Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Inherited susceptibility to melanoma

Hensin Tsao, MD, PhD
Linda Rodgers, MGC, CGC
Devanshi Patel, MS, CGC
Section Editors
Michael B Atkins, MD
Benjamin A Raby, MD, MPH
Deputy Editor
Michael E Ross, MD


The etiology of all cancers depends upon the interplay between environmental and genetic factors.

For melanoma, the most significant environmental risk factor is solar ultraviolet (UV) radiation exposure [1]. However, this risk is greatly influenced by genetic factors. As an example, skin type, a heritable trait, modifies the risk presented by a given amount of solar exposure. Dark-skinned populations have a much lower incidence of melanoma than fairer-skinned populations exposed to equivalent sunlight. In the United States, the risk of melanoma in African-Americans is approximately 10 percent of that in Caucasians.

A study of familial risk and hereditability identified 23,980 people who had cancer and were twins [2]. The risk of concordance for melanoma was much greater than the general population, and it was estimated that 58 percent of the risk was inherited.

Significant progress has been made toward understanding the genes that contribute to inherited susceptibility for melanoma in some patients [3]. Uncommon, but high-risk, alleles contribute to the hereditary cancer phenotype that includes multiple cases of the associated cancer or cancers on one side of the family, multiple primary cancers in a given individual, and early age of onset for a given cancer. With further advances in both genomic technologies and the conceptual framework to isolate more prevalent, but lower risk, alleles, the spectrum of genetic lesions that contribute to melanoma risk can be expected to broaden.

The genetic risk factors for melanoma are discussed here, along with potential implications for genetic screening. Other risk factors associated with the development of melanoma are discussed separately. (See "Risk factors for the development of melanoma".)

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Oct 2017. | This topic last updated: Aug 24, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Armstrong BK, English DR. Epidemiologic studies. In: Cutaneous Melanoma, Balch CM, Houghton AN, Milton GW, et al (Eds), JB Lippincott, Philadelphia 1992. p.12.
  2. Mucci LA, Hjelmborg JB, Harris JR, et al. Familial Risk and Heritability of Cancer Among Twins in Nordic Countries. JAMA 2016; 315:68.
  3. Haluska FG, Hodi FS. Molecular genetics of familial cutaneous melanoma. J Clin Oncol 1998; 16:670.
  4. Rivers JK. Melanoma. Lancet 1996; 347:803.
  5. Greene MH, Fraumeni JF, Jr. The hereditary variant of malignant melanoma. In: Human Malignant Melanoma, Clark WH, Jr, Goldman LI, Mastrangelo MJ (Eds), Grune Stratton, New York 1979. p.139.
  6. Clark WH Jr, Reimer RR, Greene M, et al. Origin of familial malignant melanomas from heritable melanocytic lesions. 'The B-K mole syndrome'. Arch Dermatol 1978; 114:732.
  7. Lynch HT, Frichot BC 3rd, Lynch JF. Familial atypical multiple mole-melanoma syndrome. J Med Genet 1978; 15:352.
  8. Crutcher WA, Sagebiel RW. Prevalence of dysplastic naevi in a community practice. Lancet 1984; 1:729.
  9. Piepkorn M, Meyer LJ, Goldgar D, et al. The dysplastic melanocytic nevus: a prevalent lesion that correlates poorly with clinical phenotype. J Am Acad Dermatol 1989; 20:407.
  10. Goldstein AM, Fraser MC, Clark WH Jr, Tucker MA. Age at diagnosis and transmission of invasive melanoma in 23 families with cutaneous malignant melanoma/dysplastic nevi. J Natl Cancer Inst 1994; 86:1385.
  11. Fountain JW, Karayiorgou M, Ernstoff MS, et al. Homozygous deletions within human chromosome band 9p21 in melanoma. Proc Natl Acad Sci U S A 1992; 89:10557.
  12. Cannon-Albright LA, Goldgar DE, Meyer LJ, et al. Assignment of a locus for familial melanoma, MLM, to chromosome 9p13-p22. Science 1992; 258:1148.
