Bladder cancer: translating molecular genetic insights into clinical practice

Liu, Cheng; Zhang, Shaobo; MacLennan, Gregory T.; Williamson, Sean R.; López-Beltrán, Antonio; Montironi, Rodolfo

doi:10.1016/j.humpath.2010.07.007

Cited by 168 publications

(128 citation statements)

References 228 publications

(309 reference statements)

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“…The nonmuscle invasive bladder tumors (Tis, Ta, and T1) account for most of the urothelial carcinomas that are confined to mucosa or submucosa (14). Remaining urothelial carcinomas are invasive that arise either de novo or from high-grade carcinoma in situ (15,16). Low-grade tumors are characterized by frequent mutations in the HRAS and fibroblast growth factor receptor 3 (FGFR3) genes.…”

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.

291

327

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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.

291

327

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“…One such study has shown the frequency of FGFR-3 and p53 mutation according to the tumour grade and stage as follows. [9] Figure 1: Prevalence of the TP53 mutation increasing with tumour grade and pathology stage. Prevalence of the FGFR3 mutation decreasing with tumour grade and pathology stage.…”

Section: Resultsmentioning

confidence: 99%

“…Prevalence of the FGFR3 mutation decreasing with tumour grade and pathology stage. [9] pRB or the retinoblastoma gene is also a tumour suppressor gene, which has a central role in apoptosis and cell growth regulation. [7] Mutation or deletion of this gene has strong association in many cancers including early phases of bladder carcinogenesis.…”

Section: Resultsmentioning

confidence: 99%

“…[8] Similar observations had been made by others as well that hypermethylation of the DNA causes inactivation of certain genes, which is an important step in the early phases of tumour pathogenesis. [9] At least more than twenty different biomarkers for bladder cancer have been investigated; some of them have been discarded and labelled as irrelevant. [2] Whilst others that are investigated frequently and show consistence relevance have been incorporated into certain prognosis programmes.…”

Section: Introductionmentioning

confidence: 99%

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A review of molecular biomarkers for bladder cancer

Miakhil¹,

Parker²,

Kommu³

et al. 2013

Int J Med Biomed Res

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“…Although there have been advances in radical cystectomy and systemic therapy, ~50% of these patients with muscle-invasion succumb from metastatic disease (6,7). Overall, ~50-80% of all treated patients with transurethral resection have tumor relapse within a period of 2 years and 10-25% of cases may present with a high grade tumor (8). Discovery of novel effective prognostic or predictive biomarkers may enable the development of therapeutics.…”

Section: Introductionmentioning

confidence: 99%

TRAF6 expression is associated with poorer prognosis and high recurrence in urothelial bladder cancer

Hao

Cui

et al. 2017

Oncology Letters

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Abstract. The aim of the present study was to investigate the clinical significance of TNF receptor-associated factor 6 (TRAF6) expression in urothelial bladder cancer. TRAF6 expression was detected by immunohistochemistry in 126 samples of patients with urothelial bladder cancer. The association between clinicopathological factors and TRAF6 expression was analyzed by χ 2 test. The association between TRAF6 expression, overall survival rate and the recurrence-free survival rate was evaluated in univariate analysis with Kaplan-Meier test and in multivariate analysis with Cox-regression model. In the cohort tested, the rate of high TRAF6 expression was 61.9% (78/126). TRAF6 expression was demonstrated to be significantly associated with positive metastasis (P=0.001) with χ 2 test. Furthermore, TRAF6 expression was demonstrated to be associated with overall survival rate (P=0.016) and recurrence-free survival rate (P=0.016). With Cox-regression model, it was indicate that TRAF6 high expression was an independent predictive factor of poor prognosis (P=0.037) and high recurrence (P=0.011). High TRAF6 expression may predict unfavorable prognosis and high recurrence in urothelial bladder cancer, indicating that TRAF6 may be a potential and promising therapeutic target in urothelial bladder cancer.

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Bladder cancer: translating molecular genetic insights into clinical practice

Cited by 168 publications

References 228 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

A review of molecular biomarkers for bladder cancer

TRAF6 expression is associated with poorer prognosis and high recurrence in urothelial bladder cancer

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