Skip to main content
NCBI home page
Sarcoma logoLink to Sarcoma
. 1997 Mar;1(1):17–22. doi: 10.1080/13577149778434

Amplification and Over-Expression of the MDM2 Gene in Human Soft Tissue Tumours

Helen Patterson 1,✉, Diana Barnes 2, Sandra Gill 1, James Spicer 2, Cyril Fisher 3, Merion Thomas 4, Robert Grimer 5, Chris Fletcher 6, Barry Gusterson 7, Colin Cooper 1
PMCID: PMC2373578  PMID: 18521196

Abstract

Purpose. Amplification of genetic sequences on chromosome 12q13 is frequently found in soft tissue tumours. However, for the MDM2 gene, over-expression of the MDM2 protein has not always been shown to accompany gene amplification, raising the possibility that amplification of genetic sequences targets alternative genes on chromosome 12q13 for over-expression. To investigate this discrepancy, we have examined 129 soft tissue tumours for amplification of the MDM2 gene using Southern analysis, and 39 of these tumours were also examined by immunohistochemical staining for MDM2 over-expression.

Results. Gene amplification was identified in 14/114 (12.3%) of the malignant tumours, but was not identified in any of the benign tumours; 21/39 (54%) of the malignant tumours also demonstrated MDM2 over-expression. Within this group the MDM2 gene was over-expressed in every tumour in which the gene amplification was found, and over-expression in the absence of gene amplification was also found in an additional 10 tumours.

Discussion. These data demonstrate a clear correlation between the presence of MDM2 amplification and MDM2 over-expression, and provide persuasive evidence therefore that the amplification of genetic sequences on chromosome 12q13 in soft tissue sarcomas targets the MDM2 gene for over-expression. These data also indicate that alternative mechanisms may contribute to MDM2 over-expression within some tumours.

Full Text

The Full Text of this article is available as a PDF (244.7 KB).

