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Molecular Nevogenesis: An Update

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Nevogenesis

Abstract

Nevogenesis is a multifactorial process that involves a complex interplay of genetic and environmental factors. Growth promoting mutations (NRAS, HRAS, BRAF, and GNAQ) known to be present in various types of malignant melanoma have also been identified in benign nevi. Their presence roughly correlates with congenital, Spitz, acquired, and blue nevi, respectively. These mutations are likely to play a critical role in driving nevogenesis through activation of the MAP kinase pathway. However, mutations in these genes result in different cellular effects that cause the cells to migrate, proliferate, and differentiate to different extents within the skin. This causes each mutation to give rise to a characteristic growth pattern. Further research is necessary to fully understand nevus development given that most of the same developmental pathways are also present in melanoma.

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References

  1. Ross AL, Sanchez MI, Grichnik JM. Molecular nevogenesis. Dermatol Res Pract. 2011;2011:463184.

    PubMed  Google Scholar 

  2. Robinson WA, Lemon M, Elefanty A, et al. Human acquired naevi are clonal. Melanoma Res. 1998;8(6):499–503.

    Article  PubMed  CAS  Google Scholar 

  3. Hui P, Perkins A, Glusac E. Assessment of clonality in melanocytic nevi. J Cutan Pathol. 2001;28(3):140–4.

    Article  PubMed  CAS  Google Scholar 

  4. Takata M, Saida T. Genetic alterations in melanocytic tumors. J Dermatol Sci. 2006;43(1):1–10.

    Article  PubMed  CAS  Google Scholar 

  5. Demunter A, Stas M, Degreef H, De Wolf-Peeters C, van den Oord JJ. Analysis of N- and K-ras mutations in the distinctive tumor progression phases of melanoma. J Invest Dermatol. 2001;117(6):1483–9.

    Article  PubMed  CAS  Google Scholar 

  6. Kumar R, Angelini S, Hemminki K. Activating BRAF and N-Ras mutations in sporadic primary melanomas: an inverse association with allelic loss on chromosome 9. Oncogene. 2003;22(58):9217–24.

    Article  PubMed  CAS  Google Scholar 

  7. van Dijk MC, Bernsen MR, Ruiter DJ. Analysis of mutations in B-RAF, N-RAS, and H-RAS genes in the differential diagnosis of Spitz nevus and spitzoid melanoma. Am J Surg Pathol. 2005;29(9):1145–51.

    Article  PubMed  Google Scholar 

  8. Bauer J, Curtin JA, Pinkel D, Bastian BC. Congenital melanocytic nevi frequently harbor NRAS mutations but no BRAF mutations. J Invest Dermatol. 2007;127(1):179–82.

    Article  PubMed  CAS  Google Scholar 

  9. Carr J, Mackie RM. Point mutations in the N-ras oncogene in malignant melanoma and congenital naevi. Br J Dermatol. 1994;131(1):72–7.

    Article  PubMed  CAS  Google Scholar 

  10. Jafari M, Papp T, Kirchner S, et al. Analysis of ras mutations in human melanocytic lesions: activation of the ras gene seems to be associated with the nodular type of human malignant melanoma. J Cancer Res Clin Oncol. 1995;121(1):23–30.

    Article  PubMed  CAS  Google Scholar 

  11. Papp T, Pemsel H, Zimmermann R, et al. Mutational analysis of the N-ras, p53, p16INK4a, CDK4, and MC1R genes in human congenital melanocytic naevi. J Med Genet. 1999;36(8):610–4.

    PubMed  CAS  Google Scholar 

  12. Pollock PM, Harper UL, Hansen KS, et al. High frequency of BRAF mutations in nevi. Nat Genet. 2003;33(1):19–20.

    Article  PubMed  CAS  Google Scholar 

  13. Yazdi AS, Palmedo G, Flaig MJ, et al. Mutations of the BRAF gene in benign and malignant melanocytic lesions. J Invest Dermatol. 2003;121(5):1160–2.

    Article  PubMed  CAS  Google Scholar 

  14. Papp T, Schipper H, Kumar K, Schiffmann D, Zimmermann R. Mutational analysis of the BRAF gene in human congenital and dysplastic melanocytic naevi. Melanoma Res. 2005;15(5):401–7.

    Article  PubMed  CAS  Google Scholar 

  15. De Raeve LE, Claes A, Ruiter DJ, et al. Distinct phenotypic changes between the superficial and deep component of giant congenital melanocytic naevi: a rationale for curettage. Br J Dermatol. 2006;154(3):485–92.

    Article  PubMed  Google Scholar 

  16. Ichii-Nakato N, Takata M, Takayanagi S, et al. High frequency of BRAFV600E mutation in acquired nevi and small congenital nevi, but low frequency of mutation in medium-sized congenital nevi. J Invest Dermatol. 2006;126(9):2111–8.

