Skip to main content
NCBI home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1995 Oct;147(4):1112–1122.

Intratumor Cellular Heterogeneity and Alterations in ras Oncogene and p53 Tumor Suppressor Gene in Human Prostate Carcinoma

Noboru Konishi, Yoshio Hiasa, Hirofumi Matsuda, Ming Tao, Toshihide Tsuzuki, Isao Hayashi, Yoshiteru Kitahori, Taizo Shiraishi, Ryuichi Yatani, Jun Shimazaki, Jung-Chung Lin
PMCID: PMC1871010  PMID: 7573356

Abstract

To assess the potential role of ras oncogene activation and P53 tumor suppressor gene mutations in the development of human prostate carcinoma, nine cases of histologically heterogeneous prostate tumors obtained from total prostatectomies were probed for these specific events. Each tumor was divided into 5 to 10 areas according to different growth or histological patterns. Targeted DNA sequences coding for ras and p53 were amplified by the polymerase chain reaction, analyzed by single-strand conformational polymorphisms, and confirmed by direct DNA sequencing. Point mutations of the ras gene were found in three of the nine tumors. Two contained K-ras codon 13 and H-ras codon 61 mutations, found in only one and three areas of each lesion, respectively. The third tumor contained two different point mutations in K-ras codons 13 and 61 in different foci of the sample. Loss of heterozygosity at the polymorphic codon 72 in the p53 gene was detected in two of four informative cases (50%) showing fragment cleavage by restriction fragment length polymorphism analysis. Mutations in p53, missense transversions, single base insertions, and two base deletions were also detected in three tumors. The present results reveal mutated ras and p53 occasionally occurring in small foci of the tumor and that genetic mutations in p53, as opposed to those in ras, are more closely associated with invasive growth of heterogeneous prostate carcinoma.

Full text

PDF
1112

Images in this article

1115Figure 1
on p.1115
1117Figure 2
on p.1117
1117Figure 3
on p.1117
1118Figure 4
on p.1118
1119Figure 5
on p.1119

