Skip to main content
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Jun;84(11):1505–1511. doi: 10.1054/bjoc.2001.1823

p53 mutations in urinary bladder cancer

P Berggren 1,2, G Steineck 2, J Adolfsson 3, J Hansson 2, O Jansson 4, P Larsson 5, B Sandstedt 6, H Wijkström 7, K Hemminki 1
PMCID: PMC2363660  PMID: 11384101

Abstract

We have screened for mutations in exons 5–8 of the p53 gene in a series consisting of 189 patients with urinary bladder neoplasms. 82 (44%) neoplasms were lowly malignant (Ta, G1–G2a) and 106 (56%) were highly malignant (G2b–G4 or ≥T1). Only one mutation was in a lowly malignant urinary bladder neoplasm, in total we found p53 mutations in 26 (14%) of the 189 patients. 30% of the samples had loss of heterozygosity (LOH) for one or both of the p53 exogenic (CA)n repeat and the p53 intragenic (AAAAT)n repeat markers. 31 samples (21%) showed LOH but were not mutated, suggesting other mechanisms inactivating p53 than mutations. 4 mutations were found at codon 280 and 2 mutations were found at codon 285, 2 previously reported hot spots for urinary bladder cancer. The study indicate a boundary between G2a and G2b tumours concerning the occurrence of genetic events affecting p53 function; moderately differentiated (G2) urinary bladder neoplasms probably are genetically heterogeneous which supports the suggestion that they should not be grouped together but instead, for example, be categorized as either lowly or highly malignant. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: p53, urinary bladder cancer, PCR, F-SSCP

Full Text

The Full Text of this article is available as a PDF (97.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bennett W. P., Hussain S. P., Vahakangas K. H., Khan M. A., Shields P. G., Harris C. C. Molecular epidemiology of human cancer risk: gene-environment interactions and p53 mutation spectrum in human lung cancer. J Pathol. 1999 Jan;187(1):8–18. doi: 10.1002/(SICI)1096-9896(199901)187:1<8::AID-PATH232>3.0.CO;2-Y. [DOI] [PubMed] [Google Scholar]
  2. Berggren P., Hemminki K., Steineck G. p53 intron 7 polymorphisms in urinary bladder cancer patients and controls. Stockholm Bladder Cancer Group. Mutagenesis. 2000 Jan;15(1):57–60. doi: 10.1093/mutage/15.1.57. [DOI] [PubMed] [Google Scholar]
  3. Berggren P., Steineck G., Hemminki K. A rapid fluorescence based multiplex polymerase chain reaction--single-strand conformation polymorphism method for p53 mutation detection. Electrophoresis. 2000 Jul;21(12):2335–2342. doi: 10.1002/1522-2683(20000701)21:12<2335::AID-ELPS2335>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  4. Bergkvist A., Ljungqvist A., Moberger G. Classification of bladder tumours based on the cellular pattern. Preliminary report of a clinical-pathological study of 300 cases with a minimum follow-up of eight years. Acta Chir Scand. 1965 Oct;130(4):371–378. [PubMed] [Google Scholar]
  5. Bringuier P. P., McCredie M., Sauter G., Bilous M., Stewart J., Mihatsch M. J., Kleihues P., Ohgaki H. Carcinomas of the renal pelvis associated with smoking and phenacetin abuse: p53 mutations and polymorphism of carcinogen-metabolising enzymes. Int J Cancer. 1998 Oct 23;79(5):531–536. doi: 10.1002/(sici)1097-0215(19981023)79:5<531::aid-ijc15>3.0.co;2-4. [DOI] [PubMed] [Google Scholar]
