BASE47 gene set predictor as an identifier of “basal-like” subtype of urothelial carcinoma of the bladder in African Americans.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 300-300
Author(s):  
David D. Chism ◽  
Jeffrey S. Damrauer ◽  
Andrew S. Miller ◽  
Matthew I. Milowsky ◽  
William Y. Kim
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
African Americans ◽  
Urothelial Carcinoma ◽  
High Grade ◽  
Intrinsic Subtypes ◽  
Bladder Tumors ◽  
Gene Expressions ◽  
Luminal A ◽  
Gene Set

300 Background: African-Americans [AAs] have a higher cancer-specific mortality when compared to whites with urothelial carcinoma (UC) of the bladder. Recent gene expression studies identified two intrinsic, molecular subsets of high-grade bladder cancer: “luminal” and “basal-like”, which can be accurately classified using the BASE47 gene set predictor. We applied the BASE47 gene set predictor to AA tumors and assessed enrichment for basal-like bladder tumors. Methods: Gene expression data from 179 high-grade, muscle invasive bladder tumors—9 AAs and 170 non-AAs (whites, Asians, and race not defined) from the TCGA was analyzed. Prediction analysis of microarrays (PAM) was used to derive the Bladder cancer Analysis of Subtypes by Expression (BASE47) gene set predictor and validated with 2 independent datasets. Comparisons of gene expressions patterns between bladder and breast intrinsic subtypes were peformed. Results: The BASE47 subtype classifier was highly concordant with Consensus Cluster subtype calls on 2 independent datasets. Based on the BASE47 gene classifier, a significant fraction of the tumors from AA (7/9) were classified as “basal-like” (P=0.07 Two tail). Basal-like bladder tumors trended strongly towards a worse prognosis (P=0.09 TCGA, 0.0194 MSKCC). Gene expressions patterns for“basal-like” and luminal bladder cancer correlated highly with basal-like breast and luminal A/B subtypes respectively. In addition, a subset of “basal-like” bladder cancer was found to be a claudin-low subtype. Conclusions: We have identified two molecular subtypes of high-grade bladder cancer that highly reflect the intrinsic subtypes of breast cancer. The BASE47 is a robust subtype classifier that can reliably distinguish basal and luminal bladder cancers. African-Americans have enrichment in the “basal-like” subtype of bladder cancer. These results will be validated in an independent set of samples as well as on FFPE tumors.

Risk factors for bladder cancer recurrence survival in patients with upper-tract urothelial carcinoma

2018 ◽  
Vol 104 (6) ◽  
pp. 451-458 ◽  
Author(s):  
Yu-Peng Wu ◽  
Yun-Zhi Lin ◽  
Min-Yi Lin ◽  
Ting-Ting Lin ◽  
Shao-Hao Chen ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Urothelial Carcinoma ◽  
Cancer Recurrence ◽  
Cox Proportional Hazards Model ◽  
Upper Tract Urothelial Carcinoma ◽  
Intravesical Therapy ◽  
Low Grade ◽  
High Grade ◽  
Upper Tract ◽  
Bladder Cancer Recurrence

Purpose: The aim of this work was to investigate the predictive factors for bladder cancer recurrence survival (BCRS) in patients with upper-tract urothelial carcinoma (UTUC). Methods: We selected patients with UTUC who underwent segmental ureterectomy (Su) or nephroureterectomy (Nu) from 2004 to 2013 from the Surveillance, Epidemiology, and End Results (SEER) database. Patients with a history of intravesical therapy for bladder cancer and bladder cancer prior to the diagnosis of UTUC were excluded. We used Kaplan-Meier analysis, log-rank tests, and Cox proportional hazards model to compare overall survival, cancer-specific survival, and BCRS. Results: In a cohort of 1,454 patients, 169 (11.6%) had low-grade tumors and 1,285 (88.4%) had high-grade tumors; 239 (16.4%) underwent Su and 1,215 (83.6%) underwent Nu. We found that T4 grade (hazard ratio [HR] = 6.216; 95% confidence interval [CI], 3.197-12.087) and ureteral tumors (HR = 1.764; 95% CI, 1.173-2.652) were predictors of shorter BCRS, whereas Nu (HR = 0.608; 95% CI, 0.388-0.953) predicted longer BCRS. Five-year BCRS rates were low-grade tumors: 94.1%, high-grade tumors: 85.4% (p = 0.038); plus Su: 82.9%, and Nu: 87.6% (p = 0.016). Conclusions: Use of Su should be more selective for high-grade tumors, as it correlates with shorter BCRS. Tumors located in the ureter are associated with shorter BCRS than those located in the renal pelvis.

Novel oncogenic function of ATDC in bladder cancer.

