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. 1999 Jan;83(1):110–114. doi: 10.1136/bjo.83.1.110

c-myc, p53, and Bcl-2 expression and clinical outcome in uveal melanoma

J Chana 1, G Wilson 1, I Cree 1, R Alexander 1, N Myatt 1, M Neale 1, A Foss 1, J Hungerford 1
PMCID: PMC1722798  PMID: 10209447

Abstract

AIMS—Overexpression of c-myc protein has independent prognostic significance in a variety of primary and metastatic cutaneous melanomas which suggests a possible role for this gene in melanomagenesis. We have therefore examined the importance of this oncogene in uveal melanoma and studied the coexpression of two other gene products, Bcl-2 and p53, which might contribute to its effect.
METHODS—The percentage of cells positive for nuclear c-myc expression was estimated by flow cytometric analysis of nuclei extracted from paraffin blocks. The expression of Bcl-2 and p53 protein was assessed by immunohistochemistry. A total of 71 tumours were studied and the results compared with survival with a mean follow up period of 6 years.
RESULTS—c-myc was expressed in >50% of the cells by 70% of the tumours, and was independently associated with improved survival in a Cox multiple regression model. Although Bcl-2 was expressed by the majority of the cells in 67% tumours, it was without effect on prognosis. None of the cases studied showed convincing positivity for p53. Analysis of coexpression showed that the best survival was seen in c-myc+/Bcl-2+ tumours and the worst in c-myc−/Bcl-2− tumours.
CONCLUSION—The finding of improved rather than reduced survival in c-myc positive tumours is at variance with skin melanoma. There was no evidence to suggest that c-myc was modulated by upregulation of Bcl-2 or p53 inactivation/mutation. Although Bcl-2 is unlikely to have any effect on tumour growth or metastasis, it could contribute to the general lack of susceptibility to apoptosis in these tumours.

 Keywords: uveal melanoma; c-myc; p53; Bcl-2

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Figure 1  .

Figure 1  

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Kaplan-Meier curve for c-myc showing improved survival in the tumours with higher c-myc positivity (n = 71, log rank test, p <0.01). (a) High c-myc, (b) low c-myc.

Figure 2  .

Figure 2  

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Representative examples of Bcl-2 staining in choroidal melanomas. Section (A) was graded +++ and section (B) was graded negative (original magnification ×400).

Figure 3  .

Figure 3  

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Kaplan-Meier graph for Bcl-2 showing no influence on survival (n = 96, log rank test, NS). (a) High Bcl-2, (b) low Bcl-2.

Figure 4  .

Figure 4  

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Kaplan-Meier graph for grouped c-myc and Bcl-2 showing influence on survival (n = 96, log rank test, df=3, NS). (a) c-myc+/Bcl-2+; (b) c-myc+/Bcl-2−; (c) c-myc−/Bcl-2+; (d) c-myc−/Bcl-2−.

