Skip to main content
SpringerLink
Log in

Melanoma Biomarkers

Current Status and Utility in Diagnosis, Prognosis, and Response to Therapy

  • Review Article
  • Published:
Molecular Diagnosis & Therapy Aims and scope Submit manuscript

Abstract

Melanoma is the most devastating form of skin cancer and represents a leading cause of cancer death, particularly in young adults. As even relatively small melanomas can readily metastasize, accurate staging of progression is critical. Diagnosis is typically made on the basis of histopathologic criteria; with tumor thickness (Breslow), invasion level (Clark), ulceration, and the extent of lymph node involvement being important prognostic indicators. However, histologic criteria alone cannot diagnose all melanomas and there are often problems in distinguishing subsets of benign nevi from melanoma. There also exists a group of patients with thin primary melanomas for whom surgery should be curative but who ultimately go on to develop metastases. Therefore, there is an urgent need to develop molecular biomarkers that identify melanoma patients with high-risk primary lesions to facilitate greater surveillance and possible adjuvant therapy.

The advent of large-scale genomic profiling of melanoma is revealing considerable heterogeneity, suggesting that melanomas could be subgrouped according to their patterns of oncogenic mutation and gene expression. It is hoped that this subgrouping will allow for the personalization of melanoma therapy using novel molecularly targeted agents. Much effort is now geared toward defining the genetic markers that may predict response to targeted therapy agents as well as identifying pharmacodynamic markers of therapy response. In this review, we discuss the utility of melanoma biomarkers for diagnosis and prognosis and suggest how novel molecular signatures can help guide both melanoma diagnosis and therapy selection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008 Mar–Apr; 58(2): 71–96

    Article  PubMed  Google Scholar 

  2. Carlson JA, Ross JS, Slominski AJ. New techniques in dermatopathology that help to diagnose and prognosticate melanoma. Clin Dermatol 2009 Jan–Feb; 27(1): 75–102

    Article  PubMed  Google Scholar 

  3. Carlson JA, Ross JS, Slominski A, et al. Molecular diagnostics in melanoma. J Am Acad Dermatol 2005 May; 52(5): 743–75; quiz 75-8

    Article  PubMed  Google Scholar 

  4. Gould Rothberg BE, Bracken MB, Rimm DL. Tissue biomarkers for prognosis in cutaneous melanoma: a systematic review and meta-analysis. J Natl Cancer Inst 2009 Apr 1; 101(7): 452–74

    Article  CAS  Google Scholar 

  5. Smalley KS, Brafford PA, Herlyn M. Selective evolutionary pressure from the tissue microenvironment drives tumor progression. Semin Cancer Biol 2005 Dec; 15(6): 451–9

    Article  PubMed  CAS  Google Scholar 

  6. Haass NK, Smalley KS, Herlyn M. The role of altered cell-cell communication in melanoma progression. J Mol Histol 2004 Mar; 35(3): 309–18

    Article  PubMed  CAS  Google Scholar 

  7. Haass NK, Herlyn M. Normal human melanocyte homeostasis as a paradigm for understanding melanoma. J Investig Dermatol Symp Proc 2005 Nov; 10(2): 153–63

    Article  PubMed  CAS  Google Scholar 

  8. Haass NK, Smalley KS, Li L, et al. Adhesion, migration and communication in melanocytes and melanoma. Pigment Cell Res 2005 Jun; 18(3): 150–9

    Article  PubMed  CAS  Google Scholar 

  9. Santiago-Walker A, Li L, Haass NK, et al. Melanocytes: from morphology to application. Skin Pharmacol Physiol 2009; 22(2): 114–21

    Article  PubMed  CAS  Google Scholar 

  10. Villanueva J, Herlyn M. Melanoma and the tumor microenvironment. Curr Oncol Rep 2008 Sep; 10(5): 439–46

    Article  PubMed  CAS  Google Scholar 

  11. Larson AR, Konat E, Alani RM. Melanoma biomarkers: current status and vision for the future. Nat Clin Pract Oncol 2009 Feb; 6(2): 105–17

    Article  PubMed  CAS  Google Scholar 

  12. Bosserhoff AK. Novel biomarkers in malignant melanoma. Clin Chim Acta 2006 May; 367(1–2): 28–35

    Article  PubMed  CAS  Google Scholar 

  13. Ohsie SJ, Sarantopoulos GP, Cochran AJ, et al. Immunohistochemical characteristics of melanoma. J Cutan Pathol 2008 May; 35(5): 433–44

    Article  PubMed  Google Scholar 

  14. Prieto VG, Shea CR. Use of immunohistochemistry in melanocytic lesions. J Cutan Pathol 2008 Nov; 35Suppl. 2: 1–10

    Article  PubMed  Google Scholar 

  15. Thies A, Berlin A, Brunner G, et al. Glycoconjugate profiling of primary melanoma and its sentinel node and distant metastases: implications for diagnosis and pathophysiology of metastases. Cancer Lett 2007 Apr 8; 248(1): 68–80

    Article  PubMed  CAS  Google Scholar 

  16. Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001 Aug 15; 19(16): 3622–34

