Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Melanoma biomarkers: current status and vision for the future

Abstract

Melanoma is the leading cause of death from skin cancer in industrialized countries. Clinical and histological variables such as primary tumor invasion, ulceration, and lymph node status might fail to identify early-stage disease that will eventually progress. Tumor biomarkers might help to identify patients with early-stage melanoma who are likely to develop advanced disease and would benefit from additional therapies. These biomarkers offer the possibility of improved tumor staging through the molecular detection of microscopic lymph node metastases that are not visible on routine histological examination. We focus on biomarkers localized to the tumor tissue and those of prognostic value. We give an overview of the melanoma biomarkers that are most helpful for prediction of patients' outcomes, and discuss the primary melanoma biomarkers that have been shown to be of prognostic significance independent of primary tumor thickness and other common clinical prognostic indicators. Although such tumor-associated biomarkers are thought to have the greatest potential, a lack of reliable data makes their true clinical utility difficult to determine. We conclude that several biomarkers show promise in early studies; however, additional large-scale studies are warranted. We suggest cautious optimism for the field of melanoma biomarkers, which we expect to be translated into clinical practice over the next few years.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Slingluff CL et al. (1988) Lethal “thin” malignant melanoma. Identifying patients at risk. Ann Surg 208: 150–161

    Article  PubMed  PubMed Central  Google Scholar 

  2. Balch CM et al. (2001) Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 19: 3622–3634

    Article  CAS  PubMed  Google Scholar 

  3. Bosserhoff AK (2006) Novel biomarkers in malignant melanoma. Clin Chim Acta 367: 28–35

    Article  CAS  PubMed  Google Scholar 

  4. Ilmonen S et al. (2005) Ki-67, Bcl-2, and p53 expression in primary and metastatic melanoma. Melanoma Res 15: 375–381

    Article  CAS  PubMed  Google Scholar 

  5. Carlson JA et al. (2005) Molecular diagnostics in melanoma. J Am Acad Dermatol 52: 743–775

    Article  PubMed  Google Scholar 

  6. Alonso SR et al. (2004) Progression in cutaneous malignant melanoma is associated with distinct expression profiles. Am J Pathol 164: 193–203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Väisänen A et al. (1998) Prognostic value of MMP-2 immunoreactive protein (72 kD type IV collagenase) in primary skin melanoma. J Pathol 186: 51–58

    Article  PubMed  Google Scholar 

  8. Dai DL et al. (2005) Prognostic significance of activated Akt expression in melanoma: a clinicopathologic study of 292 cases. J Clin Oncol 23: 1473–1482

    Article  CAS  PubMed  Google Scholar 

  9. Thies A et al. (2002) CEACAM1 expression in cutaneous malignant melanoma predicts the development of metastatic disease. J Clin Oncol 20: 2530–2536

    Article  CAS  PubMed  Google Scholar 

  10. Scala S et al. (2005) Expression of CXCR4 predicts poor prognosis in patients with malignant melanoma. Clin Cancer Res 11: 1835–1841

    Article  CAS  PubMed  Google Scholar 

  11. Giatromanolaki A et al. (2003) Hypoxia-inducible factors 1α and 2α are related to vascular endothelial growth factor expression and a poor prognosis in nodular malignant melanomas of the skin. Melanoma Res 13: 493–501

    Article  CAS  PubMed  Google Scholar 

  12. Straume O et al. (2000) Loss of nuclear p16 protein expression correlates with increased tumor cell proliferation (Ki-67) and poor prognosis in patients with vertical growth phase melanoma. Clin Cancer Res 6: 1845–1853

    CAS  PubMed  Google Scholar 

  13. Straume O and Akslen LA (1997) Alterations and prognostic significance of p16 and p53 protein expression in subgroups of cutaneous melanoma. Int J Cancer 74: 535–539

    Article  CAS  PubMed  Google Scholar 

  14. Hieken TJ et al. (1999) Molecular prognostic markers in intermediate-thickness cutaneous malignant melanoma. Cancer 85: 375–382

