Genomic Predictors of Survival in Patients with High-grade Urothelial Carcinoma of the Bladder

Kim, Philip H.; Eugene, K.; Sfakianos, John P.; Iyer, Gopa; Zabor, Emily C.; Scott, Sasinya N.; Ostrovnaya, Irina; Ramirez, Ricardo; Sun, Arony; Shah, Ronak; Yee, Alyssa; Reuter, Victor E.; Bajorin, Dean F.; Rosenberg, Jonathan E.; Schultz, Nikolaus; Berger, Michael F.; Al‐Ahmadie, Hikmat; Solit, David B.; Bochner, Bernard H.

doi:10.1016/j.eururo.2014.06.050

Cited by 131 publications

(109 citation statements)

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“…The discovery of the molecular pathways involved in urothelial cancer recurrence and progression has allowed for the identification of potential prognostic and predictive markers [116,129,130]. It has also permitted the development of novel noninvasive detection and surveillance strategies and revealed potential therapeutic targets [131][132][133][134][135][136].…”

Section: Genomics Of Urothelial Carcinomamentioning

confidence: 99%

The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs—Part B: Prostate and Bladder Tumours

et al. 2016

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It has been 12 yr since the publication of the last World Health Organization (WHO) classification of tumours of the prostate and bladder. During this time, significant new knowledge has been generated about the pathology and genetics of these tumours. Intraductal carcinoma of the prostate is a newly recognized entity in the 2016 WHO classification. In most cases, it represents intraductal spread of aggressive prostatic carcinoma and should be separated from high-grade prostatic intraepithelial neoplasia. New acinar adenocarcinoma variants are microcystic adenocarcinoma and pleomorphic giant cell adenocarcinoma. Modifications to the Gleason grading system are incorporated into the 2016 WHO section on grading of prostate cancer, and it is recommended that the percentage of pattern 4 should be reported for Gleason score 7. The new WHO classification further recommends the recently developed prostate cancer grade grouping with five grade groups. For bladder cancer, the 2016 WHO classification continues to recommend the 1997 International Society of Urological Pathology grading classification. Newly described or better defined noninvasive urothelial lesions include urothelial dysplasia and urothelial proliferation of uncertain malignant potential, which is frequently identified in patients with a prior history of urothelial carcinoma. Invasive urothelial carcinoma with divergent differentiation refers to tumours with some percentage of "usual type" urothelial carcinoma combined with other morphologies. Pathologists should mention the percentage of divergent histologies in the pathology report. PATIENT SUMMARY Intraductal carcinoma of the prostate is a newly recognized entity in the 2016 World Health Organization classification. Better defined noninvasive urothelial lesions include urothelial dysplasia and urothelial proliferation of uncertain malignant potential. v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j AbstractIt has been 12 yr since the publication of the last World Health Organization (WHO) classification of tumours of the prostate and bladder. During this time, significant new knowledge has been generated about the pathology and genetics of these tumours.

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Section: Genomics Of Urothelial Carcinomamentioning

confidence: 99%

The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs—Part B: Prostate and Bladder Tumours

et al. 2016

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“…These studies revealed high alteration frequencies in genes participating in chromatin remodeling. In particular, 83% of patients in one study exhibited mutations in the chromatin remodeling genes (6) while our previous study identified EP300 and CREBBP as 2 of the 4 most frequently mutated genes in human bladder cancer (7). …”

Section: Introductionmentioning

confidence: 95%

“…We and others have used next-generation sequencing (NGS) technology to identify the mutational spectrum of urothelial carcinomas of the bladder with the hope that this will provide therapeutic insights and actionable targets. To date, four independent studies performed whole-genome and whole-exome sequencing in bladder tumor samples to catalog genetic alterations to identify the dysregulated signaling pathways of bladder cancer tumorigenesis and metastasis (3–6). These studies revealed high alteration frequencies in genes participating in chromatin remodeling.…”

Section: Introductionmentioning

confidence: 99%

Functional Impact of Chromatin Remodeling Gene Mutations and Predictive Signature for Therapeutic Response in Bladder Cancer

Duex¹,

Swain²,

Dancik

et al. 2018

Molecular Cancer Research

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Urothelial carcinoma accounts for most of the bladder cancer cases. Using next-generation sequencing (NGS) technology, we found that a significant percentage (83%) of tumors had mutations in chromatin-remodeling genes. Here, we examined the functional relevance of mutations in two chromatin-remodeling genes, EP300 and its paralog, CREBBP, which are mutated in almost one-third of patients. Interestingly, almost half of missense mutations cluster in the histone-acetyltransferase (HAT) domain of EP300/CREBBP. This domain catalyzes the transfer of an acetyl group to target molecules such as histones, thereby regulating chromatin dynamics. Thus, patients with EP300 or CREBBP mutations may have alterations in the ability of the corresponding proteins to modify histone proteins and control transcriptional profiles. In fact, it was determined that many of the missense HAT mutations in EP300 (64%) and CREBBP (78%) were HAT-inactivating. These inactivating mutations also correlated with invasive disease in patients. Strikingly, the prediction software Mutation Assessor accurately predicted the functional consequences of each HAT missense mutation. Finally, a gene expression signature was developed that associated with loss of HAT activity and that this signature was associated with more aggressive cancer in four patient datasets. Further supporting the notion that this score accurately reflects HAT activity, we found it is responsive to treatment of cancer cells to mocetinostat, a histone deacetylase (HDAC) inhibitor. Implication This study provides a rationale for targeted sequencing of EP300 and CREBBP and use of a gene profiling signature for predicting therapeutic response in patients.

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“…PIK3CA mutations are associated with FGFR3 mutations, suggesting that both mutations may be involved in the same pathway of tumor progression [22,24,44]. PIK3CA mutation may be associated with an improved recurrence-free survival and improved cancer-specific survival in patients treated with radical cystectomy [46].…”

Section: Rationale For Targeted Therapies In Ucmentioning

confidence: 97%

Molecular biology and targeted therapies for urothelial carcinoma

Seront

Machiels

2015

Cancer Treatment Reviews

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Genomic Predictors of Survival in Patients with High-grade Urothelial Carcinoma of the Bladder

Cited by 131 publications

References 10 publications

The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs—Part B: Prostate and Bladder Tumours

The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs—Part B: Prostate and Bladder Tumours

Functional Impact of Chromatin Remodeling Gene Mutations and Predictive Signature for Therapeutic Response in Bladder Cancer

Molecular biology and targeted therapies for urothelial carcinoma

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