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Papadodima et al. J Transl Genet Genom 2019;3:7. I https://doi.org/10.20517/jtgg.2018.33 Page 7 of 12

PTEN phosphatase is a fundamental regulator of the PI3K/AKT pathway, exerting its inhibitory effects
on AKT signaling, by dephosphorylating PIP3. PIP3 acts as a second messenger, triggering a number of
signaling cascades- among them AKT- which play a key role in processes like cell survival and proliferation,
apoptosis, and cellular metabolism [131] . Somatic mutations in PTEN, primarily deletions but also loss-of-
function SNVs - 18 % and 8% respectively in CM [129] , result in PTEN inactivation and promote cell survival
through sustained activation of the PI3K signaling pathway [132] .

MITF
Microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix/leucine zipper
transcription factor required for melanocyte development. MITF is essential for establishing the melanocytic
lineage during differentiation of neural crest cells [133] . Transcriptional targets of MITF, include genes
encoding for components of melanosomes, enzymes of the melanin synthesis pathway, as well as genes
involved in cell cycle regulation and cell survival. Somatic amplification of MITF has been identified in
melanomas, but MITF activity is mainly altered by its upstream activators and suppressors acting on the
transcriptional, post-transcriptional and post-translational levels.

Other genes in melanomagenesis
Other genes causatively implicated in melanomagenesis and progression include KIT, RAC1 and ARID2.
KIT encodes for a tyrosine kinase, which is the receptor of the Stem Cell Factor. Upon ligand binding,
multiple signalling pathways affecting cell growth, proliferation, survival, and migration are activated. In
CM, mutations in KIT occur most commonly in melanomas originating from chronically sun damaged skin
and in the acral subtype [118] . The RAC1 gene encodes for a GTPase of the Ras superfamily with important
roles in cell motility. A hot spot mutation at P29S, is the result of a C>T transition, consistent with the
[18]
molecular signature associated with UV damage . The ARID2 gene encodes for a subunit of the switch/
sucrose non-fermentable (SWI/SNF) chromatin remodelling complex, a multiprotein complex that alters
chromatin structure to regulate gene expression [134] . Recent evidence suggests that components of the SWI/
SNF complex, function as tumour suppressors in several types of cancer. In the case of CM, loss-of-function
mutations in the ARID2 gene are the most frequent among SWI/SNF enzymes.

CONCLUSION
In this review, we present the main genetic features contributing to the development of CM. Marked
advances in dealing with this complex disease have been achieved over the last years, due to the diligent
efforts of researchers to shed light on the biological mechanisms involved in melanoma manifestation,
assisted by the advent of NGS technologies. Elucidating the mechanisms underlying melanoma biology
and progression can enable the development of targeted and immune-related therapeutic approaches. Still,
melanoma remains one of the most lethal types of cancer. Additional understanding of the resistance to
targeted therapies is crucial, and ought to remain a central aspect of cancer research. The intervention
schemes based on combination approaches are the most promising therapeutic ways, in the context of
personalised treatment.

DECLARATIONS
Acknowledgments
The authors would like to thank Dr. S. Kyrtopoulos and G. Sotiroudis, MSc, for proofreading this paper.

Authors’ contributions
Design: Papadodima O, Maglogiannis I, Chatziioannou A
Literature research: Papadodima O, Kontogianni G, Pyroti G, Chatziioannou A
Manuscript writing, editing, revision: Papadodima O, Kontogianni G, Pyroti G, Maglogiannis I,