Genetic determinants of cutaneous melanoma predisposition

Abstract

In the last 2 decades, advances in genomic technologies and molecular biology have accelerated the identification of multiple genetic loci that confer risk for cutaneous melanoma. The risk alleles range from rarely occurring, high-risk variants with a strong familial predisposition to low-risk to moderate-risk variants with modest melanoma association. Although the high-risk alleles are limited to the CDKN2A and CDK4 loci, the authors of recent genome-wide association studies have uncovered a set of variants in pigmentation loci that contribute to low risk. A biological validation of these new findings would provide greater understanding of the disease. In this review we describe some of the important risk loci and their association to risk of developing cutaneous melanoma and also address the current clinical challenges in CDKN2A genetic testing.

Figure 1

High-risk melanoma predisposition loci. The schematic represents the signaling pathways controlled by CDKN2A loci. The 2 different protein products encoded by the splice variants - p14Arf and p16Ink4a, converge on the same cellular function—cell-cycle regulation. The p14Arf regulates the p53 tumor suppressor network and the P16Ink4a regulates the Rb network. Variants in p14Arf, p16Ink4a, Cdk4, and Rb contribute to deregulated signaling and uncontrolled cell proliferation.

Figure 2

Mc1r pigmentation pathway implicated in melanoma risk. Alpha-melanocyte stimulating hormone (α-MSH) serves as a ligand of Mc1r. Agouti protein antagonizes this interaction. Binding of MSH to Mc1r stimulates adenylate cyclase to generate cAMP. cAMP is one of the key mediators of a series of events that leads to the conversion of pheomelanin to a photoprotective eumelanin during melanogenesis. The tyrosinase (Tyr) and the tyrosine-related protein kinase 1 (Tyrp-1) are the key enzymes that regulate this process. The variants of the MC1R, TYR, and TYRP-1, presumably lead to pigmentation differences, photosensitivity, and predisposition to cutaneous melanoma.