Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

The molecular biology of melanoma

Ryan J Sullivan, MD
David E Fisher, MD, PhD
Section Editor
Michael B Atkins, MD
Deputy Editor
Michael E Ross, MD


Melanoma is among the most common cancers in the United States, causing 87,000 cases and 9700 deaths annually, and its incidence has risen dramatically [1]. Worldwide, melanoma accounts for 352,000 cases and 60,000 deaths annually [2]. (See "Risk factors for the development of melanoma", section on 'Epidemiology'.)

Although patients with localized disease can be treated successfully with surgical resection in the majority of cases, some individuals present with or subsequently develop disseminated disease. The prognosis for patients with distant metastases from melanoma is poor, and the vast majority of those with stage IV melanoma will die from their disease.

An increasing understanding of melanocyte biology and melanoma pathogenesis is leading to the development of targeted therapies and the potential for major improvements in the care of patients with advanced melanoma. The most important breakthroughs have been the discovery that the mitogen-activated protein kinase (MAPK) pathway is the key signaling pathway and the elucidation of the critical role of microphthalmia-associated transcription factor (MITF).

This topic provides an overview of melanocyte biology and the important molecular alterations of genes and signaling pathways that are critical to the development and pathogenesis of melanoma. The clinical results with targeted agents that are being developed based upon this information are discussed separately. (See "Molecularly targeted therapy for metastatic melanoma".)


Melanocytes are the pigment-containing cells of the skin that produce melanin in response to stimuli such as ultraviolet (UV) radiation. Melanocytes also make the pigment that determines skin and hair color.


