Summary
The tumour suppressor gene PTEN/MMAC1, which is mutated or homozygously deleted in glioma, breast and prostate cancer, is mapped to a region of 10q which shows loss of heterozygosity (LOH) in bladder cancer. We screened 123 bladder tumours for LOH in the region of PTEN. In 53 informative muscle invasive tumours (≥ pT2), allele loss was detected in 13 (24.5%) and allelic imbalance in four tumours (overall frequency 32%). LOH was found in four of 60 (6.6%) informative, non-invasive tumours (pTa/pT1). We screened 63 muscle invasive tumours for PTEN mutations by single-strand conformation polymorphism (SSCP) analysis and for homozygous deletion by duplex quantitative polymerase chain reaction (PCR). Two homozygous deletions were identified but no mutations. Of 15 bladder tumour cell lines analysed, three showed homozygous deletion of all or part of the PTEN gene, but none had mutations detectable by SSCP analysis. Our results indicate that PTEN is involved in the development of some bladder tumours. The low frequency of mutation of the retained allele in tumours with 10q23 LOH suggests that there may be another predominant mechanism of inactivation of the second allele, for example small intragenic deletions, that hemizygosity may be sufficient for phenotypic effect, or that there is another target gene at 10q23.
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References
Atkin, N. B. & Baker, M. C. (1985). Cytogenetic study of ten carcinomas of the bladder: involvement of. Cancer Genet Cytogenet 15: 253–268.
Babu, V. R., Lutz, M. D., Miles, B. J., Farah, R. N., Weiss, L. & Van Dyke, D. L. (1987). Tumor behavior in transitional cell carcinoma of the bladder in relation to chromosomal markers and histopathology. Cancer Res 47: 6800–6805.
Berger, C. S., Sandberg, A. A., Todd, I. A., Pennington, R. D., Haddad, F. S., Hecht, B. K. & Hecht, F. (1986). Chromosomes in kidney, ureter, and bladder cancer. Cancer Genet Cytogenet 23: 1–24.
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., Okami, K., Halachmi, S., Halachmi, N., Esteller, M., Herman, J. G., Jen, J., Isaacs, W. B., Bova, G. S. & Sidransky, D. (1997). Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res 57: 4997–5000.
Cairns, P., Evron, E., Okami, K., Halachmi, N., Esteller, M., Herman, J. G., Bose, S., Wang, S. I., Parsons, R. & Sidransky, D. (1998). Point mutation and homozygous deletion of PTEN/MMAC1 in primary bladder cancers. Oncogene 16: 3215–3218.
Cappellen, D., Gil Diez de Medina, S., Chopin, D., Thiery, J. P. & Radvanyi, F. (1997). Frequent loss of heterozygosity on chromosome 10q in muscle-invasive transitional cell carcinomas of the bladder. Oncogene 14: 3059–3066.
Chang, WY-H, Cairns, P., Schoenberg, M. P., Polascik, T. J. & Sidransky, D. (1995). Novel suppressor loci on chromosome 14q in primary bladder cancer. Cancer Res 55: 3246–3249.
Dahia, P. L., Marsh, D. J., Zheng, Z., Zedenius, J., Komminoth, P., Frisk, T., Wallin, G., Parsons, R., Longy, M., Larsson, C. & Eng, C. (1997). Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumors. Cancer Res 57: 4710–4713.
Dahia, P. L., FitzGerald, M. G., Zhang, X., Marsh, D. J., Zheng, Z., Pietsch, T., von Deimling, A., Haluska, F. G., Haber, D. A. & Eng, C. (1998). A highly conserved processed PTEN pseudogene is located on chromosome band 9p21. Oncogene 16: 2403–2406.
Gibas, Z., Prout, G. R. Jr, Connolly, J. G., Pontes, J. E. & Sandberg, A. A. (1984). Nonrandom chromosomal changes in transitional cell carcinoma of the bladder. Cancer Res 44: 1257–1264.