  13. Kamb A, Gruis NA, Weaver-Feldhaus J, et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science 1994; 264:436.
  14. Nobori T, Miura K, Wu DJ, et al. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 1994; 368:753.
  15. Piepkorn M. Melanoma genetics: an update with focus on the CDKN2A(p16)/ARF tumor suppressors. J Am Acad Dermatol 2000; 42:705.
  16. Goldstein AM, Chan M, Harland M, et al. High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res 2006; 66:9818.
  17. Goldstein AM, Chan M, Harland M, et al. Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents. J Med Genet 2007; 44:99.
  18. Binni F, Antigoni I, De Simone P, et al. Novel and recurrent p14 mutations in Italian familial melanoma. Clin Genet 2010; 77:581.
  19. Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 1993; 366:704.
  20. Ohtani N, Zebedee Z, Huot TJ, et al. Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence. Nature 2001; 409:1067.
  21. Hunter T, Pines J. Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age. Cell 1994; 79:573.
  22. Sviderskaya EV, Hill SP, Evans-Whipp TJ, et al. p16(Ink4a) in melanocyte senescence and differentiation. J Natl Cancer Inst 2002; 94:446.
  23. Sviderskaya EV, Gray-Schopfer VC, Hill SP, et al. p16/cyclin-dependent kinase inhibitor 2A deficiency in human melanocyte senescence, apoptosis, and immortalization: possible implications for melanoma progression. J Natl Cancer Inst 2003; 95:723.
  24. Soufir N, Avril MF, Chompret A, et al. Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France. The French Familial Melanoma Study Group. Hum Mol Genet 1998; 7:209.
  25. Goldstein AM, Fraser MC, Struewing JP, et al. Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. N Engl J Med 1995; 333:970.
  26. Bruno W, Ghiorzo P, Battistuzzi L, et al. Clinical genetic testing for familial melanoma in Italy: a cooperative study. J Am Acad Dermatol 2009; 61:775.
  27. Potrony M, Puig-Butillé JA, Aguilera P, et al. Increased prevalence of lung, breast, and pancreatic cancers in addition to melanoma risk in families bearing the cyclin-dependent kinase inhibitor 2A mutation: implications for genetic counseling. J Am Acad Dermatol 2014; 71:888.
  28. Begg CB, Orlow I, Hummer AJ, et al. Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample. J Natl Cancer Inst 2005; 97:1507.
  29. Berwick M, Orlow I, Hummer AJ, et al. The prevalence of CDKN2A germ-line mutations and relative risk for cutaneous malignant melanoma: an international population-based study. Cancer Epidemiol Biomarkers Prev 2006; 15:1520.
  30. Bishop DT, Demenais F, Goldstein AM, et al. Geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst 2002; 94:894.
  31. Chaudru V, Chompret A, Bressac-de Paillerets B, et al. Influence of genes, nevi, and sun sensitivity on melanoma risk in a family sample unselected by family history and in melanoma-prone families. J Natl Cancer Inst 2004; 96:785.
  32. Tsao H, Zhang X, Kwitkiwski K, et al. Low prevalence of germline CDKN2A and CDK4 mutations in patients with early-onset melanoma. Arch Dermatol 2000; 136:1118.
  33. Goggins WB, Tsao H. A population-based analysis of risk factors for a second primary cutaneous melanoma among melanoma survivors. Cancer 2003; 97:639.
  34. Blackwood MA, Holmes R, Synnestvedt M, et al. Multiple primary melanoma revisited. Cancer 2002; 94:2248.
  35. Monzon J, Liu L, Brill H, et al. CDKN2A mutations in multiple primary melanomas. N Engl J Med 1998; 338:879.
  36. Auroy S, Avril MF, Chompret A, et al. Sporadic multiple primary melanoma cases: CDKN2A germline mutations with a founder effect. Genes Chromosomes Cancer 2001; 32:195.
  37. Puig S, Malvehy J, Badenas C, et al. Role of the CDKN2A locus in patients with multiple primary melanomas. J Clin Oncol 2005; 23:3043.
