Molecular hypothesis of tumor progression in uveal melanoma, highlighting the role of PRAME reported herein. Increased PRAME mRNA expression in Class 1 uveal melanomas is associated with transcriptional up-regulation of key genes involved in chromosome maintenance and stability, many of which are located on chromosome 1q and 6p and contain regulatory elements for transcription factors that interact with PRAME, including the retinoic acid receptor and NFY complexes. These observations suggest a possible feed-forward mechanism in which progressively increasing PRAME expression and specific chromosomal gains mutually reinforce one another to promote Class 1 tumor progression. There was a significant association of this pathway with SF3B1 mutations, which were mutually exclusive with EIF1AX mutations, suggesting a bifurcated pathway. This Class 1 metastatic pathway was distinct from the more common pathway leading to metastasis through the bi-allelic loss of BAP1 and acquisition of the Class 2 gene expression profile.