Uveal melanoma (UM), a rare cancer originating from uveal tract melanocytes, exhibits four distinct molecular subsets. We conducted comprehensive multi-omics analysis comparing aggressive UM patient-derived xenograft models with normal melanocytes. Our findings highlight genomic instability as a UM hallmark. A recurrent BAP1 promoter deletion, linked to metastasis risk, was identified. Hi-C analysis unveiled chromatin topology changes linked to PRAME upregulation, an independent UM prognostic biomarker and potential therapeutic target. Our study showcases multi-omics’ role in elucidating UM tumorigenesis, revealing two distinct gene expression dysregulation mechanisms within this rare cancer.