    Article  CAS  PubMed  Google Scholar 

  15. Salti GI et al. (2000) Micropthalmia transcription factor: a new prognostic marker in intermediate-thickness cutaneous malignant melanoma. Cancer Res 60: 5012–5016

    CAS  PubMed  Google Scholar 

  16. Vereecken P et al. (2007) Significance of cell kinetic parameters in the prognosis of malignant melanoma: a review. J Cutan Pathol 34: 139–145

    Article  PubMed  Google Scholar 

  17. Fang D et al. (2001) Expression of microtubule-associated protein 2 in benign and malignant melanocytes: implications for differentiation and progression of cutaneous melanoma. Am J Pathol 158: 2107–2115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Soltani MH et al. (2005) 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 166: 1841–1850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lehmann JM et al. (1987) 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 47: 841–845

    CAS  PubMed  Google Scholar 

  20. Pacifico et al. (2005) 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 115: 367–375

    Article  CAS  PubMed  Google Scholar 

  21. Ostmeier H et al. (2001) Prognostic immunohistochemical markers of primary human melanomas. Br J Dermatol 145: 203–209

    Article  CAS  PubMed  Google Scholar 

  22. Danen EH et al. (1996) E-cadherin expression in human melanoma. Melanoma Res 6: 127–131

    Article  CAS  PubMed  Google Scholar 

  23. Nishizawa et al. (2005) Clinicopathologic significance of dysadherin expression in cutaneous malignant melanoma: immunohistochemical analysis of 115 patients. Cancer 103: 1693–1700

    Article  CAS  PubMed  Google Scholar 

  24. Curtin et al. (2005) Distinct sets of genetic alterations in melanoma. N Engl J Med 353: 2135–2147

    Article  CAS  PubMed  Google Scholar 

  25. Bachmann IM et al. (2005) Importance of P-cadherin, β-catenin, and Wnt5a/Frizzled for progression of melanocytic tumors and prognosis in cutaneous melanoma. Clin Cancer Res 11: 8606–8614

    Article  CAS  PubMed  Google Scholar 

  26. Kageshita T et al. (2001) Loss of β-catenin expression associated with disease progression in malignant melanoma. Br J Dermatol 145: 210–216

    Article  CAS  PubMed  Google Scholar 

  27. Weinlich G et al. (2006) Metallothionein—overexpression as a highly significant prognostic factor in melanoma: a prospective study on 1,270 patients. Br J Cancer 94: 835–841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Winnepenninckx V et al. (2006) Gene expression profiling of primary cutaneous melanoma and clinical outcome. J Natl Cancer Inst 98: 472–482

    Article  CAS  PubMed  Google Scholar 

  29. Rangel J et al. (2006) Prognostic significance of nuclear receptor coactivator-3 overexpression in primary cutaneous melanoma. J Clin Oncol 24: 4565–4569

    Article  CAS  PubMed  Google Scholar 

  30. McKusick-Nathans Institute of Genetic Medicine (1985) Online Mendelian Inheritance in Man [http://www.ncbi.nlm.nih.gov/omim/] (accessed 25 September 2008)

  31. McKusick-Nathans Institute of Genetic Medicine (1985) OMIM Nuclear Receptor Coactivator 3 [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601937] (accessed 25 September 2008)

  32. Barks JH et al. (1997) Increased chromosome 20 copy number detected by fluorescence in situ hybridization (FISH) in malignant melanoma. Genes Chromosomes Cancer 19: 278–285

    Article  CAS  PubMed  Google Scholar 

  33. Thies A et al. (2004) The developmentally regulated neural crest-associated glycotope HNK-1 predicts metastasis in cutaneous malignant melanoma. J Pathol 203: 933–939

    Article  CAS  PubMed  Google Scholar 

  34. Vincent M et al. (1984) A cell surface marker for neural crest and placodal cells: further evolution in peripheral and central nervous system. Dev Biol 103: 468–481