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.

scholarly journals Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology

2014 ◽  
Vol 111 (8) ◽  
pp. 3110-3115 ◽  
Author(s):  
J. S. Damrauer ◽  
K. A. Hoadley ◽  
D. D. Chism ◽  
C. Fan ◽  
C. J. Tiganelli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bladder Cancer ◽  
Cancer Biology ◽  
High Grade ◽  
Intrinsic Subtypes

scholarly journals Prevalence and Co-Occurrence of Actionable Genomic Alterations in High-Grade Bladder Cancer

2013 ◽  
Vol 31 (25) ◽  
pp. 3133-3140 ◽  
Author(s):  
Gopa Iyer ◽  
Hikmat Al-Ahmadie ◽  
Nikolaus Schultz ◽  
Aphrothiti J. Hanrahan ◽  
Irina Ostrovnaya ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Copy Number ◽  
Genomic Diversity ◽  
Comparative Genomic ◽  
Therapeutic Drug ◽  
Cancer Type ◽  
High Grade ◽  
Bladder Tumors ◽  
Genomic Alterations ◽  
Data Set

Purpose We sought to define the prevalence and co-occurrence of actionable genomic alterations in patients with high-grade bladder cancer to serve as a platform for therapeutic drug discovery. Patients and Methods An integrative analysis of 97 high-grade bladder tumors was conducted to identify actionable drug targets, which are defined as genomic alterations that have been clinically validated in another cancer type (eg, BRAF mutation) or alterations for which a selective inhibitor of the target or pathway is under clinical investigation. DNA copy number alterations (CNAs) were defined by using array comparative genomic hybridization. Mutation profiling was performed by using both mass spectroscopy-based genotyping and Sanger sequencing. Results Sixty-one percent of tumors harbored potentially actionable genomic alterations. A core pathway analysis of the integrated data set revealed a nonoverlapping pattern of mutations in the RTK-RAS-RAF and phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathways and regulators of G1-S cell cycle progression. Unsupervised clustering of CNAs defined two distinct classes of bladder tumors that differed in the degree of their CNA burden. Integration of mutation and copy number analyses revealed that mutations in TP53 and RB1 were significantly more common in tumors with a high CNA burden (P < .001 and P < .003, respectively). Conclusion High-grade bladder cancer possesses substantial genomic heterogeneity. The majority of tumors harbor potentially tractable genomic alterations that may predict for response to target-selective agents. Given the genomic diversity of bladder cancers, optimal development of target-specific agents will require pretreatment genomic characterization.

scholarly journals Complications of radical cystectomy for bladder cancer

2018 ◽  
Vol 6 (12) ◽  
pp. 3898
Author(s):  
Maliikarjuna Gurram ◽  
Ravichander G. ◽  
Ravi Jahagidar ◽  
Vinay Reddy
Keyword(s):  
Bladder Cancer ◽  
Urothelial Carcinoma ◽  
Radical Cystectomy ◽  
Bladder Tumor ◽  
Invasive Bladder Cancer ◽  
Safe Procedure ◽  
High Grade ◽  
Early Complications ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

Background: Radical cystectomy with pelvic lymph node dissection is the standard treatment for muscle-invasive bladder cancer. With the advent of improved surgical techniques and postoperative management, the complications and mortality rates have reduced. The present study was done to analyse the perioperative, early and late compilations following radical cystectomy for bladder tumor.Methods: This is a prospective observational study of patients who underwent radical cystectomy for invasive bladder tumor from February 2016 to November 2017. Radical cystectomy was done through midline transperitoneal approach.  Urinary diversion was done by ileal conduit. All patients were followed at 6th week, 3rd month, 6th month, and at 1 year.Results: Total 21 patients underwent radical cystectomy, 17(80.95%) were males and 4 (19.04%) females. The median age was 60 years, ranging from 40 to 73 years. The   most common age group was 60 to 75 years (52.3%). Thirteen (61.9%) patients were smokers and all were males. Painless haematuria alone was most common presentation (of bladder tumor) seen in 15 (71.4%) patients. Early complications were seen in 8 (38.09%) patients, most common early complication was urinary leak 2 (9.5%) patents, other early complications were bowel leak, wound dehiscence, pelvic collection, burst abdomen, prolonged ileus, subacute intestinal obstruction, acute kidney injury and sepsis seen in one (4.25%) patient each. Late complications were seen in 4 (19.04%) patients.  Pelvic recurrence was the most common late complication seen in 2 (9.55%) patients. Ureteric stricture was seen in one patient (4.75%) for which percutaneous nephrostomy and antegrade DJ stenting was done. Among the histopathological variants of tumor 20 (95.25%) patients had high grade variants and only one (4.75%) had low grade papillary urothelial carcinoma. Among the high grade variants most common pathology was urothelial carcinoma in 17 (80.9%) patients.Conclusions: Radical cystectomy remains the main stay of treatment in muscle-invasive bladder cancer. This is relatively safe procedure with minimal morbidity and mortality.

scholarly journals APOBEC-mediated mutagenesis in urothelial carcinoma is associated with improved survival, mutations in DNA damage response genes, and immune response

