Summary
The most frequent genetic alterations in transitional cell carcinoma (TCC) of the bladder involve loss of heterozygosity (LOH) on chromosome 9p and 9q. The LOH on chromosome 9p most likely targets the CDKN2 locus, which is inactivated in about 50% of TCCs. Candidate genes that are the target for LOH on chromosome 9q have yet to be identified. To narrow the localization of one or more putative tumour suppressor genes on this chromosome that play a role in TCC of the bladder, we examined 59 tumours with a panel of microsatellite markers along the chromosome. LOH was observed in 26 (44%) tumours. We present evidence for two different loci on the long arm of chromosome 9 where potential tumour suppressor genes are expected. These loci are delineated by interstitial deletions in two bladder tumours. Our results confirm the results of others and contribute to a further reduction of the size of these regions, which we called TCC1 and TCC2. These regions were examined for homozygous deletions with EST and STS markers. No homozygous deletions were observed in 17 different bladder tumour cell lines.
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References
Ah-See, K. W., Cooke, T. G., Pickford, I. R., Soutar, D. & Balmain, A. (1994). An allelotype of squamous carcinoma of the head and neck using microsatellite markers. Cancer Res 54: 1617–1621.
Akao, T., Kakehi, Y., Itoh, N., Ozdemir, E., Shimizu, T., Tachibana, A., Sasaki, M. S. & 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.
Brewster, S. F., Gingell, J. C., Browne, S. & Brown, K. W. (1994). Loss of heterozygosity on chromosome 18q is associated with muscle-invasive transitional cell carcinoma of the bladder. Br J Cancer 70: 697–700.
Cairns, P. (1995). Frequency of homozygous deletion at p16/CDKN2 in primary human tumours. Nat Genet 11: 210–212.
Cairns, P., Shaw, M. E. & Knowles, M. A. (1993). Initiation of bladder cancer may involve deletion of a tumour-suppressor gene on chromosome 9. Oncogene 8: 1083–1085.
Cairns, P., Tokino, K., Eby, Y. & Sidransky, D. (1995). Localization of tumour suppressor loci on chromosome 9 in primary human renal cell carcinomas. Cancer Res 55: 224–227.
Chang, W. Y. H. (1995). Novel suppressor loci on chromosome 14q in primary bladder cancer. Cancer Res 55: 3246–3249.
Corcoran, M. M., Rasool, O., Liu, Y., Iyengar, A., Grander, D., Ibbotson, R. E., Merup, M., Wu, X., Brodyansky, V., Gardiner, A. C., Juliusson, G., Chapman, R. M., Ivanova, G., Tiller, M., Gahrton, G., Yankovsky, N., Zabarovsky, E., Oscier, D. G. & Einhorn, S. (1998). Detailed molecular delineation of 13q14.3 loss in B-cell chronic lymphocytic leukemia. Blood 91: 1382–1390.
Devlin, J., Keen, A. J. & Knowles, M. A. (1994). Homozygous deletion mapping at 9p21 in bladder carcinoma defines a critical region within 2 cM of IFN-A. Oncogene 9: 2757–2760.
Elder, P. A., Bell, S. M. & Knowles, M. A. (1994). Deletion of two regions on chromosome 4 in bladder carcinoma: definition of a critical 750 kb region at 4p16.3. Oncogene 9: 3433–3436.
Habuchi, T., Devlin, J., Elder, P. A. & Knowles, M. A. (1995). Detailed deletion mapping of chromosome 9q in bladder cancer: evidence for two tumour suppressor loci. Oncogene 11: 1671–1674.
Habuchi, T., Yoshida, O. & Knowles, M. A. (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, P. A. & Knowles, M. A. (1998). Structure and methylation-based silencing of a gene (DBCCR1) within a candidate bladder cancer tumor suppressor region at 9q32–33. Genomics 48: 277–288.
Jacoby, L. B., MacCollin, M., Louis, D. N., Mohney, T., Rubio, M. P., Pulaski, K., Trofatter, J. A., Kley, N., Seizinger, B., Ramesh, V. & Gusella, J. F. (1994). Exon scanning for mutation of the NF2 gene in schwannomas. Hum Mol Genet 3: 413–419.
Keen, A. J. & Knowles, M. A. (1994). Definition of two regions of deletion on chromosome 9 in carcinoma of the bladder. Oncogene 9: 2083–2088.
Knowles, M. A., Shaw, M. E. & Proctor, A. J. (1993). Deletion mapping of chromosome 8 in cancers of the urinary bladder using restriction fragment length polymorphisms and microsatellite polymorphisms. Oncogene 8: 1357–1364.
