July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Class 2 metastasizing uveal melanomas arise through BAP1 loss and epigenetic reprogramming to a migratory neural crest-like state
Author Affiliations & Notes
  • Matthew Field
    University of Miami, Miami Beach, Florida, United States
  • Parker Bussies
    University of Miami, Miami Beach, Florida, United States
  • Louie Cai
    University of Miami, Miami Beach, Florida, United States
  • Christina Decatur
    University of Miami, Miami Beach, Florida, United States
  • Jeffim Kuznetsov
    University of Miami, Miami Beach, Florida, United States
  • Stefan Kurtenbach
    University of Miami, Miami Beach, Florida, United States
  • J. William Harbour
    University of Miami, Miami Beach, Florida, United States
  • Footnotes
    Commercial Relationships   Matthew Field, None; Parker Bussies, None; Louie Cai, None; Christina Decatur, None; Jeffim Kuznetsov, None; Stefan Kurtenbach, None; J. William Harbour, Castle Biosciences (C)
  • Footnotes
    Support  F30CA206430
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 957. doi:https://doi.org/
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      Matthew Field, Parker Bussies, Louie Cai, Christina Decatur, Jeffim Kuznetsov, Stefan Kurtenbach, J. William Harbour; Class 2 metastasizing uveal melanomas arise through BAP1 loss and epigenetic reprogramming to a migratory neural crest-like state . Invest. Ophthalmol. Vis. Sci. 2019;60(9):957. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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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.

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