Familial Melanoma and Susceptibility Genes: A Review of the Most Common Clinical and Dermoscopic Phenotypic Aspect, Associated Malignancies and Practical Tips for Management

Abstract

A family history of melanoma greatly increases the risk of developing cutaneous melanoma, a highly aggressive skin cancer whose incidence has been steadily increasing worldwide. Familial melanomas account for about 10% of all malignant melanomas and display an inheritance pattern consistent with the presence of pathogenic germline mutations, among which those involving CDKN2A are the best characterized. In recent years, a growing number of genes, such as MC1R, MITF, CDK4, POT1, TERT, ACD, TERF2IP, and BAP1, have been implicated in familial melanoma. The fact that individuals harboring these germline mutations along with their close blood relatives have a higher risk of developing multiple primary melanomas as well as other internal organ malignancies, especially pancreatic cancer, makes cascade genetic testing and surveillance of these families of the utmost importance. Unfortunately, due to a polygenic inheritance mechanism involving multiple low-risk alleles, genetic modifiers, and environmental factors, it is still very difficult to predict the presence of these mutations. It is, however, known that germline mutation carriers can sometimes develop specific clinical traits, such as high atypical nevus counts and specific dermoscopic features, which could theoretically help clinicians predict the presence of these mutations in prone families. In this review, we provide a comprehensive overview of the high- and intermediate-penetrance genes primarily linked to familial melanoma, highlighting their most frequently associated non-cutaneous malignancies and clinical/dermoscopic phenotypes.

The Interplay between Tumour Microenvironment Components in Malignant Melanoma

“…Individual genetic susceptibility accounts for about 10% of all malignant melanomas and displays a predisposition pattern with variable gene penetrance (low, medium, and high). The genes that are associated with cases of familial melanoma are: cyclin-dependent kinase inhibitor 2A ( CDKN2A ), melanocortin-1 receptor ( MC1R ), MITF , cyclin-dependent kinase 4 ( CDK4 ), protection of telomeres 1 ( POT1 ), telomerase reverse transcriptase (TERT) promoter region (TERT) , adrenocortical dysplasia protein homolog ( ACD ), telomeric repeat-binding factor 2-interacting protein 1 ( TERF2IP ), and BRCA1 associated protein 1 ( BAP1 ) [ 57 ]. It seems that high penetrance genes ( CDKN2A , CDK4 , POT1 , TERT , ACD , TERF2IP , and BAP1 ) can induce different intrinsic mechanisms, such as cell cycle dysregulation, or even have the capacity to encode two tumour-suppressor proteins, while genes with intermediate penetrance ( MC1R and MITF ) act on melanin production and development [ 57 ].…”

“…Inherited anomalies of MC1R play a significant role in melanoma development [ 24 ]. Specific polymorphism of Melanocortin-1 receptor (MC1R) locus, with its variants (R151C, R160W, D294H, R142H, R163Q, and I155T), is potentially mutagenic in melanocytes [ 57 ]. Loss of function of this polymorphic gene corresponds to a UV-sensitive, fair skinned, melanoma-susceptible phenotype [ 58 ].…”

Multiple primary melanomas: Is there a correlation between dermoscopic features and germline mutations?

“…Structureless areas are often detected in case of CDKN2A mutations with a couple of variants of MC1R of the RHC type and streaks/pigmented networks in their absence. MITF ‐mutated subjects may show a nonspecific pattern (amelanotic/hypomelanotic nodular CM) with atypical polymorphic vessels 6,7 . RHC MC1R variants were reported to influence CM features, reducing the pigmentation and the development of dermoscopic structures, including a lower number of blotches, due to the reduced synthesis of eumelanin.…”

Melanoma Management: From Epidemiology to Treatment and Latest Advances

“…Germline mutations account for about 5-10% of cases, and among these, the cyclin-dependent kinase inhibitor 2A (CDKN2A) mutation is the most prevalent. However, mutations in several other genes such as melanocortin 1 receptor (MC1R), microphthalmia-associated transcription factor (MITF), cyclin-dependent kinase 4 (CDK4), protection of telomeres 1 (POT1), telomerase reverse transcriptase (TERT), adrenocortical dysplasia (ACD), telomeric repeat-binding factor 2-interacting protein 1 (TERF2IP) and BRCA1-Associated Protein 1 (BAP1) are also present in melanoma-prone families [72,73]. On the other hand, somatic mutations are mostly associated with mitogen-activated protein kinase cascade.…”