Gray, I. C., Phillips, S. M., Lee, S. J., Neoptolemos, J. P., Weissenbach, J. & Spurr, N. K. (1995). Loss of the chromosomal region 10q23–25 in prostate cancer. Cancer Res 55: 4800–4803.
Guldberg, P., thor Straten, P., Birck, A., Ahrenkiel, V., Kirkin, A. F. & Zeuthen, J. (1997). Disruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma. Cancer Res 57: 3660–3663.
Isshiki, K., Elder, D. E., Guerry, D. & Linnenbach, A. J. (1993). Chromosome 10 allelic loss in malignant melanoma. Genes Chromosomes Cancer 8: 178–184.
Jones, M. H., Koi, S., Fujimoto, I., Hasumi, K., Kato, K. & Nakamura, Y. (1994). Allelotype of uterine cancer by analysis of RFLP and microsatellite. Genes Chromosomes Cancer 9: 119–123.
Kagan, J., Liu, J., Stein, J. D., Wagner, S. S., Babkowski, R., Grossman, B. H. & Katz, R. L. (1998). Cluster of allele losses within a 2.5 cM region of chromosome 10 in high-grade invasive bladder cancer. Oncogene 16: 909–913.
Kallioniemi, A., Kallioniemi, O-P, Sudar, D., Rutovitz, D., Gray, J. W., Waldman, F. M. & Pinkel, D. (1992). Comparative genomic hybridization for molecular genetic analysis of solid tumors. Science 258: 818–821.
Kallioniemi, A., Kallioniemi, O-P, Citro, G., Sauter, G., DeVries, S., Kerschmann, R., Caroll, P. & Waldman, F. (1995). Identification of gains and losses of DNA sequences in primary bladder cancer by comparative genomic hybridisation. Genes Chromosomes Cancer 12: 213–219.
Knowles, M. (1992). Human papillomavirus sequences are not detectable by Southern blotting or general primer-mediated polymerase chain reaction in transitional cell tumours of the bladder. Urol Res 20: 297–301.
Knowles, M. A. & Williamson, M. (1993). Mutation of H-ras is infrequent in bladder cancer: confirmation by single-strand conformation polymorphism analysis, designed restriction fragment length polymorphisms, and direct sequencing. Cancer Res 53: 133–139.
Knowles, M. A., Elder, P. A., Williamson, M., Cairns, J. P., Shaw, M. E. & Law, M. (1994). Allelotype of human bladder cancer. Cancer Res 54: 531–538.
Kong, D., Suzuki, A., Zou, T. T., Sakurada, A., Kemp, L. W., Wakatsuki, S., Yokoyama, T., Yamakawa, H., Furukawa, T., Sato, M., Ohuchi, N., Sato, S., Yin, J., Wang, S., Abraham, J. M., Souza, R. F., Smolinski, K. N., Meltzer, S. J. & Horii, A. (1997). PTEN1 is frequently mutated in primary endometrial carcinomas [letter]. Nat Genet 17: 143–144.
Li, J., Yen, C., Liaw, D., Podsypanina, K., Bose, S., Wang, S. I., Puc, J., Miliaresis, C., Rodgers, L., McCombie, R., Bigner, S. H., Giovanella, B. C., Ittmann, M., Tycko, B., Hibshoosh, H., Wigler, M. H. & Parsons, R. (1997). PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275: 1943–1947.
Liaw, D., Marsh, D. J., Li, J., Dahia, P. L., Wang, S. I., Zheng, Z., Bose, S., Call, K. M., Tsou, H. C., Peacocke, M., Eng, C. & Parsons, R. (1997). Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 16: 64–67.
Marsh, D. J., Dahia, P. L., Zheng, Z., Liaw, D., Parsons, R., Gorlin, R. J. & Eng, C. (1997). Germline mutations in PTEN are present in Bannayan–Zonana syndrome. Nat Genet 16: 333–334.
Nelen, M. R., van Staveren, W. C., Peeters, E. A., Hassel, M. B., Gorlin, R. J., Hamm, H., Lindboe, C. F., Fryns, J. P., Sijmons, R. H., Woods, D. G., Mariman, E. C., Padberg, G. W. & Kremer, H. (1997). Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Hum Mol Genet 6: 1383–1387.
Pesche, S., Latil, A., Muzeau, F., Cussenot, O., Fournier, G., Longy, M., Eng, C. & Liderea, R. (1998). PTEN/MMAC1/TEP1 involvement in primary prostate cancers. Oncogene 16: 2879–2883.
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.
Presti, J. C., Jr Reuter, V. E., Galan, T., Fair, W. R. & Cordon-Cardo, C. (1991). Molecular genetic alterations in superficial and locally advanced human bladder cancer. Cancer Res 51: 5405–5409.
Proctor, A. J., Coombs, L. M., Cairns, J. P. & Knowles, M. A. (1991). Amplification at chromosome 11q13 in transitional cell tumours of the bladder. Oncogene 6: 789–795.
Rasheed, B. K., Fuller, G. N., Friedman, A. H., Bigner, D. D. & Bigner, S. H. (1992). Loss of heterozygosity for 10q loci in human gliomas. Genes Chromosomes Cancer 5: 75–82.
Rempel, S. A., Schwechheimer, K., Davis, R. L., Cavenee, W. K. & Rosenblum, M. L. (1993). Loss of heterozygosity for loci on chromosome 10 is associated with morphologically malignant meningioma progression. Cancer Res 53: 2386–2392.
Rhei, E., Kang, L., Bogomolniy, F., Federici, M. G., Borgen, P. I. & Boyd, J. (1997). Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in primary breast carcinomas. Cancer Res 57: 3657–3659.
Risinger, J. I., Hayes, A. K., Berchuck, A. & Barrett, J. C. (1997). PTEN/MMAC1 mutations in endometrial cancers. Cancer Res 57: 4736–4738.
Smeets, W., Pauwels, R., Laarakkers, L., Debruyne, F. & Geraedts, J. (1987). Chromosomal analysis of bladder cancer. III. Nonrandom alterations. Cancer Genet Cytogenet 29: 29–41.
Steck, P. A., Pershouse, M. A., Jasser, S. A., Yung, W. K., Lin, H., Ligon, A. H., Langford, L. A., Baumgard, M. L., Hattier, T., Davis, T., Frye, C., Hu, R., Swedlund, B., Teng, D. H. & Tavtigian, S. V. (1997). Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15: 356–362.
Teng, D. H., HU, R., Lin, H., Davis, T., Iliev, D., Frye, C., Swedlund, B., Hansen, K. L., Vinson, V. L., Gumpper, K. L., Ellis, L., El-Naggar, A., Frazier, M., Jasser, S., Langford, L. A., Lee, J., Mills, G. B., Pershouse, M. A., Pollack, R. E., Tornos, C., Troncoso, P., Yung, W. K., Fujii, G., Berson, A., Bookstein, R., Bolen, J. B., Tautigian, S. V. & Steck, P. A. (1997). MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res 57: 5221–5225.
UICC (1978). TNM Classification of Malignant Tumors, Bladder, pp. 113–117. Union Internationale Contre le Cancer: Geneva
Wang, M. R., Perissel, B., Taillandier, J., Kemeny, J. L., Fonck, Y., Lautier, A., Benkhalifa, M. & Malet, P. (1994). Nonrandom changes of chromosome 10 in bladder cancer. Detection by FISH. Cancer Genet Cytogenet 73: 8–10.
Whang, Y. E., Wu, X., Suzuki, H., Reiter, R. E., Tran, C., Vessella, R. L., Said, J. W., Isaacs, W. B. & Sawyers, C. L. (1998). Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proc Natl Acad Sci US A 95: 5246–5250.
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Aveyard, J., Skilleter, A., Habuchi, T. et al. Somatic mutation of PTEN in bladder carcinoma. Br J Cancer 80, 904–908 (1999). https://doi.org/10.1038/sj.bjc.6690439
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DOI: https://doi.org/10.1038/sj.bjc.6690439
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