Uveal Melanoma (UM) is a rare and malignant intraocular tumor with dismal prognosis. Despite the efficient control of the primary tumor by radiation or surgery, up to 50% of patients subsequently develop metastasis, mainly in the liver. Once the tumor has spread from the eye, the treatment is challenging and the median survival is only nine months. UM represents an intriguing model of oncogenesis that is characterized by a relatively homogeneous histopathological architecture and a low burden of genetic alterations, in contrast to other melanomas. UM is driven by recurrent activating mutations in Gαq pathway, which are associated with a second mutation in BRCA1 associated protein 1 (BAP1), splicing factor 3b subunit 1 (SF3B1), or eukaryotic translation initiation factor 1A X-linked (EIF1AX), occurring in an almost mutually exclusive manner. The monosomy of chromosome 3 is also a recurrent feature that is associated with high metastatic risk. These events driving UM oncogenesis have been thoroughly investigated over the last decade. However, no efficient related therapeutic strategies are yet available and the metastatic disease remains mostly incurable. Here, we review current knowledge regarding the molecular biology and the genetics of uveal melanoma and highlight the related therapeutic applications and perspectives.

Introduction: Uveal melanoma (UM) is a rare and malignant intraocular tumour with a dismal prognosis. Despite a good control of the primary tumour by radiation or surgery, up to 50% of patients subsequently develop metastasis for which no efficient treatment is yet available. Methodology: To identify therapeutic opportunities, we performed an in vitro screen of 30 combinations of different inhibitors of pathways that are dysregulated in UM. Effects of drug combinations on viability, cell cycle and apoptosis were assessed in eight UM cell lines. The best synergistic combinations were further evaluated in six UM patient-derived xenografts (PDXs). Results: We demonstrated that the Bcl-2/X L /W inhibitor (ABT263) sensitised the UM cell lines to other inhibitors, mainly to mammalian target of rapamycin (mTOR), mitogen-activated protein kinase kinase (MEK) and murine double minute 2 (MDM2) inhibitors. mTOR (RAD001) and MEK1/2 (trametinib) inhibitors were efficient as single agents, but their combinations with ABT263 displayed no synergism in UM PDXs. In contrast, the combination of

Genes involved in 3′-splice site recognition during mRNA splicing constitute an emerging class of oncogenes. SF3B1 is the most frequently mutated splicing factor in cancer, and SF3B1 mutants corrupt branchpoint recognition leading to usage of cryptic 3′-splice sites and subsequent aberrant junctions. For a comprehensive determination of alterations leading to this splicing pattern, we performed a pan-TCGA screening for SF3B1-specific aberrant acceptor usage. While the most of aberrant 3′-splice patterns were explained by SF3B1 mutations, we also detected nine SF3B1 wild-type tumors (including five lung adenocarcinomas). Genomic profile analysis of these tumors identified somatic mutations combined with loss-of-heterozygosity in the splicing factor SUGP1 in five of these cases. Modeling of SUGP1 loss and mutations in cell lines showed that both alterations induced mutant-SF3B1-like aberrant splicing. Our study provides definitive evidence that genetic alterations of SUGP1 genocopy SF3B1 mutations in lung adenocarcinoma and other cancers.