  38. de Snoo FA, Bishop DT, Bergman W, et al. Increased risk of cancer other than melanoma in CDKN2A founder mutation (p16-Leiden)-positive melanoma families. Clin Cancer Res 2008; 14:7151.
  39. Borg A, Sandberg T, Nilsson K, et al. High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. J Natl Cancer Inst 2000; 92:1260.
  40. Goldstein AM, Struewing JP, Chidambaram A, et al. Genotype-phenotype relationships in U.S. melanoma-prone families with CDKN2A and CDK4 mutations. J Natl Cancer Inst 2000; 92:1006.
  41. Mantelli M, Barile M, Ciotti P, et al. High prevalence of the G101W germline mutation in the CDKN2A (P16(ink4a)) gene in 62 Italian malignant melanoma families. Am J Med Genet 2002; 107:214.
  42. Azizi E, Friedman J, Pavlotsky F, et al. Familial cutaneous malignant melanoma and tumors of the nervous system. A hereditary cancer syndrome. Cancer 1995; 76:1571.
  43. Randerson-Moor JA, Harland M, Williams S, et al. A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family. Hum Mol Genet 2001; 10:55.
  44. Harland M, Taylor CF, Chambers PA, et al. A mutation hotspot at the p14ARF splice site. Oncogene 2005; 24:4604.
  45. Walsh KM, de Smith AJ, Hansen HM, et al. A Heritable Missense Polymorphism in CDKN2A Confers Strong Risk of Childhood Acute Lymphoblastic Leukemia and Is Preferentially Selected during Clonal Evolution. Cancer Res 2015; 75:4884.
  46. Helgadottir H, Höiom V, Tuominen R, et al. Germline CDKN2A Mutation Status and Survival in Familial Melanoma Cases. J Natl Cancer Inst 2016; 108.
  47. Zuo L, Weger J, Yang Q, et al. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat Genet 1996; 12:97.
  48. Puntervoll HE, Yang XR, Vetti HH, et al. Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants. J Med Genet 2013; 50:264.
  49. Kraemer KH, Lee MM, Andrews AD, Lambert WC. The role of sunlight and DNA repair in melanoma and nonmelanoma skin cancer. The xeroderma pigmentosum paradigm. Arch Dermatol 1994; 130:1018.
  50. Li C, Hu Z, Liu Z, et al. Polymorphisms in the DNA repair genes XPC, XPD, and XPG and risk of cutaneous melanoma: a case-control analysis. Cancer Epidemiol Biomarkers Prev 2006; 15:2526.
  51. Njauw CN, Kim I, Piris A, et al. Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families. PLoS One 2012; 7:e35295.
  52. Pilarski R, Cebulla CM, Massengill JB, et al. Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases. Genes Chromosomes Cancer 2014; 53:177.
  53. Harbour JW, Onken MD, Roberson ED, et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 2010; 330:1410.
  54. Shah AA, Bourne TD, Murali R. BAP1 protein loss by immunohistochemistry: a potentially useful tool for prognostic prediction in patients with uveal melanoma. Pathology 2013; 45:651.
  55. Gupta MP, Lane AM, DeAngelis MM, et al. Clinical Characteristics of Uveal Melanoma in Patients With Germline BAP1 Mutations. JAMA Ophthalmol 2015; 133:881.
  56. Testa JR, Cheung M, Pei J, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet 2011; 43:1022.
  57. Aoude LG, Gartside M, Johansson P, et al. Prevalence of Germline BAP1, CDKN2A, and CDK4 Mutations in an Australian Population-Based Sample of Cutaneous Melanoma Cases. Twin Res Hum Genet 2015; 18:126.
  58. Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 1999; 91:1310.
  59. Sinilnikova OM, Egan KM, Quinn JL, et al. Germline brca2 sequence variants in patients with ocular melanoma. Int J Cancer 1999; 82:325.
  60. Kadouri L, Temper M, Grenader T, et al. Absence of founder BRCA1 and BRCA2 mutations in cutaneous malignant melanoma patients of Ashkenazi origin. Fam Cancer 2009; 8:29.
