Abstract
Uveal melanoma (UM) is the most common primary intraocular malignancy of the eye. It has a high metastatic potential and mainly spreads to the liver. Genetics play a vital role in tumor classification and prognostication of UM metastatic disease. One of the driver genes mutated in metastasized UM is subunit 1 of splicing factor 3b (SF3B1), a component of the spliceosome complex. Recurrent mutations in components of the spliceosome complex are observed in UM and other malignancies, suggesting an important role in tumorigenesis. SF3B1 is the most common mutated spliceosome gene and in UM it is associated with late-onset metastasis. This review summarizes the genetic and epigenetic insights of spliceosome mutations in UM. They form a distinct subgroup of UM and have similarities with other spliceosome mutated malignancies.
Highlights
Uveal melanoma (UM) is the most common primary ocular malignancy in adults [1]
Metastatic disease is very rare at presentation [4] and in our cohort only 10 out of 808 (1.2%) UM patients presented with detectable metastatic disease at the time of diagnosis with ultrasonographic screening of the abdomen
Secondary driver genes are strongly associated with prognosis and include BAP1 [19], EIF1AX [20] and SF3B1 [21]
Summary
Uveal melanoma (UM) is the most common primary ocular malignancy in adults [1]. The European incidence varies between approximately 2 to 8 per million with the southern parts of Europe having the lowest incidence and the northern parts having the highest [1]. Secondary driver genes are strongly associated with prognosis and include BAP1 [19], EIF1AX [20] and SF3B1 [21]. EIF1AX encodes the eukaryotic translation initiation factor 1A, an X-chromosomal protein and mutations in the N terminal region of this gene are found in approximately 20% of UM patients [20]. SF3B1 encodes splicing factor 3B subunit 1 and mutations in the SF3B1 gene occur in approximately 20% of UM cases [20,25,26]. Mutations in this motif have been shown to affect the interaction with the DDX46 (DEAD-Box Helicase 46) protein (prp in yeast) necessary for stable association of U2 snRNP to the pre-mRNA [41]. Molecular modeling shows location of hotspot mutations in secondary structures of splicing genes (Figure 4). As in case of the SF3B1 mutations, these in-frame deletions are typical for UM and are not observed in other malignancies where nucleotide change are more prevalent
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