Selected References

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

  1. Albert D. M., Niffenegger A. S., Willson J. K. Treatment of metastatic uveal melanoma: review and recommendations. Surv Ophthalmol. 1992 May-Jun;36(6):429–438. doi: 10.1016/s0039-6257(05)80024-4. [DOI] [PubMed] [Google Scholar]
  2. Bedikian A. Y., Legha S. S., Mavligit G., Carrasco C. H., Khorana S., Plager C., Papadopoulos N., Benjamin R. S. Treatment of uveal melanoma metastatic to the liver: a review of the M. D. Anderson Cancer Center experience and prognostic factors. Cancer. 1995 Nov 1;76(9):1665–1670. doi: 10.1002/1097-0142(19951101)76:9<1665::aid-cncr2820760925>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
  3. Cristofolini M., Boi S., Girlando S., Zumiani G., Cristofolini P., Dalla Palma P., Doglioni C., Barbareschi M. p53 Protein expression in nevi and melanomas. Arch Dermatol. 1993 Jun;129(6):739–743. [PubMed] [Google Scholar]
  4. Evan G. I., Littlewood T. D. The role of c-myc in cell growth. Curr Opin Genet Dev. 1993 Feb;3(1):44–49. doi: 10.1016/s0959-437x(05)80339-9. [DOI] [PubMed] [Google Scholar]
  5. Evan G. I., Wyllie A. H., Gilbert C. S., Littlewood T. D., Land H., Brooks M., Waters C. M., Penn L. Z., Hancock D. C. Induction of apoptosis in fibroblasts by c-myc protein. Cell. 1992 Apr 3;69(1):119–128. doi: 10.1016/0092-8674(92)90123-t. [DOI] [PubMed] [Google Scholar]
  6. Field J. K., Spandidos D. A., Stell P. M., Vaughan E. D., Evan G. I., Moore J. P. Elevated expression of the c-myc oncoprotein correlates with poor prognosis in head and neck squamous cell carcinoma. Oncogene. 1989 Dec;4(12):1463–1468. [PubMed] [Google Scholar]
  7. Foss A. J., Alexander R. A., Jefferies L. W., Hungerford J. L., Harris A. L., Lightman S. Microvessel count predicts survival in uveal melanoma. Cancer Res. 1996 Jul 1;56(13):2900–2903. [PubMed] [Google Scholar]
  8. Gordon K. B., Thompson C. T., Char D. H., O'Brien J. M., Kroll S., Ghazvini S., Gray J. W. Comparative genomic hybridization in the detection of DNA copy number abnormalities in uveal melanoma. Cancer Res. 1994 Sep 1;54(17):4764–4768. [PubMed] [Google Scholar]
  9. Grover R., Ross D. A., Wilson G. D., Sanders R. Measurement of c-myc oncoprotein provides an independent prognostic marker for regional metastatic melanoma. Br J Plast Surg. 1997 Oct;50(7):478–482. doi: 10.1016/s0007-1226(97)91295-9. [DOI] [PubMed] [Google Scholar]
  10. Grover R., Wilson G. D. Bcl-2 expression in malignant melanoma and its prognostic significance. Eur J Surg Oncol. 1996 Aug;22(4):347–349. doi: 10.1016/s0748-7983(96)90176-6. [DOI] [PubMed] [Google Scholar]
  11. Horsthemke B., Prescher G., Bornfeld N., Becher R. Loss of chromosome 3 alleles and multiplication of chromosome 8 alleles in uveal melanoma. Genes Chromosomes Cancer. 1992 Apr;4(3):217–221. doi: 10.1002/gcc.2870040305. [DOI] [PubMed] [Google Scholar]
  12. Jay V., Yi Q., Hunter W. S., Zielenska M. Expression of bcl-2 in uveal malignant melanoma. Arch Pathol Lab Med. 1996 May;120(5):497–498. [PubMed] [Google Scholar]
  13. Jay V., Yi Q., Hunter W. S., Zielenska M. p53 expression in uveal malignant melanomas. Pathology. 1996 Nov;28(4):306–308. doi: 10.1080/00313029600169234. [DOI] [PubMed] [Google Scholar]
  14. Kishore K., Ghazvini S., Char D. H., Kroll S., Selle J. p53 gene and cell cycling in uveal melanoma. Am J Ophthalmol. 1996 May;121(5):561–567. doi: 10.1016/s0002-9394(14)75431-5. [DOI] [PubMed] [Google Scholar]
  15. Lassam N. J., From L., Kahn H. J. Overexpression of p53 is a late event in the development of malignant melanoma. Cancer Res. 1993 May 15;53(10 Suppl):2235–2238. [PubMed] [Google Scholar]
  16. Lowe S. W., Schmitt E. M., Smith S. W., Osborne B. A., Jacks T. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature. 1993 Apr 29;362(6423):847–849. doi: 10.1038/362847a0. [DOI] [PubMed] [Google Scholar]