Selected References

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

  1. Anwar K., Nakakuki K., Shiraishi T., Naiki H., Yatani R., Inuzuka M. Presence of ras oncogene mutations and human papillomavirus DNA in human prostate carcinomas. Cancer Res. 1992 Nov 1;52(21):5991–5996. [PubMed] [Google Scholar]
  2. Ara S., Lee P. S., Hansen M. F., Saya H. Codon 72 polymorphism of the TP53 gene. Nucleic Acids Res. 1990 Aug 25;18(16):4961–4961. doi: 10.1093/nar/18.16.4961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bastacky S. I., Wojno K. J., Walsh P. C., Carmichael M. J., Epstein J. I. Pathological features of hereditary prostate cancer. J Urol. 1995 Mar;153(3 Pt 2):987–992. [PubMed] [Google Scholar]
  4. Battifora H. p53 immunohistochemistry: a word of caution. Hum Pathol. 1994 May;25(5):435–437. doi: 10.1016/0046-8177(94)90113-9. [DOI] [PubMed] [Google Scholar]
  5. Bookstein R., MacGrogan D., Hilsenbeck S. G., Sharkey F., Allred D. C. p53 is mutated in a subset of advanced-stage prostate cancers. Cancer Res. 1993 Jul 15;53(14):3369–3373. [PubMed] [Google Scholar]
  6. Brawn P. N., Ayala A. G., Von Eschenbach A. C., Hussey D. H., Johnson D. E. Histologic grading study of prostate adenocarcinoma: the development of a new system and comparison with other methods--a preliminary study. Cancer. 1982 Feb 1;49(3):525–532. doi: 10.1002/1097-0142(19820201)49:3<525::aid-cncr2820490321>3.0.co;2-m. [DOI] [PubMed] [Google Scholar]
  7. Brooks B., Miller G. J. Evaluation of prostatic cancer histology and grade distribution: experience with the Colorado Central Cancer Registry. Prostate. 1986;8(2):139–150. doi: 10.1002/pros.2990080205. [DOI] [PubMed] [Google Scholar]
  8. Carroll A. G., Voeller H. J., Sugars L., Gelmann E. P. p53 oncogene mutations in three human prostate cancer cell lines. Prostate. 1993;23(2):123–134. doi: 10.1002/pros.2990230206. [DOI] [PubMed] [Google Scholar]
  9. Carter B. S., Epstein J. I., Isaacs W. B. ras gene mutations in human prostate cancer. Cancer Res. 1990 Nov 1;50(21):6830–6832. [PubMed] [Google Scholar]
  10. Carter B. S., Ewing C. M., Ward W. S., Treiger B. F., Aalders T. W., Schalken J. A., Epstein J. I., Isaacs W. B. Allelic loss of chromosomes 16q and 10q in human prostate cancer. Proc Natl Acad Sci U S A. 1990 Nov;87(22):8751–8755. doi: 10.1073/pnas.87.22.8751. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dinjens W. N., van der Weiden M. M., Schroeder F. H., Bosman F. T., Trapman J. Frequency and characterization of p53 mutations in primary and metastatic human prostate cancer. Int J Cancer. 1994 Mar 1;56(5):630–633. doi: 10.1002/ijc.2910560504. [DOI] [PubMed] [Google Scholar]
  12. Effert P. J., McCoy R. H., Walther P. J., Liu E. T. p53 gene alterations in human prostate carcinoma. J Urol. 1993 Jul;150(1):257–261. doi: 10.1016/s0022-5347(17)35458-7. [DOI] [PubMed] [Google Scholar]
  13. Enomoto T., Fujita M., Inoue M., Rice J. M., Nakajima R., Tanizawa O., Nomura T. Alterations of the p53 tumor suppressor gene and its association with activation of the c-K-ras-2 protooncogene in premalignant and malignant lesions of the human uterine endometrium. Cancer Res. 1993 Apr 15;53(8):1883–1888. [PubMed] [Google Scholar]
  14. Fearon E. R., Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990 Jun 1;61(5):759–767. doi: 10.1016/0092-8674(90)90186-i. [DOI] [PubMed] [Google Scholar]
  15. Gaeta J. F., Asirwatham J. E., Miller G., Murphy G. P. Histologic grading of primary prostatic cancer: a new approach to an old problem. J Urol. 1980 May;123(5):689–693. doi: 10.1016/s0022-5347(17)56093-0. [DOI] [PubMed] [Google Scholar]
  16. Gleason D. F. Classification of prostatic carcinomas. Cancer Chemother Rep. 1966 Mar;50(3):125–128. [PubMed] [Google Scholar]
