Allelic changes at multiple regions of chromosome 5 are associated with progression of urinary bladder cancer

Knobloch, Rolf von; Bugert, Peter; Jauch, Anna; Kälble, T.; Kovács, George L.

doi:10.1002/(sici)1096-9896(200002)190:2<163::aid-path509>3.0.co;2-0

Cited by 20 publications

(15 citation statements)

References 21 publications

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“…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 Alsupporting

confidence: 82%

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 Alsupporting

confidence: 82%

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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“…16,17 In confirmation with our previous finding in which we identified 5q-LOH as frequent progression-associated alterations in bladder cancer, in the present study the tumors displayed 5q-AI in 33%. 18 Nevertheless, only 18% (7 of 39 patients) of the serum DNA samples also had 5q alterations. The different penetration rates of alterations detected in the tumor compared to alterations in serum may be explained by the fact that serum DNA is most probably fragmented to a high extent and alterations may therefore be detected only if the amplified microsatellite is small with less than 200 base pairs (bp) and has a high heterozygosity rate.…”

Section: Discussionsupporting

confidence: 56%

Serum DNA and urine DNA alterations of urinary transitional cell bladder carcinoma detected by fluorescent microsatellite analysis

et al. 2001

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There are no reliable serologic tumor markers for transitional cell carcinoma (TCC) of the urinary bladder and noninvasive urine investigations are inadequate. We used fluorescent microsatellite analysis (MSA) to detect serum DNA and urine-sediment DNA alterations in patients with bladder cancer and prospectively collected fresh tumor, peripheral blood, serum and spontaneous urine specimens from 39 consecutive patients treated for TCC of the bladder to obtain the corresponding DNA. Urinary bladder cancer accounts for approximately 3% of all newly diagnosed malignancies in Western countries. In contrast to most other tumors, bladder carcinoma offers the opportunity of noninvasive diagnosis via urinary cytology. Yet a reliable serologic tumor marker is not available. Follow-up for bladder carcinoma is demanding and time consuming, as most bladder cancers at diagnosis grow superficially and will recur in 70% of cases within 2 years of primary treatment. 1 The intensive follow-up for transitional cell carcinoma (TCC) of the bladder still relies on invasive diagnostic measures such as cystoscopy and bladder washings for urine cytology. Cytology has a low sensitivity in the diagnosis of well-differentiated papillary tumors. A reliable serologic marker and a highly sensitive urinary investigation could reduce the requirement and frequency of invasive procedures during follow-up.In recent studies molecular techniques have proved applicable for the detection of smallest amounts of free circulating tumor DNA in serum and plasma of cancer patients. 2,3 Using microsatellite analysis (MSA) Goessl et al. 3 identified plasma DNA alterations in 63% of patients with renal cell carcinoma. In recent studies MSA was also used to detect tumor-specific DNA alterations in urine sediment samples of patients with TCC of the urinary bladder. 4,5 In a pilot study Steiner et al. 4 achieved a sensitivity of 90% for the urinary cancer diagnosis with radiolabeled microsatellite markers. In contrast to cytology, this method is independent of tumor histomorphologic features, and thus offers high sensitivity in well-differentiated tumors. This molecular genetic assay, not previously looked at in TCC, could reliably identify tumor-specific alterations in the serum of patients and its use in follow-up after radical surgical therapy could lead to early tumor recurrence identification. In the case of superficial bladder cancers, MSA may be helpful in diagnosing local recurrence without the need for invasive measures dependent on morphologic tumor features. We therefore used MSA with 17 highly polymorphic fluorescently labeled microsatellite markers from the chromosomal regions 5q, 8p, 9p, 9q, 13q, 14q, 17p, 17q and 20q to detect serum DNA and sediment-DNA alterations from spontaneous urine samples of 39 consecutive patients treated for TCC of the urinary bladder, to evaluate the sensitivity of the method in the serologic and urinary diagnosis of bladder TCC. MATERIAL AND METHODS Tumor, blood and urine samplingIn 1999, we prospectively collected preo...