    PubMed  CAS  Google Scholar 

  17. Breslow A. Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg 1970 Nov; 172(5): 902–8

    Article  PubMed  CAS  Google Scholar 

  18. Clark Jr WH, From L, Bernardino EA, et al. The histogenesis and biologic behavior of primary human malignant melanomas of the skin. Cancer Res 1969 Mar; 29(3): 705–27

    PubMed  Google Scholar 

  19. McDermott NC, Hayes DP, al-Sader MH, et al. Identification of vertical growth phase in malignant melanoma: a study of interobserver agreement. Am J Clin Pathol 1998 Dec; 110(6): 753–7

    PubMed  CAS  Google Scholar 

  20. Lens MB, Dawes M, Newton-Bishop JA, et al. Tumour thickness as a predictor of occult lymph node metastases in patients with stage I and II melanoma undergoing sentinel lymph node biopsy. Br J Surg 2002 Oct; 89(10): 1223–7

    Article  PubMed  CAS  Google Scholar 

  21. Gonzalez U. Cloud over sentinel node biopsy: unlikely survival benefit in melanoma. Arch Dermatol 2007 Jun; 143(6): 775–6

    Article  PubMed  Google Scholar 

  22. Kanzler MH. The current status of evaluation and treatment of high-risk cutaneous melanoma: therapeutic breakthroughs remain elusive. Arch Dermatol 2007 Jun; 143(6): 785–7

    Article  PubMed  Google Scholar 

  23. Morton DL, Thompson JF, Cochran AJ, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 2006 Sep 28; 355(13): 1307–17

    Article  PubMed  CAS  Google Scholar 

  24. Kashani-Sabet M, Rangel J, Torabian S, et al. A multi-marker assay to distinguish malignant melanomas from benign nevi. Proc Natl Acad Sci U S A 2009 Apr 14; 106(15): 6268–72

    Article  PubMed  CAS  Google Scholar 

  25. Shih IM, Speicher D, Hsu MY, et al. Melanoma cell-cell interactions are mediated through heterophilic Mel-CAM/ligand adhesion. Cancer Res 1997 Sep 1; 57(17): 3835–40

    PubMed  CAS  Google Scholar 

  26. Johnson JP, Bar-Eli M, Jansen B, et al. Melanoma progression-associated glycoprotein MUC18/MCAM mediates homotypic cell adhesion through interaction with a heterophilic ligand. Int J Cancer 1997 Nov 27; 73(5): 769–74

    Article  PubMed  CAS  Google Scholar 

  27. Shih LM, Hsu MY, Palazzo JP, et al. The cell-cell adhesion receptor Mel-CAM acts as a tumor suppressor in breast carcinoma. Am J Pathol 1997 Sep; 151(3): 745–51

    PubMed  CAS  Google Scholar 

  28. Shih IM, Elder DE, Speicher D, et al. Isolation and functional characterization of the A32 melanoma-associated antigen. Cancer Res 1994 May 1; 54(9): 2514–20

    PubMed  CAS  Google Scholar 

  29. Kraus A, Masat L, Johnson JP. Analysis of the expression of intercellular adhesion molecule-1 and MUC18 on benign and malignant melanocytic lesions using monoclonal antibodies directed against distinct epitopes and recognizing denatured, non-glycosylated antigen. Melanoma Res 1997 Aug; 7Suppl. 2: S75–81

    PubMed  CAS  Google Scholar 

  30. Xie S, Luca M, Huang S, et al. Expression of MCAM/MUC18 by human melanoma cells leads to increased tumor growth and metastasis. Cancer Res 1997 Jun 1; 57(11): 2295–303

    PubMed  CAS  Google Scholar 

  31. Johnson JP, Rummel MM, Rothbacher U, et al. MUC18: a cell adhesion molecule with a potential role in tumor growth and tumor cell dissemination. Curr Top Microbiol Immunol 1996; 213(Pt 1): 95–105

    Article  PubMed  CAS  Google Scholar 

  32. Lehmann JM, Holzmann B, Breitbart EW, et al. Discrimination between benign and malignant cells of melanocytic lineage by two novel antigens, a glycoprotein with a molecular weight of 113,000 and a protein with a molecular weight of 76,000. Cancer Res 1987 Feb 1; 47(3): 841–5

    PubMed  CAS  Google Scholar 

  33. Lehmann JM, Riethmuller G, Johnson JP. MUC18, a marker of tumor progression in human melanoma, shows sequence similarity to the neural cell adhesion molecules of the immunoglobulin superfamily. Proc Natl Acad Sci U S A 1989 Dec; 86(24): 9891–5

    Article  PubMed  CAS  Google Scholar 

  34. Pacifico MD, Grover R, Richman PI, et al. Development of a tissue array for primary melanoma with long-term follow-up: discovering melanoma cell adhesion molecule as an important prognostic marker. Plast Reconstr Surg 2005 Feb; 115(2): 367–75

    Article  PubMed  CAS  Google Scholar 

  35. Ostmeier H, Fuchs B, Otto F, et al. Prognostic immunohistochemical markers of primary human melanomas. Br J Dermatol 2001 Aug; 145(2): 203–9