  6. Carbin B. E., Ekman P., Gustafson H., Christensen N. J., Sandstedt B., Silfverswärd C. Grading of human urothelial carcinoma based on nuclear atypia and mitotic frequency. I. Histological description. J Urol. 1991 May;145(5):968–971. doi: 10.1016/s0022-5347(17)38502-6. [DOI] [PubMed] [Google Scholar]
  7. Carbone D., Chiba I., Mitsudomi T. Polymorphism at codon 213 within the p53 gene. Oncogene. 1991 Sep;6(9):1691–1692. [PubMed] [Google Scholar]
  8. Cohen S. M., Shirai T., Steineck G. Epidemiology and etiology of premalignant and malignant urothelial changes. Scand J Urol Nephrol Suppl. 2000;(205):105–115. doi: 10.1080/00365590050509869. [DOI] [PubMed] [Google Scholar]
  9. Coles C., Thompson A. M., Elder P. A., Cohen B. B., Mackenzie I. M., Cranston G., Chetty U., Mackay J., Macdonald M., Nakamura Y. Evidence implicating at least two genes on chromosome 17p in breast carcinogenesis. Lancet. 1990 Sep 29;336(8718):761–763. doi: 10.1016/0140-6736(90)93236-i. [DOI] [PubMed] [Google Scholar]
  10. Epstein J. I., Amin M. B., Reuter V. R., Mostofi F. K. The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol. 1998 Dec;22(12):1435–1448. doi: 10.1097/00000478-199812000-00001. [DOI] [PubMed] [Google Scholar]
  11. Esposti P. L., Zajicek J. Grading of transitional cell neoplasms of the urinary bladder from smears of bladder washings. A critical review of 326 tumors. Acta Cytol. 1972 Nov-Dec;16(6):529–537. [PubMed] [Google Scholar]
  12. Feinstein E., Cimino G., Gale R. P., Alimena G., Berthier R., Kishi K., Goldman J., Zaccaria A., Berrebi A., Canaani E. p53 in chronic myelogenous leukemia in acute phase. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6293–6297. doi: 10.1073/pnas.88.14.6293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fields S., Jang S. K. Presence of a potent transcription activating sequence in the p53 protein. Science. 1990 Aug 31;249(4972):1046–1049. doi: 10.1126/science.2144363. [DOI] [PubMed] [Google Scholar]
  14. Fujimoto K., Yamada Y., Okajima E., Kakizoe T., Sasaki H., Sugimura T., Terada M. Frequent association of p53 gene mutation in invasive bladder cancer. Cancer Res. 1992 Mar 15;52(6):1393–1398. [PubMed] [Google Scholar]
  15. Futreal P. A., Barrett J. C., Wiseman R. W. An Alu polymorphism intragenic to the TP53 gene. Nucleic Acids Res. 1991 Dec 25;19(24):6977–6977. doi: 10.1093/nar/19.24.6977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Greenblatt M. S., Bennett W. P., Hollstein M., Harris C. C. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994 Sep 15;54(18):4855–4878. [PubMed] [Google Scholar]
  17. Hainaut P., Hernandez T., Robinson A., Rodriguez-Tome P., Flores T., Hollstein M., Harris C. C., Montesano R. IARC Database of p53 gene mutations in human tumors and cell lines: updated compilation, revised formats and new visualisation tools. Nucleic Acids Res. 1998 Jan 1;26(1):205–213. doi: 10.1093/nar/26.1.205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hainaut P., Hollstein M. p53 and human cancer: the first ten thousand mutations. Adv Cancer Res. 2000;77:81–137. doi: 10.1016/s0065-230x(08)60785-x. [DOI] [PubMed] [Google Scholar]
  19. Hall R. R., Prout G. R. Staging of bladder cancer: is the tumor, node, metastasis system adequate? Semin Oncol. 1990 Oct;17(5):517–523. [PubMed] [Google Scholar]
  20. Hollstein M., Moeckel G., Hergenhahn M., Spiegelhalder B., Keil M., Werle-Schneider G., Bartsch H., Brickmann J. On the origins of tumor mutations in cancer genes: insights from the p53 gene. Mutat Res. 1998 Sep 20;405(2):145–154. doi: 10.1016/s0027-5107(98)00131-6. [DOI] [PubMed] [Google Scholar]