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Dec 2016. | This topic last updated: Tue Jan 10 00:00:00 GMT 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. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin 2017.
  2. Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, et al. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncol 2016.
  3. Chin L, Garraway LA, Fisher DE. Malignant melanoma: genetics and therapeutics in the genomic era. Genes Dev 2006; 20:2149.
  4. Lin JY, Fisher DE. Melanocyte biology and skin pigmentation. Nature 2007; 445:843.
  5. Rees JL. Genetics of hair and skin color. Annu Rev Genet 2003; 37:67.
  6. Cui R, Widlund HR, Feige E, et al. Central role of p53 in the suntan response and pathologic hyperpigmentation. Cell 2007; 128:853.
  7. Fisher DE, James WD. Indoor tanning--science, behavior, and policy. N Engl J Med 2010; 363:901.
  8. Khaled M, Levy C, Fisher DE. Control of melanocyte differentiation by a MITF-PDE4D3 homeostatic circuit. Genes Dev 2010; 24:2276.
  9. D'Orazio JA, Nobuhisa T, Cui R, et al. Topical drug rescue strategy and skin protection based on the role of Mc1r in UV-induced tanning. Nature 2006; 443:340.
  10. Omholt K, Platz A, Kanter L, et al. NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Clin Cancer Res 2003; 9:6483.
  11. Krauthammer M, Kong Y, Bacchiocchi A, et al. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas. Nat Genet 2015; 47:996.
  12. Cancer Genome Atlas Network. Genomic Classification of Cutaneous Melanoma. Cell 2015; 161:1681.
  13. Bardeesy N, Kim M, Xu J, et al. Role of epidermal growth factor receptor signaling in RAS-driven melanoma. Mol Cell Biol 2005; 25:4176.
  14. Furge KA, Kiewlich D, Le P, et al. Suppression of Ras-mediated tumorigenicity and metastasis through inhibition of the Met receptor tyrosine kinase. Proc Natl Acad Sci U S A 2001; 98:10722.
  15. Monsel G, Ortonne N, Bagot M, et al. c-Kit mutants require hypoxia-inducible factor 1alpha to transform melanocytes. Oncogene 2010; 29:227.
  16. Maertens O, Johnson B, Hollstein P, et al. Elucidating distinct roles for NF1 in melanomagenesis. Cancer Discov 2013; 3:338.
  17. Beeram M, Patnaik A, Rowinsky EK. Raf: a strategic target for therapeutic development against cancer. J Clin Oncol 2005; 23:6771.
  18. Chong H, Guan KL. Regulation of Raf through phosphorylation and N terminus-C terminus interaction. J Biol Chem 2003; 278:36269.
  19. Fischer A, Hekman M, Kuhlmann J, et al. B- and C-RAF display essential differences in their binding to Ras: the isotype-specific N terminus of B-RAF facilitates Ras binding. J Biol Chem 2007; 282:26503.
  20. Tran NH, Wu X, Frost JA. B-Raf and Raf-1 are regulated by distinct autoregulatory mechanisms. J Biol Chem 2005; 280:16244.
  21. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417:949.
  22. Garnett MJ, Rana S, Paterson H, et al. Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Mol Cell 2005; 20:963.
  23. Terai K, Matsuda M. The amino-terminal B-Raf-specific region mediates calcium-dependent homo- and hetero-dimerization of Raf. EMBO J 2006; 25:3556.
  24. Pollock PM, Harper UL, Hansen KS, et al. High frequency of BRAF mutations in nevi. Nat Genet 2003; 33:19.
  25. Dong J, Phelps RG, Qiao R, et al. BRAF oncogenic mutations correlate with progression rather than initiation of human melanoma. Cancer Res 2003; 63:3883.
  26. Poynter JN, Elder JT, Fullen DR, et al. BRAF and NRAS mutations in melanoma and melanocytic nevi. Melanoma Res 2006; 16:267.
  27. Lin J, Goto Y, Murata H, et al. Polyclonality of BRAF mutations in primary melanoma and the selection of mutant alleles during progression. Br J Cancer 2011; 104:464.
  28. Lin J, Takata M, Murata H, et al. Polyclonality of BRAF mutations in acquired melanocytic nevi. J Natl Cancer Inst 2009; 101:1423.
  29. Sharma A, Trivedi NR, Zimmerman MA, et al. Mutant V599EB-Raf regulates growth and vascular development of malignant melanoma tumors. Cancer Res 2005; 65:2412.
  30. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005; 353:2135.
  31. Van Raamsdonk CD, Bezrookove V, Green G, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 2009; 457:599.
  32. Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med 2010; 363:2191.
  33. Harbour JW, Onken MD, Roberson ED, et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 2010; 330:1410.
  34. Kong Y, Si L, Zhu Y, et al. Large-scale analysis of KIT aberrations in Chinese patients with melanoma. Clin Cancer Res 2011; 17:1684.
  35. Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA 2011; 305:2327.
  36. Guo J, Si L, Kong Y, et al. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 2011; 29:2904.
  37. Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 2006; 24:4340.
  38. Beadling C, Jacobson-Dunlop E, Hodi FS, et al. KIT gene mutations and copy number in melanoma subtypes. Clin Cancer Res 2008; 14:6821.
  39. Albino AP, Le Strange R, Oliff AI, et al. Transforming ras genes from human melanoma: a manifestation of tumour heterogeneity? Nature 1984; 308:69.
  40. Ball NJ, Yohn JJ, Morelli JG, et al. Ras mutations in human melanoma: a marker of malignant progression. J Invest Dermatol 1994; 102:285.
  41. Platz A, Ringborg U, Brahme EM, Lagerlöf B. Melanoma metastases from patients with hereditary cutaneous malignant melanoma contain a high frequency of N-ras activating mutations. Melanoma Res 1994; 4:169.
  42. van 't Veer LJ, Burgering BM, Versteeg R, et al. N-ras mutations in human cutaneous melanoma from sun-exposed body sites. Mol Cell Biol 1989; 9:3114.
  43. Jin SA, Chun SM, Choi YD, et al. BRAF mutations and KIT aberrations and their clinicopathological correlation in 202 Korean melanomas. J Invest Dermatol 2013; 133:579.
  44. Lin YC, Chang YM, Ho JY, et al. C-kit expression of melanocytic neoplasm and association with clinicopathological parameters and anatomic locations in Chinese people. Am J Dermatopathol 2013; 35:569.
  45. Hodis E, Watson IR, Kryukov GV, et al. A landscape of driver mutations in melanoma. Cell 2012; 150:251.
  46. Menzies AM, Haydu LE, Visintin L, et al. Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res 2012; 18:3242.
  47. Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol 2011; 29:1239.
  48. Shain AH, Yeh I, Kovalyshyn I, et al. The Genetic Evolution of Melanoma from Precursor Lesions. N Engl J Med 2015; 373:1926.
  49. Carvajal RD, Sosman JA, Quevedo JF, et al. Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. JAMA 2014; 311:2397.
