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

Gentien, D.; Saberi-Ansari, E.; Servant, N.; Jolly, A.; De la Grange, P.; Nemati, F.; Liot, G.; Saule, S.; Teissandier, A.; Bourc'his, D.; Girard, E.; Wong, J.; Masliah-Planchon, J.; Rodrigues, M.; Villoing Gaude, L.; Reyes, C.; Henry, E.; Baulande, S.; M'kacher, R.; Jeandidier, E.; Nicolas, A.; Decaudin, D.; Cassoux, N.; Piperno-Neumann, S.; Stern, M.-H.; Gibcus, J. H.; Dekker, J.; Heard, E.; Roman-Roman, S.; Waterfall, J. J.

doi:10.1101/2022.03.11.483767

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bioRxiv · 10.1101/2022.03.11.483767

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

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Abstract

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

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Gentien, D., Saberi-Ansari, E., Servant, N., Jolly, A., De la Grange, P., Nemati, F., Liot, G., Saule, S., Teissandier, A., Bourc'his, D., Girard, E., Wong, J., Masliah-Planchon, J., Rodrigues, M., Villoing Gaude, L., Reyes, C., Henry, E., Baulande, S., M'kacher, R., Jeandidier, E., Nicolas, A., Decaudin, D., Cassoux, N., Piperno-Neumann, S., Stern, M.-H., Gibcus, J. H., Dekker, J., Heard, E., Roman-Roman, S., Waterfall, J. J.. 2022-03-11. Multi-omics comparison of malignant and normal uveal melanocytes reveals novel molecular features of uveal melanoma.. https://doi.org/10.1101/2022.03.11.483767

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