Familial Melanoma: Diagnostic and Management Implications

Abstract

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.

Keywords: CDK4; CDKN2A; cancer screening; familial melanoma; genetic counseling; genetic testing.

Figure 1

Pathways of high-risk genes involved in melanoma susceptibility. (A) CDKN2A encodes 2 proteins: p16^INK4a and p14^ARF. Mutations in CDKN2A gene allow the cells to escape from cell cycle arrest. In detail, p16^INK4a inhibits cyclin D1/CDK4/6 complex to release E2F through RB phosphorylation. p14^ARF interacts with MDM2 to block p53 ubiquitination, thus promoting apoptosis. When mutated, CDKN2A produces 2 dysfunctional proteins inducing cell cycle progression and avoiding p53 degradation. (B) Mutations in CDK4 promote the G1 to S phase transition, escaping the p16^INK4a inhibition. (C) TERT encodes the telomerase reverse transcriptase, involved in the maintenance of telomere length. Mutations in the promoter region of TERT increase telomerase activity resulting in chromosomal instability. POT1 interacts with the shelterin complex acting as protective structure which prevents access of TERT to telomeres. The S270N mutation in the POT1 gene has been associated with familial melanoma. CDK = cyclin-dependent kinase; CDKN2A = cyclin-dependent kinase inhibitor 2A; MDM2 = mouse double minute 2; POT1 = protection of telomeres 1; RB = retinoblastoma. [Copyright: ©2019 Rossi et al.]