Uveal melanoma: Towards a molecular understanding

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 BAP1 mut , SF3B1 mut and EIF1AX mut 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.

Iris Colour and the Risk of Developing Uveal Melanoma

“…Whereas GNAQ and GNA11 mutations occur early in tumour formation and are not associated with prognosis, EIF1AX , SF3B1 and BAP1 mutations occur later in the development of the tumour and are related to prognosis. A mutation in EIF1AX is present in 17% of primary UM, a mutation in SF3B1 in 25% and a mutation in BAP1 in about 45% of primary UM [ 71 ]. These three mutations are almost always mutually exclusive [ 41 , 72 ].…”

“…BAP1 -mutated tumours are strongly associated with metastases and have a high melanoma-specific mortality [ 72 , 73 , 74 ]. The EIF1AX mutation is responsible for unsuccessful protein translation, and the SF3B1 mutation affects gene splicing [ 71 ]. The lack of the BAP1 protein interferes with a wide range of normal cell processes such as DNA damage repair; 40% of UM metastases have a BAP1 mutation [ 75 ].…”

MicroRNAs and Uveal Melanoma: Understanding the Diverse Role of These Small Molecular Regulators

“…Tumours with a high metastatic risk have a loss of one copy of chromosome 3, termed monosomy 3 (M3), and those at low risk have the normal two copies, termed disomy 3 (D3) [13]. Other genetic aberrations, including gains of chromosome 8q [12][13][14], and inactivating mutations of BRCA1 associated protein (BAP1) gene have been correlated to a high metastatic risk and hence poor outcome [15][16][17][18][19][20][21]. Mutually exclusive mutations in two other genes, eukaryotic translation initiation factor 1A (EIF1AX) and splicing factor 3 subunit 1 (SF3B1), have allowed further subdivision of the low metastatic risk D3 group, with EIF1AX mutations associated with non-metastasising tumours [20,22], whereas SF3B1 mutations are associated with a delayed metastatic onset (intermediate risk) [11,23].…”

Update on uveal melanoma: Translational research from biology to clinical practice (Review)

“…Tumour size, extraocular extension, mitotic activity and epithelioid cell type are considered important risk factors for melanoma (182). As previously stated, genetic mutations and chromosome abnormalities are also directly associated with patient outcomes and shed light into the prognosis of uveal melanoma.…”