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Page 8 of 13 Shaughnessy et al. J Transl Genet Genom 2018;2:14. I https://doi.org/10.20517/jtgg.2018.25
[75]
mune surveillance . Even among cutaneous melanoma genomic subgroups, mutational load shows minor
variations, with NF1-subtype tumors displaying a higher TMB compared to BRAF, NRAS, and triple wild-
[20]
type tumors .

Mutational Signatures
Different environmental and molecular forces, such as exposure to carcinogens (smoking, UV light, etc.),
result in distinct mutational processes leaving unique DNA “footprints,” or combinations of mutation types
[76]
termed “signatures.” Over twenty mutational signatures have been described to date . Cutaneous melanoma
mutational spectra are most highly enriched in Signature 7, which is associated with ultraviolet radiation and
a predominance of cytosine to thymine transitions. These C to T transitions are driven predominantly by
photodimer creation through direct UV exposure or by indirect DNA damage from UV radiation [20,77] . The
mutational signatures in NACM are entirely distinct from the non-ultraviolet radiation associated signatures
found in acral and mucosal melanomas. Of the nine signatures characteristic of ACM and MuM, signature
1 (associated with increased patient age) and signature 5 (unknown etiology) are the most common, which is
fitting given these tumors arise in infrequently sun-exposed areas. These observations reflect how differing
levels of UV carcinogen exposure result in profound genomic delineation of these melanoma subtypes.

Structural variants
Structural variants include copy number variants (CNVs), amplifications, duplications, deletions, and fold-
back inversions involving DNA regions of 1 kb or longer [78,79] , and provides another dimension to tumor
genetic diversity. Candidate CNV discovery and genotyping has already identified important genetic links to
[79]
several complex disorders such as psoriasis and Crohn’s disease .

The four genomic subtypes of NACM exhibit preferential gene amplifications. BRAF and MITF gene ampli-
fications are more characteristic of the BRAF-mutant subtype, while the triple wild-type subtype frequently
reveals KIT oncogene 4p12 focal amplification. The triple wild-type subtype also has significantly more copy-
number segments overall than BRAF, NRAS, and NF1 types. ACM and MuM both exhibit a higher frequen-
cy of chromosomal aberrations and CNVs compared to NACM [20,80] . ACM and MuM also are both more
likely to show higher copy number alterations in CDK4 and lower copy number alterations in CDKN2A and
[80]
[81]
PTEN . ACM reveal copy number gains in TERT in approximately one-fourth of cases . KIT copy num-
ber gains or amplifications are also common in both ACM and MuM, observed in approximately one-fourth
[82]
of cases of each tumor .
Gene expression profiling
The broad analysis of mRNA levels across thousands of known genes has significantly contributed
to our understanding of the cellular and molecular mechanisms underlying melanoma develop-
[83]
ment . An early gene expression profiling (GEP) analysis of metastatic melanoma revealed 4
molecular subclasses (high immune, pigmentation, proliferative and normal-like) with the pro-
[84]
liferative subclass having the worst outcome . This 4-class categorization and prognostic as-
[85]
sociation have since been validated in primary melanomas . In TCGA melanoma specimens,
GEP revealed 3 molecular subclasses of melanoma (keratin, MITF-low, and immune gene expression
[6]
classes) . Some metastatic melanomas show keratin class expression patterns with increased expression of
keratins, kallikreins, and other genes of the epidermis. The MITF-low subclass, in contrast, is characterized
by low expression of epithelial expression and pigmentation genes, as well as genes responsible for immuno-
modulation, adhesion, and migration. The immune class is characterized by a high expression of immune
signaling molecules, checkpoint proteins, and cytokines. This subset of melanoma patients presents with
tumors containing an inflammatory infiltrate of T-lymphocytes and cytokines. Patients who develop tumors
with the molecular expression pattern of the immune class show improved survival compared to keratin
and MITF-low subclasses [6,86] . Given the expanding armamentarium and widespread use of immunotherapy,