Abstract
BACKGROUND/AIMS—Uveal melanoma is the commonest malignancy of the eye, with a high proportion of patients dying of metastatic disease. Tumours showing a loss of chromosome 3 and gains of chromosome 8 are associated with a worse prognosis. The efficiency of fluorescence in situ hybridisation (FISH) in determining copy numbers of these chromosomes was assessed in individual tumours and related to patient survival. METHODS—33 fresh frozen samples were analysed with centromeric probes for chromosomes 3 and 8. Patient outcomes were divided into two groups: (1) absence of genetic abnormalities (no genetic imbalance) and (2) presence of genetic abnormalities (genetic imbalance). The log rank test was used to compare survival, which was represented by Kaplan-Meier survival curves. RESULTS—Of the 33 tumours analysed, 16 showed evidence of genetic imbalances. Of these 16 tumours, 14 patients had died by the end of the study, with 10 having died of liver metastases. Of the tumours without evidence of genetic imbalances, five patients had died by the end of the study, although none had died as a result of either liver metastases or from the primary uveal melanoma. The difference in survival between the two groups was highly significant (p<0.0001). CONCLUSION—The authors have shown that FISH analysis for chromosome 3 and 8 is a reliable and efficient technique in the analysis of fresh frozen tumour specimens and is valuable in the prediction of prognosis in individuals with uveal melanomas.
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Figure 1 .
Three captured FISH images. (A) A disaggregated uveal melanoma tissue sample with cells showing a normal complement of two target hybridisation signals for each chromosome, thus signifying no genetic imbalance. (B) An image showing cells with monosomy 3 (red target hybridisation signals, rhodamine) and trisomy 8 (green target hybridisation signals, FITC), thus signifying genetic imbalance. (C) Another image also showing genetic imbalance but with a normal complement of two hybridisation signals for chromosome 3 but with four hybridisation signals for chromosome 8.
Figure 2 .
Kaplan-Meier survival curve for deaths due to liver metastases.
Figure 3 .
Kaplan-Meier survival curve for all deaths.
Selected References
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- Ambiru S., Miyazaki M., Isono T., Ito H., Nakagawa K., Shimizu H., Kusashio K., Furuya S., Nakajima N. Hepatic resection for colorectal metastases: analysis of prognostic factors. Dis Colon Rectum. 1999 May;42(5):632–639. doi: 10.1007/BF02234142. [DOI] [PubMed] [Google Scholar]
- Coleman K., Baak J. P., Van Diest P., Mullaney J., Farrell M., Fenton M. Prognostic factors following enucleation of 111 uveal melanomas. Br J Ophthalmol. 1993 Nov;77(11):688–692. doi: 10.1136/bjo.77.11.688. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cree I. A. Cell cycle and melanoma--two different tumours from the same cell type. J Pathol. 2000 Jun;191(2):112–114. doi: 10.1002/(SICI)1096-9896(200006)191:2<112::AID-PATH592>3.0.CO;2-N. [DOI] [PubMed] [Google Scholar]
- Dahlenfors R., Törnqvist G., Wettrell K., Mark J. Cytogenetical observations in nine ocular malignant melanomas. Anticancer Res. 1993 Sep-Oct;13(5A):1415–1420. [PubMed] [Google Scholar]
- Diener-West M., Hawkins B. S., Markowitz J. A., Schachat A. P. A review of mortality from choroidal melanoma. II. A meta-analysis of 5-year mortality rates following enucleation, 1966 through 1988. Arch Ophthalmol. 1992 Feb;110(2):245–250. doi: 10.1001/archopht.1992.01080140101036. [DOI] [PubMed] [Google Scholar]
- Egan K. M., Seddon J. M., Glynn R. J., Gragoudas E. S., Albert D. M. Epidemiologic aspects of uveal melanoma. Surv Ophthalmol. 1988 Jan-Feb;32(4):239–251. doi: 10.1016/0039-6257(88)90173-7. [DOI] [PubMed] [Google Scholar]
- Folberg R., Rummelt V., Parys-Van Ginderdeuren R., Hwang T., Woolson R. F., Pe'er J., Gruman L. M. The prognostic value of tumor blood vessel morphology in primary uveal melanoma. Ophthalmology. 1993 Sep;100(9):1389–1398. doi: 10.1016/s0161-6420(93)31470-3. [DOI] [PubMed] [Google Scholar]
- Harmon K. E., Ryan J. A., Jr, Biehl T. R., Lee F. T. Benefits and safety of hepatic resection for colorectal metastases. Am J Surg. 1999 May;177(5):402–404. doi: 10.1016/s0002-9610(99)00070-7. [DOI] [PubMed] [Google Scholar]