  17. Mooy C. M., Luyten G. P., de Jong P. T., Luider T. M., Stijnen T., van de Ham F., van Vroonhoven C. C., Bosman F. T. Immunohistochemical and prognostic analysis of apoptosis and proliferation in uveal melanoma. Am J Pathol. 1995 Oct;147(4):1097–1104. [PMC free article] [PubMed] [Google Scholar]
  18. Myatt N., Cree I. A., Kurbacher C. M., Foss A. J., Hungerford J. L., Plowman P. N. The ex vivo chemosensitivity profile of choroidal melanoma. Anticancer Drugs. 1997 Sep;8(8):756–762. doi: 10.1097/00001813-199709000-00004. [DOI] [PubMed] [Google Scholar]
  19. Petty R. D., Cree I. A., Sutherland L. A., Hunter E. M., Lane D. P., Preece P. E., Andreotti P. E. Expression of the p53 tumour suppressor gene product is a determinant of chemosensitivity. Biochem Biophys Res Commun. 1994 Feb 28;199(1):264–270. doi: 10.1006/bbrc.1994.1223. [DOI] [PubMed] [Google Scholar]
  20. Prescher G., Bornfeld N., Hirche H., Horsthemke B., Jöckel K. H., Becher R. Prognostic implications of monosomy 3 in uveal melanoma. Lancet. 1996 May 4;347(9010):1222–1225. doi: 10.1016/s0140-6736(96)90736-9. [DOI] [PubMed] [Google Scholar]
  21. Ramsay J. A., From L., Kahn H. J. bcl-2 protein expression in melanocytic neoplasms of the skin. Mod Pathol. 1995 Feb;8(2):150–154. [PubMed] [Google Scholar]
  22. Royds J. A., Sharrard R. M., Parsons M. A., Lawry J., Rees R., Cottam D., Wagner B., Rennie I. G. C-myc oncogene expression in ocular melanomas. Graefes Arch Clin Exp Ophthalmol. 1992;230(4):366–371. doi: 10.1007/BF00165947. [DOI] [PubMed] [Google Scholar]
  23. Singh A. D., Wang M. X., Donoso L. A., Shields C. L., De Potter P., Shields J. A. Genetic aspects of uveal melanoma: a brief review. Semin Oncol. 1996 Dec;23(6):768–772. [PubMed] [Google Scholar]
  24. Sisley K., Cottam D. W., Rennie I. G., Parsons M. A., Potter A. M., Potter C. W., Rees R. C. Non-random abnormalities of chromosomes 3, 6, and 8 associated with posterior uveal melanoma. Genes Chromosomes Cancer. 1992 Oct;5(3):197–200. doi: 10.1002/gcc.2870050304. [DOI] [PubMed] [Google Scholar]
  25. Sisley K., Rennie I. G., Parsons M. A., Jacques R., Hammond D. W., Bell S. M., Potter A. M., Rees R. C. Abnormalities of chromosomes 3 and 8 in posterior uveal melanoma correlate with prognosis. Genes Chromosomes Cancer. 1997 May;19(1):22–28. doi: 10.1002/(sici)1098-2264(199705)19:1<22::aid-gcc4>3.0.co;2-2. [DOI] [PubMed] [Google Scholar]
  26. Speicher M. R., Prescher G., du Manoir S., Jauch A., Horsthemke B., Bornfeld N., Becher R., Cremer T. Chromosomal gains and losses in uveal melanomas detected by comparative genomic hybridization. Cancer Res. 1994 Jul 15;54(14):3817–3823. [PubMed] [Google Scholar]
  27. Tobal K., Warren W., Cooper C. S., McCartney A., Hungerford J., Lightman S. Increased expression and mutation of p53 in choroidal melanoma. Br J Cancer. 1992 Nov;66(5):900–904. doi: 10.1038/bjc.1992.382. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Tron V. A., Krajewski S., Klein-Parker H., Li G., Ho V. C., Reed J. C. Immunohistochemical analysis of Bcl-2 protein regulation in cutaneous melanoma. Am J Pathol. 1995 Mar;146(3):643–650. [PMC free article] [PubMed] [Google Scholar]
  29. Watson J. V., Sikora K., Evan G. I. A simultaneous flow cytometric assay for c-myc oncoprotein and DNA in nuclei from paraffin embedded material. J Immunol Methods. 1985 Oct 24;83(1):179–192. doi: 10.1016/0022-1759(85)90071-7. [DOI] [PubMed] [Google Scholar]
  30. Watson J. V., Stewart J., Evan G. I., Ritson A., Sikora K. The clinical significance of flow cytometric c-myc oncoprotein quantitation in testicular cancer. Br J Cancer. 1986 Mar;53(3):331–337. doi: 10.1038/bjc.1986.56. [DOI] [PMC free article] [PubMed] [Google Scholar]

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