The Genetics and Genomics of Melanoma and Benign Melanocytic Neoplasms


This collated research topic comprises three main sections: 1) Genetic susceptibility of melanoma and benign melanocytic neoplasms; 2) genomic analysis/molecular characterization of melanoma and benign melanocytic neoplasms; and 3) biomarkers of melanoma progression.

Melanoma is a malignant neoplasm that arises from melanocytes of the skin and other organs. The incidence of cutaneous melanoma, which is the most aggressive of the common skin cancers, is rapidly increasing especially in Caucasian populations. Melanocyte transformation occurs when DNA repair or cell-cycle control mechanisms are damaged, which in cutaneous melanoma, is largely due to repeated insult by ultra-violet radiation (UVR). In most cases melanocyte transformation results in a benign melanocytic neoplasm (such as a naevus) forming, rather than its malignant counterpart (melanoma). Naevi can and do transform into primary melanoma, given the right conditions, but in most cases naevi stay as benign entities. The aetiology of melanoma or naevi is complex and heterogeneous, as it is an interplay between the environment, a person's phenotype and genetic risk, along with acquired molecular alterations.

The genetic and genomic analysis of melanoma has had a long history, with the initial discovery of CDKN2A as a key tumour suppressor gene in familial melanoma in the early 1990's. Thereafter, through to high frequency of BRAF hotspot mutations in melanoma and naevi (2000's), through to the advent of next generation sequencing and the world's first cancer whole genome sequencing from a melanoma cell line.

Melanoma susceptibility genes have varying degrees of risk associated with the disease. There are high penetrance variants, which cause significantly increased risk to melanoma development in carriers, which become evident in melanoma prone families. To date, several genes conferring high risk such as CDKN2A, CDK4, TERT, POT1, ACD TERF2IP; and genes conferring moderate risk such as MC1R, MITF and those associated with oculocutaneous albinism (TYR, OCA2, TYRP1 and SLC45A2) have been described. In addition, low risk variants involving multiple genes have been detected by analysing large numbers of sporadic melanoma cases. Melanoma and naevi share genetic risk factors since certain genes have been associated with both entities. However, naevi susceptibility has been less explored.

Melanoma progression from early atypical melanocytes, through to invasive primary and later metastasis can be considered to be due to the accumulation of somatic mutations. This leads to clonal expansions (e.g in-situ melanoma), followed by chromosomal copy number losses and gains that promote invasive/metastatic disease. Mitogen-activated protein kinase (MAPK) pathway activation is an initial common event observed in both naevi and cutaneous melanoma. However, there are numerous others that have been discovered, particularly in the less common melanoma subtypes (acral, uveal and mucosal). These discoveries have been made possible by whole genome landscape analysis via technologies such as microarrays (gene expression and copy number) and next-generation sequencing (whole genome/exome, transcriptome, etc.).

In this research topic, we would like to highlight the use of current technologies for the discovery of new melanoma susceptibility genes, new molecular targets for therapy, novel pathways to understand melanomagenesis and naevogenesis as well as biomarkers for early detection and disease progression.

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Media Contact:

Kathy Andrews
Journal Manager
Journal of Clinical & Experimental Dermatology Research