    Article  PubMed  CAS  Google Scholar 

  36. Pearl RA, Pacifico MD, Richman PI, et al. Stratification of patients by melanoma cell adhesion molecule (MCAM) expression on the basis of risk: implications for sentinel lymph node biopsy. J Plast Reconstr Aesthet Surg 2008; 61(3): 265–71

    Article  PubMed  CAS  Google Scholar 

  37. Nolte C, Moos M, Schachner M. Immunolocalization of the neural cell adhesion molecule L1 in epithelia of rodents. Cell Tissue Res 1999 Nov; 298(2): 261–73

    Article  PubMed  CAS  Google Scholar 

  38. Thies A, Schachner M, Moll I, et al. Overexpression of the cell adhesion molecule L1 is associated with metastasis in cutaneous malignant melanoma. Eur J Cancer 2002 Sep; 38(13): 1708–16

    Article  PubMed  CAS  Google Scholar 

  39. Hortsch M. The L1 family of neural cell adhesion molecules: old proteins performing new tricks. Neuron 1996 Oct; 17(4): 587–93

    Article  PubMed  CAS  Google Scholar 

  40. Montgomery AM, Becker JC, Siu CH, et al. Human neural cell adhesion molecule L1 and rat homologue NILE are ligands for integrin alpha v beta 3. J Cell Biol 1996 Feb; 132(3): 475–85

    Article  PubMed  CAS  Google Scholar 

  41. Voura EB, Ramjeesingh RA, Montgomery AM, et al. Involvement of integrin alpha(v)beta(3) and cell adhesion molecule L1 in transendothelial migration of melanoma cells. Mol Biol Cell 2001 Sep; 12(9): 2699–710

    PubMed  CAS  Google Scholar 

  42. Meier F, Busch S, Gast D, et al. The adhesion molecule L1 (CD171) promotes melanoma progression. Int J Cancer 2006 Aug 1; 119(3): 549–55

    Article  PubMed  CAS  Google Scholar 

  43. Fogel M, Mechtersheimer S, Huszar M, et al. L1 adhesion molecule (CD 171) in development and progression of human malignant melanoma. Cancer Lett 2003 Jan 28; 189(2): 237–47

    Article  PubMed  CAS  Google Scholar 

  44. Talantov D, Mazumder A, Yu JX, et al. Novel genes associated with malignant melanoma but not benign melanocytic lesions. Clin Cancer Res 2005 Oct 15; 11(20): 7234–42

    Article  PubMed  CAS  Google Scholar 

  45. Degen WG, van Kempen LC, Gijzen EG, et al. MEMD, a new cell adhesion molecule in metastasizing human melanoma cell lines, is identical to ALCAM (activated leukocyte cell adhesion molecule). Am J Pathol 1998 Mar; 152(3): 805–13

    PubMed  CAS  Google Scholar 

  46. Patel DD, Wee SF, Whichard LP, et al. Identification and characterization of a 100-kD ligand for CD6 on human thymic epithelial cells. J Exp Med 1995 Apr 1; 181(4): 1563–8

    Article  PubMed  CAS  Google Scholar 

  47. van Kempen LC, van den Oord JJ, van Muijen GN, et al. Activated leukocyte cell adhesion molecule/CD166, a marker of tumor progression in primary malignant melanoma of the skin. Am J Pathol 2000 Mar; 156(3): 769–74

    Article  PubMed  Google Scholar 

  48. van Kempen LC, Meier F, Egeblad M, et al. Truncation of activated leukocyte cell adhesion molecule: a gateway to melanoma metastasis. J Invest Dermatol 2004 May; 122(5): 1293–301

    Article  PubMed  Google Scholar 

  49. Klein WM, Wu BP, Zhao S, et al. Increased expression of stem cell markers in malignant melanoma. Mod Pathol 2007 Jan; 20(1): 102–7

    Article  PubMed  CAS  Google Scholar 

  50. Van de Stolpe A, van der Saag PT. Intercellular adhesion molecule-1. J Mol Med 1996 Jan; 74(1): 13–33

    Article  PubMed  Google Scholar 

  51. Johnson JP, Stade BG, Holzmann B, et al. De novo expression of intercellular-adhesion molecule 1 in melanoma correlates with increased risk of metastasis. Proc Natl Acad Sci U S A 1989 Jan; 86(2): 641–4

    Article  PubMed  CAS  Google Scholar 

  52. Natali P, Nicotra MR, Cavaliere R, et al. Differential expression of intercellular adhesion molecule 1 in primary and metastatic melanoma lesions. Cancer Res 1990 Feb 15; 50(4): 1271–8

    PubMed  CAS  Google Scholar 

  53. Natali PG, Hamby CV, Felding-Habermann B, et al. Clinical significance of alpha(v)beta3 integrin and intercellular adhesion molecule-1 expression in cutaneous malignant melanoma lesions. Cancer Res 1997 Apr 15; 57(8): 1554–60

