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Maner et al. J Cancer Metastasis Treat 2020;6:37 I http://dx.doi.org/10.20517/2394-4722.2020.60 Page 23 of 40

lentiginous melanoma (ALM) [152] . Cutaneous SSMs account for 70% of melanomas, while NMs account
for 15%-30% of melanomas. Both SSM and NM subtypes are often associated with the BRAF V600E
mutation [152] . ALM (2%-10%) and LMM (5%) are rarer types that are both associated with mutations in the
C-kit gene [152] .

The transformation of melanocytes into melanoma cells and further progression to metastasis involves
the complex interaction of signaling pathways with multiple environmental, genetic, and host factors. The
primary contributor is DNA damage from UV light exposure, although genetic disorders like xeroderma
pigmentosum and familial history of melanoma can strongly increase a person’s risk [153] . Occupational
exposure to ionizing radiation among radiologic technologists has been shown to increase risk to
developing skin cancer and melanoma [154] . A recent literature review suggests airline pilots and cabin
crew may have twice the risk of melanoma compared to the general population and increased melanoma
mortality among pilots from possible cumulative cosmic radiation [155] . However, much of the relevant
evidence is considered out-of-date as it reflects environment and behaviors in the late twentieth century
and is incongruent with modern day standards. Immunosuppressed populations like organ-transplant
recipients have an increased risk of many malignant cancers, with skin cancer being the most common [156] .
Understanding the mechanisms in various signaling pathways can provide insight into providing
personalized and effective treatment. This amalgamation of genetic crosstalk modulates the transformation
process and involves the hallmarks of cancers: (1) cell growth; (2) prevention of apoptosis; (3) supporting
stroma and vascularization; and (4) modulating immune response.

Cell growth
UV-induced damage
Within hours, UVA causes immediate and lasting hyperpigmentation (tanning) due to induction
of oxidative stress in melanocytes. UVA damages the extracellular matrix and induces an immune
response facilitating invasion and metastasis of skin cancer cells [113] . In contrast, UVB directly causes
skin cancer genesis and induces a slower delayed tanning through a nascent melanin synthesis pathway
[3]
and melanocortin receptor-1 (MC1R) signaling . MC1R activates the DNA damage response causing
the formation of cyclobutene pyrimidine dimers and 6-4 photoproducts that distort the DNA helix and
when unrepaired lead to mutations [157] . In addition, UVB triggers an inflammatory response by recruiting
neutrophils and macrophages and promotion of angiogenesis contributing to melanoma cell survival and
[3]
metastasis .
CDKN2A/p16 deletion
The CDKN2A/p16 protein is a crucial cell cycle gatekeeper at the G -S checkpoint and its location encodes
1
for tumor suppressors p16 INK4a and p14 ARF[158] . As mentioned in the cSCC section, P16 INK4a inhibits cdk4 and
cdk6 [Figure 10], activating RB protein and preventing cell cycle progression into S from G1 phase [159,160] .
ARF
On the other hand, p14 positively regulates p53 [Figure 10] by inhibiting negative regulator MDM2 [161,162] .
Deletions in the CDKN2A locus was found in 50% of all melanomas and had high penetrance in familial
melanoma [153,163] . The inactivation of CDKN2A and p53 inactivation leads to uncontrolled cell proliferation
of melanocytes.

Apoptosis evasion
BRAF in RAS/RAF/MAPK/ERK pathway
The most prevalent and highly studied oncogenic melanoma mutation is BRAF with the most common
mutation substituting glutamic acid for valine (V600E) [164] . An estimated 40%-50% of mutated melanomas
are of BRAF V600E mutation [165] . In the MAPK pathway [Figure 10], the presence of the oncogenic
BRAF V600E mutation drives constitutive phosphorylation of MEK1 and 2, activating ERK 1 and 2 and
reprograming cellular metabolism to sustain cell survival and growth [166] . In major melanoma subtypes