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. © 2001 Cancer Research Campaign
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References
Akao T, Kakehi Y, Itoh N, Özdemir E, Shimizu T, Tachibana A, Sasaki MS and Yoshida O (1997) A high prevalence of functional inactivation by methylation modification of p16INK4A/CDKN2/MTS1 gene in primary urothelial cancers. Jpn J Cancer Res 88: 1078–1086
Bender CM, Pao MM and Jones PA (1998) Inhibition of DNA methylation by 5-aza-2′-deoxycytidine suppresses the growth of human tumor cell lines. Cancer Res 58: 95–101
Bruch J, Wohr G, Hautmann R, Mattfeldt T, Bruderlein S, Moller P, Sauter S, Hameister H, Vogel W and Paiss T (1998) Chromosomal changes during progression of transitional cell carcinoma of the bladder and delineation of the amplified interval on chromosome arm 8q. Genes Chromosom Cancer 23: 167–174
Chow NH, Cairns P, Eisenberger CF, Schoenberg MP, Taylor DC, Epstein JI and Sidransky D (2000) Papillary urothelial hyperplasia is a clonal precursor to papillary transitional cell bladder cancer. Int J Cancer 89: 514–518
Fadl-Elmula I, Gorunova L, Mandahl N, Elfving P, Lundgren R, Mitelman F and Heim S (2000) Karyotypic characterization of urinary bladder transitional cell carcinomas. Genes Chromosom Cancer 29: 256–265
Florl AR, Loewer R, Schmitz-Dräger BJ and Schulz WA (1999) DNA methylation and expression of L1 LINE and HERV-K provirus sequences in urothelial and renal cell carcinoma. Br J Cancer 80: 1312–1321
Florl AR, Franke KH, Niederacher D, Gerharz CD, Seifert HH and Schulz WA (2000) DNA methylation and the mechanisms of CDKN2A inactivation in transitional cell carcinoma of the urinary bladder. Lab Invest 80: 1513–1522
Gonzalgo ML, Hayshida T, Bender CM, Pao MM, Tsai YC, Gonzales FA, Nguyen HD, Nguyen TT and Jones PA (1998) The role of DNA methylation in expression of the p19/p16 locus in human bladder cancer cell lines. Cancer Res 58: 1245–1252
Grim J, d'Amico A, Frizelle S, Zhou J, Kratzke RA and Curiel DT (1997) Adenovirus-mediated delivery of p16 to p16-deficient human bladder cancer cells confers chemoresistance to cisplatin and paclitaxel. Clin Cancer Res 3: 2415–2423
Habuchi T, Devlin J, Elder PA and Knowles MA (1995) Detailed deletion mapping of chromosome 9q in bladder cancer: evidence for two tumour suppressor loci. Oncogene 11: 1671–1674
Habuchi T, Yoshida O and Knowles MA (1997) A novel candidate tumour suppressor locus at 9q32-33 in bladder cancer: localization of the candidate region within a single 840 kb YAC. Hum Mol Genet 6: 913–919
Habuchi T, Luscombe M, Elder PA and Knowles MA (1998) Structure and methylation-based silencing of a gene (DBCCR1) within a candidate bladder cancer tumor suppressor region at 9q32-q33. Genomics 48: 277–288
Hornigold N, Devlin J, Davies AM, Aveyard JS, Habuchi T and Knowles MA (1999) Mutation of the 9q34 gene TSC1 in sporadic bladder cancer. Oncogene 18: 2657–2661
Jürgens B, Schmitz-Dräger BJ and Schulz WA (1996) Hypomethylation of L1 LINE sequences prevailing in human urothelial carcinoma. Cancer Res 56: 5698–5703
Kai M, Arakawa H, Sugimoto Y, Murata Y, Ogawa M and Nakamura Y (1995) Infrequent somatic mutation of the MTS1 gene in primary bladder carcinomas. Jpn J Cancer Res 86: 249–251
Kallioniemi A, Kallioniemi OP, Citro G, Sauter G, DeVries S, Kerschmann R, Caroll P and Waldman F (1995) Identification of gains and losses of DNA sequences in primary bladder cancer by comparative genomic hybridization. Genes Chromosom Cancer 12: 213–219
Knowles MA, Elder PA, Williamson M, Cairns JP, Shaw ME and Law M (1994) Allelotype of human bladder cancer. Cancer Res 54: 531–538
Knowles MA (1999) The genetics of transitional cell carcinoma: progress and potential clinical application. BJU Int 84: 412–427
Kuklin A, Munson K, Gjerde D, Haefele R and Taylor P (1997) Detection of single-nucleotide polymorphisms with the WAVE DNA fragment analysis system. Genet Test 1: 201–206
Lindblom A (2001) Different mechanisms in the tumorigenesis of proximal and distal colon cancers. Curr Opin Oncol 13: 63–69
McGarvey TW, Maruta Y, Tomaszewski JE, Linnenbach AJ and Malkowicz SB (1998) PTCH gene mutations in invasive transitional cell carcinoma of the bladder. Oncogene 17: 1167–1172
McGarvey TW, Tait E, Tomaszewski JE and Malkowicz SB (1999) Expression of transforming growth factor-beta receptors and related cell-cycle components in transitional-cell carcinoma of the bladder. Mol Urol 3: 371–380
Nishiyama H, Takahashi T, Kakehi Y, Habuchi T and Knowles MA (1999) Homozygous deletion at the 9q32–33 candidate tumor suppressor locus in primary human bladder cancer. Genes Chromosom Cancer 26: 171–175