    PubMed  CAS  Google Scholar 

  54. Schadendorf D, Gawlik C, Haney U, et al. Tumour progression and metastatic behaviour in vivo correlates with integrin expression on melanocytic tumours. J Pathol 1993 Aug; 170(4): 429–34

    Article  PubMed  CAS  Google Scholar 

  55. Schadendorf D, Heidel J, Gawlik C, et al. Association with clinical outcome of expression of VLA-4 in primary cutaneous malignant melanoma as well as P-selectin and E-selectin on intratumoral vessels. J Natl Cancer Inst 1995 Mar 1; 87(5): 366–71

    Article  PubMed  CAS  Google Scholar 

  56. Miele ME, Bennett CF, Miller BE, et al. Enhanced metastatic ability of TNF-alpha-treated malignant melanoma cells is reduced by intercellular adhesion molecule-1 (ICAM-1, CD54) antisense oligonucleotides. Exp Cell Res 1994 Sep; 214(1): 231–41

    Article  PubMed  CAS  Google Scholar 

  57. Aeed PA, Nakajima M, Welch DR. The role of polymorphonuclear leukocytes (PMN) on the growth and metastatic potential of 13762NF mammary adenocarcinoma cells. Int J Cancer 1988 Nov 15; 42(5): 748–59

    Article  PubMed  CAS  Google Scholar 

  58. Giavazzi R, Chirivi RG, Garofalo A, et al. Soluble intercellular adhesion molecule 1 is released by human melanoma cells and is associated with tumor growth in nude mice. Cancer Res 1992 May 1; 52(9): 2628–30

    PubMed  CAS  Google Scholar 

  59. Becker JC, Termeer C, Schmidt RE, et al. Soluble intercellular adhesion molecule-1 inhibits MHC-restricted specific T cell/tumor interaction. J Immunol 1993 Dec 15; 151(12): 7224–32

    PubMed  CAS  Google Scholar 

  60. Sienel W, Dango S, Woelfle U, et al. Elevated expression of carcinoembryonic antigen-related cell adhesion molecule 1 promotes progression of non-small cell lung cancer. Clin Cancer Res 2003 Jun; 9(6): 2260–6

    PubMed  CAS  Google Scholar 

  61. Brummer J, Ebrahimnejad A, Flayeh R, et al. cis Interaction of the cell adhesion molecule CEACAM1 with integrin beta(3). Am J Pathol 2001 Aug; 159(2): 537–46

    Article  PubMed  CAS  Google Scholar 

  62. Thies A, Moll I, Berger J, et al. CEACAM1 expression in cutaneous malignant melanoma predicts the development of metastatic disease. J Clin Oncol 2002 May 15; 20(10): 2530–6

    Article  PubMed  CAS  Google Scholar 

  63. Ebrahimnejad A, Streichert T, Nollau P, et al. CEACAM1 enhances invasion and migration of melanocytic and melanoma cells. Am J Pathol 2004 Nov; 165(5): 1781–7

    Article  PubMed  CAS  Google Scholar 

  64. Hsu MY, Wheelock MJ, Johnson KR, et al. Shifts in cadherin profiles between human normal melanocytes and melanomas. J Investig Dermatol Symp Proc 1996 Apr; 1(2): 188–94

    PubMed  CAS  Google Scholar 

  65. Tang A, Eller MS, Hara M, et al. E-cadherin is the major mediator of human melanocyte adhesion to keratinocytes in vitro. J Cell Sci 1994 Apr; 107 (Pt 4): 983–92

    PubMed  CAS  Google Scholar 

  66. Smalley KS, Brafford P, Haass NK, et al. Up-regulated expression of zonula occludens protein-1 in human melanoma associates with N-cadherin and contributes to invasion and adhesion. Am J Pathol 2005 May; 166(5): 1541–54

    Article  PubMed  CAS  Google Scholar 

  67. Danen EH, de Vries TJ, Morandini R, et al. E-cadherin expression in human melanoma. Melanoma Res 1996 Apr; 6(2): 127–31

    Article  PubMed  CAS  Google Scholar 

  68. Sanders DS, Blessing K, Hassan GA, et al. Alterations in cadherin and catenin expression during the biological progression of melanocytic tumours. Mol Pathol 1999 Jun; 52(3): 151–7

    Article  PubMed  CAS  Google Scholar 

  69. Krengel S, Groteluschen F, Bartsch S, et al. Cadherin expression pattern in melanocytic tumors more likely depends on the melanocyte environment than on tumor cell progression. J Cutan Pathol 2004 Jan; 31(1): 1–7

    Article  PubMed  Google Scholar 

  70. Andersen K, Nesland JM, Holm R, et al. Expression of S100A4 combined with reduced E-cadherin expression predicts patient outcome in malignant melanoma. Mod Pathol 2004 Aug; 17(8): 990–7

    Article  PubMed  CAS  Google Scholar 

  71. Nishizawa A, Nakanishi Y, Yoshimura K, et al. Clinicopathologic significance of dysadherin expression in cutaneous malignant melanoma: immunohistochemical analysis of 115 patients. Cancer 2005 Apr 15; 103(8): 1693–700

    Article  PubMed  CAS  Google Scholar 

  72. Ino Y, Gotoh M, Sakamoto M, et al. Dysadherin, a cancer-associated cell membrane glycoprotein, down-regulates E-cadherin and promotes metastasis. Proc Natl Acad Sci U S A 2002 Jan 8; 99(1): 365–70

    Article  PubMed  CAS  Google Scholar 

  73. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005 Nov 17; 353(20): 2135–47

    Article  PubMed  CAS  Google Scholar 

  74. Yap AS, Brieher WM, Gumbiner BM. Molecular and functional analysis of cadherin-based adherens junctions. Annu Rev Cell DevBiol 1997; 13:119–46

    Article  CAS  Google Scholar 

  75. Funayama N, Fagotto F, McCrea P, et al. Embryonic axis induction by the armadillo repeat domain of beta-catenin: evidence for intracellular signaling. J Cell Biol 1995 Mar; 128(5): 959–68

    Article  PubMed  CAS  Google Scholar 

  76. Sharpe C, Lawrence N, Martinez Arias A. Wnt signalling: a theme with nuclear variations. Bioessays 2001 Apr; 23(4): 311–8

    Article  PubMed  CAS  Google Scholar 

  77. Bachmann IM, Straume O, Puntervoll HE, et al. Importance of P-cadherin, beta-catenin, and Wnt5a/frizzled for progression of melanocytic tumors and prognosis in cutaneous melanoma. Clin Cancer Res 2005 Dec 15; 11 (24 Pt 1): 8606–14

    Article  PubMed  CAS  Google Scholar 

  78. Kageshita T, Hamby CV, Ishihara T, et al. Loss of beta-catenin expression associated with disease progression in malignant melanoma. Br J Dermatol 2001 Aug; 145(2): 210–6

    Article  PubMed  CAS  Google Scholar 

  79. Osborne JE. Loss of beta-catenin expression is associated with disease progression in malignant melanoma. Br J Dermatol 2002 Jun; 146(6): 1104

    Article  PubMed  CAS  Google Scholar 

  80. Tucci MG, Lucarini G, Brancorsini D, et al. Involvement of E-cadherin, beta-catenin, Cdc42 and CXCR4 in the progression and prognosis of cutaneous melanoma. Br J Dermatol 2007 Dec; 157(6): 1212–6

    Article  PubMed  CAS  Google Scholar 

  81. Djalilian AR, McGaughey D, Patel S, et al. Connexin 26 regulates epidermal barrier and wound remodeling and promotes psoriasiform response. J Clin Invest 2006 May; 116(5): 1243–53

    Article  PubMed  CAS  Google Scholar 

  82. Langlois S, Maher AC, Manias JL, et al. Connexin levels regulate keratinocyte differentiation in the epidermis. J Biol Chem 2007 Oct 12; 282(41): 30171–80

    Article  PubMed  CAS  Google Scholar 

  83. Maass K, Ghanem A, Kim JS, et al. Defective epidermal barrier in neonatal mice lacking the C-terminal region of connexin43. Mol Biol Cell 2004 Oct; 15(10): 4597–608

    Article  PubMed  CAS  Google Scholar 

  84. Man YK, Trolove C, Tattersall D, et al. A deafness-associated mutant human connexin 26 improves the epithelial barrier in vitro. J Membr Biol 2007 Aug; 218(1–3): 29–37

    PubMed  CAS  Google Scholar 

  85. Kretz M, Maass K, Willecke K. Expression and function of connexins in the epidermis, analyzed with transgenic mouse mutants. Eur J Cell Biol 2004 Dec; 83(11–12): 647–54

    Article  PubMed  CAS  Google Scholar 

  86. Mese G, Richard G, White TW. Gap junctions: basic structure and function. J Invest Dermatol 2007 Nov; 127(11): 2516–24

    Article  PubMed  CAS  Google Scholar 

  87. Haass NK, Wladykowski E, Kief S, et al. Differential induction of connexins 26 and 30 in skin tumors and their adjacent epidermis. J Histochem Cytochem 2006 Feb; 54(2): 171–82

    Article  PubMed  CAS  Google Scholar 

  88. Haass NK, Houdek P, Brandner JM, et al. Expression patterns of connexins in Merkel cell carcinoma and adjacent epidermis. In: Baumann KI, Moll I, Halata Z, editors. The Merkel cell: structure — development - function — and cancerogenesis. Berlin, Heidelberg, New York, Tokyo: Springer-Verlag, 2003: 219–22

    Google Scholar 

  89. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002 Jun 27; 417(6892): 949–54

    Article  PubMed  CAS  Google Scholar 

  90. Lin WM, Baker AC, Beroukhim R, et al. Modeling genomic diversity and tumor dependency in malignant melanoma. Cancer Res 2008 Feb 1; 68(3): 664–73

    Article  PubMed  CAS  Google Scholar 

  91. Smalley KS, Nathanson KL, Flaherty KT. Genetic subgrouping of melanoma reveals new opportunities for targeted therapy. Cancer Res 2009 Apr 15; 69(8): 3241–4

