Abstract
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.
Highlights
Uveal melanoma (UM) is the most frequent eye cancer in adults, representing 5% of all types of melanoma [1]
MBD4 plays a role in repairing DNA mismatches and its inactivation leads to a hypermutated tumor profile that is sensitive to immune checkpoint inhibitors [19,20]
SF3B1 and SRSF2 mutations are recurrent in UMs and they lead to a change of function of the splicing factor (SF) [109]
Summary
Uveal melanoma (UM) is the most frequent eye cancer in adults, representing 5% of all types of melanoma [1]. Uveal melanoma primary tumor can be effectively treated with radiation or surgical removal (enucleation) [4,5,6]. The prognosis of this cancer remains poor due to the development of metastases in 20–50% of patients, despite good local control [7]. These metastases mainly appear in the liver (89%) and they are resistant to treatment, leading to an overall survival of six to twelve months. Current therapeutic approaches, including chemotherapies or targeted therapies, yield very low response rates (0–15%) in clinical trials, which highlights the need for more effective therapeutic strategies by identifying new targets or combined approaches [8,9]
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