  17. Gleason D. F., Mellinger G. T. Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J Urol. 1974 Jan;111(1):58–64. doi: 10.1016/s0022-5347(17)59889-4. [DOI] [PubMed] [Google Scholar]
  18. Gumerlock P. H., Poonamallee U. R., Meyers F. J., deVere White R. W. Activated ras alleles in human carcinoma of the prostate are rare. Cancer Res. 1991 Mar 15;51(6):1632–1637. [PubMed] [Google Scholar]
  19. Harris C. C. Chemical and physical carcinogenesis: advances and perspectives for the 1990s. Cancer Res. 1991 Sep 15;51(18 Suppl):5023s–5044s. [PubMed] [Google Scholar]
  20. Hollingsworth R. E., Lee W. H. Tumor suppressor genes: new prospects for cancer research. J Natl Cancer Inst. 1991 Jan 16;83(2):91–96. doi: 10.1093/jnci/83.2.91. [DOI] [PubMed] [Google Scholar]
  21. Konishi N., Enomoto T., Buzard G., Ohshima M., Ward J. M., Rice J. M. K-ras activation and ras p21 expression in latent prostatic carcinoma in Japanese men. Cancer. 1992 May 1;69(9):2293–2299. doi: 10.1002/1097-0142(19920501)69:9<2293::aid-cncr2820690915>3.0.co;2-o. [DOI] [PubMed] [Google Scholar]
  22. Konishi N., Hiasa Y., Hayashi I., Matsuda H., Tsuzuki T., Ming T., Kitahori Y., Shiraishi T., Yatani R., Shimazaki J. p53 mutations occur in clinical, but not latent, human prostate carcinoma. Jpn J Cancer Res. 1995 Jan;86(1):57–63. doi: 10.1111/j.1349-7006.1995.tb02988.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Konishi N., Nakaoka S., Tsuzuki T., Kitahori Y., Nishii K., Kitamura M., Ohshima M., Hiasa Y. Progressive activity in latent prostate carcinoma defined by argyrophilic staining of the nucleolar organizer regions (AgNOR). Pathol Int. 1994 Apr;44(4):297–302. doi: 10.1111/j.1440-1827.1994.tb03367.x. [DOI] [PubMed] [Google Scholar]
  24. Lehman T. A., Bennett W. P., Metcalf R. A., Welsh J. A., Ecker J., Modali R. V., Ullrich S., Romano J. W., Appella E., Testa J. R. p53 mutations, ras mutations, and p53-heat shock 70 protein complexes in human lung carcinoma cell lines. Cancer Res. 1991 Aug 1;51(15):4090–4096. [PubMed] [Google Scholar]
  25. Levine A. J., Momand J., Finlay C. A. The p53 tumour suppressor gene. Nature. 1991 Jun 6;351(6326):453–456. doi: 10.1038/351453a0. [DOI] [PubMed] [Google Scholar]
  26. Matlashewski G. J., Tuck S., Pim D., Lamb P., Schneider J., Crawford L. V. Primary structure polymorphism at amino acid residue 72 of human p53. Mol Cell Biol. 1987 Feb;7(2):961–963. doi: 10.1128/mcb.7.2.961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Merlo G. R., Cropp C. S., Callahan R., Takahashi T. Detection of loss of heterozygosity in tumor DNA samples by PCR. Biotechniques. 1991 Aug;11(2):166-8, 170-1. [PubMed] [Google Scholar]
  28. Miller G. J., Cygan J. M. Morphology of prostate cancer: the effects of multifocality on histological grade, tumor volume and capsule penetration. J Urol. 1994 Nov;152(5 Pt 2):1709–1713. doi: 10.1016/s0022-5347(17)32368-6. [DOI] [PubMed] [Google Scholar]
  29. Mitsudomi T., Steinberg S. M., Nau M. M., Carbone D., D'Amico D., Bodner S., Oie H. K., Linnoila R. I., Mulshine J. L., Minna J. D. p53 gene mutations in non-small-cell lung cancer cell lines and their correlation with the presence of ras mutations and clinical features. Oncogene. 1992 Jan;7(1):171–180. [PubMed] [Google Scholar]
  30. Mostofi F. K. Grading of prostatic carcinoma. Cancer Chemother Rep. 1975 Jan-Feb;59(1):111–117. [PubMed] [Google Scholar]
  31. Navone N. M., Troncoso P., Pisters L. L., Goodrow T. L., Palmer J. L., Nichols W. W., von Eschenbach A. C., Conti C. J. p53 protein accumulation and gene mutation in the progression of human prostate carcinoma. J Natl Cancer Inst. 1993 Oct 20;85(20):1657–1669. doi: 10.1093/jnci/85.20.1657. [DOI] [PubMed] [Google Scholar]