    Article  PubMed  CAS  Google Scholar 

  92. Curtin JA, Busam K, Pinkel D, et al. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 2006 Sep 10; 24(26): 4340–6

    Article  PubMed  CAS  Google Scholar 

  93. Brose MS, Volpe P, Feldman M, et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res 2002 Dec 1; 62(23): 6997–7000

    PubMed  CAS  Google Scholar 

  94. Padua RA, Barrass NC, Currie GA. Activation of N-ras in a human melanoma cell line. Mol Cell Biol 1985 Mar; 5(3): 582–5

    PubMed  CAS  Google Scholar 

  95. Viros A, Fridlyand J, Bauer J, et al. Improving melanoma classification by integrating genetic and morphologic features. PLoS Med 2008 Jun 3; 5(6): e120

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  97. Michaloglou C, Vredeveld LC, Soengas MS, et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 2005 Aug 4; 436(7051): 720–4

    Article  PubMed  CAS  Google Scholar 

  98. Gray-Schopfer VC, Cheong SC, Chong H, et al. Cellular senescence in naevi and immortalisation in melanoma: a role for p16? Br J Cancer 2006 Aug 21; 95(4): 496–505

    Article  PubMed  CAS  Google Scholar 

  99. Grichnik JM. Kit and melanocyte migration. J Invest Dermatol 2006 May; 126(5): 945–7

    Article  PubMed  CAS  Google Scholar 

  100. Huang S, Jean D, Luca M, et al. Loss of AP-2 results in downregulation of c-KIT and enhancement of melanoma tumorigenicity and metastasis. Embo J 1998 Aug 3; 17(15): 4358–69

    Article  PubMed  CAS  Google Scholar 

  101. Huang S, Luca M, Gutman M, et al. Enforced c-KIT expression renders highly metastatic human melanoma cells susceptible to stem cell factor-induced apoptosis and inhibits their tumorigenic and metastatic potential. Oncogene 1996 Dec 5; 13(11): 2339–47

    PubMed  CAS  Google Scholar 

  102. Satyamoorthy K, Li G, Gerrero MR, et al. Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation. Cancer Res 2003 Feb 15; 63(4): 756–9

    PubMed  CAS  Google Scholar 

  103. Smalley KS, Contractor R, Nguyen TK, et al. Identification of a novel subgroup of melanomas with KIT/cyclin-dependent kinase-4 overexpression. Cancer Res 2008 Jul 15; 68(14): 5743–52

    Article  PubMed  CAS  Google Scholar 

  104. Sherr CJ. G1 phase progression: cycling on cue. Cell 1994 Nov 18; 79(4): 551–5

    Article  PubMed  CAS  Google Scholar 

  105. Bhatt KV, Spofford LS, Aram G, et al. Adhesion control of cyclin D1 and p27Kip1 levels is deregulated in melanoma cells through BRAF-MEK-ERK signaling. Oncogene 2005 May 12; 24(21): 3459–71

    Article  PubMed  CAS  Google Scholar 

  106. Zhuang L, Lee CS, Scolyer RA, et al. Activation of the extracellular signal regulated kinase (ERK) pathway in human melanoma. J Clin Pathol 2005 Nov; 58(11): 1163–9

    Article  PubMed  CAS  Google Scholar 

  107. Haass NK, Sproesser K, Nguyen TK, et al. The mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor AZD6244 (ARRY-142886) induces growth arrest in melanoma cells and tumor regression when combined with docetaxel. Clin Cancer Res 2008 Jan 1; 14(1): 230–9

    Article  PubMed  CAS  Google Scholar 

  108. Houben R, Vetter-Kauczok CS, Ortmann S, et al. Phospho-ERK staining is a poor indicator of the mutational status of BRAF and NRAS in human melanoma. J Invest Dermatol 2008 Aug; 128(8): 2003–12

    Article  PubMed  CAS  Google Scholar 

  109. Robertson GP. Functional and therapeutic significance of Akt deregulation in malignant melanoma. Cancer Metastasis Rev 2005 Jun; 24(2): 273–85

    Article  PubMed  CAS  Google Scholar 

  110. Stahl JM, Sharma A, Cheung M, et al. Deregulated AKT3 activity promotes development of malignant melanoma. Cancer Res 2004 Oct 1; 64(19): 7002–10

    Article  PubMed  CAS  Google Scholar 

  111. Tsao H, Goel V, Wu H, et al. Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma. J Invest Dermatol 2004 Feb; 122(2): 337–41

    Article  PubMed  CAS  Google Scholar 

  112. Tsao H, Zhang X, Fowlkes K, et al. Relative reciprocity of NRAS and PTEN/MMAC1 alterations in cutaneous melanoma cell lines. Cancer Res 2000 Apr 1; 60(7): 1800–4

    PubMed  CAS  Google Scholar 

  113. Davies MA, Stemke-Hale K, Tellez C, et al. A novel AKT3 mutation in melanoma tumours and cell lines. Br J Cancer 2008 Oct 21; 99(8): 1265–8

    Article  PubMed  CAS  Google Scholar 

  114. Jiang X, Zhou J, Yuen NK, et al. Imatinib targeting of KIT-mutant oncoprotein in melanoma. Clin Cancer Res 2008 Dec 1; 14(23): 7726–32

    Article  PubMed  CAS  Google Scholar 

  115. Spofford LS, Abel EV, Boisvert-Adamo K, et al. Cyclin D3 expression in melanoma cells is regulated by adhesion-dependent phosphatidylinositol 3-kinase signaling and contributes to G1-S progression. J Biol Chem 2006 Sep 1; 281(35): 25644–51

    Article  PubMed  CAS  Google Scholar 

  116. Datta SR, Dudek H, Tao X, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997 Oct 17; 91(2): 231–41

    Article  PubMed  CAS  Google Scholar 

  117. Dai DL, Martinka M, Li G. Prognostic significance of activated Akt expression in melanoma: a clinicopathologic study of 292 cases. J Clin Oncol 2005 Mar 1; 23(7): 1473–82

    Article  PubMed  CAS  Google Scholar 

  118. Niu G, Bowman T, Huang M, et al. Roles of activated Src and Stat3 signaling in melanoma tumor cell growth. Oncogene 2002 Oct 10; 21(46): 7001–10

    Article  PubMed  CAS  Google Scholar 

  119. Stecca B, Mas C, Clement V, et al. Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proc Natl Acad Sci U S A 2007 Apr 3; 104(14): 5895–900

    Article  PubMed  CAS  Google Scholar 

  120. Liu ZJ, Xiao M, Balint K, et al. Notch1 signaling promotes primary melanoma progression by activating mitogen-activated protein kinase/ phosphatidylinositol 3-kinase-Akt pathways and up-regulating N-cadherin expression. Cancer Res 2006 Apr 15; 66(8): 4182–90

    Article  PubMed  CAS  Google Scholar 

  121. Yang J, Richmond A. Constitutive IkappaB kinase activity correlates with nuclear factor-kappaB activation in human melanoma cells. Cancer Res 2001 Jun 15; 61(12): 4901–9

    PubMed  CAS  Google Scholar 

  122. O’Reilly KE, Warycha M, Davies MA, et al. Phosphorylated 4E-BP1 is associated with poor survival in melanoma. Clin Cancer Res 2009 Apr 15; 15(8): 2872–8

    Article  PubMed  Google Scholar 

  123. Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol 2000 Mar; 182(3): 311–22

    Article  PubMed  CAS  Google Scholar 

  124. Gimotty PA, Van Belle P, Elder DE, et al. Biologic and prognostic significance of dermal Ki67 expression, mitoses, and tumorigenicity in thin invasive cutaneous melanoma. J Clin Oncol 2005 Nov 1; 23(31): 8048–56

    Article  PubMed  Google Scholar 

  125. Findeisen P, Zapatka M, Peccerella T, et al. Serum amyloid A as a prognostic marker in melanoma identified by proteomic profiling. J Clin Oncol 2009 May 1; 27(13): 2199–208

    Article  PubMed  CAS  Google Scholar 

  126. Niezabitowski A, Czajecki K, Rys J, et al. Prognostic evaluation of cutaneous malignant melanoma: a clinicopathologic and immunohistochemical study. J Surg Oncol 1999 Mar; 70(3): 150–60

    Article  PubMed  CAS  Google Scholar 

  127. Winnepenninckx V, Lazar V, Michiels S, et al. Gene expression profiling of primary cutaneous melanoma and clinical outcome. J Natl Cancer Inst 2006 Apr 5; 98(7): 472–82

    Article  PubMed  CAS  Google Scholar 

  128. Fang D, Hallman J, Sangha N, et al. Expression of microtubule-associated protein 2 in benign and malignant melanocytes: implications for differentiation and progression of cutaneous melanoma. Am J Pathol 2001 Jun; 158(6): 2107–15

    Article  PubMed  CAS  Google Scholar 

  129. Soltani MH, Pichardo R, Song Z, et al. Microtubule-associated protein 2, a marker of neuronal differentiation, induces mitotic defects, inhibits growth of melanoma cells, and predicts metastatic potential of cutaneous melanoma. Am J Pathol 2005 Jun; 166(6): 1841–50

    Article  PubMed  CAS  Google Scholar 

  130. Sawyers C. Targeted cancer therapy. Nature 2004 Nov 18; 432(7015): 294–7

    Article  PubMed  CAS  Google Scholar 

  131. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001 Apr 5; 344(14): 1031–7

    Article  PubMed  CAS  Google Scholar 

  132. Bauer S, Duensing A, Demetri GD, et al. KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway. Oncogene 2007 Nov 29; 26(54): 7560–8

    Article  PubMed  CAS  Google Scholar 

  133. Karasarides M, Chiloeches A, Hayward R, et al. B-RAF is a therapeutic target in melanoma. Oncogene 2004 Aug 19; 23(37): 6292–8

    Article  PubMed  CAS  Google Scholar 

  134. Wellbrock C, Ogilvie L, Hedley D, et al. V599EB-RAF is an oncogene in melanocytes. Cancer Res 2004 Apr 1; 64(7): 2338–42

