Abstract
Purpose :
The recent discovery of polycomb mutations in metastasizing uveal melanomas suggest that epigenetic regulation of tumor suppressor genes may play a significant role in tumor progression and metastasis. We have used an integrated approach to characterize the epigenetic changes underlying the shift in uveal melanomas to the metastasizing, class 2 phenotype.
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Methods :
We used human global methylation and promoter tiling arrays to assay methylated fractions of genomic DNA from Class 1 and Class 2 primary uveal melanoma tumors, and compared the results to gene expression profiles of the same tumors.
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Results :
Using global analyses we identified highly significant hypermethylation on chromosome 3 that correlated strongly with down-regulation of gene expression and centered at several loci, including 3p21 where BAP1 is located. Gene set analysis of the genes with decreased gene expression and hypermethylation identified axon guidance and melanogenesis as key dysregulated pathways, with several of the key genes located in hypermethylated loci on chromosome 3. Further, a novel hypermethylated site was found on BAP1 in all Class 2 tumors assessed, independent of BAP1 mutation status, suggesting that BAP1 is epigenetically regulated in Class 2 tumors. Blinded validation of hypermethylated probes sites successfully identified Class 1 and Class 2 tumors in 100% of cases. Similar to the actual UM tumors, pathway analysis of global methylation in BAP1KO UM cell lines showed enrichment for axon guidance and developmental pathways.
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Conclusions :
Therefore, our analysis suggests that the epigenetic phenotype associated with the Class 2, metastasizing UMs shows high regional specificity for chromosome 3 and appears to target guidance cue and melanogenesis genes that may be important regulators of tumor cell migration and differentiation.
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This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.