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Multi-omics comparison of malignant and normal uveal melanocytes reveals novel molecular features of uveal melanoma

bioRxiv 2022
Gentien D, et al.

David Gentien, Elnaz Saberi-Ansari, Nicolas Servant, Ariane Jolly, Pierre de la Grange, Fariba Nemati, Geraldine Liot, Simon Saule, Aurélie Teissandier, Deborah Bourchis, Elodie Girard, Jennifer Wong, Julien Masliah Planchon, Manuel Rodrigues, Laure Villoing Gaudé, Cécile Reyes, Emilie Henry, Sylvain Baulande, Radhia M’kacher, Eric Jeandidier, André Nicolas, Didier Decaudin, Nathalie Cassoux, Sophie Piperno-Neumann, Marc-Henri Stern, Johan H. Gibcus, Job Dekker, Edith Heard, Sergio Roman-Roman, Joshua J. Waterfall

Uveal Melanoma (UM) is a rare cancer resulting from the transformation of melanocytes residing in the uveal tract. Integrative analysis has identified four molecular and clinical subsets in UM. To improve our understanding of UM we performed extensive multi-omics characterization comparing pure melanoma populations obtained from two aggressive UM patient-derived xenograft models with normal choroidal melanocytes. Our study addresses for the first time DNA optical mapping, specific histone mark modifications, DNA topology analysis by Hi-C. Gene expression and cytogenetic analyses suggest that genomic instability is a hallmark of UM. Our study also identified a recurrent deletion in the BAP1 promoter which results in the absence of expression of BAP1 which is associated with high risk of metastases in UM patients. Chromatin topology changes are associated with up-regulation of PRAME, a recognized independent prognostic biomarker in UM and potential therapeutic target. Our findings illustrate how multi-omics integrative approaches can improve the understanding of tumorigenesis and reveals two novel mechanisms of gene expression dysregulation in UM.


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