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Destabilization of chromosome 9 in transitional cell carcinoma of the urinary bladder
F Kimura1, A R Florl, H H Seifert
1Urologische Klinik, Heinrich-Heine Universität, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
Abstract:
The most frequent genetic alteration in transitional cell carcinoma of the urinary bladder (TCC) is loss of chromosome 9 which targets CDKN2A on 9p. The targets on 9q are not confirmed. Here, 81 advanced TCC specimens were investigated for loss of heterozygosity (LOH) and homozygous deletions (HD) on chromosome 9q using multiplex analysis of microsatellite markers. 41/81 tumours (51%) showed LOH on 9q, with LOH at all markers in 33 cases. Eight partial losses involved three regions in 9q12, 9q22.3, and 9q33- 9q34. No mutations were identified in the candidate tumour suppressor gene DBCCR1 in three tumours showing restricted LOH at 9q32-33. 22% of the specimens had HD at CDKN2A, but no HD was found on 9q. Two tumours had lost 9p only and five 9q only. 9q LOH was not related to tumour grade or stage and present or absent with equal frequency in recurrent TCC. LOH on 9q correlated with the extent of genome-wide hypomethylation (P < 0.0001) which extended into satellite sequences located in 9q12 juxtacentromeric heterochromatin. While the high frequency of chromosome 9q loss in TCC may reflect destabilization of the chromosome related to hypomethylation of repetitive DNA, the data are compatible with the existence of tumour suppressor genes on this chromosome arm.
Insights
Loss of chromosome 9q occurs in over half of advanced bladder cancers (TCC). This genetic alteration correlates with genome-wide hypomethylation, suggesting potential tumor suppressor genes on 9q.
Area of Science:
- Cancer Genetics
- Urologic Oncology
- Molecular Biology
Background:
- Transitional cell carcinoma (TCC) of the urinary bladder frequently involves genetic alterations.
- Loss of chromosome 9, particularly 9p targeting CDKN2A, is common, but targets on 9q remain unconfirmed.
- Understanding chromosomal abnormalities in TCC is crucial for identifying potential tumor suppressor genes.
Purpose of the Study:
- To investigate the frequency and patterns of loss of heterozygosity (LOH) and homozygous deletions (HD) on chromosome 9q in advanced TCC.
- To identify potential tumor suppressor genes on chromosome 9q.
- To explore the relationship between 9q LOH and genome-wide hypomethylation.
Main Methods:
- Analysis of 81 advanced TCC specimens using multiplex analysis of microsatellite markers.
- Assessment for LOH and HD on chromosome 9q.
- Mutation analysis of the candidate tumor suppressor gene DBCCR1.
Main Results:
- 51% of TCC tumors exhibited LOH on chromosome 9q, with 33 cases showing loss at all markers.
- Partial losses on 9q involved specific regions (9q12, 9q22.3, 9q33-34); no homozygous deletions were found on 9q.
- 9q LOH correlated significantly with genome-wide hypomethylation, extending to juxtacentromeric heterochromatin.
Conclusions:
- Chromosome 9q loss is a frequent event in advanced TCC, potentially linked to chromosome destabilization via hypomethylation.
- The findings support the existence of tumor suppressor genes on chromosome 9q.
- Further research is warranted to pinpoint specific tumor suppressor genes on 9q involved in bladder cancer development.