Genetics of Uveal Melanoma

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Rachel E. Doherty
Mohammed Alfawaz
Jessica Francis
Beckie Lijka-Jones
Karen Sisley


Uveal melanomas (UMs) comprise only 3% of all melanomas, but they are the most common primary intraocular malignancy in adults. The disease is associated with high mortality, with the liver being the most common site for secondary tumors. Genetic studies performed over the last 30 years have provided a wealth of information on the changes found in primary posterior UM (ciliary body and choroid), but less is known about the specific alterations of the rarer and the more benign iris melanomas, or the metastatic lesions. Early cytogenetic studies identified consistent chromosomal abnormalities, including monosomy 3 (M3), gain of the long arm of chromosome 8, and changes affecting both arms of chromosomes 1 and 6. More recently, specific genetic mutations have been related to UM. Prominent among these are mutations of guanine nucleotide-binding protein Q polypeptide/guanine nucleotide-binding protein alpha-11 (GNAQ/GNA11), which are mutually exclusive and occur in approximately 90% of posterior UMs. Other mutations such as BRCA1-associated protein (BAP1), splicing factor 3B subunit 1 (SF3B1), eukaryotic translation initiation factor 1A, X-linked (EIF1AX), and telomerase reverse transcriptase promoter (TERTp) have also been associated with UM. There are clear relationships between cytogenetic alterations and prognosis, and M3, 8q+ 6p+, and 1p- can be considered as biomarkers. An improved understanding has also been gained regarding the impact of genetic mutations, but ultimately the underlying drivers of the most predictive changes are poorly understood. This review discusses the cytogenetic alterations and gene mutations of UM and the relationship they have, if any, with the outcome.


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