Is chromosome 9 loss a marker of disease recurrence in transitional cell carcinoma of the urinary bladder?

Bartlett, John M.S.; Watters, A.D.; Ballantyne, Stuart; Going, James J.; Grigor, Ken; Cooke, TG

doi:10.1038/bjc.1998.365

Cited by 46 publications

(33 citation statements)

References 7 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: 78%

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: 78%

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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“…FISH was performed as previously described [27,28]; brie¯y, slides were pretreated with 0.2 mol/L HCl, 8% sodium thiosulphate at 80uC and 0.5% pepsin at 37uC. Sections were post-®xed in 10% neutral buffered formalin.…”

Section: Methodsmentioning

confidence: 99%

Gene amplification and overexpression of HER2 in renal cell carcinoma

Latif

Watters

Bartlett

et al. 2002

BJU Int

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Objective To determine the frequency of HER2 genetic abnormalities in renal cell carcinoma (RCC) and hence assess the potential suitability of Herceptin TM immunotherapy. Patients and methods Tumours from 27 patients with RCC were assessed; all patients had undergone nephrectomy. Benign renal tissue from the nephrectomy specimens was studied in seven patients. Gene ampli®cation was assessed using¯uorescent in-situ hybridization, and protein over-expression using immunohistochemistry. Results Twenty-four patients had clear cell renal carcinoma, two had papillary renal carcinoma and one a sarcomatoid variant carcinoma. There was no HER2 ampli®cation in the tumours or the benign renal tissue. Polysomy 17 was detected in 11 of 27 tumours (41%) and increased HER2 copy number in seven (26%). Both polysomy 17 and increased HER2 copy number were absent in the benign renal tissue. Three tumours (11%) and six of the seven benign renal tissue samples over-expressed the HER2 protein. Conclusions HER2 ampli®cation is absent and protein over-expression uncommon in RCC. This casts doubt on the suitability of Herceptin TM in the treatment of RCC.

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“…Control sections from normal bladder tissue obtained from post mortem normal bladder were included in the analysis. Values for disomy were derived from the analysis of these tissue sections as previously reported (Bartlett et al, 1998;Watters et al, 2000).…”

Section: Scoring Criteriamentioning

confidence: 99%

“…Previous research within this laboratory demonstrated that polysomy of chromosomes 9, 7 and 17 are associated with recurrence (Bartlett et al, 1998, Watters et al, 2000, but that these genetic events are not linked with polyploidy (Bartlett et al, 1999). A small study within this laboratory investigating the drug metabolising enzyme NAT2 (the gene is located at chromosome 8p22) in TCC recurrence or progression suggested that polysomy 8 was associated with disease progression .…”

mentioning

confidence: 96%

“…Following on from previous studies within this laboratory (Bartlett et al, 1998(Bartlett et al, , 1999Watters et al, 2000Watters et al, , 2001) which associated specific chromosomal aberrations with recurrence or progression, we hypothesised that alteration of key cell cycle modulators c-myc and CCND1 via gene alterations drives progression of superficial and locally invasive TCC (pTa/pT1). This study determined chromosome and gene copy number by FISH in a cohort of patients with either detrusor muscle invasive TCC at presentation or who developed detrusor muscle invasive TCC following a presentation with non-muscle invasive (pTa/pT1) TCC.…”

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confidence: 99%

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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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Is chromosome 9 loss a marker of disease recurrence in transitional cell carcinoma of the urinary bladder?

Cited by 46 publications

References 7 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

Gene amplification and overexpression of HER2 in renal cell carcinoma

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

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