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J. W. Harbour, M. D. Onken, L. A. Worley; Association Between Molecular Class, Proliferative Rate and Metastasis in Uveal Melanoma. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3805.
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Uveal melanomas cluster into two molecular groups based on their gene expression profile (GEP). Tumors with the class 1 signature rarely metastasize, whereas those with the class 2 signature have a very high rate of metastasis. Class 2 tumors are associated with loss of chromosomes 3 and 8p, and increased aneuploidy. However, the biological basis for the metastatic propensity of class 2 tumors remains unclear. Towards such an explanation, this study was conducted to determine whether class 2 tumors are more proliferative than class 1 tumors.
IRB approval was obtained. The study included 28 primary uveal melanomas with long follow-up and extensive clinical, pathologic and genetic annotation. Clinical and pathologic features were recorded, including age, gender, ciliary body involvement, tumor basal diameter, thickness, cell type and final patient status. GEP was performed using a previously described multi-gene assay. Status of chromosomes 3 and 8p were determined using a single nucleotide polymorphism (SNP) assay. Aneuploidy was calculated using global array-based comparative genomic hybridization (aCGH). Immunopositivity for Ki-67 was determined by counting positive nuclei in at least ten high power fields .
Class 2 GEP signature, loss of chromosomes 3 and 8p (Mann-Whitney test, P=0.04, P=0.004 and P=0.02, respectively), and increased aneuploidy (Spearman correlation, P=0.03) were significantly associated with Ki-67 positivity. Tumor thickness (Spearman correlation, P=0.06) and epithelioid cell type (Mann-Whitney test, P=0.07) showed a borderline significant association with Ki-67 positivity. Using Receiver Operating Characteristic (ROC) analysis of Ki-67 positivity, and using class 2 GEP signature as a surrogate endpoint for metastasis, a Ki-67 score of 1.5 cells per high power field was identified as the optimal cutoff to distinguish between patients at low versus high risk for metastasis. Using this dichotomous classification, Ki-67 positivity exhibited a significant association with metastasis (log rank test, P=0.01).
On average, class 2 uveal melanomas have a higher proliferation rate than class 1 tumors. This finding may explain, at least in part, the strong tendency for class 2 tumors to metastasize. Further work is needed to determine whether loss of chromosomes 3 and/or 8p, increased aneuploidy, or other factors may be responsible for the increased proliferation rate.
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