Uveal melanoma : cytogenetics, molecular biology and tumor immunology

Uveal melanoma is the most common primary intraocular malignancy. The metastatic spread is hematogenous and exclusively to the liver. Although eye-sparing treatments are used more frequently the tumor-related mortality in uveal melanoma is still 30-50%. Only 2% of the patients have detectable metastases at the time of diagnosis. The aim of this study was to test various prognostic markers and possibly new treatment modalities.

Chromosomal aberrations were studied on 35 paraffin-embedded tumor specimens with comparative genomic hybridization (CGH) technique. 29 out of 35 tumors showed copy number changes. The most common losses were on chromosome 3, 6q, and 1p and the most common gains on chromosome 8q, 6p and 1q. The mean number of DNA copy number changes was significantly higher in the metastasizing tumors and metastases.

The expression of human leukocyte antigen (HLA) class 1, beta-2-microglobulin and HLA class 11 were studied with inummohistochemistry (IHC) on 65 tumor samples. In all three groups high expression was correlated to an adverse clinical outcome.

The insulin-like growth factor- I receptor (IGF-1R) has been implicated as an important factor for tumor progression in several different tumors. We could show by both IHC and Western blotting (WB) that IGF-1R is expressed in uveal melanoma. Furthermore we were able to induce cell growth arrest and cell death by using tunicamycin and lovastatin, which inhibit the N-linked glycosylation, and alphaIR-3 which blocks the binding domain of IGF-1R.

Previous studies have indicated that the proto-oncogene c-kit is important in tumor progression. We found when using IHC that 84 out of 134 (64%) tumors expressed c-kit. This result could be confirmed by WB where 6 out of 8 samples expressed c-kit. To study the antiproliferative effects of the tyrosine kinase inhibitor ST1571 we treated four uveal melanoma and two skin melanoma cell lines. Cell proliferation was completely inhibited after 48h by 0. 1 - I muM ST1571 in the uveal melanoma cell lines but not in the skin melanoma cell lines.

In conclusion, this study suggests that chromosomal aberrations on chromosome 1, 3, 6 and 8, and expression of HLA may be used as prognostic markers and that the IGF-1R and c-kit may in the future be used as therapeutic targets.

List of scientific papers

I. Aalto Y, Eriksson L, Seregard S, Larsson O, Knuutila S (2001). "Concomitant loss of chromosome 3 and whole arm losses and gains of chromosome 1, 6, or 8 in metastasizing primary uveal melanoma. " Invest Ophthalmol Vis Sci 42(2): 313-7
https://pubmed.ncbi.nlm.nih.gov/11157859

II. Ericsson C, Seregard S, Bartolazzi A, Levitskaya E, Ferrone S, Kiessling R, Larsson O (2001). "Association of HLA class I and class II antigen expression and mortality in uveal melanoma. " Invest Ophthalmol Vis Sci 42(10): 2153-6
https://pubmed.ncbi.nlm.nih.gov/11527924

III. All-Ericsson C, Girnita L, Seregard S, Bartolazzi A, Jager MJ, Larsson O (2002). "Insulin-like growth factor-1 receptor in uveal melanoma: a predictor for metastatic disease and a potential therapeutic target. " Invest Ophthalmol Vis Sci 43(1): 1-8
https://pubmed.ncbi.nlm.nih.gov/11773005

IV. All-Ericsson C, Girnita L, Brodin B, Seregard S, Ostman A, Larsson O (2002). "Inhibition of proto-oncogene c-kit; a potential therapeutic target in metastasizing uveal melanoma." (Manuscript)