  50. Prescher G, Bornfeld N, Hirche H, et al. Prognostic implications of monosomy 3 in uveal melanoma. Lancet 1996; 347:1222.
  51. Desjardins L, Levy-Gabriel C, Lumbroso-Lerouic L, et al. [Prognostic factors for malignant uveal melanoma. Retrospective study on 2,241 patients and recent contribution of monosomy-3 research]. J Fr Ophtalmol 2006; 29:741.
  52. Sisley K, Rennie IG, Parsons MA, et al. Abnormalities of chromosomes 3 and 8 in posterior uveal melanoma correlate with prognosis. Genes Chromosomes Cancer 1997; 19:22.
  53. Becher R, Korn WM, Prescher G. Use of fluorescence in situ hybridization and comparative genomic hybridization in the cytogenetic analysis of testicular germ cell tumors and uveal melanomas. Cancer Genet Cytogenet 1997; 93:22.
  54. Parrella P, Sidransky D, Merbs SL. Allelotype of posterior uveal melanoma: implications for a bifurcated tumor progression pathway. Cancer Res 1999; 59:3032.
  55. Shields CL, Ganguly A, Bianciotto CG, et al. Prognosis of uveal melanoma in 500 cases using genetic testing of fine-needle aspiration biopsy specimens. Ophthalmology 2011; 118:396.
  56. Griewank KG, Westekemper H, Murali R, et al. Conjunctival melanomas harbor BRAF and NRAS mutations and copy number changes similar to cutaneous and mucosal melanomas. Clin Cancer Res 2013; 19:3143.
  57. Haq R, Fisher DE. Biology and clinical relevance of the micropthalmia family of transcription factors in human cancer. J Clin Oncol 2011; 29:3474.
  58. Garraway LA, Widlund HR, Rubin MA, et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 2005; 436:117.
  59. Ugurel S, Houben R, Schrama D, et al. Microphthalmia-associated transcription factor gene amplification in metastatic melanoma is a prognostic marker for patient survival, but not a predictive marker for chemosensitivity and chemotherapy response. Clin Cancer Res 2007; 13:6344.
  60. Bertolotto C, Lesueur F, Giuliano S, et al. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature 2011; 480:94.
  61. Yokoyama S, Woods SL, Boyle GM, et al. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature 2011; 480:99.
  62. Hemesath TJ, Price ER, Takemoto C, et al. MAP kinase links the transcription factor Microphthalmia to c-Kit signalling in melanocytes. Nature 1998; 391:298.
  63. Wu M, Hemesath TJ, Takemoto CM, et al. c-Kit triggers dual phosphorylations, which couple activation and degradation of the essential melanocyte factor Mi. Genes Dev 2000; 14:301.
  64. Boni A, Cogdill AP, Dang P, et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res 2010; 70:5213.
  65. Haq R, Shoag J, Andreu-Perez P, et al. Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF. Cancer Cell 2013; 23:302.
  66. Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 2010; 467:596.
  67. Joseph EW, Pratilas CA, Poulikakos PI, et al. The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc Natl Acad Sci U S A 2010; 107:14903.
  68. Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 2010; 140:209.
  69. Poulikakos PI, Zhang C, Bollag G, et al. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 2010; 464:427.
  70. Hatzivassiliou G, Song K, Yen I, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 2010; 464:431.
  71. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364:2507.
  72. Johannessen CM, Boehm JS, Kim SY, et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 2010; 468:968.
  73. Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 2010; 468:973.
  74. Tap WD, Gong KW, Dering J, et al. Pharmacodynamic characterization of the efficacy signals due to selective BRAF inhibition with PLX4032 in malignant melanoma. Neoplasia 2010; 12:637.
  75. Trunzer K, Pavlick AC, Schuchter L, et al. Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma. J Clin Oncol 2013; 31:1767.
  76. Montagut C, Sharma SV, Shioda T, et al. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res 2008; 68:4853.
  77. Wagle N, Emery C, Berger MF, et al. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol 2011; 29:3085.
  78. Wang H, Daouti S, Li WH, et al. Identification of the MEK1(F129L) activating mutation as a potential mechanism of acquired resistance to MEK inhibition in human cancers carrying the B-RafV600E mutation. Cancer Res 2011; 71:5535.
  79. Shi H, Moriceau G, Kong X, et al. Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat Commun 2012; 3:724.
  80. Whittaker SR, Theurillat JP, Van Allen E, et al. A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition. Cancer Discov 2013; 3:350.
  81. Poulikakos PI, Persaud Y, Janakiraman M, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 2011; 480:387.
  82. Villanueva J, Vultur A, Lee JT, et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 2010; 18:683.
  83. Shi H, Hong A, Kong X, et al. A novel AKT1 mutant amplifies an adaptive melanoma response to BRAF inhibition. Cancer Discov 2014; 4:69.
  84. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010; 363:809.
  85. Smalley KS, Lioni M, Dalla Palma M, et al. Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas. Mol Cancer Ther 2008; 7:2876.
  86. Nathanson KL, Martin AM, Wubbenhorst B, et al. Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor dabrafenib (GSK2118436). Clin Cancer Res 2013; 19:4868.
  87. Haq R, Yokoyama S, Hawryluk EB, et al. BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition. Proc Natl Acad Sci U S A 2013; 110:4321.
  88. Wilson TR, Fridlyand J, Yan Y, et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 2012; 487:505.
  89. Straussman R, Morikawa T, Shee K, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 2012; 487:500.
  90. Solit DB, Garraway LA, Pratilas CA, et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature 2006; 439:358.
  91. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012; 367:107.
  92. Carvajal et al. ASCO 2013 Annual Meeting. J Clin Oncol 31, 2013. Abstract: CRS9003.
  93. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012; 367:1694.
  94. Ribas A, Gonzalez R, Pavlick A, et al. Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. Lancet Oncol 2014; 15:954.
  95. Sullivan RJ, Weber JS, Patel SP, et al. A phase 1b/2 study of BRAF inhibitor (BRAFi) encorafenib (ENCO) plus MEK inhibitor (MEKi) binimetinib (BINI) in cutaneous melanoma patients naïve to BRAFi treatment. ASCO 2015 Annual Meeting, abstr 9007; Chicago, IL.
  96. Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 2014; 371:1867.
  97. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2015; 372:30.
  98. Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 2014; 371:1877.