2017 ◽  
Author(s):  
Alexander P. Glaser ◽  
Damiano Fantini ◽  
Kalen J. Rimar ◽  
Joshua J. Meeks
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Dna Damage ◽  
Bladder Cancer ◽  
Urothelial Carcinoma ◽  
Dna Damage Response ◽  
Molecular Subtype ◽  
Regulatory Genes ◽  
Enrichment Score ◽  
Damage Response

AbstractBackgroundThe APOBEC family of enzymes is responsible for a mutation signature characterized by a TCW>T/G mutation. APOBEC-mediated mutagenesis is implicated in a wide variety of tumors, including bladder cancer. In this study, we explore the APOBEC mutational signature in bladder cancer and the relationship with specific mutations, molecular subtype, gene expression, and survival. We hypothesized that tumors with high levels of APOBEC-mediated mutagenesis would be enriched for mutations in DNA damage response genes and associated with higher expression of genes related to activation of the immune system.MethodsGene expression (n=408) and mutational (n=395) data from the Cancer Genome Atlas (TCGA) bladder urothelial carcinoma provisional dataset was utilized for analysis. Tumors were split into “APOBEC-high” and “APOBEC-low” tumors based on APOBEC enrichment score. Analysis was performed with R.FindingsPatients with APOBEC-high tumors have better overall survival compared to those with APOBEC-low tumors (38.2 vs 18.5 months, p=0.005). Tumors enriched for APOBEC mutagenesis are more likely to have mutations in DNA damage response genes (TP53, ATR, BRCA2), and chromatin regulatory genes (MLL, MLL3), while APOBEC-low tumors are more likely to have mutations inFGFR3andKRAS. APOBEC3AandAPOBEC3Bexpression correlates with total mutational burden, regardless of bladder tumor molecular subtype. APOBEC mutagenesis and enrichment is associated with increased expression of immune-related genes, including interferon signaling.InterpretationTumors enriched for APOBEC mutagenesis are more likely to have mutations in DNA damage response genes and chromatin regulatory genes, potentially providing more single-strand DNA substrate forAPOBEC3AandAPOBEC3B, leading to a hypermutational phenotype and the subsequent immune response.HighlightsABPOEC enzymes, particularlyAPOBEC3AandAPOBEC3B, are responsible for the predominant pattern of mutagenesis in bladder cancerTumors enriched for APOBEC-mediated mutagenesis are more likely to have mutations in DNA damage response genes and chromatin regulatory genes, while tumors not enriched for APOBEC-mediated mutagenesis are more likely to have mutations inKRASandFGFR3APOBEC enrichment is associated with upregulation of genes involved in the immune response

ATDC as a novel oncogene in bladder cancer.

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.

RNA-seq analysis of non-muscular invasive bladder cancer to reveal different gene expression profiles between smoking and non-smoking patients.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 478-478
Author(s):  
Zhichao Fu ◽  
Shenghua Liu ◽  
Jianfei Wang ◽  
Ning He ◽  
Yadong Yang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Tumor Progression ◽  
Urothelial Carcinoma ◽  
Differentially Expressed Genes ◽  
Poor Prognosis ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Differentially Expressed ◽  
Rna Seq

478 Background: Bladder cancer is the ninth most common malignancy in the world, approximately 75% of patients are diagnosed with non-muscle invasive bladder cancer (NMIBC). Smoking has been established to be a carcinogenic risk factor of bladder cancer. Nevertheless, the detailed relationship between smoking and progression of NMIBC are poorly understood. In this study, we revealed high expressed genes in smoking patients were significantly related to tumor progression in NMIBC patients. Methods: A total of 54 NMIBC patients including 19 never smokers and 35 smokers (current smokers and previous smokers) were enrolled in this study.The gene expression profiles were obtained by RNA-seq and the differentially expressed genes between smoking and non-smoking patients were identified using DESeq2 .The further analysis of the association between genes expression and patient survival in NMIBC cohorts(Jakob et al., 2016)and IMvigor 210 cohorts(Jonathan et al., 2016)by Kaplan-Meier survival estimate. Results: We identified 46 differentially expressed genes (p<0.05) in smoking and non-somking NMIBC patients. IDO1 and KRT14 gene, which related to bladder cancer progression and poor prognosis, was identified significantly higher expressed in somking group compared with non-smoking and they have a logFC of 2.6,3.9 with FDR 1.83E-5,3.40E-5 respectively. The expression of other genes, including KRT6A, CASP14, SERPINA1, MYO3A and IL20RB, were significantly higher in smoking patients compared to non-somking. Notably, survival data analysis from 476 NMIBC cohorts showed that IL20RB had a significant relationship with poor PFS(p = 0.021) and in the Mvigor 210 Cohort including 310 advanced or metastatic urothelial carcinoma patients treated with atezolizumab, we found that the high expression of IL20RB was significantly related to poor OS(p = 0.002). Conclusions: We identified 14 genes related to tumor progression were significantly higher in smoking NMIBC patients than in non-smoking. Among these genes, the expression of IL20RB was related to the poor prognosis of NMIBC, and it may correlates with reduced clinical benefit of immunotherapeutic in patients with urothelial carcinoma.

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