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33% of uveal and 1.4% of cutaneous melanoma, and variants in GNA11 have been identified in 39% of uveal
[31]
and 1.3% of cutaneous . They are the most common UM driver mutations, and they were among the first
to be described. The proteins these two genes encode are close relatives of the large GTPases in the G alpha
subunit (Ga ) family, which are subunits of heterotrimeric G proteins operating downstream of G protein-
q
[65]
coupled receptors (GPCRs) . GNAQ and GNA11 encode the Ga and alpha subunit 11 (Ga11) respec-
q
[66]
tively . Both proteins mediate signaling between GPCRs and downstream effectors. Recurrent activating
GNAQ (p.Q209) and GNA11 (p.Q209) mutations converge on the MAPK/ERK pathway and serve to con-
stitutively upregulate the MAP kinase pathway, similarly to BRAF and NRAS activation in cutaneous mela-
noma [59,67] [Figure 1]. GNAQ and GNA11 gene mutations display mutual exclusivity and are very rarely found
to co-occur in the same tumor. Mutations in these genes are also present in benign uveal nevi and dermal
melanocytic tumors and are considered an early event in uveal melanoma development and progression.

Despite GNA11 mutations displaying a stronger association with metastasis than those of GNAQ, neither
mutation reveals any correlation with prognosis [30,32] . There have been very few promising trials to date.
However, some moderate effects have been demonstrated with the MEK inhibitor, selumetinib, and recent
[33]
studies are currently investigating protein kinase C as a potential target .

BAP1
BRCA1-associated protein 1, or BAP1, is a tumor suppressor gene that is lost due to the occurrence of mono-
[30]
somy 3 in 45% of UM . The protein product of BAP1 is a deubiquitinating hydrolase. BAP1 loss results
in severe dysregulation of cell cycle regulation, DNA repair, and gene expression in multiple genomic re-
gions [5,68] .

Tumors with BAP1 alterations or loss are potentially more aggressive with a poor prognosis. They are often
[34]
found in older patients and are associated with as many as 80% of metastatic UMs . Germline BAP1 muta-
tions are found in BAP1 cancer syndrome, which predisposes patients to UM along with renal carcinoma,
mesothelioma, and several other tumors. However, they are detected far more frequently as somatic vari-
[69]
ants . Patients with BAP1 cancer syndrome are often recommended to pursue more frequent and thorough
cancer screening along with genetic counseling. Unfortunately, few options remain for patients with BAP1
mutations once their UM becomes metastatic. Unlike oncogenes that can be targeted with any number of
small molecule inhibitors, the nature of BAP1 as a loss-of-function tumor suppressor gene has posed a chal-
lenge for the development of a targeted therapy.

EIF1AX and SF3B1
[30]
EIF1AX and SF3B1 mutations are less common among UM, found in 14% and 22% of samples, respectively .
The two proteins encoded by these genes are responsible for the nuclear processes of translation initiation
and pre-mRNA splicing, respectively. Mutations in EIF1AX and SF3B1 are nearly mutually exclusive with
each other as well as with BAP1 variants. EIF1AX mutations are associated with a favorable prognosis, while
[34]
SF3B1 mutations are found in younger patients and are associated with the development of late metastasis .
MELANOMA GENOMICS

Mutational Burden
Apart from differences in the underlying driver mutations, melanoma subtypes reveal variations in other
key genomic attributes. For example, NACM has one of the highest tumor mutational burdens (TMB)
among all human malignancies with around 10-50 mutations per megabase; in contrast, UM has one of the
lowest and ACM/MuM only have around 2-3 mutations per megabase [20,70-72] . High TMB was initially estab-
lished as a marker of clinical benefit in NACM after immunotherapy with CTLA-4 blockade by ipilimumab,
and a high TMB in TCGA metastatic melanoma cohort was associated with improved survival [73,74] . One
hypothesis is that increased TMB causes higher rates of neoantigen presentation and increased tumor im-