Objective  To determine features that are predictive of growth of choroidal nevi into melanoma.

Methods  This was a retrospective medical record review of 2514 consecutive eyes; Kaplan-Meier estimates and Cox regression analyses were used.

Results  The median tumor basal diameter was 5.0 mm and thickness was 1.5 mm. Nevus growth into melanoma occurred in 2%, 9%, and 13% of eyes at 1, 5, and 10 years, respectively. Factors predictive of growth into melanoma by multivariable analysis included tumor thickness greater than 2 mm (P < .001), subretinal fluid (P = .002), symptoms (P = .002), orange pigment (P < .001), tumor margin within 3 mm of the optic disc (P = .001), ultrasonographic hollowness (P < .001), and halo absence (P = .009). A mnemonic device to recall risk factors of ocular melanoma is "To find small ocular melanoma using helpful hints," representing thickness, fluid, symptoms, orange pigment, margin, ultrasonographic hollowness, and halo absence. The median hazard ratio for those with 1 to 2 risk factors was 3; for 3 or 4 factors, 5; for 5 to 6 factors, 9; and for all 7 factors, 21.

Conclusions  In an analysis of 2514 choroidal nevi, factors predictive of growth into melanoma included greater thickness, subretinal fluid, symptoms, orange pigment, margin near disc, and 2 new features: ultrasonographic hollowness and absence of halo.

Objective  To determine the rate of metastasis of uveal melanoma on the basis of tumor thickness in millimeters.

Methods  Retrospective medical record review.

Results  The mean (median) patient age was 58 (59) years. A total of 8033 eyes were examined. Of the 285 eyes with iris melanoma, the mean tumor thickness was 2.7 mm and metastasis occurred in 0.5%, 4%, and 7% at 3, 5, and 10 years, respectively. Of the 492 eyes with ciliary body melanoma, the mean tumor thickness was 6.6 mm and metastasis occurred in 12%, 19%, and 33% at 3, 5, and 10 years, respectively. Of the 7256 eyes with choroidal melanoma, the mean tumor thickness was 5.5 mm and metastasis occurred in 8%, 15%, and 25% at 3, 5, and 10 years, respectively. For all uveal melanoma, metastasis at 5, 10, and 20 years was 6%, 12%, and 20% for small melanoma (0-3.0 mm thickness), 14%, 26%, and 37% for medium melanoma (3.1-8.0 mm), and 35%, 49%, and 67% for large melanoma (>8.0 mm). More specifically, metastasis per millimeter increment at 10 years was 6% (0-1.0 mm thickness), 12% (1.1-2.0 mm), 12% (2.1-3.0 mm), 16% (3.1-4.0 mm), 27% (4.1-5.0 mm), 28% (5.1-6.0 mm), 29% (6.1-7.0 mm), 41% (7.1-8.0 mm), 50% (8.1-9.0 mm), 44% (9.1-10.0 mm), and 51% (>10.0 mm). Clinical factors predictive of metastasis by multivariate analysis included increasing patient age, ciliary body location, increasing tumor diameter, increasing tumor thickness, having a brown tumor, and the presence of subretinal fluid, intraocular hemorrhage, or extraocular extension.

Conclusion  Increasing millimeter thickness of uveal melanoma is associated with increasing risk for metastasis.

MicroRNAs (miRNAs) are a class of small non-coding RNAs that, in general, negatively regulate gene expression. They have been identified in various tumor types, showing that different sets of miRNAs are usually deregulated in different cancers. Some miRNA genes harboring CpG islands undergo methylation-mediated silencing, a characteristic of many tumor suppressor genes. To identify such miRNAs in hepatocellular carcinoma (HCC), we first examined the methylation status of 43 loci containing CpG islands around 39 mature miRNA genes in a panel of HCC cell lines and non-cancerous liver tissues as controls. Among 11 miRNA genes frequently methylated in HCC cell lines but not in non-cancerous liver tissues, three miRNA genes, i.e. miR-124, miR-203 and miR-375, were selected as silenced miRNAs through CpG-island methylation by comparing methylation and expression status and evaluating restored expression after treatment with 5-aza-2'-deoxycytidine. In primary tumors of HCC with paired non-tumorous liver tissues, only miR-124 and miR-203 showed frequent tumor-specific methylation, and their expression status was inversely correlated with methylation status. Ectopic expression of miR-124 or miR-203 in HCC cells lacking their expression inhibited cell growth, with direct downregulation of possible targets, cyclin-dependent kinase 6 (CDK6), vimentin (VIM), SET and MYND domain containing 3 (SMYD3) and IQ motif containing GTPase activating protein 1 (IQGAP1) or ATP-binding cassette, subfamily E, member 1 (ABCE1), respectively. Our results suggest that miR-124 and miR-203 are novel tumor-suppressive miRNAs for HCC epigenetically silenced and activating multiple targets during hepatocarcinogenesis.

DNA topoisomerase II (TopoII) is an essential chromosome-associated enzyme with activity implicated in the resolution of tangled DNA at centromeres before anaphase onset. However, the regulatory mechanism of TopoII activity is not understood. Here, we show that PIASy-mediated small ubiquitin-like modifier 2/3 (SUMO2/3) modification of TopoII strongly inhibits TopoII decatenation activity. Using mass spectrometry and biochemical analysis, we demonstrate that TopoII is SUMOylated at lysine 660 (Lys660), a residue located in the DNA gate domain, where both DNA cleavage and religation take place. Remarkably, loss of SUMOylation on Lys660 eliminates SUMOylation-dependent inhibition of TopoII, which indicates that Lys660 SUMOylation is critical for PIASy-mediated inhibition of TopoII activity. Together, our findings provide evidence for the regulation of TopoII activity on mitotic chromosomes by SUMOylation. Therefore, we propose a novel mechanism for regulation of centromeric DNA catenation during mitosis by PIASy-mediated SUMOylation of TopoII.