    Article  CAS  PubMed  Google Scholar 

  35. Hao H et al. (2007) E2F-1 induces melanoma cell apoptosis via PUMA up-regulation and Bax translocation. BMC Cancer 7: 24–35

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Karst A et al. (2005) PUMA expression is significantly reduced in human cutaneous melanomas. Oncogene 24: 1111–1116

    Article  CAS  PubMed  Google Scholar 

  37. Hammock L et al. (2006) Chromogenic in situ hybridization analysis of melastatin mRNA expression in melanomas from American Joint Committee on Cancer stage I and II patients with recurrent melanoma. J Cutan Pathol 33: 599–607

    Article  CAS  PubMed  Google Scholar 

  38. Duncan LM et al. (2001) Melastatin expression and prognosis in cutaneous malignant melanoma. J Clin Oncol 19: 568–576

    Article  CAS  PubMed  Google Scholar 

  39. Deeds J et al. (2000) Patterns of melastatin mRNA expression in melanocytic tumors. Hum Pathol 31: 1346–1356

    Article  CAS  PubMed  Google Scholar 

  40. Korabiowska M et al. (2002) GADD153 is an independent prognostic factor in melanoma: immunohistochemical and molecular genetic analysis. Histol Histopathol 17: 805–811

    CAS  PubMed  Google Scholar 

  41. Korabiowska M (1997) Differential expression of growth arrest, DNA damage genes and tumour suppressor gene p53 in naevi and malignant melanoma. Anticancer Res 17: 3697–3700

    CAS  PubMed  Google Scholar 

  42. Straume O and Akslen LA (2002) Importance of vascular phenotype by basic fibroblast growth factor, and influence of the angiogenic factors basic fibroblast growth factor/fibroblast growth factor receptor-1 and ephrin-A1/EphA2 on melanoma progression. Am J Pathol 160: 1009–1019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wang Y and Becker D (1997) Antisense targeting of basic fibroblast growth factor and fibroblast growth factor receptor-1 in human melanomas blocks intratumoral angiogenesis and tumor growth. Nat Med 3: 887–893

    Article  CAS  PubMed  Google Scholar 

  44. Tran TA et al. (1998) Mitotic cyclins and cyclin-dependent kinases in melanocytic lesions. Hum Pathol 20: 1085–1090

    Article  Google Scholar 

  45. Florenes VA et al. (2001) Cyclin A expression in superficial spreading malignant melanomas correlates with clinical outcome. J Pathol 195: 530–536

    Article  CAS  PubMed  Google Scholar 

  46. Ostmeier H et al. (2001) Prognostic immunohistochemical markers of primary human melanomas. Br J Dermatol 145: 203–209

    Article  CAS  PubMed  Google Scholar 

  47. Ohno H (2006) Pathogenetic and clinical implications of non-immunoglobulin; BCL6 translocations in B-cell non-Hodgkin's lymphoma. J Clin Exp Hematop 46: 43–53

    Article  PubMed  Google Scholar 

  48. Massi D et al. (2006) Tumour lymphangiogenesis is a possible predictor of sentinel lymph node status in cutaneous melanoma: a case–control study. J Clin Pathol 59: 166–173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Dadras SS et al. (2003) Tumor lymphaniogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival. Am J Pathol 162: 1951–1960

    Article  PubMed  PubMed Central  Google Scholar 

  50. Dadras SS et al. (2005) Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes. Mod Pathol 18: 1232–1242

    Article  PubMed  Google Scholar 

  51. Straume O et al. (2003) Independent prognostic impact of lymphatic vessel density and presence of low-grade lymphangiogenesis in cutaneous melanoma. Clin Cancer Res 9: 250–256

    CAS  PubMed  Google Scholar 

  52. Mariani G et al. (2002) Radioguided sentinel lymph node biopsy in malignant cutaneous melanoma. J Nuclear Med 43: 811–827