  32. Nigro J. M., Baker S. J., Preisinger A. C., Jessup J. M., Hostetter R., Cleary K., Bigner S. H., Davidson N., Baylin S., Devilee P. Mutations in the p53 gene occur in diverse human tumour types. Nature. 1989 Dec 7;342(6250):705–708. doi: 10.1038/342705a0. [DOI] [PubMed] [Google Scholar]
  33. Orita M., Iwahana H., Kanazawa H., Hayashi K., Sekiya T. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2766–2770. doi: 10.1073/pnas.86.8.2766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Parda D. S., Thraves P. J., Kuettel M. R., Lee M. S., Arnstein P., Kaighn M. E., Rhim J. S., Dritschilo A. Neoplastic transformation of a human prostate epithelial cell line by the v-Ki-ras oncogene. Prostate. 1993;23(2):91–98. doi: 10.1002/pros.2990230202. [DOI] [PubMed] [Google Scholar]
  35. Peehl D. M. Oncogenes in prostate cancer. An update. Cancer. 1993 Feb 1;71(3 Suppl):1159–1164. doi: 10.1002/1097-0142(19930201)71:3+<1159::aid-cncr2820711439>3.0.co;2-u. [DOI] [PubMed] [Google Scholar]
  36. Peehl D. M., Wehner N., Stamey T. A. Activated Ki-ras oncogene in human prostatic adenocarcinoma. Prostate. 1987;10(4):281–289. doi: 10.1002/pros.2990100402. [DOI] [PubMed] [Google Scholar]
  37. Pergolizzi R. G., Kreis W., Rottach C., Susin M., Broome J. D. Mutational status of codons 12 and 13 of the N- and K-ras genes in tissue and cell lines derived from primary and metastatic prostate carcinomas. Cancer Invest. 1993;11(1):25–32. doi: 10.3109/07357909309020257. [DOI] [PubMed] [Google Scholar]
  38. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Studzinsky G. P., Moore D. C., Carter D. L. "Suppressor genes; restraint of growth or of tumor progression"? Lab Invest. 1990 Sep;63(3):279–282. [PubMed] [Google Scholar]
  40. Suzuki H., Aida S., Akimoto S., Igarashi T., Yatani R., Shimazaki J. State of adenomatous polyposis coli gene and ras oncogenes in Japanese prostate cancer. Jpn J Cancer Res. 1994 Aug;85(8):847–852. doi: 10.1111/j.1349-7006.1994.tb02957.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Suzuki Y., Orita M., Shiraishi M., Hayashi K., Sekiya T. Detection of ras gene mutations in human lung cancers by single-strand conformation polymorphism analysis of polymerase chain reaction products. Oncogene. 1990 Jul;5(7):1037–1043. [PubMed] [Google Scholar]
  42. Thompson A. M., Anderson T. J., Condie A., Prosser J., Chetty U., Carter D. C., Evans H. J., Steel C. M. p53 allele losses, mutations and expression in breast cancer and their relationship to clinico-pathological parameters. Int J Cancer. 1992 Feb 20;50(4):528–532. doi: 10.1002/ijc.2910500405. [DOI] [PubMed] [Google Scholar]
  43. Uchida T., Wada C., Shitara T., Egawa S., Koshiba K. Infrequent involvement of p53 gene mutations in the tumourigenesis of Japanese prostate cancer. Br J Cancer. 1993 Oct;68(4):751–755. doi: 10.1038/bjc.1993.423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Van Veldhuizen P. J., Sadasivan R., Garcia F., Austenfeld M. S., Stephens R. L. Mutant p53 expression in prostate carcinoma. Prostate. 1993;22(1):23–30. doi: 10.1002/pros.2990220104. [DOI] [PubMed] [Google Scholar]
  45. Voeller H. J., Sugars L. Y., Pretlow T., Gelmann E. P. p53 oncogene mutations in human prostate cancer specimens. J Urol. 1994 Feb;151(2):492–495. doi: 10.1016/s0022-5347(17)35000-0. [DOI] [PubMed] [Google Scholar]
  46. Vähäkangas K. H., Samet J. M., Metcalf R. A., Welsh J. A., Bennett W. P., Lane D. P., Harris C. C. Mutations of p53 and ras genes in radon-associated lung cancer from uranium miners. Lancet. 1992 Mar 7;339(8793):576–580. doi: 10.1016/0140-6736(92)90866-2. [DOI] [PubMed] [Google Scholar]
  47. Weinberg R. A. Tumor suppressor genes. Science. 1991 Nov 22;254(5035):1138–1146. doi: 10.1126/science.1659741. [DOI] [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES