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Page 6 of 13 Shaughnessy et al. J Transl Genet Genom 2018;2:14. I https://doi.org/10.20517/jtgg.2018.25

melanoma [58,59] . A few of their most frequently recognized mutations are in the KIT, PDGFRA, and Cyclin D1
genes [Table 1].

KIT (MuM and ACM)
KIT mutations are present in just 3% of all melanomas but are found in as many as 39% of MuM and 36%
[21]
of ACM, making them the most common variant in both of these subtypes . Additionally, it is the most
[21]
commonly identified mutation in chronically sun-damaged skin at 28% . KIT encodes a type III transmem-
brane receptor tyrosine kinase that is vital for normal melanocyte development, as it is the receptor for stem
cell factor (SCF). Upon binding SCF, KIT dimerizes and subsequently activates signaling pathways, includ-
ing the MAPK/ERK and the PI3K/AKT/mTOR survival pathways [Figure 1]. Activating KIT mutations sim-
ulate this very same SCF ligand binding, thus activating pathways that influence cancer cell growth, prolif-
[60]
eration, invasion, metastasis, and apoptosis evasion . In melanoma, KIT mutations correlate with increased
[22]
disease invasion and metastasis, highlighting its tumor suppressive function . They are mutually exclusive
with mutations in BRAF and NRAS, but still induce the same MAPK and PI3K pathways that are crucial to
the tumorigenesis of several other melanoma subtypes.

Clinical trials have focused on the use of various kinase inhibitors, such as imatinib, dasatinib, sorafenib,
[23]
and nilotinib, all with limited results in the attempted treatment of KIT-mutated tumors .

PDGFRA (MuM and ACM)
A cell surface type III receptor tyrosine kinase, PDGFRA normally binds to platelet-derived growth factors
and leads to the activation of cell signaling pathways essential for growth and differentiation. Mutations have
also been implicated in the dysregulation of survival and tumor progression. Mutant PDGFRA is present in
around 7% of ACM and 4% of MuM. PDGFRA mutations are mutually exclusive with KIT mutations and
[24]
occur almost entirely in skin without chronic sun-damage .

CCND1 (ACM)
CCND1 encodes the major cell cycle control protein cyclin D1. Cyclin D1 effectively controls cell prolifera-
tion through binding and stimulating CDK4/6, resulting in the phosphorylation of the retinoblastoma pro-
[61]
tein and subsequent cell cycle entry . Amplification of the CCND1 gene is present in approximately 45% of
[26]
ACMs , and it is considered an ACM driver. However, the gene is also amplified in 6% of NACMs, particu-
[26]
larly in chronically sun-damaged skin . CCND1 variants have even been found to incur resistance to BRAF
[61]
inhibitors in NACM .
UVEAL MELANOMA
Uveal melanoma (UM) arises from melanocytes of the uveal tract of the eye, and it is both the most com-
mon primary intraocular malignancy and the most common of the non-cutaneous melanomas (compris-
ing 80% of these tumors) [34,62] . UM has a poor prognosis, with nearly half of affected patients developing
metastatic disease with an expected survival ranging from months to a year. The rarity of the disease limits
[63]
patient availability for clinical trials and currently no effective systemic therapy exists . Like cutaneous
forms of melanoma, UM occurs primarily in white patients, particularly in those with light skin and light
eyes, highlighting the possible significance of UV radiation in its development or the inherent susceptibility
of melanocytes from these vulnerable populations [63,64] . The genetic landscape of UM is distinct from other
melanomas, as evidenced by observations that UM rarely exhibits BRAF or NRAS mutations, which are
characteristically present at all other melanoma sites, but rather is defined by GNAQ, GNA11, BAP1, EIF1AX,
and SF3B1 mutations [Table 1].

GNAQ and GNA11
[30]
Up to 99% of UM harbor GNAQ or GNA11 gene mutations . GNAQ mutations alone have been found in