Current Oncology Reports

, Volume 14, Issue 5, pp 449–457

Driver Mutations in Melanoma: Lessons Learned From Bench-to-Bedside Studies

Melanoma (K Margolin, Section Editor)

Abstract

The identification of somatic driver mutations in human samples has allowed for the development of a molecular classification for melanoma. Recent breakthroughs in the treatment of metastatic melanoma have arisen as a result of these significant new insights into the molecular biology of the disease, particularly the development of inhibitors of activating BRAFV600E mutations. In this article the roles of several mutations known to be involved in the malignant transformation of melanocytes are reviewed including BRAF, PTEN, NRAS, ckit, and p16 as well as some of the emerging mutations in cutaneous and uveal melanoma. The bench to bedside collaborations that resulted in these discoveries are summarized, and potential therapeutic strategies to target driver mutations in specific patient subsets are discussed.

Keywords

Melanoma Somatic mutations Drug targeting 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Siegel R, Naishadham D, Jemal A. Cancer statistics. CA Cancer J Clin. 2012;62:1029.Google Scholar
  2. 2.
    Jilaveanu LB, Aziz SA, Kluger HM. Chemotherapy and biologic therapies for melanoma: do they work? Clin Dermatol. 2009;27:61425.CrossRefGoogle Scholar
  3. 3.
    Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:94954.CrossRefGoogle Scholar
  4. 4.
    • Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:250716. This paper summarizes for the first time, prolonged survival in patients treated with the BRAF V600E inhibitor vemurafenib.Google Scholar
  5. 5.
    Brose MS, Volpe P, Feldman M, et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 2002;62:69977000.Google Scholar
  6. 6.
    Tuveson DA, Weber BL, Herlyn M. BRAF as a potential therapeutic target in melanoma and other malignancies. Cancer Cell. 2003;4:958.CrossRefGoogle Scholar
  7. 7.
    Rimoldi D, Salvi S, Lienard D, et al. Lack of BRAF mutations in uveal melanoma. Cancer Res. 2003;63:57125.Google Scholar
  8. 8.
    Cruz III F, Rubin BP, Wilson D, et al. Absence of BRAF and NRAS mutations in uveal melanoma. Cancer Res. 2003;63:57616.Google Scholar
  9. 9.
    Maldonado JL, Fridlyand J, Patel H, et al. Determinants of BRAF mutations in primary melanomas. J Natl Cancer Inst. 2003;95:187890.CrossRefGoogle Scholar
  10. 10.
    Buery RR, Siar CH, Katase N, et al. NRAS and BRAF mutation frequency in primary oral mucosal melanoma. Oncol Rep. 26:7837.Google Scholar
  11. 11.
    Lang J, MacKie RM. Prevalence of exon 15 BRAF mutations in primary melanoma of the superficial spreading, nodular, acral, and lentigo maligna subtypes. J Invest Dermatol. 2005;125:5759.CrossRefGoogle Scholar
  12. 12.
    Omholt K, Platz A, Kanter L, Ringborg U, Hansson J. NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Clin Cancer Res. 2003;9:64838.Google Scholar
  13. 13.
    Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29:123946.CrossRefGoogle Scholar
  14. 14.
    Davies MA, Liu P, McIntyre S, et al. Prognostic factors for survival in melanoma patients with brain metastases. Cancer. 2011;117:168796.CrossRefGoogle Scholar
  15. 15.
    Flaherty KT, Schiller J, Schuchter LM, et al. A phase I trial of the oral, multikinase inhibitor sorafenib in combination with carboplatin and paclitaxel. Clin Cancer Res. 2008;14:483642.CrossRefGoogle Scholar
  16. 16.
    Hauschild A, Agarwala SS, Trefzer U, et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009;27:282330.Google Scholar
  17. 17.
    Agarwala SS, Becker JC, Eggermont AM, et al. Meeting report: consensus from the first and second Global Workshops in Melanoma, November 19–20, 2008. Pigment Cell Melanoma Res. 2009;22:53243.CrossRefGoogle Scholar
  18. 18.
    Su Y, Vilgelm AE, Kelley MC, et al. RAF265 inhibits the growth of advanced human melanoma tumors. Clin Cancer Res. 2012;18:218498.CrossRefGoogle Scholar
  19. 19.
    Ribas A, Flaherty KT. BRAF targeted therapy changes the treatment paradigm in melanoma. Nat Rev Clin Oncol. 2011;8:42633.CrossRefGoogle Scholar
  20. 20.
    Trefzer U. A phase IIA trial of the selective BRAF kinase inhibitor GSK2118436 in patients with BRAF (V600E/K) positive metastatic melanoma. In: Proceedings of the Society for Melanoma Research 2011.Tampa, FL;2011.Google Scholar
  21. 21.
    Rubinstein JC, Sznol M, Pavlick AC, et al. Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. J Transl Med. 2010;8:67.PubMedCrossRefGoogle Scholar
  22. 22.
    Anderson S, Bloom KJ, Vallera DU, et al. Multisite analytic performance studies of a real-time polymerase chain reaction assay for the eetection of BRAF V600E mutations in formalin-fixed paraffin-embedded tissue specimens of malignant melanoma. Arch Pathol Lab Med. 2012;(Epub ahead of print).Google Scholar
  23. 23.
    Johannessen CM, Boehm JS, Kim SY, et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010;468:96872.CrossRefGoogle Scholar
  24. 24.
    Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468:9737.CrossRefGoogle Scholar
  25. 25.
    Villanueva J, Vultur A, Herlyn M. Resistance to BRAF inhibitors: unraveling mechanisms and future treatment options. Cancer Res. 2011;71:713740.Google Scholar
  26. 26.
    Solit DB, Rosen N. Resistance to BRAF inhibition in melanomas. N Engl J Med. 2011;364:7724.CrossRefGoogle Scholar
  27. 27.
    Joneson T, Bar-Sagi D. Ras effectors and their role in mitogenesis and oncogenesis. J Mol Med (Berl). 1997;75:58793.CrossRefGoogle Scholar
  28. 28.
    Padua RA, Barrass N, Currie GA. A novel transforming gene in a human malignant melanoma cell line. Nature. 1984;311:6713.CrossRefGoogle Scholar
  29. 29.
    Omholt K, Karsberg S, Platz A, Kanter L, Ringborg U, Hansson J. Screening of N-ras codon 61 mutations in paired primary and metastatic cutaneous melanomas: mutations occur early and persist throughout tumor progression. Clin Cancer Res. 2002;8:346874.Google Scholar
  30. 30.
    Kelleher FC, McArthur GA. Targeting NRAS in Melanoma. Cancer J. 2012;18:1326.CrossRefGoogle Scholar
  31. 31.
    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;66:948391.CrossRefGoogle Scholar
  32. 32.
    Goel VK, Lazar AJ, Warneke CL, Redston MS, Haluska FG. Examination of mutations in BRAF, NRAS, and PTEN in primary cutaneous melanoma. J Invest Dermatol. 2006;126:15460.CrossRefGoogle Scholar
  33. 33.
    Davies MA, Stemke-Hale K, Lin E, et al. Integrated molecular and clinical analysis of AKT activation in metastatic melanoma. Clin Cancer Res. 2009;15:753846.CrossRefGoogle Scholar
  34. 34.
    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;129:13947.CrossRefGoogle Scholar
  35. 35.
    Ackermann J, Frutschi M, Kaloulis K, McKee T, Trumpp A, Beermann F. Metastasizing melanoma formation caused by expression of activated N-RasQ61K on an INK4a-deficient background. Cancer Res. 2005;65:400511.CrossRefGoogle Scholar
  36. 36.
    Lin J, Takata M, Murata H, et al. Polyclonality of BRAF mutations in acquired melanocytic nevi. J Natl Cancer Inst. 2009;101:14237.CrossRefGoogle Scholar
  37. 37.
    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;21:71626.CrossRefGoogle Scholar
  38. 38.
    Ross AL, Sanchez MI, Grichnik JM. Molecular nevogenesis. Dermatol Res Pract. 2011;2011:463184.PubMedGoogle Scholar
  39. 39.
    Akslen LA, Angelini S, Straume O, et al. BRAF and NRAS mutations are frequent in nodular melanoma but are not associated with tumor cell proliferation or patient survival. J Invest Dermatol. 2005;125:3127.Google Scholar
  40. 40.
    Ugurel S, Thirumaran RK, Bloethner S, et al. B-RAF and N-RAS mutations are preserved during short time in vitro propagation and differentially impact prognosis. PLoS One. 2007;2:e236.PubMedCrossRefGoogle Scholar
  41. 41.
    Lee JH, Choi JW, Kim YS. Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: a meta-analysis. Br J Dermatol. 2011;164:77684.Google Scholar
  42. 42.
    Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:213547.CrossRefGoogle Scholar
  43. 43.
    Devitt B, Liu W, Salemi R, et al. Clinical outcome and pathological features associated with NRAS mutation in cutaneous melanoma. Pigment Cell Melanoma Res. 2011;24:66672.CrossRefGoogle Scholar
  44. 44.
    Ellerhorst JA, Greene VR, Ekmekcioglu S, et al. Clinical correlates of NRAS and BRAF mutations in primary human melanoma. Clin Cancer Res. 2011;17:22935.CrossRefGoogle Scholar
  45. 45.
    Jakob JA, Bassett RL Jr., Ng CS, et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer. 2011;Epub ahead of print.Google Scholar
  46. 46.
    Flaherty KT, Fisher DE. New strategies in metastatic melanoma: oncogene-defined taxonomy leads to therapeutic advances. Clin Cancer Res. 2011;17:49228.CrossRefGoogle Scholar
  47. 47.
    Jaiswal BS, Janakiraman V, Kljavin NM, et al. Combined targeting of BRAF and CRAF or BRAF and PI3K effector pathways is required for efficacy in NRAS mutant tumors. PLoS One. 2009;4:e5717.PubMedCrossRefGoogle Scholar
  48. 48.
    Chattopadhyay C, Ellerhorst JA, Ekmekcioglu S, Greene VR, Davies MA, Grimm EA. Association of activated c-Met with NRAS-mutated human melanomas. Int J Cancer. 2011;(Epub ahead of print).Google Scholar
  49. 49.
    Larue L, Dougherty N, Porter S, Mintz B. Spontaneous malignant transformation of melanocytes explanted from Wf/Wf mice with a Kit kinase-domain mutation. Proc Natl Acad Sci USA. 1992;89:781620.Google Scholar
  50. 50.
    Montone KT, van Belle P, Elenitsas R, Elder DE. Proto-oncogene c-kit expression in malignant melanoma: protein loss with tumor progression. Mod Pathol. 1997;10:93944.Google Scholar
  51. 51.
    Baldi A, Santini D, Battista T, et al. Expression of AP-2 transcription factor and of its downstream target genes c-kit, E-cadherin and p21 in human cutaneous melanoma. J Cell Biochem. 2001;83:36472.CrossRefGoogle Scholar
  52. 52.
    Guerriere-Kovach PM, Hunt EL, Patterson JW, Glembocki DJ, English III JC, Wick MR. Primary melanoma of the skin and cutaneous melanomatous metastases: comparative histologic features and immunophenotypes. Am J Clin Pathol. 2004;122:707.CrossRefGoogle Scholar
  53. 53.
    Mouriaux F, Kherrouche Z, Maurage CA, Demailly FX, Labalette P, Saule S. Expression of the c-kit receptor in choroidal melanomas. Melanoma Res. 2003;13:1616.CrossRefGoogle Scholar
  54. 54.
    Fiorentini G, Rossi S, Lanzanova G, Bernardeschi P, Dentico P, De Giorgi U. Potential use of imatinib mesylate in ocular melanoma and liposarcoma expressing immunohistochemical c-KIT (CD117). Ann Oncol. 2003;14:805.PubMedCrossRefGoogle Scholar
  55. 55.
    McGary EC, Onn A, Mills L, et al. Imatinib mesylate inhibits platelet-derived growth factor receptor phosphorylation of melanoma cells but does not affect tumorigenicity in vivo. J Invest Dermatol. 2004;122:4005.CrossRefGoogle Scholar
  56. 56.
    Lefevre G, Glotin AL, Calipel A, et al. Roles of stem cell factor/c-Kit and effects of Glivec/STI571 in human uveal melanoma cell tumorigenesis. J Biol Chem. 2004;279:3176979.CrossRefGoogle Scholar
  57. 57.
    All-Ericsson C, Girnita L, Muller-Brunotte A, et al. c-Kit-dependent growth of uveal melanoma cells: a potential therapeutic target? Invest Ophthalmol Vis Sci. 2004;45:207582.CrossRefGoogle Scholar
  58. 58.
    Ugurel S, Hildenbrand R, Zimpfer A, et al. Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer. 2005;92:1398405.CrossRefGoogle Scholar
  59. 59.
    Wyman K, Atkins MB, Prieto V, et al. Multicenter Phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy. Cancer. 2006;106:200511.CrossRefGoogle Scholar
  60. 60.
    Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol. 2006;24:43406.CrossRefGoogle Scholar
  61. 61.
    Kim KB, Eton O, Davis DW, et al. Phase II trial of imatinib mesylate in patients with metastatic melanoma. Br J Cancer. 2008;99:73440.Google Scholar
  62. 62.
    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;29:29049.CrossRefGoogle Scholar
  63. 63.
    Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA. 2011;305:232734.CrossRefGoogle Scholar
  64. 64.
    Woodman SE, Trent JC, Stemke-Hale K, et al. Activity of dasatinib against L576P KIT mutant melanoma: molecular, cellular, and clinical correlates. Mol Cancer Ther. 2009;8:207985.CrossRefGoogle Scholar
  65. 65.
    Kluger HM, Dudek AZ, McCann C, et al. A phase 2 trial of dasatinib in advanced melanoma. Cancer. 2011;117:22028.CrossRefGoogle Scholar
  66. 66.
    Jilaveanu LB, Zito CR, Aziz SA, et al. In vitro studies of dasatinib, its targets and predictors of sensitivity. Pigment Cell Melanoma Res. 2011;24:3869.CrossRefGoogle Scholar
  67. 67.
    Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275:19437.CrossRefGoogle Scholar
  68. 68.
    Wu H, Goel V, Haluska FG. PTEN signaling pathways in melanoma. Oncogene. 2003;22:311322.Google Scholar
  69. 69.
    Eng C. Genetics of Cowden syndrome: through the looking glass of oncology. Int J Oncol. 1998;12:70110.Google Scholar
  70. 70.
    Tsao H, Zhang X, Fowlkes K, Haluska FG. Relative reciprocity of NRAS and PTEN/MMAC1 alterations in cutaneous melanoma cell lines. Cancer Res. 2000;60:1800–4.PubMedGoogle Scholar
  71. 71.
    Stahl JM, Cheung M, Sharma A, Trivedi NR, Shanmugam S, Robertson GP. Loss of PTEN promotes tumor development in malignant melanoma. Cancer Res. 2003;63:288190.Google Scholar
  72. 72.
    Guldberg P, thor Straten P, Birck A, Ahrenkiel V, Kirkin AF, Zeuthen J. Disruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma. Cancer Res. 1997;57:36603.Google Scholar
  73. 73.
    Zhou XP, Gimm O, Hampel H, Niemann T, Walker MJ, Eng C. Epigenetic PTEN silencing in malignant melanomas without PTEN mutation. Am J Pathol. 2000;157:11238.CrossRefGoogle Scholar
  74. 74.
    Lahtz C, Stranzenbach R, Fiedler E, Helmbold P, Dammann RH. Methylation of PTEN as a prognostic factor in malignant melanoma of the skin. J Invest Dermatol. 2010;130:6202.CrossRefGoogle Scholar
  75. 75.
    Tsao H, Zhang X, Benoit E, Haluska FG. Identification of PTEN/MMAC1 alterations in uncultured melanomas and melanoma cell lines. Oncogene. 1998;16:3397402.CrossRefGoogle Scholar
  76. 76.
    Fecher LA, Cummings SD, Keefe MJ, Alani RM. Toward a molecular classification of melanoma. J Clin Oncol. 2007;25:160620.CrossRefGoogle Scholar
  77. 77.
    You MJ, Castrillon DH, Bastian BC, et al. Genetic analysis of Pten and Ink4a/Arf interactions in the suppression of tumorigenesis in mice. Proc Natl Acad Sci USA. 2002;99:145560.CrossRefGoogle Scholar
  78. 78.
    • Dankort D, Curley DP, Cartlidge RA, et al. Braf(V600E) cooperates with PTEN loss to induce metastatic melanoma. Nat Genet. 2009;41:54452. This paper summarizes an elegant preclinical mouse model where PTEN deficiency cooperates with mutant BRAF V600E to induce melanoma with salient features of the human disease, a powerful tool to test potential therapeutic combinations in a preclinical setting.CrossRefGoogle Scholar
  79. 79.
    Madhunapantula SV, Robertson GP. The PTEN-AKT3 signaling cascade as a therapeutic target in melanoma. Pigment Cell Melanoma Res. 2009;22:40019.CrossRefGoogle Scholar
  80. 80.
    Sigalotti L, Covre A, Fratta E, et al. Epigenetics of human cutaneous melanoma: setting the stage for new therapeutic strategies. J Transl Med. 2010;8:56.PubMedCrossRefGoogle Scholar
  81. 81.
    Kamb A, Gruis NA, Weaver-Feldhaus J, et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science. 1994;264:43640.CrossRefGoogle Scholar
  82. 82.
    Goldstein AM, Chan M, Harland M, et al. High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res. 2006;66:981828.CrossRefGoogle Scholar
  83. 83.
    Hunter T, Pines J. Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age. Cell. 1994;79:57382.CrossRefGoogle Scholar
  84. 84.
    Goldstein AM, Struewing JP, Chidambaram A, Fraser MC, Tucker MA. Genotype-phenotype relationships in U.S. melanoma-prone families with CDKN2A and CDK4 mutations. J Natl Cancer Inst. 2000;92:100610.CrossRefGoogle Scholar
  85. 85.
    Gast A, Scherer D, Chen B, et al. Somatic alterations in the melanoma genome: a high-resolution array-based comparative genomic hybridization study. Genes Chromosomes Cancer. 2010;49:73345.CrossRefGoogle Scholar
  86. 86.
    Walker GJ, Flores JF, Glendening JM, Lin AH, Markl ID, Fountain JW. Virtually 100 % of melanoma cell lines harbor alterations at the DNA level within CDKN2A, CDKN2B, or one of their downstream targets. Genes Chromosomes Cancer. 1998;22:15763.CrossRefGoogle Scholar
  87. 87.
    Cronin JC, Wunderlich J, Loftus SK, et al. Frequent. mutations in the MITF pathway in melanoma. Pigment Cell Melanoma Res. 2009;22:43544.CrossRefGoogle Scholar
  88. 88.
    Garraway LA, Widlund HR, Rubin MA, et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature. 2005;436:11722.CrossRefGoogle Scholar
  89. 89.
    Bertolotto C, Lesueur F, Giuliano S, et al. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature. 2011;480:948.CrossRefGoogle Scholar
  90. 90.
    Yokoyama S, Woods SL, Boyle GM, et al. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature. 2011;480:99103.CrossRefGoogle Scholar
  91. 91.
    Davies MA, Stemke-Hale K, Tellez C, et al. A novel AKT3 mutation in melanoma tumours and cell lines. Br J Cancer. 2008;99:12658.CrossRefGoogle Scholar
  92. 92.
    Nikolaev SI, Rimoldi D, Iseli C, et al. Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma. Nat Genet. 2012;44:1339.Google Scholar
  93. 93.
    Stark MS, Woods SL, Gartside MG, et al. Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing. Nat Genet. 2012;44:1659.Google Scholar
  94. 94.
    Wei X, Walia V, Lin JC, et al. Exome sequencing identifies GRIN2A as frequently mutated in melanoma. Nat Genet. 2011;43:4426.CrossRefGoogle Scholar
  95. 95.
    Van Raamsdonk CD, Fitch KR, Fuchs H, de Angelis MH, Barsh GS. Effects of G-protein mutations on skin color. Nat Genet. 2004;36:9618.Google Scholar
  96. 96.
    Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med. 2010;363:21919.Google Scholar
  97. 97.
    Van Raamsdonk CD, Bezrookove V, Green G, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009;457:599602.Google Scholar
  98. 98.
    Mitsiades N, Chew SA, He B, et al. Genotype-dependent sensitivity of uveal melanoma cell lines to inhibition of B-Raf, MEK, and Akt kinases: rationale for personalized therapy. Invest Ophthalmol Vis Sci. 2011;52:724855.CrossRefGoogle Scholar
  99. 99.
    • Harbour JW, Onken MD, Roberson ED, et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science. 2010;330:14103. This paper utilized exome capture coupled with parallel sequencing to identify inactivating mutations in gene encoding BRCA1-associated protein 1 (BAP1), suggesting loss of BAP1 is important in uveal melanoma metastasis.CrossRefGoogle Scholar
  100. 100.
    Schuchter LM. 2010: A Target Date for Improving Survival of Patients with Metastatic Melanoma. ASCO Education booklet. 2005;2005:64949.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.The Cancer Institute of New JerseyNew BrunswickUSA
  2. 2.Yale Cancer CenterNew HavenUSA

Personalised recommendations