    Google Scholar 

  53. Brady MS et al. (1997) Sentinel lymph node evaluation in melanoma. Arch Dermatol 133: 1014–1020

    Article  CAS  PubMed  Google Scholar 

  54. Takeuchi H et al. (2004) Prognostic significance of molecular upstaging of paraffin-embedded sentinel lymph nodes in melanoma patients. J Clin Oncol 22: 2671–2680

    Article  CAS  PubMed  Google Scholar 

  55. Li W et al. (2000) Clinical relevance of molecular staging for melanoma: comparison of RT-PCR and immunohistochemistry staining in sentinel lymph nodes of patients with melanoma. Ann Surg 231: 795–803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wang X et al. (1994) Detection of submicroscopic lymph node metastases with polymerase chain reaction in patients with malignant melanoma. Ann Surg 220: 768–774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Blaheta HJ et al. (1999) Detection of melanoma micrometastasis in sentinel nodes by reverse transcription–polymerase chain reaction correlates with tumor thickness and is predictive of micrometastatic disease in the lymph node basin. Am J Surg Pathol 23: 822–828

    Article  CAS  PubMed  Google Scholar 

  58. Blaheta HJ et al. (1998) Lymph node micrometastases of cutaneous melanoma: increased sensitivity of molecular diagnosis in comparison to immunohistochemistry. Int J Cancer 79: 318–323

    Article  CAS  PubMed  Google Scholar 

  59. Blaheta HJ et al. (2000) Examination of regional lymph nodes by sentinel node biopsy and molecular analysis provides new staging facilities in primary cutaneous melanoma. J Invest Dermatol 114: 637–642

    Article  CAS  PubMed  Google Scholar 

  60. Shivers SC et al. (1998) Molecular staging of malignant melanoma: correlation with clinical outcome. JAMA 280: 1410–1415

    Article  CAS  PubMed  Google Scholar 

  61. Bostick PJ et al. (1999) Prognostic significance of occult metastases detected by sentinel lymphadenectomy and reverse transcriptase–polymerase chain reaction in early-stage melanoma patients. J Clin Oncol 17: 3238–3244

    Article  CAS  PubMed  Google Scholar 

  62. Hoashi T et al. (2005) MART-1 is required for the function of the melanosomal matrix protein PMEL17/GP100 and the maturation of melanosomes. J Biol Chem 280: 14006–14016

    Article  CAS  PubMed  Google Scholar 

  63. Kuo CT et al. (2003) Prediction of disease outcome in melanoma patients by molecular analysis of paraffin-embedded sentinel lymph nodes. J Clin Oncol 21: 3566–3572

    Article  PubMed  Google Scholar 

  64. Starz H et al. (2003) Tyrosinase RT-PCR as a supplement to histology for detecting melanoma and nevus cells in paraffin sections of sentinel lymph nodes. Mod Pathol 16: 920–929

    Article  PubMed  Google Scholar 

  65. Rad HH et al. (2004) Tyrosinase-related proteins suppress tyrosinase-mediated cell death of melanocytes and melanoma cells. Exp Cell Res 15: 317–328

    Article  CAS  Google Scholar 

  66. Amersi F and Morton DL (2007) The role of sentinel lymph node biopsy in the management of melanoma. Adv Surg 41: 241–256

    Article  PubMed  PubMed Central  Google Scholar 

  67. Gradilone A et al. (2003) Survivin, bcl-2, bax, and bcl-X gene expression in sentinel lymph nodes from melanoma patients. J Clin Oncol 21: 306–312

    Article  CAS  PubMed  Google Scholar 

  68. Grossman D et al. (1999) Expression and targeting of the apoptosis inhibitor, survivin, in human melanoma. J Invest Dermatol 113: 1076–1081

    Article  CAS  PubMed  Google Scholar 

  69. Li Q et al. (2004) Skp2 and p27KIP1 expression in melanocytic nevi and melanoma: an inverse relationship. J Cutan Pathol 31: 633–642

    Article  PubMed  Google Scholar 

  70. Jørgensen K et al. (2006) Activation of c-jun N-terminal kinase is associated with cell proliferation and shorter relapse-free period in superficial spreading malignant melanoma. Mod Pathol 19: 1446–1455

