Melanoma Risk and Melanocyte Biology

Abstract

Cutaneous melanoma arises from melanocytes following genetic, epigenetic and allogenetic (i.e. other than epi/genetic) modifications. An estimated 10% of cutaneous melanoma cases are due to inherited variants or de novo mutations in approximately 20 genes, found using linkage, next-generation sequencing and association studies. Based on these studies, 3 classes of predisposing melanoma genes have been defined based on the frequency of the variants in the general population and lifetime risk of developing a melanoma: (i) ultra-rare variants with a high risk, (ii) rare with a moderate risk, and (iii) frequent variants with a low risk. Most of the proteins encoded by these genes have been shown to be involved in melanoma initiation, including proliferation and senescence bypass. This paper reviews the role(s) of these genes in the transformation of melanocytes into melanoma. It also describes their function in the establishment and renewal of melanocytes and the biology of pigment cells, if known.

Keywords: embryonic development; germline mutation; inherited melanoma; melanocyte stem cells.

Fig. 1

Interaction network of genes involved in melanocyte biology, and the associated melanoma risk. The list of genes involved either in the establishment and renewal of melanocytes, in the biology of pigment cells, and/or associated with increased melanoma risk, was submitted to the STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) database for analysis of the gene interaction network (122). Each circle represents 1 gene, and 1 linking line represents a direct (physical) or indirect (functional) association between the proteins encoded by the 2 genes. Green: genes with ultra-rare variants associated with a high risk of melanoma; blue: genes with rare variants associated with a moderate risk of melanoma; red: genes with frequent variants associated with a low risk of melanoma; white: genes involved in melanocyte biology with no mutation currently associated with melanoma. Note, the left cluster gathers mainly genes of melanogenesis, and the right cluster gathers genes of the cell cycle, telomere length control, and DNA repair.