Familial melanoma accounts for approximately a tenth of all
melanoma cases. The most commonly known
melanoma susceptibility gene is the highly penetrant CDKN2A (p16INK4a) locus, which is transmitted in an autosomal dominant fashion and accounts for approximately 20-50 % of
familial melanoma cases. Mutated p16INK4a shows impaired capacity to inhibit the
cyclin D1-CDK4 complex, allowing for unchecked cell cycle progression. Mutations in the second
protein coded by
CDKN2A, p14ARF, are much less common and result in proteasomal degradation of p53 with subsequent accumulation of DNA damage as the cell progresses through the cell cycle without a functional p53-mediated DNA damage response. Mutations in CDK4 that impair the inhibitory interaction with p16INK4a also increase
melanoma risk but these mutations are extremely rare. Genes of the
melanin biosynthetic pathway, including MC1R and MITF, have also been implicated in melanomagenesis. MC1R variants were traditionally thought to increase risk for
melanoma secondary to intensified UV-mediated DNA damage in the setting of absent photoprotective
eumelanin. Accumulation of
pheomelanin, which appears to have a carcinogenic effect regardless of UV exposure, may be a more likely mechanism. Impaired SUMOylation of the E318K variant of MITF results in increased transcription of genes that confer melanocytes with a pro-malignant phenotype. Mutations in the
tumor suppressor BAP1 enhance the metastatic potential of
uveal melanoma and predispose to cutaneous/ocular
melanoma, atypical melanocytic
tumors, and other internal
malignancies (COMMON syndrome). Genome-wide association studies have identified numerous low-risk alleles. Although several
melanoma susceptibility genes have been identified, risk assessment tools have been developed only for the most common gene implicated with hereditary
melanoma, CDKN2A. MelaPRO, a validated model that relies on Mendelian inheritance and Bayesian probability theories, estimates carrier probability for CDKN2A and future risk of
melanoma taking into account a patient's family and past medical history of
melanoma. Genetic testing for CDKN2A mutations is currently available but the
Melanoma Genetics Consortium recommends offering such testing to patients only in the context of research protocols because clinical utility is uncertain.