PURPOSE. To investigate the relation between patient survival and incrementally increasing percentages of fluorescence in situ hybridization-determined complete loss of chromosome 3 (monosomy 3) and gain of chromosome 8q in primary uveal melanoma cells.METHODS. Clinicopathological factors were related to diseasefree survival. Fluorescence in situ hybridization was performed using probes on chromosomes 1, 3, 6, and 8. The percentages of UM cells with monosomy 3 or chromosome 8q gain were classified in groups with incrementally increasing percentages and related to disease-free survival. Correlations between clinical factors and cytogenetic aberrations were also analyzed.RESULTS. Two-hundred twenty choroidal and ciliary body melanomas were analyzed. The following proved to be significant predictors of survival in univariate analysis: older patient age (P ¼ 0.003); large tumor diameter (P < 0.001); mixed cell type (P ¼ 0.001); presence of closed microvascular loops (P < 0.001); loss of chromosome 1p (P ¼ 0.006); monosomy 3 (P < 0.001); gain of 6p (P < 0.001); and gain of chromosome 8q (P < 0.001). Multivariate Cox analysis displayed monosomy 3 (Hazard ratio [HR] 2.83, P ¼ 0.002) and gain of chromosome 8q (HR 3.13, P ¼ 0.002) as the most important independent prognostic factors of poor survival, followed by older patient age (HR 1.02, P ¼ 0.017). Increasing percentages of monosomy 3 and gain of chromosome 8q in tumor cells showed a correlation with worse prognosis (Logrank test 49.9 and 40.4, both P < 0.001) and increased number of additional copies of 8q correlated with shorter disease-free interval (Log-rank test 45.7, P < 0.001). CONCLUSIONS.A high percentage monosomy 3 and chromosome 8q gain in primary UM cells showed a strong relation with poor disease-free survival compared with low percentage aberrations. (Invest Ophthalmol Vis Sci.

Cutaneous melanoma and uveal melanoma both derive from melanocytes but show remarkable differences in tumorigenesis, mode of metastatic spread, genetic alterations, and therapeutic response. In this review we discuss the differences and similarities along with the genetic research techniques available and the contribution to our current understanding of melanoma. The several chromosomal aberrations already identified prove to be very strong predictors of decreased survival in CM and UM patients. Especially in UM, where the overall risk of metastasis is high (45%), genetic research might aid clinicians in selecting high-risk patients for future systemic adjuvant therapies.

In uveal melanoma, loss of chromosome 3 and gain of chromosome 8q are associated with a high risk of metastasis. In this study, we validated the use of multiplex ligation-dependent probe amplification (MLPA) in detecting patients at risk for metastatic disease in comparison with the predictive power of fluorescence in-situ hybridization (FISH). For 64 uveal melanoma samples, the MLPA results of chromosome 3 and 8 were compared with the results obtained by FISH. For seven samples, a single nucleotide polymorphism array was performed to clarify discrepancies. Clinical information together with the histopathology and chromosomal aberrations of chromosomes 1, 3, 6, and 8 were evaluated for correlation with the patients' prognosis. Loss of chromosome 3, loss or gain of 8p, and gain of 8q, found with MLPA, correlated with a significantly lower disease-free survival (P<0.001). On the basis of the clinical outcome, 12 patients would have been classified incorrectly using MLPA results of chromosomes 3 and 8. FISH results led to the same incorrect classification. Four patients with abnormalities of chromosomes 3 and 8 in the tumor, detected with MLPA, are still alive without metastasis. Eight patients without concurrent aberrations of chromosomes 3 and 8 in the tumors died due to metastasis. The sensitivity of MLPA to detect patients at risk for metastatic disease is higher than with the results obtained with FISH (0.795 vs. 0.692). The specificity is equal for both techniques (0.840). MLPA is able to detect patients at risk for metastasis using the results for chromosomes 3 and 8. There is no significant difference in the predictive power of MLPA compared with FISH.

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