    Article  PubMed  CAS  Google Scholar 

  135. Solit DB, Garraway LA, Pratilas CA, et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature 2006 Jan 19; 439(7074): 358–62

    Article  PubMed  CAS  Google Scholar 

  136. Pratilas CA, Taylor BS, Ye Q, et al. (V600E)BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. Proc Natl Acad Sci U S A 2009 Mar 17; 106(11): 4519–24

    Article  PubMed  CAS  Google Scholar 

  137. Smalley KS, Lioni M, Palma MD, et al. Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas. Mol Cancer Ther 2008 Sep; 7(9): 2876–83

    Article  PubMed  CAS  Google Scholar 

  138. Pratilas CA, Hanrahan AJ, Halilovic E, et al. Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res 2008 Nov 15; 68(22): 9375–83

    Article  PubMed  CAS  Google Scholar 

  139. Mirzoeva OK, Das D, Heiser LM, et al. Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. Cancer Res 2009 Jan 15; 69(2): 565–72

    Article  PubMed  CAS  Google Scholar 

  140. Lorusso PM, Adjei AA, Varterasian M, et al. Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol 2005 Aug 10; 23(23): 5281–93

    Article  PubMed  CAS  Google Scholar 

  141. Smalley KS, Contractor R, Haass NK, et al. Ki67 expression levels are a better marker of reduced melanoma growth following MEK inhibitor treatment than phospho-ERK levels. Br J Cancer 2007 Feb 12; 96(3): 445–9

    Article  PubMed  CAS  Google Scholar 

  142. Leyton J, Smith G, Lees M, et al. Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901. Mol Cancer Ther 2008 Sep; 7(9): 3112–21

    Article  PubMed  CAS  Google Scholar 

  143. Solit DB, Santos E, Pratilas CA, et al. 3′-deoxy-3′-[18F]fluorothymidine positron emission tomography is a sensitive method for imaging the response of BRAF-dependent tumors to MEK inhibition. Cancer Res 2007 Dec 1; 67(23): 11463–9

    Article  PubMed  CAS  Google Scholar 

  144. Ugurel S, Hildenbrand R, Zimpfer A, et al. Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer 2005 Apr 25; 92(8): 1398–405

    Article  PubMed  CAS  Google Scholar 

  145. Lutzky J, Bauer J, Bastian BC. Dose-dependent, complete response to imatinib of a metastatic mucosal melanoma with a K642E KIT mutation. Pigment Cell Melanoma Res 2008 Aug; 21(4): 492–3

    Article  PubMed  Google Scholar 

  146. Hodi FS, Friedlander P, Corless CL, et al. Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol 2008 Apr 20; 26(12): 2046–51

    Article  PubMed  CAS  Google Scholar 

  147. Quintas-Cardama A, Lazar AJ, Woodman SE, et al. Complete response of stage IV anal mucosal melanoma expressing KIT Val560Asp to the multikinase inhibitor sorafenib. Nat Clin Pract Oncol 2008 Dec; 5(12): 737–40

    Article  PubMed  CAS  Google Scholar 

  148. Smalley KS, Sondak VK, Weber JS. c-KIT signaling as the driving oncogenic event in sub-groups of melanomas. Histol Histopathol 2009 May; 24(5): 643–50

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Nikolas K. Haass is a recipient of the Cameron Fellowship from the Melanoma and Skin Cancer Research Institute/Melanoma Foundation/Dermatology Foundation (Sydney, Australia) and is the Chief Investigator on Project Grant no. RG 09–08 from the Cancer Council New South Wales (Sydney, Australia), Project Grant no. 570778 from the Cure Cancer Australia Foundation (Sydney, Australia), and Research Innovation Grant no. 08/RFG/1–27 from the Cancer Institute New South Wales (Sydney, Australia). Keiran S.M. Smalley is funded by a Career Development award from the Melanoma Research Foundation (Hillsborough, NJ, USA), New Investigator Award no. 09-BN14 from the Bankhead-Coley Cancer Research Program of the State of Florida (Tallahassee, FL, USA), and Institutional Research Grant no. 93-032-13 from the American Cancer Society (Atlanta, GA, USA).

We would like to thank Dr Johanna M. Brandner for her constructive comments on the manuscript.

The authors have no conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

  1. Discipline of Dermatology, University of Sydney, Sydney, New South Wales, Australia

    Nikolas K. Haass

  2. Centenary Institute of Cancer Medicine and Cell Biology, Sydney, New South Wales, Australia

    Nikolas K. Haass

  3. Program in Molecular Oncology, Cutaneous Oncology & The Comprehensive Melanoma Research Center, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, Florida, 33612, USA

    Keiran S.M. Smalley

Authors
  1. Nikolas K. Haass
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Keiran S.M. Smalley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Keiran S.M. Smalley.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Haass, N.K., Smalley, K.S. Melanoma Biomarkers. Mol Diag Ther 13, 283–296 (2009). https://doi.org/10.1007/BF03256334

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03256334

Keywords

Search

Navigation