Melanoma susceptibility: an update on genetic and epigenetic findings

Abstract

Malignant melanoma is one of the most highly ranked cancers in terms of years of life lost. Hereditary melanoma with its increased familial susceptibility is thought to affect up to 12% of all melanoma patients. In the past, only a few high-penetrance genes associated with familial melanoma, such as CDKN2A and CDK4, have been clinically tested. However, findings now indicate that melanoma is a cancer most likely to develop not only due to high-penetrance variants but also due to polygenic inheritance patterns, leaving no clear division between the hereditary and sporadic development of malignant melanoma. Various pathogenic low-penetrance variants were recently discovered through genome-wide association studies, and are now translated into polygenic risk scores. These can show superior sensitivity rates for the prediction of melanoma susceptibility and related mixed cancer syndromes than risk scores based on phenotypic traits of the patients, with odds ratios of up to 5.7 for patients in risk groups. In addition to describing genetic findings, we also review the first results of epigenetic research showing constitutional methylation changes that alter the susceptibility to cutaneous melanoma and its risk factors.

Keywords: Melanoma susceptibility; epigenetics; familial melanoma; germline mutation; hereditary melanoma; melanoma genetics; polygenic risk score.

Figure 1

Physiological pathways of genes with possible pathogenic high-penetrance variants associated with hereditary melanoma. ACD: adrenocortical dysplasia; ATM: ataxia telangiectasia-mutated signaling pathway; BAP1: BRCA1-associated protein-1; CDK4: cyclin-dependent kinase 4; CDK6: cyclin-dependent kinase 6; CDKN2A: cyclin-dependent kinase inhibitor 2 a; IP3R3: receptor for inositol 1,4,5-trisphosphate; p14ARF: p14 alternate reading frame; p16INKA4: p16 inhibitor of cyclin-dependent kinase 4; p53: tumor protein 53; POT1: protection of telomeres 1; TERF2IP: telomeric repeat binding factor 2 interacting protein.

Figure 2

Established melanoma susceptibility genes with high and medium-penetrance variants and their most closely related genes. Utilizing the GeneMania framework (Version 3.5.2) in Cytoscape (Version 3.8.2), we generated a network analysis based on the established hereditary melanoma susceptibility genes, usually bearing high-and medium-penetrance pathogenic variants. These are shown in red. The most closely related genes are shown in gray. Genes were visually grouped according to molecular function. ACD: adrenocortical dysplasia; BAP1: BRCA1-associated protein-1; CDK4: cyclin-dependent kinase 4; CDKN2A: cyclin-dependent kinase inhibitor 2 a; MC1R: melanocortin 1 receptor gene; MITF: microphthalmia-associated transcription factor; POT1: protection of telomeres 1; SLC45A2: solute carrier family 45 member 2; TERF2IP: telomeric repeat binding factor 2 interacting protein; TERT: telomerase reverse transcriptase.

Figure 3

Melanoma susceptibility candidate genes grouped by molecular function. We used the ClueGO framework (Version 2.5.8) in Cytoscape (Version 3.8.2) to visualize a gene network analysis of melanoma susceptibility candidate genes [101,102]. Colors represent affiliations to gene groups with similar molecular functions. The node size and leading GO term were based on the gene quantity per term. GO term fusion was applied.

Figure 4

Constitutional epigenetic changes of specific genes associated with melanoma and its risk factors. Me: methyl group.