Abstract
Uveal melanoma is an aggressive malignancy that originates from melanocytes in the eye. Even if the primary tumor has been successfully treated with radiation or surgery, up to half of all UM patients will eventually develop metastatic disease. Despite the common origin from neural crest-derived cells, uveal and cutaneous melanoma have few overlapping genetic signatures and uveal melanoma has been shown to have a lower mutational burden. As a consequence, many therapies that have proven effective in cutaneous melanoma -such as immunotherapy- have little or no success in uveal melanoma. Several independent studies have recently identified the underlying genetic aberrancies in uveal melanoma, which allow improved tumor classification and prognostication of metastatic disease. In most cases, activating mutations in the Gα11/Q pathway drive uveal melanoma oncogenesis, whereas mutations in the BAP1, SF3B1 or EIF1AX genes predict progression towards metastasis. Intriguingly, the composition of chromosomal anomalies of chromosome 3, 6 and 8, shown to correlate with an adverse outcome, are distinctive in the BAP1mut, SF3B1mut and EIF1AXmut uveal melanoma subtypes. Expression profiling and epigenetic studies underline this subdivision in high-, intermediate-, or low-metastatic risk subgroups and suggest a different approach in the future towards prevention and/or treatment based on the specific mutation present in the tumor of the patients. In this review we discuss the current knowledge of the underlying genetic events that lead to uveal melanoma, their implication for the disease course and prognosis, as well as the therapeutic possibilities that arise from targeting these different aberrant pathways.
Highlights
Uveal melanoma (UM) is the second most common form of melanoma, arising from melanocytes located in the uveal tract of the eye
Several studies have showed that guanine nucleotide-binding protein alpha Q (GNAQ) and GNA11-mutations could be detected in cell-free DNA (cfDNA) from metastatic UM patients and that their presence showed an association with metastases-volume and overall survival (Beasley et al, 2018; Bidard et al, 2014; Metz et al, 2013)
Even though our understanding of UM has advanced in the last decade, UM remains one of the very few malignancies for which there is no treatment available for metastatic disease
Summary
Uveal melanoma (UM) is the second most common form of melanoma, arising from melanocytes located in the uveal tract of the eye. At the time of diagnosis of the primary tumor, only 4% of patients show detectable metastases; up to half of all UM patients will eventually develop metastatic disease despite earlier successful local treatment of the primary tumor This implies that UM already develops micro-metastases early during tumorigenesis and that these micro-metastases may remain dormant for several months or even years (Eskelin et al, 2000). The survival of metastasized UM patients did not improve over the last three decades (Singh et al, 2011) Whereas treatments such as immunotherapy and BRAF-inhibitors show promising results in patients with cutaneous melanoma (CM), UM seem to be unresponsive despite their shared origin as neural-crest derived melanocytes. UM clinical trials have focused on treatment modalities copied from CM Despite these therapeutic options, the prognosis of patients with metastatic UM has not improved, which emphasizes the need to explore and develop UM-specific therapies. Elucidating the development of UM and obtaining a better understanding of the complex interaction between genetic factors, molecular signaling and potential targets will aid in developing new therapies specific for UM
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