FAM70Bas a Novel Prognostic Marker for Cancer Progression and Cancer-Specific Death in Muscle-Invasive Bladder Cancer

Approximately 80% of all new bladder cancer patients are diagnosed with non-muscle invasive bladder cancer (NMIBC). However, approximately 15% of them progress to muscle-invasive bladder cancer (MIBC), for which prognosis is poor. The current study aimed to improve diagnostic accuracy associated with clinical outcomes in NMIBC patients. Nevertheless, it has been challenging to identify molecular biomarkers that accurately predict MIBC progression because this disease is complex and heterogeneous. Through integrative transcriptome profiling, we showed that high SKA3 expression is associated with poor clinical outcomes and MIBC progression. We performed RNA sequencing on human tumor tissues to identify candidate biomarkers in NMIBC. We then selected genes with prognostic significance by analyzing public datasets from multiple cohorts of bladder cancer patients. We found that SKA3 was associated with NMIBC pathophysiology and poor survival. We analyzed public single-cell RNA-sequencing (scRNA-seq) data for bladder cancer to dissect transcriptional tumor heterogeneity. SKA3 was expressed in an epithelial cell subpopulation expressing genes regulating the cell cycle. Knockdown experiments confirmed that SKA3 promotes bladder cancer cell proliferation by accelerating G2/M transition. Hence, SKA3 is a new prognostic marker for predicting NMIBC progression. Its inhibition could form part of a novel treatment lowering the probability of bladder cancer progression.

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Tumour-Infiltrating lymphocytes in muscle-invasive bladder cancer: immunoscore as a prognostic marker

European Urology Open Science ◽

10.1016/s2666-1683(20)35634-2 ◽

2020 ◽

Vol 20 ◽

pp. S174-S175

Author(s):

P. Traverso ◽

F. Grillo ◽

F. Balzarini ◽

F. Ambrosini ◽

L. Mastracci ◽

...

Keyword(s):

Bladder Cancer ◽

Prognostic Marker ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Tumour Infiltrating Lymphocytes ◽

Muscle Invasive ◽

Infiltrating Lymphocytes

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Development of a genomic-clinical classifier for predicting progression after radical cystectomy in patients with muscle invasive bladder cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.4542 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 4542-4542

Author(s):

Anirban Pradip Mitra ◽

Nicholas Erho ◽

Lucia L.C. Lam ◽

Ismael A. Vergara ◽

Thomas Sierocinski ◽

...

Keyword(s):

Bladder Cancer ◽

Radical Cystectomy ◽

Cancer Progression ◽

External Validation ◽

Multivariable Analysis ◽

Invasive Bladder Cancer ◽

K Nearest Neighbor ◽

Muscle Invasive Bladder Cancer ◽

Validation Set ◽

Muscle Invasive

4542 Background: The mainstay of muscle-invasive bladder cancer treatment is surgical resection with/without multi-agent chemotherapy. Management decisions are based on a small number of clinical and pathologic parameters with poor prognostic and predictive power. There is an urgent need for enhanced biomarkers to guide therapy of this lethal disease. Here we have developed a genomic signature of bladder cancer progression using whole transcriptome profiling technology. Methods: 251 FFPE bladder cancer specimens were obtained from patients undergoing radical cystectomy at the University of Southern California (1998-2004). All patients had pT2-T4a,N0 urothelial carcinoma in the absence of pre-operative chemotherapy. Median follow-up was 5 years. RNA expression levels were measured with 1.4 million feature oligonucleotide microarrays. Patients were divided into a training set (2/3 of cohort) to develop a genomic classifier for risk of progression (defined as any type of bladder cancer recurrence), and a validation set (1/3 of cohort). In parallel, multivariable analysis was used to develop a clinical classifier using typical clinical and pathologic variables. Finally, a genomic-clinical classifier was built combining the genomic classifier with clinical variables using logistic regression. The receiver-operator characteristic (ROC) area under the curve (AUC) metric was used to evaluate each classifier in the validation set. Results: The genomic classifier consisted of 89 features corresponding to 80 genes that were combined in a k-nearest neighbor model (KNN89). KNN89 showed an AUC of 0.77 in ROC analysis on the validation set. The best clinical classifier showed an AUC of 0.72. The genomic-clinical classifier demonstrated an AUC of 0.81. Multivariable analysis incorporating all clinical parameters and KNN89 further revealed that KNN89 was the only significant predictor of bladder cancer progression (p=0.0077). Conclusions: We have developed a combined genomic-clinical classifier that shows improved performance over clinical models alone for prediction of progression after radical cystectomy. External validation of this classifier is ongoing.

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Evaluating cell cycle progression score as a prognostic marker for non-muscle invasive bladder cancer (NMIBC).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.476 ◽

2018 ◽

Vol 36 (6_suppl) ◽

pp. 476-476

Author(s):

Christopher J. Weight ◽

Paari J Murugan ◽

David Chesla ◽

Resha Tejpaul ◽

Ayman Soubra ◽

...

Keyword(s):

Cell Cycle ◽

Bladder Cancer ◽

Prognostic Marker ◽

Cell Cycle Progression ◽

Multivariable Analysis ◽

Invasive Bladder Cancer ◽

Prognostic Information ◽

Muscle Invasive Bladder Cancer ◽

Cycle Progression ◽

Muscle Invasive

476 Background: Accurate grading and staging from transurethral resection of bladder tumors (TURBT) is vital for appropriate clinical management. Non-muscle-invasive bladder cancer (NMIBC) can recur progress with higher grade and or stage progression to MIBC, requiring radical intervention with poorer prognosis. Further, grade and stage may change in 20-50% of TURBTs following re-review by expert GU pathologists Objective measures of stage and grade might offer additional and/or improved risk stratification; therefore we evaluated a molecular RNA signature as a prognostic marker for NMIBC. Methods: Patients were diagnosed with NMIBC at the University of Minnesota (UM)or Spectrum Health System(SHS) from 2005-2012. A Cell Cycle Progression (CCP) score was determined from the average expression of 36 CCP genes for patients with available FFPE diagnostic TURBT. The combined cohort consisted of 293 patients (UM n = 152, SHS n = 141). Study outcome was time from NMIBC diagnosis to progression to MIBC. Median follow-up for patients who did not experience an event was 4.4 years for UM and 6.9 for SHS. Association with outcomes was evaluated by Cox proportional hazards survival analysis and likelihood ratio tests. All analyses were stratified by cohort. Results: CCP score was associated with progression to MIBC in univariable analysis [hazard ratio 1.42 (95% CI 1.19, 1.68), p = 4.3x10-5]. Tumor grade and stage were also highly prognostic. CCP score was strongly associated with stage (T1 vs Ta, p < 10-6) and grade (high vs low, p < 10-14) in both cohorts. As a result, CCP score did not provide independent prognostic information in multivariable analysis after adjusting for stage and grade (p = 0.32). There was a significant interaction between stage and CCP score (p = 0.0017), justifying an exploratory analysis of CCP score in Ta disease. In this subset, CCP score trended toward (p = 0.056) after adjusting for grade. Conclusions: In NMIBC, CCP score was highly correlated with tumor stage and grade and could serve as a quantitative measure of clinical parameters. The score may also provide prognostic information regarding risk of progression to MIBC, particularly in patients with Ta disease, but requires additional validation.

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