- Horsman D. E., Sroka H., Rootman J., White V. A. Monosomy 3 and isochromosome 8q in a uveal melanoma. Cancer Genet Cytogenet. 1990 Apr;45(2):249–253. doi: 10.1016/0165-4608(90)90090-w. [DOI] [PubMed] [Google Scholar]
- Horsman D. E., White V. A. Cytogenetic analysis of uveal melanoma. Consistent occurrence of monosomy 3 and trisomy 8q. Cancer. 1993 Feb 1;71(3):811–819. doi: 10.1002/1097-0142(19930201)71:3<811::aid-cncr2820710325>3.0.co;2-f. [DOI] [PubMed] [Google Scholar]
- 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]
- Jensen O. A. Malignant melanomas of the human uvea: 25-year follow-up of cases in Denmark, 1943--1952. Acta Ophthalmol (Copenh) 1982 Apr;60(2):161–182. doi: 10.1111/j.1755-3768.1982.tb08371.x. [DOI] [PubMed] [Google Scholar]
- Kallioniemi A, Visakorpi T, Karhu R, Pinkel D, Kallioniemi OP. Gene Copy Number Analysis by Fluorescence in Situ Hybridization and Comparative Genomic Hybridization. Methods. 1996 Feb;9(1):113–121. doi: 10.1006/meth.1996.0015. [DOI] [PubMed] [Google Scholar]
- Kath R., Hayungs J., Bornfeld N., Sauerwein W., Höffken K., Seeber S. Prognosis and treatment of disseminated uveal melanoma. Cancer. 1993 Oct 1;72(7):2219–2223. doi: 10.1002/1097-0142(19931001)72:7<2219::aid-cncr2820720725>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
- Kok K., Naylor S. L., Buys C. H. Deletions of the short arm of chromosome 3 in solid tumors and the search for suppressor genes. Adv Cancer Res. 1997;71:27–92. doi: 10.1016/s0065-230x(08)60096-2. [DOI] [PubMed] [Google Scholar]
- McLean I. W., Foster W. D., Zimmerman L. E. Uveal melanoma: location, size, cell type, and enucleation as risk factors in metastasis. Hum Pathol. 1982 Feb;13(2):123–132. doi: 10.1016/s0046-8177(82)80116-0. [DOI] [PubMed] [Google Scholar]
- McNamara M., Felix C., Davison E. V., Fenton M., Kennedy S. M. Assessment of chromosome 3 copy number in ocular melanoma using fluorescence in situ hybridization. Cancer Genet Cytogenet. 1997 Oct 1;98(1):4–8. doi: 10.1016/s0165-4608(96)00405-0. [DOI] [PubMed] [Google Scholar]
- Prescher G., Bornfeld N., Becher R. Nonrandom chromosomal abnormalities in primary uveal melanoma. J Natl Cancer Inst. 1990 Nov 21;82(22):1765–1769. doi: 10.1093/jnci/82.22.1765. [DOI] [PubMed] [Google Scholar]
- 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]
- Prescher G., Bornfeld N., Horsthemke B., Becher R. Chromosomal aberrations defining uveal melanoma of poor prognosis. Lancet. 1992 Mar 14;339(8794):691–692. [PubMed] [Google Scholar]
- Pyrhönen S. The treatment of metastatic uveal melanoma. Eur J Cancer. 1998 Jul;34 (Suppl 3):S27–S30. doi: 10.1016/s0959-8049(97)10161-7. [DOI] [PubMed] [Google Scholar]
- Salmon R. J., Levy C., Plancher C., Dorval T., Desjardins L., Leyvraz S., Pouillart P., Schlienger P., Servois V., Asselain B. Treatment of liver metastases from uveal melanoma by combined surgery-chemotherapy. Eur J Surg Oncol. 1998 Apr;24(2):127–130. doi: 10.1016/s0748-7983(98)91485-8. [DOI] [PubMed] [Google Scholar]
- Scotto J., Fraumeni J. F., Jr, Lee J. A. Melanomas of the eye and other noncutaneous sites: epidemiologic aspects. J Natl Cancer Inst. 1976 Mar;56(3):489–491. doi: 10.1093/jnci/56.3.489. [DOI] [PubMed] [Google Scholar]
- Singh A. D., Boghosian-Sell L., Wary K. K., Shields C. L., De Potter P., Donoso L. A., Shields J. A., Cannizzaro L. A. Cytogenetic findings in primary uveal melanoma. Cancer Genet Cytogenet. 1994 Feb;72(2):109–115. doi: 10.1016/0165-4608(94)90125-2. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Sisley K., Rennie I. G., Cottam D. W., Potter A. M., Potter C. W., Rees R. C. Cytogenetic findings in six posterior uveal melanomas: involvement of chromosomes 3, 6, and 8. Genes Chromosomes Cancer. 1990 Sep;2(3):205–209. doi: 10.1002/gcc.2870020307. [DOI] [PubMed] [Google Scholar]
- 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]
- White V. A., Chambers J. D., Courtright P. D., Chang W. Y., Horsman D. E. Correlation of cytogenetic abnormalities with the outcome of patients with uveal melanoma. Cancer. 1998 Jul 15;83(2):354–359. [PubMed] [Google Scholar]
- Wiltshire R. N., Elner V. M., Dennis T., Vine A. K., Trent J. M. Cytogenetic analysis of posterior uveal melanoma. Cancer Genet Cytogenet. 1993 Mar;66(1):47–53. doi: 10.1016/0165-4608(93)90148-f. [DOI] [PubMed] [Google Scholar]
- Wöll E., Bedikian A., Legha S. S. Uveal melanoma: natural history and treatment options for metastatic disease. Melanoma Res. 1999 Dec;9(6):575–581. [PubMed] [Google Scholar]