    Article  PubMed  CAS  Google Scholar 

  17. Wu J, Rosenbaum E, Begum S, Westra WH. Distribution of BRAF T1799A(V600E) mutations across various types of benign nevi: implications for melanocytic tumorigenesis. Am J Dermatopathol. 2007;29(6):534–7.

    Article  PubMed  Google Scholar 

  18. Dessars B, De Raeve LE, Morandini R, et al. Genotypic and gene expression studies in congenital melanocytic nevi: insight into initial steps of melanotumorigenesis. J Invest Dermatol. 2009;129(1):139–47.

    Article  PubMed  CAS  Google Scholar 

  19. Wu D, Wang M, Wang X, et al. Lack of BRAF(V600E) mutations in giant congenital melanocytic nevi in a Chinese population. Am J Dermatopathol. 2011;33(4):341–4.

    Article  PubMed  Google Scholar 

  20. Dumaz N, Hayward R, Martin J, et al. In melanoma, RAS mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling. Cancer Res. 2006;66(19):9483–91.

    Article  PubMed  CAS  Google Scholar 

  21. Wojnowski L, Stancato LF, Larner AC, Rapp UR, Zimmer A. Overlapping and specific functions of Braf and Craf-1 proto-oncogenes during mouse embryogenesis. Mech Dev. 2000;91(1–2):97–104.

    Article  PubMed  CAS  Google Scholar 

  22. Smalley KS, Xiao M, Villanueva J, et al. CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations. Oncogene. 2009;28(1):85–94.

    Article  PubMed  CAS  Google Scholar 

  23. Bastian BC, LeBoit PE, Pinkel D. Mutations and copy number increase of HRAS in Spitz nevi with distinctive histopathological features. Am J Pathol. 2000;157(3):967–72.

    Article  PubMed  CAS  Google Scholar 

  24. Hussein MR, Wood GS. Molecular aspects of melanocytic dysplastic nevi. J Mol Diagn. 2002;4(2):71–80.

    Article  PubMed  Google Scholar 

  25. Blokx WA, van Dijk MC, Ruiter DJ. Molecular cytogenetics of cutaneous melanocytic lesions – diagnostic, prognostic and therapeutic aspects. Histopathology. 2010;56(1):121–32.

    Article  PubMed  Google Scholar 

  26. Bastian BC, Wesselmann U, Pinkel D, Leboit PE. Molecular cytogenetic analysis of Spitz nevi shows clear differences to melanoma. J Invest Dermatol. 1999;113(6):1065–9.

    Article  PubMed  CAS  Google Scholar 

  27. Palmedo G, Hantschke M, Rutten A, et al. The T1796A mutation of the BRAF gene is absent in Spitz nevi. J Cutan Pathol. 2004;31(3):266–70.

    Article  PubMed  Google Scholar 

  28. Mihic-Probst D, Perren A, Schmid S, et al. Absence of BRAF gene mutations differentiates spitz nevi from malignant melanoma. Anticancer Res. 2004;24(4):2415–8.

    PubMed  CAS  Google Scholar 

  29. Saldanha G, Purnell D, Fletcher A, et al. High BRAF mutation frequency does not characterize all melanocytic tumor types. Int J Cancer. 2004;111(5):705–10.

    Article  PubMed  CAS  Google Scholar 

  30. Gill M, Renwick N, Silvers DN, Celebi JT. Lack of BRAF mutations in Spitz nevi. J Invest Dermatol. 2004;122(5):1325–6.

    Article  PubMed  Google Scholar 

  31. Turner DJ, Zirvi MA, Barany F, Elenitsas R, Seykora J. Detection of the BRAF V600E mutation in melanocytic lesions using the ligase detection reaction. J Cutan Pathol. 2005;32(5):334–9.

    Article  PubMed  Google Scholar 

  32. Fullen DR, Poynter JN, Lowe L, et al. BRAF and NRAS mutations in spitzoid melanocytic lesions. Mod Pathol. 2006;19(10):1324–32.

    Article  PubMed  CAS  Google Scholar 

  33. La Porta CA, Cardano R, Facchetti F, et al. BRAF V599E mutation occurs in Spitz and Reed naevi. J Eur Acad Dermatol Venereol. 2006;20(9):1164–5.

    Article  PubMed  Google Scholar 

  34. Takata M, Lin J, Takayanagi S, et al. Genetic and epigenetic alterations in the differential diagnosis of malignant melanoma and spitzoid lesion. Br J Dermatol. 2007;156(6):1287–94.

    Article  PubMed  CAS  Google Scholar 

  35. Da Forno PD, Pringle JH, Fletcher A, et al. BRAF, NRAS and HRAS mutations in spitzoid tumours and their possible pathogenetic significance. Br J Dermatol. 2009;161(2):364–72.

