Loss of Polycomb Repressive Complex 1 activity and chromosomal instability drive uveal melanoma progression

Chromosomal instability (CIN) and epigenetic alterations have been implicated in tumor progression and metastasis. Yet, how these two hallmarks of cancer are related remains poorly understood. By integrating genetic, epigenetic, and functional analyses at the single cell level, we show that the progression of uveal melanoma (UM), the most common intraocular primary cancer, is driven by loss of Polycomb Repressive Complex 1 (PRC1) in a subpopulation of tumor cells. This is done by transcriptionally profiling 17,074 single cells obtained from fresh surgical human samples taken from primary tumors (n = 6). These samples were derived from patients spanning various stages of tumour progression without enrichment for a specific cell type, such that the entire tumour and its microenvironment were sampled in an unbiased manner. Data from all patients were merged to create a global cell atlas. Single-cell RNA sequencing was performed on 6 donors using inDrops protocol.