Ohgaki K, Minobe K, Kurose K, Iida A, Habuchi T, Ogawa O, Kubota Y, Akimoto M and Emi M (1999) Two target regions of allelic loss on chromosome 9 in urinary-bladder cancer. Jpn J Cancer Res 90: 957–964
Orlow I, LaRue H, Osman I, Lacombe L, Moore L, Rabbani F, Meyer F, Fradet Y and Cordon-Cardo C (1999) Deletions of the INK4A gene in superficial bladder tumors. Am J Pathol 155: 105–113
Ørntoft TF and Wolf H (1998) Molecular alterations in bladder cancer. Urol Res 26: 223–233
Packenham JP, Taylor JA, Anna CH, White CM and Devereux TR (1995) Homozygous deletions but no sequence mutations in coding regions of p15 or p16 in human primary bladder tumors. Mol Carcinog 14: 147–151
Qu GZ, Grundy PE, Narayan A and Ehrlich M (1999a) Frequent hypomethylation in Wilms tumors of pericentromeric DNA in chromosomes 1 and 16. Cancer Genet Cytogenet 109: 34–39
Qu G, Dubeau L, Narayan A, Yu MC and Ehrlich M (1999b) Satellite DNA hypomethylation vs. overall genomic hypomethylation in ovarian epithelial tumors of different malignant potential. Mutat Res 423: 91–101
Quelle DE, Zindy F, Ashmun RA and Sherr CJ (1995) Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 83: 993–1000
Richter J, Wagner U, Schraml P, Maurer R, Alund G, Knonagel H, Moch H, Mihatsch MJ, Gasser TC and Sauter G (1999) Chromosomal imbalances are associated with a high risk of progression in early invasive (pT1) urinary bladder cancer. Cancer Res 59: 5687–5691
Rocchi M, Archidiacono N, Ward DC and Baldini A (1991) A human chromosome 9-specific alphoid DNA repeat spatially resolvable from satellite 3 DNA by fluorescent in situ hybridization. Genomics 9: 517–523
Saito Y, Kanai Y, Sakamoto M, Saito H, Ishii H and Hirohashi S (2001) Expression of mRNA for DNA methyltransferases and methyl-CpG-binding proteins and DNA methylation status on CpG islands and pericentromeric satellite regions during human hepatocarcinogenesis. Hepatology 33: 561–568
Simoneau AR, Spruck CH 3rd, Gonzalez-Zulueta M, Gonzalgo ML, Chan MF, Tsai YC, Dean M, Steven K, Horn T and Jones PA (1996) Evidence for two tumor suppressor loci associated with proximal chromosome 9p to q and distal chromosome 9q in bladder cancer and the initial screening for GAS1 and PTC mutations. Cancer Res 56: 5039–5043
Simoneau M, LaRue H, Aboulkassim TO, Meyer F, Moore L and Fradet Y (2000) Chromosome 9 deletions and recurrence of superficial bladder cancer: identification of four regions of prognostic interest. Oncogene 19: 6317–6323
Tokunaga H, Lee DH, Kim IY, Wheeler TM and Lerner SP (1999) Decreased expression of transforming growth factor beta receptor type 1 is associated with poor prognosis in bladder transitional cell carcinoma patients. Clin Cancer Res 5: 2520–2525
Tuck-Muller CM, Narayan A, Tsien F, Smeets DF, Sawyer J, Fiala ES, Sohn OS and Ehrlich M (2000) DNA hypomethylation and unusual chromosome instability in cell lines from ICF syndrome patients. Cytogenet Cell Genet 89: 121–128
Van Tilborg AA, Hekman AC, Vissers KJ, van der Kwast TH and Zwarthoff EC (1998) Loss of heterozygosity on chromosome 9 and loss of chromosome 9 copy number are separate events in the pathogenesis of transitional cell carcinoma of the bladder. Int J Cancer 75: 9–14
Van Tilborg AAG, Groenfeld LE, van der Kwast TH and Zwarthoff EC (1999) Evidence for two candidate tumour suppressor loci on chromosome 9q in transitional cell carcinoma (TCC) of the bladder but no homozygous deletions in bladder tumour cell lines. Br J Cancer 80: 489–494
Van Tilborg AAG, de Vries A, de Bont M, Groenfeld LE, van der Kwast TH and Zwarthoff EC (2000) Molecular evolution of multiple recurrent cancers of the bladder. Hum Mol Genet 9: 2973–2980
Williamson MP, Elder PA, Shaw ME, Devlin J and Knowles MA (1995) p16 (CDKN2) is a major deletion target at 9p21 in bladder cancer. Hum Mol Genet 4: 1569–1577
Xu GL, Bestor TH, Bourc'his,, Hsieh CL, Tommerup N, Bugge M, Hulten M, Qu X, Russo JJ and Viegas-Pequinot E (1999) Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402: 187–191
Zhao J, Richter J, Wagner U, Roth B, Schraml P, Zellweger T, Ackermann D, Schmid U, Moch H, Mihatsch MJ, Gasser TC and Sauter G (1999) Chromosomal imbalances in noninvasive papillary bladder neoplasms (pTa). Cancer Res 59: 4658–4661
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Kimura, F., Florl, A., Seifert, HH. et al. Destabilization of chromosome 9 in transitional cell carcinoma of the urinary bladder. Br J Cancer 85, 1887–1893 (2001). https://doi.org/10.1054/bjoc.2001.2154
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DOI: https://doi.org/10.1054/bjoc.2001.2154
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