Familial Melanoma: Diagnostic and Management Implications

Background An estimated 5%–10% of all cutaneous melanoma cases occur in families. This review describes susceptibility genes currently known to be involved in melanoma predisposition, genetic testing of familial melanoma patients, and management implications. Results CDKN2A is the major high-penetrance susceptibility gene with germline mutations identified in 20%–40% of melanoma families. A positive CDKN2A mutation status has been associated with a high number of affected family members, multiple primary melanomas, pancreatic cancer, and early age at melanoma onset. Mutations in the other melanoma predisposition genes—CDK4, BAP1, TERT, POT1, ACD, TERF2IP, and MITF—are rare, overall contributing to explain a further 10% of familial clustering of melanoma. The underlying genetic susceptibility remains indeed unexplained for half of melanoma families. Genetic testing for melanoma is currently recommended only for CDKN2A and CDK4, and, at this time, the role of multigene panel testing remains under debate. Individuals from melanoma families must receive genetic counseling to be informed about the inclusion criteria for genetic testing, the probability of an inconclusive result, the genetic risk for melanoma and other cancers, and the debatable role of medical management. They should be counseled focusing primarily on recommendations on appropriate lifestyle, encouraging skin self-examination, and regular dermatological screening. Conclusions Genetic testing for high-penetrance melanoma susceptibility genes is recommended in melanoma families after selection of the appropriate candidates and adequate counseling of the patient. All patients and relatives from melanoma kindreds, irrespective of their mutation status, should be encouraged to adhere to a correct ultraviolet exposure, skin self-examination, and surveillance by physicians.


Introduction
Cutaneous melanoma is one of the most aggressive human cancers, with an increasing incidence worldwide [1]. When detected at an early stage, high survival rates are reported 5 years after diagnosis [2]. Although new therapies are currently available for metastatic disease, survival for patients with advanced disease is still poor.
Melanoma pathogenesis is complex and heterogeneous, with environmental, phenotypic, and genetic factors contributing to its development. The main risk factors involved in the etiopathogenesis of cutaneous melanoma are a large number of common acquired melanocytic nevi, atypical melanocytic nevi, light skin phenotype, exposure to ultraviolet (UV) radiation, and a family history of melanoma [3][4][5].
An estimated 5%-10% of all cutaneous melanoma cases occur in families. Familial melanoma is defined as a family in which either 2 first-degree relatives or 3 or more melanoma patients on the same side of the family (irrespective of degree of relationship) are diagnosed with melanoma [5]. In these families the pattern of heritability is consistent with an autosomal dominant inheritance with incomplete penetrance.
Currently, genetic testing is recommended in high-risk melanoma patients and families to improve early detection and reduce mortality. Individuals from high-risk melanoma families must receive genetic counseling so that they receive full information about the inclusion criteria for genetic test- and Greece, respectively [37,38]. The association between pancreatic cancer and melanoma is often observed in CDKN2A-mutated melanoma families  resulting in a reduced receptor function with a switch from eumelanin to pheomelanin synthesis are classified as red hair color (RHC) or "R" variants and have been strongly associated with fair skin, freckling, UV radiation sensitivity, and inability to tan [24,57].
MC1R variants, mainly R alleles, have been associated with an increased risk of melanoma independently of phenotypic features [56]. Notably, a stronger risk has been reported for patients with darkly pigmented skin [23]. It is indeed recognized that MC1R influences melanoma risk not only through its effect on pigmentation and UV sensitivity but also through additional biological pathways, including induction of antioxidant defenses, DNA repair mechanisms, and melanocyte proliferation, regulation, and differentiation [58]. In addition, inheritance of MC1R variants with CDKN2A mutations has been shown to increase penetrance of melanoma in families carrying CDKN2A mutations [23,24]. Finally, carrying R variants has been associated with specific clinicodermoscopic features of melanoma such as hypopigmentation, structureless areas, atypia, and vessels [59][60][61].
The MITF gene is a master regulator of melanocyte homeostasis encoding a lineage-specific transcription factor, involved in cell survival, differentiation, and proliferation [62]. A rare functional variant p.E318K in the MITF gene has been implicated in familial melanoma and in melanoma/renal cell carcinoma susceptibility [25,26] Telomere maintenance has been recently discovered as a key pathway in melanoma predisposition ( Figure 1C).
The TERT gene encodes the catalytic subunit of telomerase, which is the ribonucleoprotein complex that maintains telomere length. TERT mutations induce increased expression of telomerase, thus promoting telomere stabilization and acting on cell aging, turnover, and senescence. A novel mutation occurring in the promoter region of the TERT gene, encoding the catalytic subunit of telomerase, has been recently identified in 2 melanoma families [18,19].
POT1 is a crucial member of the shelterin complex proteins, important for telomere maintenance. Mutations in the POT1 gene have been recently identified in a total of 12 CDKN2A-negative melanoma families [20,21]. Additional shelterin complex genes, such as ACD and TERF2IP, were later found to be mutated in familial melanoma patients [54]. Overall

Management of Familial Melanoma Patients
Carriers of a CDKN2A mutation are at high risk of developing multiple melanomas and, in some families, pancreatic cancer [12,13].  Geographic area/population with low melanoma incidence Geographic area/population with moderate-high melanoma incidence The recommendation of avoiding smoking in cancer prevention programs has been recently suggested for CDKN2A mutation carriers after the description of an increased prevalence of tobacco-associated cancers in CDKN2A-mutated families [67].
First-degree relatives (parents, siblings, children) will have a 50% chance of harboring the same mutation and risk. It is also prudent for children from familial melanoma kindreds to undergo routine skin examinations beginning at puberty.
Increased skin cancer screening, patients' skin self-examination education, and surveillance by physicians should be encouraged in all patients and relatives, irrespective of mutation status, for early detection of melanoma.