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Section: Abstract: Urothelial Cancer; Loss Of Heterozygosity; Bayesimentioning

confidence: 51%

“…2 The vast majority of UCs acquire several additional genetic alterations during progression, including deletion of chromosome 2q, 5q and 8p, deletion/ mutation of the p53 and Rb genes or amplification and overexpression of the ERBB-2 gene. [3][4][5][6][7][8] Although some of the genetic alterations occur at random, the recurrent changes may refer to a network of genes that are specifically involved in tumor development and progression.Several models indicating a step-by-step order of genetic changes as a single pathway from normal urothelial cell to malignant tumor have been proposed. [9][10][11] Desper et al 12 and Schäffer et al 13 applied mathematical models to infer the order of genetic changes during progression of UCs.…”

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Pathways of urothelial cancer progression suggested by Bayesian network analysis of allelotyping data

Bulashevska

Szakács

Brors

et al. 2004

Intl Journal of Cancer

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Urothelial cancers of the bladder (UC) comprise biologically heterogeneous group of tumors and display complex genetic alterations. Several genetic changes have been analyzed in detail and some of them are associated with the development and progression of UCs. Only a few studies, however, are focused on identifying the order in which the aberrations may appear during UC tumorigenesis. We have analyzed 123 papillary UCs of the bladder by microsatellites for each of the chromosomal regions that have been suggested to be specifically involved in this type of tumor. We used Bayesian network modeling that enables to uncover multivariate probabilistic dependencies between variables. This methodology applied to LOH data allowed us to discover patterns of losses in UCs. Exploiting the mechanism of probabilistic reasoning in Bayesian networks we suggest primary and secondary events in tumor pathogenesis and reconstruct the possible flow of progression of allelic changes. Key words: urothelial cancer; loss of heterozygosity; Bayesian networks; network inference; genetic pathwaysUrothelial carcinoma of the bladder (UC) comprise biologically and morphologically heterogenous groups of neoplasms. During the last decade a broad spectrum of genetic alterations has been described in UCs. Cytogenetic, CGH and microsatellite analyses showed loss, gain and amplification of DNA sequences at several chromosomal regions. 1 Hemi-and homozygous deletion at and methylation/mutation of the CDKN2A gene at chromosome 9p21 is considered to be an early genetic event. 2 The vast majority of UCs acquire several additional genetic alterations during progression, including deletion of chromosome 2q, 5q and 8p, deletion/ mutation of the p53 and Rb genes or amplification and overexpression of the ERBB-2 gene. [3][4][5][6][7][8] Although some of the genetic alterations occur at random, the recurrent changes may refer to a network of genes that are specifically involved in tumor development and progression.Several models indicating a step-by-step order of genetic changes as a single pathway from normal urothelial cell to malignant tumor have been proposed. [9][10][11] Desper et al. 12 and Schäffer et al. 13 applied mathematical models to infer the order of genetic changes during progression of UCs. They described the progression of alterations as a tree with a root representing the normal cell and used 2 different tree models. In a distance-based tree leaf nodes represent genetic aberrations. The distance function between the nodes in the tree was defined based on probabilities of the co-occurrence of genetic events. A distance-based phylogenetic tree-building algorithm was used to infer the tree structure that fits the pairwise distances at best. Alternatively, a maximum weight branching algorithm was used to reconstruct a tree in which both internal nodes and leaf nodes correspond to aberrations. A major limitation of these models is that they describe the progression of genetic events as trees, whereas the biological intuition suggests that this...

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Allelic changes at multiple regions of chromosome 5 are associated with progression of urinary bladder cancer

Cited by 20 publications

References 21 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

Serum DNA and urine DNA alterations of urinary transitional cell bladder carcinoma detected by fluorescent microsatellite analysis

Pathways of urothelial cancer progression suggested by Bayesian network analysis of allelotyping data

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