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

Given our growing understanding of the mutations driving melanoma progression, we now have multiple
options for recurrent and metastatic tumors that were once considered untreatable. We are also better able
to identify those patients who would benefit from earlier and more thorough cancer screening due to the
[5]
discovery of hereditary forms of cancer and their associations with cancers of other organs . Despite our
expanding knowledge of melanoma’s genetic landscape with over 40 culprit mutated genes identified to date,
[6]
a relatively small number of clinically-relevant drugs have been developed . This disparity is due to the re-
markably intricate nature of cancer genetics, involving the complex interplay between driver and passenger
mutations and variability in gene expression and gene-gene interactions. Considering the modest progress
towards improving the prognosis of uveal melanoma, or in developing a universal melanoma chemothera-
peutic agent, it is clear that much remains to be discovered.

We will focus largely on somatic driver mutations in melanoma. An extensive discussion of germline vari-
ants and their associated familial cancer syndromes is beyond the scope of this review.

NON-ACRAL CUTANEOUS MELANOMA
Non-acral cutaneous melanoma (NACM), comprised of the superficial spreading, nodular, lentigo maligna,
and desmoplastic subtypes, is the most common type of melanoma, and thus the most well-studied and well-
understood in terms of its genetic foundation. NACM predominantly affects sun-exposed surfaces of white
[7]
individuals with fair skin, and its risk is highly associated with UV radiation exposure . Superficial spread-
ing melanoma is the most common form, representing 70% of all cases of melanoma, and is more likely to
[8]
be associated with a prior nevus and a history of sporadic and intense UV exposure . Nodular melanoma
often presents as a darkly-pigmented or amelanotic nodule that is thicker than other subtypes at the time of
diagnosis. Lentigo maligna melanoma primarily arises in chronically sun-damaged skin of older individuals.
Finally, the desmoplastic subtype is marked by an amelanotic scar-like formation that is characterized his-
[9]
tologically by spindled melanocytes and abundant stroma . From a genomic standpoint, NACM is generally
characterized as being made up of four major subclasses: BRAF, NRAS, NF1, and triple-wild type [Table 1].

BRAF
[36]
Mutations in BRAF are the most frequently occurring driver mutations in melanoma (60% of all tumors) .
BRAF encodes a serine/threonine protein kinase that regulates the mitogen-activated protein kinase (MAPK)
pathway, which is involved in cell proliferation, differentiation, and survival. BRAF mutations have been
implicated in several other malignancies, such as colorectal carcinoma, ovarian carcinoma, and various
[36]
sarcomas . The V600E missense mutation, which results in a valine to glutamic acid substitution, is present
in 80% of BRAF-mutated melanomas. This mutation significantly upregulates BRAF kinase activity thereby
[36]
activating downstream MAPK signaling and driving cancer progression .

BRAF-mutated melanomas are more often found in younger patients and in areas exposed to intermittent
[10]
sunlight , but the same V600E mutation is also present in 80% of benign nevi, suggesting that tumorigen-
[11]
esis requires additional co-mutations .
BRAF-mutated melanomas were first successfully treated with the BRAF inhibitor vemurafenib in 2010, and
now are treated with the gold standard combination of dabrafenib (BRAF inhibitor, BRAFi) and trametinib
(MEK inhibitor, MEKi) [3,12,37] . Trametinib targets downstream MEK1 and MEK2. The combination of
[38]
BRAFi+MEKi suppresses MAPK signaling at two points which enhances efficacy . Several resistance mech-
anisms have developed in response to BRAF inhibitors including novel splice variants in BRAF, BRAF gene
amplification, activation of receptor tyrosine kinases and other kinases, or through an immune-mediated
[23]
mechanism . Clinical trials are currently investigating treatments for these resistance patterns. One prom-
ising option may be a combination of the current standard of dabrafenib/trametinib with immunomodula-