Molecular cytogenetic alterations associated with rapid tumor cell proliferation in advanced urinary bladder cancer

Tomovska, Sanja; Richter, Jan; Süess, Katrin; Wagner, Urs; Rozenblum, Ester; Gasser, Thomas C.; Moch, Holger; Mihatsch, Michael J.; Sauter, Guido; Schraml, Peter

doi:10.3892/ijo.18.6.1239

Cited by 15 publications

(23 citation statements)

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“…In bladder cancer cells, which contain amplification and overexpress E2F3 at a high level, we found that reduction of E2F3 protein using siRNA technology was accompanied by a reduction in BrdU incorporation and cellular proliferation. This is consistent with the observation that the presence of the 6p22 amplicon correlates with tumour cell proliferation rate (Tomovska et al, 2001) and with the observed correlation between expression of E2F3 and the Ki67 proliferation marker (Oeggerli et al, 2004). In contrast, we failed to find evidence to support the view that CDKAL1 represents the bladder cancer oncogene within the 6p22 amplicon (Hurst et al, 2004): knocking down expression of this gene did not alter the BrdU incorporation.…”

Section: Discussionsupporting

confidence: 91%

“…Gain and amplification at 6p22 has frequently been reported as a recurrent abnormality in human bladder cancer (Hovey et al, 1998;Koo et al, 1999;Terracciano et al, 1999;Simon et al, 2000). The presence of this amplification was shown to correlate with tumour grade Prat et al, 2001) and, in high-grade cancers, with tumour cell proliferation rate (Tomovska et al, 2001). Initial mapping studies indicated that the 6p22 amplicon spanned the SOX4, PRL and E2F3 genes (Bruch et al, 2000;Veltman et al, 2003) and in CGH studies onto cDNA microarrays, we found that only two genes from this region, E2F3 and CDKAL1/FLJ20342 (hereafter called CDKAL1), were consistently amplified in bladder cancers (Feber et al, 2004).…”

Section: Introductionmentioning

confidence: 95%

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Role of E2F3 expression in modulating cellular proliferation rate in human bladder and prostate cancer cells

et al. 2006

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Amplification and overexpression of the E2F3 gene at 6p22 in human bladder cancer is associated with increased tumour stage, grade and proliferation index, and in prostate cancer E2F3 overexpression is linked to tumour aggressiveness. We first used small interfering RNA technology to confirm the potential importance of E2F3 overexpression in bladder cancer development. Knockdown of E2F3 expression in bladder cells containing the 6p22 amplicon strongly reduced the extent of bromodeoxyuridine (BrdU) incorporation and the rate of cellular proliferation. In contrast, knockdown of CDKAL1/ FLJ20342, another proposed oncogene, from this amplicon had no effect. Expression cDNA microarray analysis on bladder cancer cells following E2F3 knockdown was then used to identify genes regulated by E2F3, leading to the identification of known E2F3 targets such as Cyclin A and CDC2 and novel targets including pituitary tumour transforming gene 1, Polo-like kinase 1 (PLK1) and Caveolin-2. For both bladder and prostate cancer, we have proposed that E2F3 protein overexpression may cooperate with removal of the E2F inhibitor retinoblastoma tumor suppressor protein (pRB) to drive cellular proliferation. In support of this model, we found that ectopic expression of E2F3a enhanced the BrdU incorporation, a marker of cellular proliferation rate, of prostate cancer DU145 cells, which lack pRB, but had no effect on the proliferation rate of PC3 prostate cancer cells that express wild-type pRB. BrdU incorporation in PC3 cells could, however, be increased by overexpressing E2F3a in cells depleted of pRB. When taken together, these observations indicate that E2F3 levels have a critical role in modifying cellular proliferation rate in human bladder and prostate cancer.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 95%

Role of E2F3 expression in modulating cellular proliferation rate in human bladder and prostate cancer cells

et al. 2006

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“…In this study, and previously, we have shown that there are higher rates of aneusomy in patients who progress to muscle invasion compared to those who recur with pTa/pT1 disease (Watters et al, 2000(Watters et al, , 2002. Muscle-invasive TCCs are characterised by a large number of cytogenetic alterations including overrepresentation of 8q and 11q13 (Tomovska et al, 2001). Thus this study would support the finding by Tsao et al (2000) that the majority of genetic alterations in TCC occur prior to progression.…”