Selected References

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

  1. Bueso-Ramos C. E., Yang Y., deLeon E., McCown P., Stass S. A., Albitar M. The human MDM-2 oncogene is overexpressed in leukemias. Blood. 1993 Nov 1;82(9):2617–2623. [PubMed] [Google Scholar]
  2. Church G. M., Gilbert W. Genomic sequencing. Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991–1995. doi: 10.1073/pnas.81.7.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cordon-Cardo C., Latres E., Drobnjak M., Oliva M. R., Pollack D., Woodruff J. M., Marechal V., Chen J., Brennan M. F., Levine A. J. Molecular abnormalities of mdm2 and p53 genes in adult soft tissue sarcomas. Cancer Res. 1994 Feb 1;54(3):794–799. [PubMed] [Google Scholar]
  4. Fakharzadeh S. S., Trusko S. P., George D. L. Tumorigenic potential associated with enhanced expression of a gene that is amplified in a mouse tumor cell line. EMBO J. 1991 Jun;10(6):1565–1569. doi: 10.1002/j.1460-2075.1991.tb07676.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  6. Flørenes V. A., Maelandsmo G. M., Forus A., Andreassen A., Myklebost O., Fodstad O. MDM2 gene amplification and transcript levels in human sarcomas: relationship to TP53 gene status. J Natl Cancer Inst. 1994 Sep 7;86(17):1297–1302. doi: 10.1093/jnci/86.17.1297. [DOI] [PubMed] [Google Scholar]
  7. Forus A., Flørenes V. A., Maelandsmo G. M., Meltzer P. S., Fodstad O., Myklebost O. Mapping of amplification units in the q13-14 region of chromosome 12 in human sarcomas: some amplica do not include MDM2. Cell Growth Differ. 1993 Dec;4(12):1065–1070. [PubMed] [Google Scholar]
  8. Garvin A. J., Stanley W. S., Bennett D. D., Sullivan J. L., Sens D. A. The in vitro growth, heterotransplantation, and differentiation of a human rhabdomyosarcoma cell line. Am J Pathol. 1986 Oct;125(1):208–217. [PMC free article] [PubMed] [Google Scholar]
  9. Jankowski S. A., Mitchell D. S., Smith S. H., Trent J. M., Meltzer P. S. SAS, a gene amplified in human sarcomas, encodes a new member of the transmembrane 4 superfamily of proteins. Oncogene. 1994 Apr;9(4):1205–1211. [PubMed] [Google Scholar]
  10. Khatib Z. A., Matsushime H., Valentine M., Shapiro D. N., Sherr C. J., Look A. T. Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. Cancer Res. 1993 Nov 15;53(22):5535–5541. [PubMed] [Google Scholar]
  11. Kinzler K. W., Ruppert J. M., Bigner S. H., Vogelstein B. The GLI gene is a member of the Kruppel family of zinc finger proteins. Nature. 1988 Mar 24;332(6162):371–374. doi: 10.1038/332371a0. [DOI] [PubMed] [Google Scholar]
  12. Ladanyi M., Cha C., Lewis R., Jhanwar S. C., Huvos A. G., Healey J. H. MDM2 gene amplification in metastatic osteosarcoma. Cancer Res. 1993 Jan 1;53(1):16–18. [PubMed] [Google Scholar]
  13. Landers J. E., Haines D. S., Strauss J. F., 3rd, George D. L. Enhanced translation: a novel mechanism of mdm2 oncogene overexpression identified in human tumor cells. Oncogene. 1994 Sep;9(9):2745–2750. [PubMed] [Google Scholar]
  14. Leach F. S., Tokino T., Meltzer P., Burrell M., Oliner J. D., Smith S., Hill D. E., Sidransky D., Kinzler K. W., Vogelstein B. p53 Mutation and MDM2 amplification in human soft tissue sarcomas. Cancer Res. 1993 May 15;53(10 Suppl):2231–2234. [PubMed] [Google Scholar]
  15. 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]
  16. Mandahl N., Heim S., Willén H., Rydholm A., Eneroth M., Nilbert M., Kreicbergs A., Mitelman F. Characteristic karyotypic anomalies identify subtypes of malignant fibrous histiocytoma. Genes Chromosomes Cancer. 1989 Sep;1(1):9–14. doi: 10.1002/gcc.2870010104. [DOI] [PubMed] [Google Scholar]
  17. Martin K., Trouche D., Hagemeier C., Sørensen T. S., La Thangue N. B., Kouzarides T. Stimulation of E2F1/DP1 transcriptional activity by MDM2 oncoprotein. Nature. 1995 Jun 22;375(6533):691–694. doi: 10.1038/375691a0. [DOI] [PubMed] [Google Scholar]
  18. Mertens F., Johansson B., Mandahl N., Heim S., Bennet K., Rydholm A., Willén H., Mitelman F. Clonal chromosome abnormalities in two liposarcomas. Cancer Genet Cytogenet. 1987 Sep;28(1):137–144. doi: 10.1016/0165-4608(87)90363-3. [DOI] [PubMed] [Google Scholar]
  19. Momand J., Zambetti G. P., Olson D. C., George D., Levine A. J. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell. 1992 Jun 26;69(7):1237–1245. doi: 10.1016/0092-8674(92)90644-r. [DOI] [PubMed] [Google Scholar]
  20. Nakayama T., Toguchida J., Wadayama B., Kanoe H., Kotoura Y., Sasaki M. S. MDM2 gene amplification in bone and soft-tissue tumors: association with tumor progression in differentiated adipose-tissue tumors. Int J Cancer. 1995 Oct 20;64(5):342–346. doi: 10.1002/ijc.2910640511. [DOI] [PubMed] [Google Scholar]
  21. Oliner J. D., Kinzler K. W., Meltzer P. S., George D. L., Vogelstein B. Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature. 1992 Jul 2;358(6381):80–83. doi: 10.1038/358080a0. [DOI] [PubMed] [Google Scholar]
  22. Patterson H., Gill S., Fisher C., Law M. G., Jayatilake H., Fletcher C. D., Thomas M., Grimer R., Gusterson B. A., Cooper C. S. Abnormalities of the p53 MDM2 and DCC genes in human leiomyosarcomas. Br J Cancer. 1994 Jun;69(6):1052–1058. doi: 10.1038/bjc.1994.207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Picksley S. M., Vojtesek B., Sparks A., Lane D. P. Immunochemical analysis of the interaction of p53 with MDM2;--fine mapping of the MDM2 binding site on p53 using synthetic peptides. Oncogene. 1994 Sep;9(9):2523–2529. [PubMed] [Google Scholar]
  24. Steffen D., Weinberg R. A. The integrated genome of murine leukemia virus. Cell. 1978 Nov;15(3):1003–1010. doi: 10.1016/0092-8674(78)90284-2. [DOI] [PubMed] [Google Scholar]
  25. Stratton M. R., Moss S., Warren W., Patterson H., Clark J., Fisher C., Fletcher C. D., Ball A., Thomas M., Gusterson B. A. Mutation of the p53 gene in human soft tissue sarcomas: association with abnormalities of the RB1 gene. Oncogene. 1990 Sep;5(9):1297–1301. [PubMed] [Google Scholar]
  26. Wang-Wuu S., Soukup S., Ballard E., Gotwals B., Lampkin B. Chromosomal analysis of sixteen human rhabdomyosarcomas. Cancer Res. 1988 Feb 15;48(4):983–987. [PubMed] [Google Scholar]
  27. Wu X., Bayle J. H., Olson D., Levine A. J. The p53-mdm-2 autoregulatory feedback loop. Genes Dev. 1993 Jul;7(7A):1126–1132. doi: 10.1101/gad.7.7a.1126. [DOI] [PubMed] [Google Scholar]
  28. Xiao Z. X., Chen J., Levine A. J., Modjtahedi N., Xing J., Sellers W. R., Livingston D. M. Interaction between the retinoblastoma protein and the oncoprotein MDM2. Nature. 1995 Jun 22;375(6533):694–698. doi: 10.1038/375694a0. [DOI] [PubMed] [Google Scholar]

Articles from Sarcoma are provided here courtesy of Wiley

RESOURCES