  21. Isobe M., Emanuel B. S., Givol D., Oren M., Croce C. M. Localization of gene for human p53 tumour antigen to band 17p13. Nature. 1986 Mar 6;320(6057):84–85. doi: 10.1038/320084a0. [DOI] [PubMed] [Google Scholar]
  22. Jones M. H., Nakamura Y. Detection of loss of heterozygosity at the human TP53 locus using a dinucleotide repeat polymorphism. Genes Chromosomes Cancer. 1992 Jul;5(1):89–90. doi: 10.1002/gcc.2870050113. [DOI] [PubMed] [Google Scholar]
  23. Kern S. E., Kinzler K. W., Bruskin A., Jarosz D., Friedman P., Prives C., Vogelstein B. Identification of p53 as a sequence-specific DNA-binding protein. Science. 1991 Jun 21;252(5013):1708–1711. doi: 10.1126/science.2047879. [DOI] [PubMed] [Google Scholar]
  24. Kleihues P., Schäuble B., zur Hausen A., Estève J., Ohgaki H. Tumors associated with p53 germline mutations: a synopsis of 91 families. Am J Pathol. 1997 Jan;150(1):1–13. [PMC free article] [PubMed] [Google Scholar]
  25. Knowles M. A. Identification of novel bladder tumour suppressor genes. Electrophoresis. 1999 Feb;20(2):269–279. doi: 10.1002/(SICI)1522-2683(19990201)20:2<269::AID-ELPS269>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar]
  26. Knowles M. A. The genetics of transitional cell carcinoma: progress and potential clinical application. BJU Int. 1999 Sep;84(4):412–427. doi: 10.1046/j.1464-410x.1999.00217.x. [DOI] [PubMed] [Google Scholar]
  27. Knudson A. G., Jr Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971 Apr;68(4):820–823. doi: 10.1073/pnas.68.4.820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lane D. P., Crawford L. V. T antigen is bound to a host protein in SV40-transformed cells. Nature. 1979 Mar 15;278(5701):261–263. doi: 10.1038/278261a0. [DOI] [PubMed] [Google Scholar]
  29. Lianes P., Orlow I., Zhang Z. F., Oliva M. R., Sarkis A. S., Reuter V. E., Cordon-Cardo C. Altered patterns of MDM2 and TP53 expression in human bladder cancer. J Natl Cancer Inst. 1994 Sep 7;86(17):1325–1330. doi: 10.1093/jnci/86.17.1325. [DOI] [PubMed] [Google Scholar]
  30. Lindahl T. DNA glycosylases, endonucleases for apurinic/apyrimidinic sites, and base excision-repair. Prog Nucleic Acid Res Mol Biol. 1979;22:135–192. doi: 10.1016/s0079-6603(08)60800-4. [DOI] [PubMed] [Google Scholar]
  31. Lohmann D., Pütz B., Reich U., Böhm J., Präuer H., Höfler H. Mutational spectrum of the p53 gene in human small-cell lung cancer and relationship to clinicopathological data. Am J Pathol. 1993 Mar;142(3):907–915. [PMC free article] [PubMed] [Google Scholar]
  32. Malmström P. U., Busch C., Norlén B. J. Recurrence, progression and survival in bladder cancer. A retrospective analysis of 232 patients with greater than or equal to 5-year follow-up. Scand J Urol Nephrol. 1987;21(3):185–195. doi: 10.3109/00365598709180320. [DOI] [PubMed] [Google Scholar]
  33. Malmström P. U. Prognosis of transitional cell bladder carcinoma. With special reference to ABH blood group isoantigen expression and DNA analysis. Scand J Urol Nephrol Suppl. 1988;112:1–55. [PubMed] [Google Scholar]
  34. Miyamoto H., Kubota Y., Shuin T., Torigoe S., Hosaka M., Iwasaki Y., Danenberg K., Danenberg P. V. Analyses of p53 gene mutations in primary human bladder cancer. Oncol Res. 1993;5(6-7):245–249. [PubMed] [Google Scholar]
  35. Nakai H., Misawa S., Toguchida J., Yandell D. W., Ishizaki K. Frequent p53 gene mutations in blast crisis of chronic myelogenous leukemia, especially in myeloid crisis harboring loss of a chromosome 17p. Cancer Res. 1992 Dec 1;52(23):6588–6593. [PubMed] [Google Scholar]
  36. Prosser J., Condie A. Biallelic ApaI polymorphism of the human p53 gene (TP53). Nucleic Acids Res. 1991 Sep 11;19(17):4799–4799. doi: 10.1093/nar/19.17.4799-a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Raycroft L., Wu H. Y., Lozano G. Transcriptional activation by wild-type but not transforming mutants of the p53 anti-oncogene. Science. 1990 Aug 31;249(4972):1049–1051. doi: 10.1126/science.2144364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Schultz D. C., Vanderveer L., Berman D. B., Hamilton T. C., Wong A. J., Godwin A. K. Identification of two candidate tumor suppressor genes on chromosome 17p13.3. Cancer Res. 1996 May 1;56(9):1997–2002. [PubMed] [Google Scholar]
  39. Sidransky D., Von Eschenbach A., Tsai Y. C., Jones P., Summerhayes I., Marshall F., Paul M., Green P., Hamilton S. R., Frost P. Identification of p53 gene mutations in bladder cancers and urine samples. Science. 1991 May 3;252(5006):706–709. doi: 10.1126/science.2024123. [DOI] [PubMed] [Google Scholar]
  40. Spruck C. H., 3rd, Rideout W. M., 3rd, Olumi A. F., Ohneseit P. F., Yang A. S., Tsai Y. C., Nichols P. W., Horn T., Hermann G. G., Steven K. Distinct pattern of p53 mutations in bladder cancer: relationship to tobacco usage. Cancer Res. 1993 Mar 1;53(5):1162–1166. [PubMed] [Google Scholar]
  41. Steineck G., Wiholm B. E., Gerhardsson de Verdier M. Acetaminophen, some other drugs, some diseases and the risk of transitional cell carcinoma. A population-based case-control study. Acta Oncol. 1995;34(6):741–748. doi: 10.3109/02841869509127181. [DOI] [PubMed] [Google Scholar]
  42. Varley J. M., Evans D. G., Birch J. M. Li-Fraumeni syndrome--a molecular and clinical review. Br J Cancer. 1997;76(1):1–14. doi: 10.1038/bjc.1997.328. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Wada T., Louhelainen J., Hemminki K., Adolfsson J., Wijkström H., Norming U., Borgström E., Hansson J., Sandstedt B., Steineck G. Bladder cancer: allelic deletions at and around the retinoblastoma tumor suppressor gene in relation to stage and grade. Clin Cancer Res. 2000 Feb;6(2):610–615. [PubMed] [Google Scholar]
  44. Wales M. M., Biel M. A., el Deiry W., Nelkin B. D., Issa J. P., Cavenee W. K., Kuerbitz S. J., Baylin S. B. p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3. Nat Med. 1995 Jun;1(6):570–577. doi: 10.1038/nm0695-570. [DOI] [PubMed] [Google Scholar]
  45. Warren W., Biggs P. J., el-Baz M., Ghoneim M. A., Stratton M. R., Venitt S. Mutations in the p53 gene in schistosomal bladder cancer: a study of 92 tumours from Egyptian patients and a comparison between mutational spectra from schistosomal and non-schistosomal urothelial tumours. Carcinogenesis. 1995 May;16(5):1181–1189. doi: 10.1093/carcin/16.5.1181. [DOI] [PubMed] [Google Scholar]
  46. Williamson M. P., Elder P. A., Knowles M. A. The spectrum of TP53 mutations in bladder carcinoma. Genes Chromosomes Cancer. 1994 Feb;9(2):108–118. doi: 10.1002/gcc.2870090206. [DOI] [PubMed] [Google Scholar]
  47. Xu X., Stower M. J., Reid I. N., Garner R. C., Burns P. A. A hot spot for p53 mutation in transitional cell carcinoma of the bladder: clues to the etiology of bladder cancer. Cancer Epidemiol Biomarkers Prev. 1997 Aug;6(8):611–616. [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES