridge-penalized logistic regression and validated in two independent cohorts (n = 255 and n = 94). Results NAC and TCGA cohorts both contained an lncRNA cluster (LC3) with favorable prognosis that was enriched with tumors of the luminal-papillary (LP) subtype. In both cohorts, patients with LP tumors in LC3 (LPL-C3) were younger and had organ-confined, node-negative disease. The LPL-C3 tumors had enhanced FGFR3, SHH, and wild-type p53 pathway activity. In the TCGA cohort, LPL-C3 tumors were enriched for FGFR3 mutations and depleted for TP53 and RB1 mutations. A GC trained to identify these LPL-C3 patients showed robust performance in two validation cohorts. Conclusions Using lncRNA expression profiles, we identified a biologically distinct subgroup of luminal-papillary MIBC with a favorable prognosis. These data suggest that lncRNAs provide additional information for higher-resolution subtyping, potentially improving precision patient management.

scholarly journals Calculated identification of mutator-derived lncRNA signatures of genomic instability to predict the clinical outcome of muscle-invasive bladder cancer

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yingchun Liang ◽  
Fangdie Ye ◽  
Zhang Cheng ◽  
Yuxi Ou ◽  
Lujia Zou ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Genomic Instability ◽  
Cox Regression ◽  
Risk Group ◽  
Risk Groups ◽  
Differentially Expressed ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Cox Regression Analysis ◽  
Muscle Invasive

Abstract Background Muscle-invasive bladder cancer (MIBC) is one of the most important type of bladder cancer, with a high morbidity and mortality rate. Studies have found that long non-coding RNA (lncRNA) plays a key role in maintaining genomic instability. However, Identification of lncRNAs related to genomic instability (GIlncRNAs) and their clinical significance in cancers have not been extensively studied yet. Methods Here, we downloaded the lncRNA expression profiles, somatic mutation profiles and clinical related data in MIBC patients from The Cancer Genome Atlas (TCGA) database. A lncRNA computational framework was used to find differentially expressed GIlncRNAs. Multivariate Cox regression analysis was used to construct a genomic instability-related lncRNA signature (GIlncSig). Univariate and multivariate Cox analyses were used to assess the independent prognostic for the GIlncSig and other key clinical factors. Results We found 43 differentially expressed GIlncRNAs and constructed the GIlncSig with 6 GIlncRNAs in the training cohort. The patients were divided into two risk groups. The overall survival of patients in the high-risk group was lower than that in the low-risk group (P < 0.001), which were further verified in the testing cohort and the entire TCGA cohort. Univariate and multivariate Cox regression showed that the GIlncSig was an independent prognostic factor. In addition, the GIlncSig correlated with the genomic mutation rate of MIBC, indicating its potential as a measure of the degree of genomic instability. The GIlncSig was able to divide FGFR3 wild- and mutant-type patients into two risk groups, and effectively enhanced the prediction effect. Conclusion Our study introduced an important reference for further research on the role of GIlncRNAs, and provided prognostic indicators and potential biological therapy targets for MIBC.

scholarly journals Perioperative Systemic Treatment for Muscle-Invasive Bladder Cancer: Current Evidence and Future Perspectives

2021 ◽  
Vol 22 (13) ◽  
pp. 7201
Author(s):  
In-Ho Kim ◽  
Hyo-Jin Lee
Keyword(s):  
Bladder Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Systemic Treatment ◽  
Checkpoint Inhibitors ◽  
Invasive Bladder Cancer ◽  
Current Evidence ◽  
Future Perspectives ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

Radical cystectomy is the primary treatment for muscle-invasive bladder cancer; however, approximately 50% of patients develop metastatic disease within 2 years of diagnosis, which results in dismal prognosis. Therefore, systemic treatment is important to improve the prognosis of muscle-invasive bladder cancer. Currently, several guidelines recommend cisplatin-based neoadjuvant chemotherapy before radical cystectomy, and adjuvant chemotherapy is recommended in patients who have not received neoadjuvant chemotherapy. Immune checkpoint inhibitors have recently become the standard treatment option for metastatic urothelial carcinoma. Owing to their clinical benefits, several immune checkpoint inhibitors, with or without other agents (including other immunotherapy, cytotoxic chemotherapy, and emerging agents such as antibody drug conjugates), are being extensively investigated in perioperative settings. Several studies for perioperative immunotherapy have shown that immune checkpoint inhibitors have promising efficacy with relatively low toxicity, and have explored the predictive molecular biomarkers. Herein, we review the current evidence and discuss the future perspectives of perioperative systemic treatment for muscle-invasive bladder cancer.

scholarly journals Management of Localized Muscle-Invasive Bladder Cancer from a Multidisciplinary Perspective: Current Position of the Spanish Oncology Genitourinary (SOGUG) Working Group

2021 ◽  
Vol 28 (6) ◽  
pp. 5084-5100
Author(s):  
Antonio Gómez Caamaño ◽  
Ana M. García Vicente ◽  
Pablo Maroto ◽  
Alfredo Rodríguez Antolín ◽  
Julián Sanz ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Working Group ◽  
Checkpoint Inhibitors ◽  
Imaging Techniques ◽  
Clinical Staging ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive ◽  
Selection Of Patients ◽  
Selection Of

This review presents challenges and recommendations on different aspects related to the management of patients with localized muscle-invasive bladder cancer (MIBC), which were discussed by a group of experts of a Spanish Oncology Genitourinary (SOGUG) Working Group within the framework of the Genitourinary Alliance project (12GU). It is necessary to clearly define which patients are candidates for radical cystectomy and which are candidates for undergoing bladder-sparing procedures. In older patients, it is necessary to include a geriatric assessment and evaluation of comorbidities. The pathological report should include a classification of the histopathological variant of MIBC, particularly the identification of subtypes with prognostic, molecular and therapeutic implications. Improvement of clinical staging, better definition of prognostic groups based on molecular subtypes, and identification of biomarkers potentially associated with maximum benefit from neoadjuvant chemotherapy are areas for further research. A current challenge in the management of MIBC is improving the selection of patients likely to be candidates for immunotherapy with checkpoint inhibitors in the neoadjuvant setting. Optimization of FDG-PET/CT reliability in staging of MIBC and the selection of patients is necessary, as well as the design of prospective studies aimed to compare the value of different imaging techniques in parallel.

Neoadjuvant or adjuvant immunotherapy in bladder cancer: biological opportunity or clinical utility?

2021 ◽  
pp. 030089162110616
Author(s):  
Fausto Petrelli ◽  
Gianluca Perego ◽  
Ivano Vavassori ◽  
Andrea Luciani
Keyword(s):  
Bladder Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Urothelial Cancer ◽  
Checkpoint Inhibitors ◽  
Phase Iii ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Cancer Of The Bladder ◽  
Muscle Invasive

In urothelial cancer of the bladder, the introduction of immunotherapy with immune checkpoint inhibitors represents progress in the management of the disease’s early and advanced stages. In particular, recent studies have implemented these drugs in the neoadjuvant and adjuvant phases to treat muscle-invasive bladder cancer. In some studies, patients received neoadjuvant immune checkpoint inhibitors alone (PURE and ABACUS) to treat muscle invasive bladder cancer, whereas other studies provided this therapy to cisplatin-ineligible patients. Furthermore, a large Phase III study (CheckMate 247) compared placebo with adjuvant nivolumab therapy in patients with high-risk urothelial cancer after neoadjuvant chemotherapy and surgery or surgery alone. Despite some uncertain niches (nonbladder, PD-L1-negative tumors, and node-negative resected cancers), certain biological opportunities (exploring new targets, evaluating in vivo pathologic response, focusing on biomarkers for response) and clinical uses (avoiding chemotherapy at all or in frail patients, attaining similar pathologic complete response rates as in cisplatin-based chemotherapy) are valid reasons for incorporating these agents into the therapeutic armamentarium of medical uro-oncologists.

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