    Article  PubMed  Google Scholar 

  36. Emley A, Yang S, Wajapeyee N, Green MR, Mahalingam M. Oncogenic BRAF and the tumor suppressor IGFBP7 in the genesis of atypical spitzoid nevomelanocytic proliferations. J Cutan Pathol. 2010;37(3):344–9.

    Article  PubMed  Google Scholar 

  37. van Engen-van Grunsven AC, van Dijk MC, Ruiter DJ, et al. HRAS-mutated Spitz tumors: a subtype of Spitz tumors with distinct features. Am J Surg Pathol. 2010;34(10):1436–41.

    Article  PubMed  Google Scholar 

  38. Simi L, Pinzani P, Salvianti F, et al. Two novel H-RAS mutations identified in a child with an atypical spitzoid tumor. Arch Dermatol. 2011;147(4):514–5.

    Article  PubMed  CAS  Google Scholar 

  39. Massi D, Cesinaro AM, Tomasini C, et al. Atypical Spitzoid melanocytic tumors: a morphological, mutational, and FISH analysis. J Am Acad Dermatol. 2011;64(5):919–35.

    Article  PubMed  Google Scholar 

  40. Raskin L, Ludgate M, Iyer RK, et al. Copy number variations and clinical outcome in atypical spitz tumors. Am J Surg Pathol. 2011;35(2):243–52.

    Article  PubMed  Google Scholar 

  41. Yan J, Roy S, Apolloni A, Lane A, Hancock JF. Ras isoforms vary in their ability to activate Raf-1 and phosphoinositide 3-kinase. J Biol Chem. 1998;273(37):24052–6.

    Article  PubMed  CAS  Google Scholar 

  42. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54.

    Article  PubMed  CAS  Google Scholar 

  43. Uribe P, Wistuba II, Gonzalez S. BRAF mutation: a frequent event in benign, atypical, and malignant melanocytic lesions of the skin. Am J Dermatopathol. 2003;25(5):365–70.

    Article  PubMed  Google Scholar 

  44. Dong J, Phelps RG, Qiao R, et al. BRAF oncogenic mutations correlate with progression rather than initiation of human melanoma. Cancer Res. 2003;63(14):3883–5.

    PubMed  CAS  Google Scholar 

  45. Poynter JN, Elder JT, Fullen DR, et al. BRAF and NRAS mutations in melanoma and melanocytic nevi. Melanoma Res. 2006;16(4):267–73.

    Article  PubMed  Google Scholar 

  46. Uribe P, Andrade L, Gonzalez S. Lack of association between BRAF mutation and MAPK ERK activation in melanocytic nevi. J Invest Dermatol. 2006;126(1):161–6.

    Article  PubMed  CAS  Google Scholar 

  47. Bloethner S, Snellman E, Bermejo JL, et al. Differential gene expression in melanocytic nevi with the V600E BRAF mutation. Genes Chromosomes Cancer. 2007;46(11):1019–27.

    Article  PubMed  CAS  Google Scholar 

  48. Venesio T, Chiorino G, Balsamo A, et al. In melanocytic lesions the fraction of BRAF V600E alleles is associated with sun exposure but unrelated to ERK phosphorylation. Mod Pathol. 2008;21(6):716–26.

    Article  PubMed  CAS  Google Scholar 

  49. Decarlo K, Yang S, Emley A, et al. Oncogenic BRAF-positive dysplastic nevi and the tumor suppressor IGFBP7 – challenging the concept of dysplastic nevi as precursor lesions? Hum Pathol. 2010;41(6):886–94.

    Article  PubMed  CAS  Google Scholar 

  50. Kanitakis J, Baldassini S, Lora V, Euvrard S. BRAF mutations in melanocytic tumors (nevi and melanomas) from organ transplant recipients. Eur J Dermatol. 2010;20(2):167–71.

    PubMed  CAS  Google Scholar 

  51. Qi RQ, He L, Zheng S, et al. BRAF exon 15 T1799A mutation is common in melanocytic nevi, but less prevalent in cutaneous malignant melanoma, in Chinese Han. J Invest Dermatol. 2011;131(5):1129–38.

    Article  PubMed  CAS  Google Scholar 

  52. Maldonado JL, Fridlyand J, Patel H, et al. Determinants of BRAF mutations in primary melanomas. J Natl Cancer Inst. 2003;95(24):1878–90.

    Article  PubMed  CAS  Google Scholar 

  53. Thomas NE, Edmiston SN, Alexander A, et al. Number of nevi and early-life ambient UV exposure are associated with BRAF-mutant melanoma. Cancer Epidemiol Biomarkers Prev. 2007;16(5):991–7.

    Article  PubMed  CAS  Google Scholar 

  54. Landi MT, Bauer J, Pfeiffer RM, et al. MC1R germline variants confer risk for BRAF-mutant melanoma. Science. 2006;313(5786):521–2.