  61. Buecher B, Gauthier-Villars M, Desjardins L, et al. Contribution of CDKN2A/P16 ( INK4A ), P14 (ARF), CDK4 and BRCA1/2 germline mutations in individuals with suspected genetic predisposition to uveal melanoma. Fam Cancer 2010; 9:663.
  62. Eng C, Li FP, Abramson DH, et al. Mortality from second tumors among long-term survivors of retinoblastoma. J Natl Cancer Inst 1993; 85:1121.
  63. Bartkova J, Lukas J, Guldberg P, et al. The p16-cyclin D/Cdk4-pRb pathway as a functional unit frequently altered in melanoma pathogenesis. Cancer Res 1996; 56:5475.
  64. Valverde P, Healy E, Jackson I, et al. Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans. Nat Genet 1995; 11:328.
  65. Landi MT, Kanetsky PA, Tsang S, et al. MC1R, ASIP, and DNA repair in sporadic and familial melanoma in a Mediterranean population. J Natl Cancer Inst 2005; 97:998.
  66. Valverde P, Healy E, Sikkink S, et al. The Asp84Glu variant of the melanocortin 1 receptor (MC1R) is associated with melanoma. Hum Mol Genet 1996; 5:1663.
  67. Palmer JS, Duffy DL, Box NF, et al. Melanocortin-1 receptor polymorphisms and risk of melanoma: is the association explained solely by pigmentation phenotype? Am J Hum Genet 2000; 66:176.
  68. Kennedy C, ter Huurne J, Berkhout M, et al. Melanocortin 1 receptor (MC1R) gene variants are associated with an increased risk for cutaneous melanoma which is largely independent of skin type and hair color. J Invest Dermatol 2001; 117:294.
  69. Box NF, Duffy DL, Chen W, et al. MC1R genotype modifies risk of melanoma in families segregating CDKN2A mutations. Am J Hum Genet 2001; 69:765.
  70. Fargnoli MC, Spica T, Sera F, et al. Re: MC1R, ASIP, and DNA repair in sporadic and familial melanoma in a Mediterranean population. J Natl Cancer Inst 2006; 98:144.
  71. Scherer D, Nagore E, Bermejo JL, et al. Melanocortin receptor 1 variants and melanoma risk: a study of 2 European populations. Int J Cancer 2009; 125:1868.
  72. Demenais F, Mohamdi H, Chaudru V, et al. Association of MC1R variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study. J Natl Cancer Inst 2010; 102:1568.
  73. Haluska FG, Tsao H, Wu H, et al. Genetic alterations in signaling pathways in melanoma. Clin Cancer Res 2006; 12:2301s.
  74. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005; 353:2135.
  75. Landi MT, Bauer J, Pfeiffer RM, et al. MC1R germline variants confer risk for BRAF-mutant melanoma. Science 2006; 313:521.
  76. Fargnoli MC, Pike K, Pfeiffer RM, et al. MC1R variants increase risk of melanomas harboring BRAF mutations. J Invest Dermatol 2008; 128:2485.
  77. Yokoyama S, Woods SL, Boyle GM, et al. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature 2011; 480:99.
  78. Bertolotto C, Lesueur F, Giuliano S, et al. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature 2011; 480:94.
  79. Potrony M, Puig-Butille JA, Aguilera P, et al. Prevalence of MITF p.E318K in Patients With Melanoma Independent of the Presence of CDKN2A Causative Mutations. JAMA Dermatol 2016; 152:405.
  80. Horn S, Figl A, Rachakonda PS, et al. TERT promoter mutations in familial and sporadic melanoma. Science 2013; 339:959.
  81. Harland M, Petljak M, Robles-Espinoza CD, et al. Germline TERT promoter mutations are rare in familial melanoma. Fam Cancer 2016; 15:139.
  82. Gillanders E, Juo SH, Holland EA, et al. Localization of a novel melanoma susceptibility locus to 1p22. Am J Hum Genet 2003; 73:301.
  83. Robles-Espinoza CD, Harland M, Ramsay AJ, et al. POT1 loss-of-function variants predispose to familial melanoma. Nat Genet 2014; 46:478.
