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Page 2 of 12 Papadodima et al. J Transl Genet Genom 2019;3:7. I https://doi.org/10.20517/jtgg.2018.33

of the eye and mucous membranes throughout the body. Accordingly, melanoma can arise at all these sites,
leading to phenotypically, histologically, clinically and genetically diverse types of disease. In Caucasian
populations, the most common type of mel anoma is cutaneous melanoma (CM), originating from the
epidermal melanocytes of non-glabrous skin. Among skin cancers, melanoma is the most aggressive, and
although it accounts for less than 5% of skin cancer incidence, it is responsible for the majority of related
[2]
deaths . In this review we will focus on CM, as there are many differences in the genetic background
implicated in different types of melanoma, such as mucosal or uveal melanoma. A distinct melanoma
subtype, often referred to as a subtype of CM, is acral melanoma, occurring on glabrous (nonhair-bearing)
acral skin of palms, soles and nail beds, which will not be further discussed in this review.

During the last decades, a continuous increase of CM frequency rates has been observed in Caucasian
populations worldwide, making CM the cancer with the most rapidly increasing occurrence. CM incidence
varies significantly between populations from different geographic regions, with Australia and New Zealand
presenting the highest incidence rates worldwide. In Europe, rates are lower, but still have shown a three-fold to
[3]
five-fold increase during this time period . CM occurrence differs substantially between European countries,
[4,5]
with Switzerland showing the highest rate and Greece belonging to the group of low-incidence countries .
CM development is a complex multi-factorial process, arising through multiple etiologic pathways and
involving the interplay of genetic and environmental risk factors. Among them, the most well-established risk
factors are exposure to ultraviolet (UV) radiation, family history, and phenotypic traits carrying a strong genetic
[2]
component - including hair and eye colour, and the number of common and atypical melanocytic nevi .

In this review, we will summarize the progress towards the genomic characterization of CM, recent
advances achieved through the exploitation of next-generation sequencing (NGS) technologies, as well as the
bioinformatics tools developed for the analysis of sequencing data.

GERM-LINE SUSCEPTIBILITY
Regarding the genetic background predisposing to melanoma, several susceptibility loci acting as high,
moderate or low penetration genes, have been identified. Cyclin-dependent kinase inhibitor 2A (CDKN2A),
[6,7]
the first familial melanoma gene identified , is found mutated in approximately 40% of melanoma high-
density families. CDKN2A encodes for two distinct proteins, p16INK4A (p16) and p14ARF (p14), both
[8]
involved in the regulation of the cell cycle . The p16 and p14 mRNAs are transcribed from alternative first
exons, so the related proteins have no similarity in their amino acid sequence, since they are translated
in alternative reading frames. Mutations in p16 are predominantly loss of-function missense mutations,
distributed throughout the protein, while in p14 inactivating mutations like whole gene deletions, insertions
or splice-site mutations are mainly observed. Germ-line mutations in CDK4 are much less frequent and were
initially identified by screening for p16 interacting partners. A mutational hotspot in codon 24, leading to an
arginine substitution, abrogates the capacity of p16 to inactivate the kinase, thus promoting the G1-S phase
transition. Other mutations have been identified in genes of more moderate penetrance, including BAP1,
[9]
TERT, POT1, ACD, TERF2IP and MITF . Genome-wide association studies have also revealed numerous
recurring single nucleotide polymorphisms (SNPs) associated with melanoma risk [10-13] .

TOWARDS THE GENOMIC CHARACTERISATION OF MELANOMA
Identifying somatic mutations in the genome of melanoma is of great importance in order to understand
the molecular basis of the disease’s genesis and progression. A number of oncogenes and tumour suppressor
genes have been found to carry causative mutations. The first oncogene identified in melanoma was
[14]
NRAS , which is also found mutated in other cancers. In 2002 the BRAF V600E somatic mutation was
[15]
identified and is the most frequent mutation found in CM patients. Since then, the advances in sequencing