Kohno, T., Kawanishi, M., Matsuda, S., Ichikawa, H., Takada, M., Ohki, M., Yamamoto, T. & Yokota, J. (1998). Homozygous deletion and frequent allelic loss of the 21q11.1–q21.1 region including the ANA gene in human lung carcinoma. Genes Chromosomes Cancer 21: 236–243.
Linnenbach, A. J., Pressler, L. B., Seng, B. A., Kimmel, B. S., Tomaszewski, J. W. & Malkowicz, S. B. (1993). Characterization of chromosome 9 deletions in transitional cell carcinoma by microsatellite assay. Hum Mol Genet 2: 1407–1411.
Merlo, A., Gabrielson, E., Mabry, M., Vollmer, R., Baylin, S. B. & Sidransky, D. (1994). Homozygous deletion on chromosome 9p and loss of heterozygosity on 9q, 6p, and 6q in primary human small cell lung cancer. Cancer Res 54: 2322–2326.
Miura, K., Suzuki, K., Tokino, T., Isomura, M., Inazawa, J., Matsuno, S. & Nakamura, Y. (1996). Detailed deletion mapping in squamous cell carcinoma of the esophagus narrows a region containing a putative tumor suppressor gene to about 200 kilobases on distal chromosome 9q. Cancer Res 56: 1629–1634.
Nobori, T., Miura, K., Wu, D. J., Lois, A., Takabayashi, K. & Carson, D. A. (1994). Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 368: 753–756.
Orlow, I., Lianes, P., Lacombe, L., Dalbagni, G., Reuter, V. E. & Cordon-Cardo, C. (1994). Chromosome 9 allelic losses and microsatellite alterations in human bladder tumors. Cancer Res 54: 2848–2851.
Polascik, T. J., Cairns, P., Chang, W. Y. H., Schoenberg, M. P. & Sidransky, D. (1995). Distinct regions of allelic loss on chromosome 4 in human primary bladder carcinoma. Cancer Res 55: 5396–5399.
Ruppert, J. M., Tokino, K. & Sidransky, D. (1993). Evidence for two bladder cancer suppressor loci on human chromosome 9. Cancer Res 53: 5093–5095.
Sambrook, J., Fritsch, E. & Maniatis, T. (1989). Molecular Cloning: a Laboratory Manual. Cold Spring Harbor Laboratory: New York
Shanley, S. M., Dawkins, H., Wainwright, B. J., Wicking, C., Heenan, P., Eldon, M., Searle, J. & Chenevix-Trench, G. (1995). Fine deletion mapping on the long arm of chromosome 9 in sporadic and familial basal cell carcinomas. Hum Mol Genet 4: 129–133.
Shipman, R., Schrami, P., Colombi, M., Raefle, G. & Ludwig, C. U. (1993). Loss of heterozygosity on chromosome 11p13 in primary bladder carcinoma. Hum Genet 91: 455–458.
Shultz, D. C., Vanderveer, L., Buetow, K. H., Boente, M. P., Ozols, R. F., Hamilto, T. C. & Godwin, A. K. (1995). Characterization of chromosome 9 in human ovarian neoplasia identifies frequent genetic imbalance on 9q and rare alterations involving 9p, including. CDKN2, Cancer Res 55: 2150–2157.
Simoneau, A. R., Spruck, C. H. Jr, Gonzalez-Zulueta, M., Gonzalgo, M. L., Chan, M. F., Tsai, Y. C., Dean, M., Steven, K., Horn, T. & Jones, P. A. (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.
Southgate, J., Proffitt, J., Roberts, P., Smith, B. & Selby, P. (1995). Loss of cyclin-dependent kinase inhibitor genes and chromosome 9 karyotypic abnormalities in human bladder cancer cell lines. Br J Cancer 72: 1214–1218.
Takle, L. A. & Knowles, M. A. (1996). Deletion mapping implicates two tumour suppressor genes on chromosome 8p in the development of bladder cancer. Oncogene 12: 1083–1087.
Tamimi, Y., Bringuier, P. P., Smit, F., van Bokhoven, A., Abbas, A., Debruyne, F. M. & Schalken, J. A. (1996). Homozygous deletions of p16(INK4) occur frequently in bilharziasis-associated bladder cancer. Int J Cancer 68: 183–187.
Van Tilborg, A. A. G., Hekman, A. C. P., Vissers, K. J., van der Kwast, T. H. & Zwarthoff, E. C. (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.
Williamson, M. P., Elder, P. A., Shaw, M. E., Devlin, J. & Knowles, M. A. (1995). p16 (CDKN2) is a major deletion target at 9p21 in bladder cancer. Hum Mol Genet 4: 1569–1577.
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Tilborg, A., Groenfeld, L., Kwast, T. et al. 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 (1999). https://doi.org/10.1038/sj.bjc.6690383
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DOI: https://doi.org/10.1038/sj.bjc.6690383
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