Melanoma Susceptibility Genes and Risk Assessment

  • Alexander Marzuka-Alcalá
  • Michele Jacobs Gabree
  • Hensin Tsao
Part of the Methods in Molecular Biology book series (MIMB, volume 1102)


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.

Key words

Familial melanoma Hereditary melanoma CDKN2A p16INK4a P14ARF MC1R MITF BAP1 Genome-wide association studies Cancer risk assessment MelaPRO COMMON syndrome 



Supervision of this scholarly activity was made possible by a grant from NIH to H.T. (K24 CA149202).


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Copyright information

© Springer Science+Business Media, New York 2014

Authors and Affiliations

  • Alexander Marzuka-Alcalá
    • 1
  • Michele Jacobs Gabree
    • 2
  • Hensin Tsao
    • 3
  1. 1.Yale School of MedicineNew HavenUSA
  2. 2.Massachusetts General HospitalCenter for Cancer Risk AssessmentBostonUSA
  3. 3.Department of Dermatology and Massachusetts General Hospital Cancer CenterMassachusetts General HospitalBostonUSA

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