Identification of loci associated with putative recurrence genes in transitional cell carcinoma of the urinary bladder

Edwards, Joanne; Duncan, Pamela; Going, James J.; Watters, A.D.; Grigor, Kenneth M.; Bartlett, John M.S.

doi:10.1002/path.1052

Cited by 32 publications

(15 citation statements)

References 35 publications

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“…Jung et al 60 reported a similar association with recurrence but others have not 61 and some studies suggest that LOH on 9q rather than 9p21 is associated with tumor recurrence. 62,63 In the present study we found no association with tumor grade or stage. In light of the finding that large tumor size is associated with 9p21 alterations, 50 it is worth noting that the 53 tumors from our previous series that were re-assessed here are those for which we still had DNA remaining and therefore represented larger tissue samples.…”

Section: Rtq-pcr (contrasting

confidence: 76%

Measurement of Relative Copy Number of CDKN2A/ARF and CDKN2B in Bladder Cancer by Real-Time Quantitative PCR and Multiplex Ligation-Dependent Probe Amplification

Aveyard¹,

Knowles²

2004

The Journal of Molecular Diagnostics

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Many tumors have large homozygous deletions of the CDKN2A locus (encoding p14 ARF and p16) and of CDKN2B (p15). Our aim was to determine which gene is the major target in bladder cancer. We used quantitative real-time PCR (RTQ-PCR) to determine copy number of p15, of p14 ARF exon 1␤, and p16 exon 2 in 22 tumor cell lines and 83 bladder tumors, some of which had been assessed previously by duplex PCR. Titration experiments showed that homozygous deletion could be detected in the presence of up to 30% normal DNA. Results for cell lines were compatible with previous cytogenetic analyses. Ten cell lines and 32 tumors (38.5%) had homozygous deletion of at least one target. Thirteen tumors (15.7%) had deletion of all three targets. Two tumors had deletion of p14 ARF exon 1␤ alone and four of p16 exon 2 alone. RTQ-PCR detected more homozygous deletions than duplex PCR. Finally we used a multiplex ligation-dependent probe amplification kit to provide independent confirmation of results. We conclude that with appropriate controls RTQ-PCR is a sensitive and robust method to detect copy number changes in tumors even in the presence of contaminating normal cell DNA. More than 60% of transitional cell carcinomas (TCC) of the bladder of all stages and grades show loss of heterozygosity (LOH) of chromosome 9. 1-6 Although many tumors have LOH on both arms of the chromosome, a significant number (ϳ10% of tumors overall) have a region of interstitial LOH of 9p. 7 Many such deletions are small and this has allowed the identification of a critical region at 9p21 that contains CDKN2B and CDKN2A/ARF. These two loci encode three tumor suppressor genes, p15, p16, and p14 ARF , all of which are cyclin-dependent kinase inhibitors with key functions in cell cycle regulation. 8,9The CDKN2A locus encodes p16 and p14 ARF , both of which are capable of inducing cell cycle arrest. 10,11 p16 and p14 ARF have different first exons (1␣ and 1␤, respectively) approximately 13 kb apart, 12 giving rise to products in alternate reading frames with no homology at the protein level 13,14 (Figure 1). Exons 1␣, 2, and 3 encode p16, which induces G1 cell cycle arrest via the Rb pathway. Exons 1␤, 2, and 3 encode p14 ARF , which inhibits p53 degradation via binding to mdm2.The mechanism of CDKN2A/ARF inactivation in human cancers is somewhat tumor specific. Homozygous deletions at CDKN2A/9p21 are common in bladder tumors 6,15-17 and have been described in a variety of other sporadic tumors, including melanomas 18 and gliomas. 19 Pancreatic adenocarcinomas show inactivation of CDKN2A by either homozygous deletion or point mutation, 20 whereas esophageal tumors commonly show inactivation by point mutation. 21 A third mechanism of inactivation, transcriptional silencing by promoter hypermethylation, is commonly found in colorectal carcinoma. 22 Point mutations have only rarely been identified in bladder tumors 15,23,24 and promoter methylation, only infrequently. 25 Since the discovery of p14 ARF , 14 much interest has centered on the relative involvement of ...