  84. Aoude LG, Pritchard AL, Robles-Espinoza CD, et al. Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma. J Natl Cancer Inst 2015; 107.
  85. Bishop DT, Demenais F, Iles MM, et al. Genome-wide association study identifies three loci associated with melanoma risk. Nat Genet 2009; 41:920.
  86. Brown KM, Macgregor S, Montgomery GW, et al. Common sequence variants on 20q11.22 confer melanoma susceptibility. Nat Genet 2008; 40:838.
  87. Gudbjartsson DF, Sulem P, Stacey SN, et al. ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma. Nat Genet 2008; 40:886.
  88. Falchi M, Bataille V, Hayward NK, et al. Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi. Nat Genet 2009; 41:915.
  89. Udayakumar D, Tsao H. Melanoma genetics: an update on risk-associated genes. Hematol Oncol Clin North Am 2009; 23:415.
  90. Chatzinasiou F, Lill CM, Kypreou K, et al. Comprehensive field synopsis and systematic meta-analyses of genetic association studies in cutaneous melanoma. J Natl Cancer Inst 2011; 103:1227.
  91. Aoude LG, Heitzer E, Johansson P, et al. POLE mutations in families predisposed to cutaneous melanoma. Fam Cancer 2015; 14:621.
  92. Holland EA, Schmid H, Kefford RF, Mann GJ. CDKN2A (P16(INK4a)) and CDK4 mutation analysis in 131 Australian melanoma probands: effect of family history and multiple primary melanomas. Genes Chromosomes Cancer 1999; 25:339.
  93. Berg P, Wennberg AM, Tuominen R, et al. Germline CDKN2A mutations are rare in child and adolescent cutaneous melanoma. Melanoma Res 2004; 14:251.
  94. Vasen HF, Gruis NA, Frants RR, et al. Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden). Int J Cancer 2000; 87:809.
  95. Whelan AJ, Bartsch D, Goodfellow PJ. Brief report: a familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor-suppressor gene. N Engl J Med 1995; 333:975.
  96. Kefford RF, Newton Bishop JA, Bergman W, Tucker MA. Counseling and DNA testing for individuals perceived to be genetically predisposed to melanoma: A consensus statement of the Melanoma Genetics Consortium. J Clin Oncol 1999; 17:3245.
  97. Kefford R, Bishop JN, Tucker M, et al. Genetic testing for melanoma. Lancet Oncol 2002; 3:653.
  98. Robson ME, Storm CD, Weitzel J, et al. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 2010; 28:893.
  99. de Snoo FA, Bergman W, Gruis NA. Familial melanoma: a complex disorder leading to controversy on DNA testing. Fam Cancer 2003; 2:109.
  100. Hansen CB, Wadge LM, Lowstuter K, et al. Clinical germline genetic testing for melanoma. Lancet Oncol 2004; 5:314.
  101. Kasparian NA, Meiser B, Butow PN, et al. Genetic testing for melanoma risk: a prospective cohort study of uptake and outcomes among Australian families. Genet Med 2009; 11:265.
  102. Kasparian NA, Meiser B, Butow PN, et al. Better the devil you know? High-risk individuals' anticipated psychological responses to genetic testing for melanoma susceptibility. J Genet Couns 2006; 15:433.
  103. Aspinwall LG, Leaf SL, Kohlmann W, et al. Patterns of photoprotection following CDKN2A/p16 genetic test reporting and counseling. J Am Acad Dermatol 2009; 60:745.
  104. Loescher LJ, Crist JD, Siaki LA. Perceived intrafamily melanoma risk communication. Cancer Nurs 2009; 32:203.
  105. Taber JM, Aspinwall LG, Stump TK, et al. Genetic test reporting enhances understanding of risk information and acceptance of prevention recommendations compared to family history-based counseling alone. J Behav Med 2015; 38:740.
  106. Aspinwall LG, Taber JM, Kohlmann W, et al. Unaffected family members report improvements in daily routine sun protection 2 years following melanoma genetic testing. Genet Med 2014; 16:846.
  107. Canto MI, Harinck F, Hruban RH, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 2013; 62:339.