Abstract
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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Goldstein AM, Tucker MA (2004) Familial melanoma and its management. In: Eeles R, Easton D, Eng C, Ponder B (eds) Genetic predisposition to cancer, 2nd edn. Arnold Publishers Ltd, London
Kamb A, Shattuck-Eidens D, Eeles R et al (1994) Analysis of the p16 gene (CDKN2A) as a candidate for the chromosome 9p melanoma susceptibility locus. Nat Genet 8:23–26
Hussussian CJ, Struewing JP, Goldstein AM et al (1994) Germline p16 mutations in familial melanoma. Nat Genet 8:15–21
Goldstein AM, Tucker MA (2001) Genetic epidemiology of cutaneous melanoma: a global perspective. Arch Dermatol 137:1493–1496
Goldstein AM, Chan M, Harland M et al (2007) Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents. J Med Genet 44:99–106
Hashemi J, Platz A, Ueno T et al (2000) CDKN2A germ-line mutations in individuals with multiple cutaneous melanomas. Cancer Res 60:6864–6867
Monzon J, Liu L, Brill H et al (1998) CDKN2A mutations in multiple primary melanomas. N Engl J Med 338:879–887
Koh J, Enders GH, Dynlacht BD et al (1995) Tumour-derived p16INK4a alleles encoding proteins defective in cell-cycle inhibition. Nature 375:506–510
Lukas J, Parry D, Aagaard L et al (1995) Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature 375:503–506
Tsao H, Chin L, Garraway LA et al (2012) Melanoma: from mutations to medicine. Genes Dev 26(11):1131–1135
Udayakumar D, Mahato B, Gabree M et al (2010) Genetic determinants of cutaneous melanoma predisposition. Semin Cutan Med Surg 29(3):190–195
Pomerantz J, Schreiber-Agus N, Liegeois NJ et al (1998) The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2’s inhibition of p53. Cell 92:713–723
Stott FJ, Bates S, James MC et al (1998) The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J 17:5001–5014
Zhang Y, Xiong Y, Yarbrough WG et al (1998) ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 92:725–734
Bishop DT, Demenais F, Goldstein AM et al (2002) Geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst 19:894–903
Begg CB, Orlow I, Hummer AJ et al (2005) Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample. J Natl Cancer Inst 97(20):1507–1515
Whiteman DC, Milligan A, Welch J et al (1997) Germline CDKN2A mutations in childhood melanoma. J Natl Cancer Inst 89:1460
Tsao H, Zhang X, Kwitkiwski K et al (2000) Low prevalence of germline CDKN2A and CDK4 mutations in patients with early-onset melanoma. Arch Dermatol 136:1118–1122
Foulkes WD, Flanders TY, Pollock PM et al (1997) The CDKN2A (p16) gene and human cancer. Mol Med 3(1):5–20
Tucker MA, Halpern A, Holly EA et al (1997) Clinically recognized dysplastic nevi. A central risk factor for cutaneous melanoma. JAMA 277:1439–1444
Puig S, Ruiz A, Castel T et al (1997) Inherited susceptibility to several cancers but absence of linkage between dysplastic nevus syndrome and CDKN2A in a melanoma family with a mutation in the CDKN2A (P16INK4A) gene. Hum Genet 101:359–364
Goldstein AM, Fraser MC, Struewing JP et al (1995) Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. N Engl J Med 333:970–974
Leachman SA, Carucci J, Kohlman W et al (2009) Selection criteria for genetic assessment of patients with melanoma. J Am Acad Dermatol 61(4):677
Wang W, Niendorf KB, Patel D et al (2010) Estimating CDKN2A carrier probability and personalizing cancer risk assessments in hereditary melanoma using MelaPRO. Cancer Res 70(2):552–559
Nikolaou V, Kang X, Stratigos A et al (2011) Comprehensive mutational analysis of CDKN2A and CDK4 in Greek patients with cutaneous melanoma. Br J Dermatol 165(6):1219–1222
Zuo L, Weger J, Yang Q et al (1996) Germline mutations in p16INK4a binding domain of CDK4 in familial melanoma. Nat Genet 12:97–99
Fitzgerald MG, Harkin DP, Silva-Arrieta S et al (1996) Prevalence of germline mutations in p16, p19ARF, and CDK4 in familial melanoma: analysis of a clinic-based population. Proc Natl Acad Sci 93:8541–8545
Soufir N, Avril MF, Chompret A et al (1998) Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France. The French Familial Melanoma Study Group. Hum Mol Genet 7:209–216
Harbour JW, Onken MD, Roberson ED et al (2010) Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 330(6009):1410–1413
Wiesner T, Obenauf AC, Murali R et al (2011) Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet 43(10):1018–1021