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Section: Rtq-pcr (contrasting

confidence: 76%

Measurement of Relative Copy Number of CDKN2A/ARF and CDKN2B in Bladder Cancer by Real-Time Quantitative PCR and Multiplex Ligation-Dependent Probe Amplification

Aveyard¹,

Knowles²

2004

The Journal of Molecular Diagnostics

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“…85 LOH of the TSC1 locus was identified in 34% of UC tumors, and a specific mutation in the second allele that conformed to the 2-hit hypothesis was detected in 30% of tumors, providing further evidence that the TSC1 gene may act as a tumor suppressor gene in UC. 86 Overexpression of the TSC1 gene in vitro triggers an increase of cyclin-dependent kinase inhibitor (p27KIP1) expression Thus, TSC1 seems to be involved in cell-cycle control through the P27KIP1 cell-cycle regulator. Loss of the TSC1 gene has been linked to bladder tumor recurrences: Results from a recent study showed that patients who had a high risk of superficial tumor recurrences presented significantly more frequently with LOH in the TSC1 region compared with patients who did not develop recurrences.…”

Section: Tumor Suppressors In Loci Of Losses and Deletionsmentioning

confidence: 99%

Genetic alterations in urothelial bladder carcinoma

Mhawech‐Fauceglia

Cheney

Schwaller

2006

Cancer

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New oncogenes and tumor suppressor genes that play an important role in the pathogenesis of urothelial bladder carcinoma have been discovered. The objectives of this review were to summarize the most important oncogenes and tumor suppressor genes involved in urothelial carcinoma and to address their role in pathogenesis, their prognostic value, and their potential use as therapeutic targets.The collected data led the authors to propose a common pathway in which the fibroblastic growth factor receptor 3 (FGFR3) mutation seems to be the earliest genetic abnormality responsible for the transformation from normal tissue to atypia and dysplasia. Three different progression pathways were proposed: The first operative pathway is from dysplasia to superficial papillary pathologic Ta

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“…This suggests that multiple genes may contribute to tumour development, that there is an associated 9qÁ phenotype in these cases and that assessment of single genes may not be informative. As indicated above, there are reports that 9p deletion is associated with tumour grade, stage and recurrence and similarly there are reports that 9q LOH or deletion is associated with increased risk of recurrence [38,39]. Currently, it is not clear whether loss of 9p or 9q is the ''earlier'' event during bladder tumour development, although several studies have reported more frequent LOH of 9q than 9p in non-invasive tumours [e.g.…”

Section: Alterations Of Chromosomementioning

confidence: 83%

Bladder cancer subtypes defined by genomic alterations

Knowles

2008

Scandinavian Journal of Urology and Nephrology

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Bladder tumours comprise a heterogeneous group with respect to both histopathology and clinical behaviour. Although many features of bladder tumours have been studied, assessment of risk for recurrence and progression to invasive disease is not precise and response to specific therapies cannot be predicted accurately. It is anticipated that a thorough knowledge of the molecular alterations that are involved in the development and progression of bladder cancer will lead to greater predictive power and the application of novel individualized therapies. This review summarizes the current state of knowledge of genomic alterations found in transitional cell carcinoma and putative precursor lesions.

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Identification of loci associated with putative recurrence genes in transitional cell carcinoma of the urinary bladder

Cited by 32 publications

References 35 publications

Measurement of Relative Copy Number of CDKN2A/ARF and CDKN2B in Bladder Cancer by Real-Time Quantitative PCR and Multiplex Ligation-Dependent Probe Amplification

Measurement of Relative Copy Number of CDKN2A/ARF and CDKN2B in Bladder Cancer by Real-Time Quantitative PCR and Multiplex Ligation-Dependent Probe Amplification

Genetic alterations in urothelial bladder carcinoma

Bladder cancer subtypes defined by genomic alterations

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