    Article  PubMed  CAS  Google Scholar 

  55. Garcia-Borron JC, Sanchez-Laorden BL, Jimenez-Cervantes C. Melanocortin-1 receptor structure and functional regulation. Pigment Cell Res. 2005;18(6):393–410.

    PubMed  CAS  Google Scholar 

  56. Mas JS, Gerritsen I, Hahmann C, Jimenez-Cervantes C, Garcia-Borron JC. Rate limiting factors in melanocortin 1 receptor signalling through the cAMP pathway. Pigment Cell Res. 2003;16(5):540–7.

    Article  PubMed  CAS  Google Scholar 

  57. Lin JY, Fisher DE. Melanocyte biology and skin pigmentation. Nature. 2007;445(7130):843–50.

    Article  PubMed  CAS  Google Scholar 

  58. Lin J, Takata M, Murata H, et al. Polyclonality of BRAF mutations in acquired melanocytic nevi. J Natl Cancer Inst. 2009;101(20):1423–7.

    Article  PubMed  CAS  Google Scholar 

  59. Van Raamsdonk CD, Fitch KR, Fuchs H, de Angelis MH, Barsh GS. Effects of G-protein mutations on skin color. Nat Genet. 2004;36(9):961–8.

    Article  PubMed  Google Scholar 

  60. Onken MD, Worley LA, Long MD, et al. Oncogenic mutations in GNAQ occur early in uveal melanoma. Invest Ophthalmol Vis Sci. 2008;49(12):5230–4.

    Article  PubMed  Google Scholar 

  61. Van Raamsdonk CD, Bezrookove V, Green G, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009;457(7229):599–602.

    Article  PubMed  Google Scholar 

  62. Lamba S, Felicioni L, Buttitta F. Mutational profile of GNAQQ209 in human tumors. PLoS One. 2009;4(8):e6833.

    Article  PubMed  Google Scholar 

  63. Bauer J, Kilic E, Vaarwater J, et al. Oncogenic GNAQ mutations are not correlated with disease-free survival in uveal melanoma. Br J Cancer. 2009;101(5):813–5.

    Article  PubMed  CAS  Google Scholar 

  64. Chang F, Steelman LS, Shelton JG, et al. Regulation of cell cycle progression and apoptosis by the Ras/Raf/MEK/ERK pathway (review). Int J Oncol. 2003;22(3):469–80.

    PubMed  CAS  Google Scholar 

  65. Medrano EE, Yang F, Boissy R, et al. Terminal differentiation and senescence in the human melanocyte: repression of tyrosine-phosphorylation of the extracellular signal-regulated kinase 2 selectively defines the two phenotypes. Mol Biol Cell. 1994;5(4):497–509.

    PubMed  CAS  Google Scholar 

  66. Wellbrock C, Rana S, Paterson H. Oncogenic BRAF regulates melanoma proliferation through the lineage specific factor MITF. PLoS One. 2008;3(7):e2734.

    Article  PubMed  Google Scholar 

  67. Voice JK, Klemke RL, Le A, Jackson JH. Four human ras homologs differ in their abilities to activate Raf-1, induce transformation, and stimulate cell motility. J Biol Chem. 1999;274(24):17164–70.

    Article  PubMed  CAS  Google Scholar 

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Conflict of Interest

DigitalDerm, Inc – major shareholder. Spectral Image, Inc – past grants and consulting. MELA Sciences, Inc – past grants and consulting. Genentech – consultant. Archives of Dermatology, skINsight section – editor.

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Authors and Affiliations

  1. Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Room 912, BRB 1501 NW 10th Ave, Miami, 33136, FL, USA

    Andrew L. Ross, Margaret I. Sanchez & James M. Grichnik M.D., Ph.D.

  2. Melanoma Program, Department of Dermatology and Cutaneous Surgery, Sylvester Comprehensive Cancer Center, Miami, FL, USA

    James M. Grichnik M.D., Ph.D.

  3. Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL, USA

    James M. Grichnik M.D., Ph.D.

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  1. Andrew L. Ross
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  2. Margaret I. Sanchez
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  3. James M. Grichnik M.D., Ph.D.
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Correspondence to James M. Grichnik M.D., Ph.D. .

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Editors and Affiliations

  1. Skin Cancer Center, Hauppauge Dermatology Section, Memorial Sloan Kettering, Veterans Memorial Highway 800, Hauppauge, 11788, New York, USA

    Ashfaq A. Marghoob

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Ross, A.L., Sanchez, M.I., Grichnik, J.M. (2012). Molecular Nevogenesis: An Update. In: Marghoob, A. (eds) Nevogenesis. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-28397-0_8

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  • DOI: https://doi.org/10.1007/978-3-642-28397-0_8

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