Testa JR, Cheung M, Pei J et al (2011) Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet 43(10):1022–1025
Njauw CN, Kim I, Piris A et al (2012) Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families. PLoS One 7(4):e35295
Carbone M, Korb FL, Baumann F et al (2012) BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs. J Transl Med 10(1):179
Wadt K, Choi J, Chung JY et al (2012) A cryptic BAP1 splice mutation in a family with uveal and cutaneous melanoma, and paraganglioma. Pigment Cell Melanoma Res. doi:10.1111/pcmr.12006
Gandini S, Sera F, Cattaruzza MS et al (2005) Meta-analysis of risk factors for cutaneous melanoma. I. Common and atypical naevi. Eur J Cancer 41:28–44
Gandini S, Sera F, Cattaruzza MS et al (2005) Meta-analysis of risk factors for cutaneous melanoma. III. Family history, actinic damage, and phenotypic factors. Eur J Cancer 41:2040–2059
Miller AJ, Tsao H (2010) New insights into pigmentary pathways and skin cancer. Br J Dermatol 162(1):22–28
Valverde F, Healy E, Jackson I et al (1995) Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans. Nat Genet 11:328–330
Kennedy C, ter Huurne J, Berkhout M et al (2001) Melanocortin 1 receptor (MC1R) gene variants are associated with an increased risk of cutaneous melanoma which is largely independent of skin type and hair color. J Invest Dermatol 117:294–300
Raimondi S, Sera F, Gandini S et al (2008) MC1R variants, melanoma, and red hair color phenotype: a meta-analysis. Int J Cancer 122:2753–2760
Kraemer KH, Lee MM, Andrews AD et al (1994) The role of sunlight and DNA repair in melanoma and nonmelanoma skin cancer. The xeroderma pigmentosum paradigm. Arch Dermatol 130(8):1018–1021
Mitra D, Luo X, Wargo J et al (2011) Why red-heads are at increased risk of melanoma: a novel BRAF mutant mouse model. Pigm Cell Melanoma R 24:1016
Levy C, Khaled M, Fisher DE et al (2006) MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol Med 12(9):406–413
Yokoyama S, Woods S, Boyle GM et al (2011) A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature 480:99–103
Bertolotto C, Lesueur F, Giuliano S et al (2011) A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature 480:94–98
Barrett JH, Iles MM, Harland M et al (2011) Genome-wide association study identifies three new melanoma susceptibility loci. Nat Genet 43(11):1108–1113
Amos CI, Wang LE, Lee JE et al (2011) Genome-wide association study identifies novel loci predisposing to cutaneous melanoma. Hum Mol Genet 20(24):5012–5023
Macgregor S, Montgomery GW, Liu JZ et al (2011) Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3. Nat Genet 43(11):1114–1118
Falchi M, Bataille V, Hayward NK et al (2009) Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi. Nat Genet 41(8):915–919
Bishop DT, Demenais F, Iles MM et al (2009) Genome-wide association study identifies three loci associated with melanoma risk. Nat Genet 41(8):920–925
Niendorf KB, Goggins W, Yang G et al (2006) MELPREDICT: a logistic regression model to estimate CDKN2A carrier probability. J Med Genet 43:501–506
Robson ME, Storm CD, Weitzel J et al (2010) Policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 28:893–901
Kefford R, Bishop JN, Tucker M et al (2002) Genetic testing for melanoma. Lancet Oncol 3:653–654
Kefford RF, Newton Bishop JA, Bergman W et al (1999) Counseling and DNA testing for individuals perceived to be genetically predisposed to melanoma: a consensus statement of the Melanoma Genetics Consortium. J Clin Oncol 17:3245–3251
Niendorf KB, Tsao H (2006) Cutaneous melanoma: family screening and genetic testing. Dermatol Ther 19:1–8
Rulyak SJ, Kimmey MB, Veenstra DL et al (2003) Cost-effectiveness of pancreatic cancer screening in familial pancreatic cancer kindreds. Gastrointest Endosc 57:23–29
Acknowledgements
Supervision of this scholarly activity was made possible by a grant from NIH to H.T. (K24 CA149202).
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media, New York
About this protocol
Cite this protocol
Marzuka-Alcalá, A., Gabree, M.J., Tsao, H. (2014). Melanoma Susceptibility Genes and Risk Assessment. In: Thurin, M., Marincola, F. (eds) Molecular Diagnostics for Melanoma. Methods in Molecular Biology, vol 1102. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-727-3_20
Download citation
DOI: https://doi.org/10.1007/978-1-62703-727-3_20
Published:
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-62703-726-6
Online ISBN: 978-1-62703-727-3
eBook Packages: Springer Protocols