Detection of Genetic Alterations in Bladder Tumors by Comparative Genomic Hybridization and Cytogenetic Analysis

Koo, Sun Hoe; Kwon, Gye Cheol; Ihm, Chun Hwa; Jeon, Young Mi; Park, Jong Woo; Sul, Chong Koo

doi:10.1016/s0165-4608(98)00193-9

Cited by 60 publications

(38 citation statements)

References 19 publications

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“…Early karyotyping studies identified deletions and amplifications of both arms of chromosome 5, suggesting the involvement of several genes in human bladder carcinogenesis (Atkin and Fox, 1990;Gibas et al, 1986;Klingelhutz et al, 1991). More recent studies using comparative genomic hybridization and hypervariable markers have identified three distinct regions on chromosome 5 as being involved in the progression of urinary bladder cancer (Bohm et al, 1997;Koo et al, 1999;von Knobloch et al, 2000;Voorter et al, 1995). An area mapping to chromosome 5p between markers D5S1473 and D5S819 was commonly amplified, and two distinct allelic regions were deleted in 5q22-q23 and 5q33-q34 (von Knobloch et al, 2000).…”

Section: Kram Et Almentioning

confidence: 99%

Mapping and Genome Sequence Analysis of Chromosome 5 Regions Involved in Bladder Cancer Progression

Kram

Zhang

et al. 2001

Laboratory Investigation

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SUMMARY:We studied the evolution of allelic losses on chromosome 5 by whole-organ histologic and genetic mapping in 234 mucosal DNA samples of 5 cystectomy specimens with invasive bladder cancer and preneoplastic changes in adjacent urothelium. The frequency of alterations in individual loci was verified on 32 tumors and 29 voided urine samples from patients with bladder cancer. Finally, deleted regions on chromosome 5 were integrated with the human genome contigs and sequence-based databases. Deleted regions on chromosome 5 involved in intraurothelial phases of bladder neoplasia defined by their nearest flanking markers and predicted size were identified as follows: q13.3-q22 (D5S424-D5S656; 38.8 centimorgan [cM]); q22-q31.1 (D5S656-D5S808; 19.2 cM), q31.1-q32 (D5S816-SPARC; 11.5 cM), and q34 (GABRA1-D5S415; 6.4 cM). The two most frequently deleted neighbor markers (D5S2055 and D5S818) mapping to q22-q31.1 defined a 9 cM region, which may contain genes that play an important role in early phases of urinary bladder carcinogenesis. Human genome database analysis provided an accurate map of deleted regions with positions of 138 known genes and revealed several smaller gene-rich areas representing putative targets for further mapping. The strategic approach presented here, which combines whole-organ histologic and genetic mapping with analysis of the rapidly emerging human genome sequence database, facilitates identification of genes potentially involved in early phases of bladder carcinogenesis. (Lab Invest 2001, 81:1039 -1048.C ancer develops via multiple, cumulative steps, many of which precede the development of clinically and even microscopically recognizable disease. Mapping and human genome sequence analysis of chromosomal regions involved in clinically occult preinvasive phases of neoplasia may provide valuable clues for more specific studies of early events in human carcinogenesis and could lead to the development of novel early detection markers as well as preventive strategies.We have previously reported the identification of several putative tumor suppressor gene loci involved in early preinvasive phases of human urinary bladder carcinogenesis (Chaturvedi et al, 1997;Czerniak et al, 1999Czerniak et al, , 2000. Bladder tumors were used as a common model of human cancer, which develops by progression of microscopically recognizable in situ precursor conditions, and are easily accessible by various minimally invasive or noninvasive techniques (Gazdar and Czerniak, 2001;Greenlee et al, 2000). The entire mucosal surface of the bladder can be examined by cystoscopy and biopsies with minimal risk for the patient, and exfoliated urothelial cells can be repeatedly tested for various alterations in voided urine at no risk at all (Gazdar and Czerniak, 2001). Moreover, the simple anatomy and appropriate size of the bladder permit the histologic and genetic mapping studies of invasive cancer and preneoplastic lesions in the entire mucosa of cystectomy specimens. The whole-organ histologic and genetic mapping combine...

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Section: Kram Et Almentioning

confidence: 99%

Mapping and Genome Sequence Analysis of Chromosome 5 Regions Involved in Bladder Cancer Progression

Kram

Zhang

et al. 2001

Laboratory Investigation

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“…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).…”

Section: Introductionmentioning

confidence: 96%

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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“…This makes it di cult to de®ne which of the ampli®ed genes provide a growth advantage to tumor cells. Studies using comparative genomic hybridization (CGH) had repeatedly revealed 12q13-q15 ampli®cations in bladder cancer (Koo et al, 1999;Richter et al, 1997Richter et al, , 1998Simon et al, 1998Simon et al, , 2000Voorter et al, 1995;Zhao et al, 1999). This genomic region contains at least 60 genes.…”

Section: Introductionmentioning

confidence: 99%

Amplification pattern of 12q13-q15 genes (MDM2, CDK4, GLI) in urinary bladder cancer

et al. 2002

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The chromosomal region 12q13-q15 is recurrently ampli®ed in bladder cancer. Putative target genes located in this region include MDM2, CDK4, and GLI. To evaluate the involvement of these genes in bladder cancer, we screened a tissue microarray (TMA) containing 2317 samples by¯uorescence in situ hybridization (FISH). Ampli®cation was found for MDM2 in 5.1%, for CDK4 in 1.1%, and for GLI in 0.4% of interpretable tumors. Among tumors having ampli®cation of at least one of these 12q13-q15 genes, 76.6% had ampli®cation of MDM2 alone and 6.4% had ampli®cation of CDK4 alone. Coampli®cations were seen of MDM2 and CDK4 in 10.6%, and of CDK4 and GLI in 6.4%. Neither coampli®cations of all three genes nor isolated GLI ampli®cations were found. These data suggest a prominent role of MDM2 as a 12q13-q15 ampli®cation target in bladder cancer. However, independent CDK4 ampli®cations do also occur suggesting either two nonoverlapping ampli®cation sites or else a minimal overlapping region between MDM2 and CDK4 perhaps containing another yet unknown oncogene. The frequency of ampli®cation increased signi®cantly from stage pTa to pT1-4 (P50.04) and from low to high grade (P50.005). These data are consistent with a high level of genetic instability in invasively growing and highgrade bladder tumors.

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Detection of Genetic Alterations in Bladder Tumors by Comparative Genomic Hybridization and Cytogenetic Analysis

Cited by 60 publications

References 19 publications

Mapping and Genome Sequence Analysis of Chromosome 5 Regions Involved in Bladder Cancer Progression

Mapping and Genome Sequence Analysis of Chromosome 5 Regions Involved in Bladder Cancer Progression

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

Amplification pattern of 12q13-q15 genes (MDM2, CDK4, GLI) in urinary bladder cancer

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