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.
Highlights
It is estimated that between 5% and 10% of malignant melanomas show familiarity [1]
Some predisposing genes have been identified [5], not all cases of familial melanoma can be associated with pathogenic germline mutations, and the genetic basis of melanoma susceptibility remains unknown in a large number of families
The risk of developing melanoma in an 80-year-old individual with a family mutation of cyclin-dependent kinase inhibitor 2A (CDKN2A) is increased by 58% in Europe, 76% in the US and 91% in Australia [22]. Another key element underscoring the multifactorial nature of melanoma is that, among families with CDKN2A mutations, family members harboring wild-type CDKN2A tend to develop melanomas at a younger age compared to individuals with sporadic melanoma, even though the frequency of multiple primary melanomas in wt relatives still remains much lower compared to that of CDKN2A mutation carriers [29]
Summary
It is estimated that between 5% and 10% of malignant melanomas show familiarity [1]. The relative risk of melanoma, doubles in subjects with first-degree relatives with melanoma and increases with the number of affected family members. The risk of developing melanoma in subjects with a predisposing mutation seems to correlate with the type of mutation, some environmental factors, and other unknown variables [6], suggesting a polygenic inheritance mechanism involving multiple low-risk alleles and genetic modifiers yet to be fully characterized [7]. When assessing the relationship between geographical location and individual risk of bearing a CDKN2A mutation, it is important to take into account the variability of melanoma incidence in the general population and the degree of penetrance of CDKN2A mutations for each specific country considered [7,16,17] It appears, that in regions with higher incidence of melanoma there is a greater possibility of finding multiple family members with melanoma or multiple primary melanomas caused by reasons other than CDKN2A mutations. Another key element underscoring the multifactorial nature of melanoma is that, among families with CDKN2A mutations, family members harboring wild-type (wt) CDKN2A (i.e., phenocopies) tend to develop melanomas at a younger age compared to individuals with sporadic melanoma, even though the frequency of multiple primary melanomas in wt relatives still remains much lower compared to that of CDKN2A mutation carriers [29]
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