Urothelial carcinoma of the bladder: definition, treatment and future efforts

Prasad, Sandip M.; DeCastro, G. Joel; Steinberg, Gary D.

doi:10.1038/nrurol.2011.144

Cited by 126 publications

(105 citation statements)

References 151 publications

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“…With prevalence of the TERT promoter mutations in two-thirds of bladder cancer, almost one-third of the patients would be vulnerable to an adverse effect on survival according to our data. The nonmuscle invasive lesions, with a propensity to recurrence, are generally not associated with mortality (22). All four patients in the TaG1 disease category, who had died due to the bladder cancer, had the TERT mutations in their tumors and were noncarriers of the variant allele.…”

Section: Discussionmentioning

confidence: 99%

TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism

Rachakonda

Hosen

Verdier

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

297

343

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The telomerase reverse transcriptase (TERT) promoter, an important element of telomerase expression, has emerged as a target of cancer-specific mutations. Originally described in melanoma, the mutations in TERT promoter have been shown to be common in certain other tumor types that include glioblastoma, hepatocellular carcinoma, and bladder cancer. To fully define the occurrence and effect of the TERT promoter mutations, we investigated tumors from a well-characterized series of 327 patients with urothelial cell carcinoma of bladder. The somatic mutations, mainly at positions −124 and −146 bp from ATG start site that create binding motifs for E-twenty six/ternary complex factors (Ets/TCF), affected 65.4% of the tumors, with even distribution across different stages and grades. Our data showed that a common polymorphism rs2853669, within a preexisting Ets2 binding site in the TERT promoter, acts as a modifier of the effect of the mutations on survival and tumor recurrence. The patients with the mutations showed poor survival in the absence [hazard ratio (HR) 2.19, 95% confidence interval (CI) 1.02-4.70] but not in the presence (HR 0.42, 95% CI 0.18-1.01) of the variant allele of the polymorphism. The mutations in the absence of the variant allele were highly associated with the disease recurrence in patients with Tis, Ta, and T1 tumors (HR 1.85, 95% CI 1.11-3.08). The TERT promoter mutations are the most common somatic lesions in bladder cancer with clinical implications. The association of the mutations with patient survival and disease recurrence, subject to modification by a common polymorphism, can be a unique putative marker with individualized prognostic potential.TERT mutations | cancer genetics | transcription factors | noncoding mutations | reporter assays T he human telomerase reverse transcriptase (TERT) gene encodes the catalytic reverse transcriptase subunit of telomerase that maintains telomere length (1). Increased telomerase activity is perceived to be one of the hallmarks of human cancers, and the transcriptional regulation of the TERT gene is the major cause of its cancer-specific activation (2, 3). The TERT promoter has been shown to be the most important element of telomerase expression because it harbors binding sites for numerous cellular transcriptional activators and repressors that directly or indirectly regulate the gene expression (4). In addition, the high GC content around the transcription start site of the TERT promoter confers epigenetic regulation through methylation and chromatin remodeling (5, 6).We previously described a high-penetrant disease segregating single-nucleotide germ-line mutation in the TERT promoter in a large melanoma family (7). The A > C (T > G) mutation at position −57 bp (from the ATG start site; Chr 5:1295161 hg19 coordinate) resulted in creation of a new binding motif GGAA/T for E-twenty six (Ets) transcription factors and a general binding CCGGAA/T motif for ternary complex factors (TCF) (8). Simultaneous screening of the TERT promoter for somatic mutations...

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Section: Discussionmentioning

confidence: 99%

TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism

Rachakonda

Hosen

Verdier

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

297

343

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“…2 The vast majority (90%) of bladder cancer cases are transitional cell carcinomas (TCC), of which 75-85% present as non-muscle invasive tumors at the time of first diagnosis (Tis/CIS, Ta, and T1). [4][5][6] The prognosis of these non-invasive tumors is favorable although up *Correspondence to: Ahmad Besaratinia; Email: besarati@med.usc.edu Submitted: 07/09/13; Revised: 07/23/13; Accepted: 07/27/13 http://dx.doi.org/10.4161/epi.25927…”

Section: Introductionmentioning

confidence: 99%

Alterations of DNA methylome in human bladder cancer

Besaratinia¹,

Cockburn

Tommasi

2013

Epigenetics

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“…An accurate assessment of tumour stage can only be achieved with a complete resection containing muscularis propria in the specimen [5]. Under staging at the time of the initial transurethral resection is common for patients with high-risk NMIBC and can delay the accurate diagnosis and definitive treatment [5].…”

Section: Introductionmentioning

confidence: 99%

Repeat transurethral resection for non‐muscle‐invasive bladder cancer: a contemporary series

et al. 2015

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ObjectivesTo evaluate the depth of transurethral resections of bladder tumour (TURBT), residual cancer rates and up-staging rates in a contemporary Australian series. Materials and MethodsSpecimen reports from a single, major reporting pathology centre, servicing a group of urological oncologists in Sydney were obtained for TURBTs performed between October 2008 and February 2013. We examined the depth of TURBT, rates of repeat-TURBT (re-TUR) and residual cancer rates at the 3-6 month check cystoscopy. ResultsOne thousand and two hundred and nine transurethral resection specimens retrieved during this period were analysed. There were 162 (13.4%) T1 specimens and 631 (52.2%) Ta specimens, 218 (34.5%) of which were high grade. Muscularis propria was present in 506 (41.9%) specimens in total and in 151 (39.7%) of 380 high-risk specimens (high grade Ta, T1). Of the 380 high-risk nonmuscle-invasive tumours, 85 (22.4%) proceeded to re-TUR. Of the 48 T1 specimens and 37 Ta high grade specimens that proceeded to re-TUR, 7 (14.6%) and 1 (2.7%) respectively were upstaged to muscle-invasive disease. Rates of residual disease/early recurrence at 3-6 months was significantly better for those with re-TUR compared to those without 56.8% vs 82.5% (P < 0.001) for Ta high grade and 39.6% vs 84% (P = 0.028) for T1 tumours respectively. ConclusionRe-TUR rates in high-risk non-muscle-invasive bladder cancer are low. However in a contemporary series, the upstaging rates are low, but residual cancer rates high, supporting the need for re-TUR in this population.

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Urothelial carcinoma of the bladder: definition, treatment and future efforts

Cited by 126 publications

References 151 publications

TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism

TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism

Alterations of DNA methylome in human bladder cancer

Repeat transurethral resection for non‐muscle‐invasive bladder cancer: a contemporary series

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