Section: Discussionsupporting

confidence: 85%

Genetic aberrations of c-myc and CCND1 in the development of invasive bladder cancer

et al. 2002

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Detrusor muscle invasive transitional cell carcinoma is associated with poor prognosis and is responsible for the majority of bladder cancer related deaths. Amplifications of c-myc and CCND1 are associated with detrusor-muscle-invasive transitional cell carcinoma, however, their precise role in driving disease progression is unclear. Fluorescence in situ hybridisation on archival tissue from 16 patients with primary diagnosis of 5pT2 transitional cell carcinoma and 15 cases with primary pTa/pT1 disease subsequently progressing to detrusor-muscle-invasion was performed, in the latter group both pre and post muscle invasive events were studied. No patients presenting with 5pT2 had amplification of c-myc, two out of 16 (12.5%) had CCND1 amplification. Of patients who developed 5pT2, two out of 15 (13.3%) had amplification of c-myc, both in 5pT2, five out of 15 (33.3%) had CCND1 amplification, two in pTa/pT1 tumours, three in 5pT2 transitional cell carcinomas. In total, two out of 31 (6.5%) of patients' 5pT2 TCCs were amplified for c-myc and six out of 31 (19%) were amplified for CCND1. Eighty-seven per cent (40 out of 46) of tumours were polysomic for chromosome 8 and 80% (37 out of 46) were polysomic for chromosome 11 and this reflected the high copy numbers of c-myc and CCND1 observed. In almost all cases an increase in c-myc/CCND1 copy number occurred prior to invasion and persisted in advanced disease. Amplification of CCND1 or alterations in c-myc/CCND1 early in bladder cancer may have clinical relevance in promoting and predicting progression to detrusor-muscle-invasive transitional cell carcinoma.

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“…Metaphase CGH studies have demonstrated copy number gains or high level amplifications at 6p22 in 7 to 55% of urothelial carcinomas, involving primarily the bladder, [3][4][5][6][7][8][9] but also those arising in the renal pelvis. 10 In addition, Bruch et al 11 reported 6p22 gains in 6 of 8 bladder cancer cell lines.…”

mentioning

confidence: 99%

“…These studies have illustrated the genomic complexity of bladder cancer and have identified recurrent regions of DNA copy number increase or high level amplification on several chromosomes including; 1q, 5p, 6p, 8q, 10p, 12q, 17q, and 20q. [3][4][5][6][7][8][9] These genomic regions are thought to contain oncogenes that may be important in tumor progression.…”

mentioning

confidence: 99%

Defining a 0.5-Mb Region of Genomic Gain on Chromosome 6p22 in Bladder Cancer by Quantitative-Multiplex Polymerase Chain Reaction

Evans

Gallie

Jewett

et al. 2004

The American Journal of Pathology

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Urothelial carcinomas, or transitional cell carcinomas, represent the vast majority of human bladder cancers. Early molecular events associated with superficial bladder cancers include losses on chromosome 9p/9q and mutations in the p53 and retinoblastoma tumor suppressor genes. 1,2 The genomic alterations associated with disease progression, defined as the evolution of superficial bladder tumors to higher pathological stages, are complex and poorly understood. Conventional metaphase-based comparative genomic hybridization (CGH) has been used by several groups of investigators to study copy number imbalances in bladder cancer specimens of all stages and grades. These studies have illustrated the genomic complexity of bladder cancer and have identified recurrent regions of DNA copy number increase or high level amplification on several chromosomes including; 1q, 5p, 6p, 8q, 10p, 12q, 17q, and 20q. 3-9 These genomic regions are thought to contain oncogenes that may be important in tumor progression.Metaphase CGH studies have demonstrated copy number gains or high level amplifications at 6p22 in 7 to 55% of urothelial carcinomas, involving primarily the bladder, 3-9 but also those arising in the renal pelvis. 10 In addition, Bruch et al 11 reported 6p22 gains in 6 of 8 bladder cancer cell lines. Recently, Veltman et al 12 confirmed the metaphase CGH findings using array-based CGH to show copy number gains at 6p22 in 11 of a series of 41 bladder tumors. The changes at 6p22 in bladder cancer have been associated with high tumor cell proliferative activity, 9 tumors of high histological grade that are predominantly invasive, 3-9 and patients with distant metastases at initial presentation. 8 Based on these findings,

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Molecular cytogenetic alterations associated with rapid tumor cell proliferation in advanced urinary bladder cancer

Cited by 15 publications

References 0 publications

Role of E2F3 expression in modulating cellular proliferation rate in human bladder and prostate cancer cells

Role of E2F3 expression in modulating cellular proliferation rate in human bladder and prostate cancer cells

Genetic aberrations of c-myc and CCND1 in the development of invasive bladder cancer

Defining a 0.5-Mb Region of Genomic Gain on Chromosome 6p22 in Bladder Cancer by Quantitative-Multiplex Polymerase Chain Reaction

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