    Article  PubMed  CAS  Google Scholar 

  71. Bachmann IM et al. (2006) EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J Clin Oncol 24: 268–273

    Article  CAS  PubMed  Google Scholar 

  72. Straume O and Akslen LA (2005) Strong expression of ID1 protein is associated with decreased survival, increased expression of ephrin-A1/EPHA2, and reduced thrombospondin-1 in malignant melanoma. Br J Cancer 93: 933–938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Andersen K et al. (2004) Expression of S100A4 combined with reduced E-cadherin expression predicts patient outcome in malignant melanoma. Mod Pathol 17: 990–997

    Article  CAS  PubMed  Google Scholar 

  74. Streit S et al. (2006) FGFR Arg388 allele correlates with tumor thickness and FGFR4 protein expression with survival of melanoma patients. Br J Cancer 94: 1879–1886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Piras F et al. (2005) The predictive value of CD8, CD4, CD68, and human leukocyte antigen-d-related cells in the prognosis of cutaneous malignant melanoma with vertical growth phase. Cancer 104: 1246–1254

    Article  CAS  PubMed  Google Scholar 

  76. Kammula US et al. (2004) Serial follow-up and the prognostic significance of reverse transcriptase–polymerase chain reaction-staged sentinel lymph nodes from melanoma patients. J Clin Oncol 19: 3989–3996

    Article  Google Scholar 

  77. Thies A et al. (2001) PAS-positive loops and networks as a prognostic indicator in cutaneous malignant melanoma. J Pathol 195: 537–542

    Article  CAS  PubMed  Google Scholar 

  78. Ricaniadis N et al. (2001) Long-term prognostic significance of HSP-70, c-myc and HLA-DR expression in patients with malignant melanoma. Eur J Surg Oncol 27: 88–93

    Article  CAS  PubMed  Google Scholar 

  79. Henrique R et al. (2000) Prognostic value of Ki-67 expression in localized cutaneous malignant melanoma. J Am Acad Dermatol 43: 991–1000

    Article  CAS  PubMed  Google Scholar 

  80. McDermott NC et al. (2000) Immunohistochemical expression of nm23 in primary invasive malignant melanoma is predictive of survival outcome. J Pathol 190: 157–162

    Article  CAS  PubMed  Google Scholar 

  81. Florenes VA et al. (2000) Levels of cyclin D1 and D3 in malignant melanoma: deregulated cyclin D3 expression is associated with poor clinical outcome in superficial melanoma. Clin Cancer Res 6: 3614–3620

    CAS  PubMed  Google Scholar 

  82. Karjalainen JM et al. (1999) p21WAF1/CIP1 expression in stage I cutaneous malignant melanoma: its relationship with p53, cell proliferation and survival. Br J Cancer 79: 895–902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Chana JS et al. (1998) The clinical significance of c-myc oncogene expression in melanomas of the scalp. Br J Plast Surg 51: 191–194

    Article  CAS  PubMed  Google Scholar 

  84. Dietrich A et al. (1997) High CD44 surface expression on primary tumours of malignant melanoma correlates with increased metastatic risk and reduced survival. Eur J Cancer 33: 926–930

    Article  CAS  PubMed  Google Scholar 

  85. Strebhardt K et al. (2000) Prognostic value of pololike kinase expression in melanomas. JAMA 283: 479–480

    Article  CAS  PubMed  Google Scholar 

  86. Grover R et al. (1999) Measurement of c-myc oncogene expression provides an accurate prognostic marker for acral lentiginous melanoma. Br J Plas Surg 52: 122–126

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rhoda M Alani.

Ethics declarations

Competing interests

Rhoda M Alani declared she is a patent holder for the Johns Hopkins University. The other authors declared no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Larson, A., Konat, E. & Alani, R. Melanoma biomarkers: current status and vision for the future. Nat Rev Clin Oncol 6, 105–117 (2009). https://doi.org/10.1038/ncponc1296

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncponc1296

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing