**Author details**

Rohinton S. Tarapore

University of Pennsylvania School of Medicine, Philadelphia, PA, USA

### **References**


[9] Jemal, A, Thun, M. J, Ries, L. A, Howe, H. L, Weir, H. K, et al. (2008). Annual report to the nation on the status of cancer, 1975-2005, featuring trends in lung cancer, to‐ bacco use, and tobacco control. J Natl Cancer Inst , 100, 1672-1694.

[25] Hussussian, C. J, Struewing, J. P, Goldstein, A. M, Higgins, P. A, Ally, D. S, et al. (1994). Germline mutations in familial melanoma. Nat Genet 8: 15-21., 16.

An Overview of Important Genetic Aspects in Melanoma

http://dx.doi.org/10.5772/55257

57

[26] Kamb, A, Shattuck-eidens, D, Eeles, R, Liu, Q, Gruis, N. A, et al. (1994). Analysis of the gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility lo‐

[27] Pomerantz, J, Schreiber-agus, N, Liegeois, N. J, Silverman, A, Alland, L, et al. (1998). The Ink4a tumor suppressor gene product, interacts with MDM2 and neutralizes

[28] Zhang, Y, Xiong, Y, & Yarbrough, W. G. (1998). ARF promotes MDM2 degradation and stabilizes ARF-INK4a locus deletion impairs both the Rb and p53 tumor sup‐

[29] Kamijo, T, Weber, J. D, Zambetti, G, Zindy, F, Roussel, M. F, et al. (1998). Functional and physical interactions of the ARF tumor suppressor with and Mdm2. Proc Natl

[30] Stott, F. J, Bates, S, James, M. C, Mcconnell, B. B, Starborg, M, et al. (1998). The alter‐ native product from the human CDKN2A locus, ARF), participates in a regulatory

[31] Chin, L, Garraway, L. A, & Fisher, D. E. (2006). Malignant melanoma: genetics and

[32] Gandini, S, Sera, F, Cattaruzza, M. S, Pasquini, P, Abeni, D, et al. (2005). Meta-analy‐ sis of risk factors for cutaneous melanoma: I. Common and atypical naevi. Eur J Can‐

[33] Gandini, S, Sera, F, Cattaruzza, M. S, Pasquini, P, Picconi, O, et al. (2005). Meta-analy‐ sis of risk factors for cutaneous melanoma: II. Sun exposure. Eur J Cancer , 41, 45-60.

[34] Zuo, L, Weger, J, Yang, Q, Goldstein, A. M, Tucker, M. A, et al. (1996). Germline mu‐ tations in the binding domain of CDK4 in familial melanoma. Nat Genet 12: 97-99.,

[35] Soufir, N, Avril, M. F, Chompret, A, Demenais, F, Bombled, J, et al. (1998). Preva‐ lence of and CDK4 germline mutations in 48 melanoma-prone families in France. The

[36] Wolfel, T, Hauer, M, Schneider, J, Serrano, M, Wolfel, C, et al. (1995). A CDK4 mu‐ tant targeted by cytolytic T lymphocytes in a human melanoma. Science 269:

[37] Eng, C, Li, F. P, Abramson, D. H, Ellsworth, R. M, Wong, F. L, et al. (1993). Mortality from second tumors among long-term survivors of retinoblastoma. J Natl Cancer

French Familial Melanoma Study Group. Hum Mol Genet 7: 209-216., 16.

feedback loop with p53 and MDM2. EMBO J 17: 5001-5014., 14.

therapeutics in the genomic era. Genes Dev , 20, 2149-2182.

cus. Nat Genet 8: 23-26., 16.

MDM2's inhibition of p53. Cell 92: 713-723., 19Arf.

pression pathways. Cell 92: 725-734., 53.

Acad Sci U S A 95: 8292-8297., 53.

cer , 41, 28-44.

16INK4a.

1281-1284., 16INK4a.

Inst , 85, 1121-1128.


[25] Hussussian, C. J, Struewing, J. P, Goldstein, A. M, Higgins, P. A, Ally, D. S, et al. (1994). Germline mutations in familial melanoma. Nat Genet 8: 15-21., 16.

[9] Jemal, A, Thun, M. J, Ries, L. A, Howe, H. L, Weir, H. K, et al. (2008). Annual report to the nation on the status of cancer, 1975-2005, featuring trends in lung cancer, to‐

[10] Linos, E, Swetter, S. M, Cockburn, M. G, Colditz, G. A, & Clarke, C. A. (2009). In‐ creasing burden of melanoma in the United States. J Invest Dermatol , 129, 1666-1674.

[11] Wargo, J. A, & Tanabe, K. (2009). Surgical management of melanoma. Hematol Oncol

[12] Glanz, K, Buller, D. B, & Saraiya, M. (2007). Reducing ultraviolet radiation exposure among outdoor workers: state of the evidence and recommendations. Environ

[13] Meeran, S. M, Punathil, T, & Katiyar, S. K. (2008). IL-12 deficiency exacerbates in‐ flammatory responses in UV-irradiated skin and skin tumors. J Invest Dermatol , 128,

[14] Benjamin, C. L, & Ananthaswamy, H. N. (2007). and the pathogenesis of skin cancer.

[15] Garbe, C, & Leiter, U. (2009). Melanoma epidemiology and trends. Clin Dermatol ,

[16] Gandini, S, Autier, P, & Boniol, M. (2011). Reviews on sun exposure and artificial

[17] Preston, D. S, & Stern, R. S. (1992). Nonmelanoma cancers of the skin. N Engl J Med ,

[18] Gilchrest, B. A, Eller, M. S, Geller, A. C, & Yaar, M. (1999). The pathogenesis of mela‐

[19] Gloster, H. M. Jr., Neal K ((2006). Skin cancer in skin of color. J Am Acad Dermatol

[20] Ma, F, Collado-mesa, F, Hu, S, & Kirsner, R. S. (2007). Skin cancer awareness and sun protection behaviors in white Hispanic and white non-Hispanic high school students

[21] Schroeder, P, Haendeler, J, & Krutmann, J. (2008). The role of near infrared radiation

[22] Bennett, D. C. (1993). Genetics, development, and malignancy of melanocytes. Int

[23] Tsao, H, Atkins, M. B, & Sober, A. J. (2004). Management of cutaneous melanoma. N

[24] Lomas, J, Martin-duque, P, Pons, M, & Quintanilla, M. (2008). The genetics of malig‐

noma induced by ultraviolet radiation. N Engl J Med , 340, 1341-1348.

bacco use, and tobacco control. J Natl Cancer Inst , 100, 1672-1694.

Clin North Am x., 23, 565-581.

Toxicol Appl Pharmacol 224: 241-248., 53.

light and melanoma. Prog Biophys Mol Biol , 107, 362-366.

in Miami, Florida. Arch Dermatol , 143, 983-988.

nant melanoma. Front Biosci , 13, 5071-5093.

in photoaging of the skin. Exp Gerontol , 43, 629-632.

Health 6: 22.

56 Highlights in Skin Cancer

2716-2727.

27, 3-9.

327, 1649-1662.

quiz 761-744., 55, 741-760.

Rev Cytol , 146, 191-260.

Engl J Med , 351, 998-1012.


[38] Fletcher, O, Easton, D, Anderson, K, Gilham, C, Jay, M, et al. (2004). Lifetime risks of common cancers among retinoblastoma survivors. J Natl Cancer Inst , 96, 357-363.

[52] Lefevre, G, Calipel, A, Mouriaux, F, Hecquet, C, Malecaze, F, et al. (2003). Opposite long-term regulation of c-Myc and through overactivation of Raf-1 and the MEK/ERK module in proliferating human choroidal melanoma cells. Oncogene 22:

An Overview of Important Genetic Aspects in Melanoma

http://dx.doi.org/10.5772/55257

59

[53] Lopez-bergami, P, Huang, C, Goydos, J. S, Yip, D, Bar-eli, M, et al. (2007). Rewired

[54] Goding, C. R. (2000). Mitf from neural crest to melanoma: signal transduction and

[55] Wu, M, Hemesath, T. J, Takemoto, C. M, Horstmann, M. A, Wells, A. G, et al. (2000). c-Kit triggers dual phosphorylations, which couple activation and degradation of the

[56] Kim, D. S, Hwang, E. S, Lee, J. E, Kim, S. Y, Kwon, S. B, et al. (2003). Sphingosine-1 phosphate decreases melanin synthesis via sustained ERK activation and subsequent

[57] Eisenmann, K. M, Vanbrocklin, M. W, Staffend, N. A, Kitchen, S. M, & Koo, H. M. (2003). Mitogen-activated protein kinase pathway-dependent tumor-specific survival signaling in melanoma cells through inactivation of the proapoptotic protein bad.

[58] Krasilnikov, M, Ivanov, V. N, Dong, J, & Ronai, Z. (2003). Erkand P. I K negatively regulate STAT-transcriptional activities in human melanoma cells: implications to‐

[59] Tower, G. B, Coon, C. C, Benbow, U, Vincenti, M. P, & Brinckerhoff, C. E. (2002). Erk 1/2 differentially regulates the expression from the 1G/2G single nucleotide polymor‐ phism in the MMP-1 promoter in melanoma cells. Biochim Biophys Acta , 1586,

[60] Ishii, Y, Ogura, T, Tatemichi, M, Fujisawa, H, Otsuka, F, et al. (2003). Induction of matrix metalloproteinase gene transcription by nitric oxide and mechanisms of MMP-1 gene induction in human melanoma cell lines. Int J Cancer , 103, 161-168.

[61] Ramos, M. C, Steinbrenner, H, Stuhlmann, D, Sies, H, & Brenneisen, P. (2004). Induc‐ tion of MMP-10 and MMP-1 in a squamous cell carcinoma cell line by ultraviolet ra‐

[62] Steelman, L. S, Bertrand, F. E, & Mccubrey, J. A. (2004). The complexity of PTEN: mu‐ tation, marker and potential target for therapeutic intervention. Expert Opin Ther

[63] Parmiter, A. H, Balaban, G, & Clark, W. H. Jr., Nowell PC ((1988). Possible involve‐ ment of the chromosome region 10q24----q26 in early stages of melanocytic neopla‐

ERK-JNK signaling pathways in melanoma. Cancer Cell , 11, 447-460.

transcription in the melanocyte lineage. Genes Dev , 14, 1712-1728.

essential melanocyte factor Mi. Genes Dev , 14, 301-312.

wards sensitization to apoptosis. Oncogene , 22, 4092-4101.

MITF degradation. J Cell Sci , 116, 1699-1706.

Cancer Res , 63, 8330-8337.

diation. Biol Chem , 385, 75-86.

sia. Cancer Genet Cytogenet , 30, 313-317.

Targets , 8, 537-550.

265-274.

8813-8822., 27Kip1.


[52] Lefevre, G, Calipel, A, Mouriaux, F, Hecquet, C, Malecaze, F, et al. (2003). Opposite long-term regulation of c-Myc and through overactivation of Raf-1 and the MEK/ERK module in proliferating human choroidal melanoma cells. Oncogene 22: 8813-8822., 27Kip1.

[38] Fletcher, O, Easton, D, Anderson, K, Gilham, C, Jay, M, et al. (2004). Lifetime risks of common cancers among retinoblastoma survivors. J Natl Cancer Inst , 96, 357-363.

[39] Druker, B. J, Talpaz, M, Resta, D. J, Peng, B, Buchdunger, E, et al. (2001). Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leu‐

[40] Demetri, G. D, Von Mehren, M, & Blanke, C. D. Van den Abbeele AD, Eisenberg B, et al. ((2002). Efficacy and safety of imatinib mesylate in advanced gastrointestinal stro‐

[41] Lynch, T. J, Bell, D. W, Sordella, R, Gurubhagavatula, S, Okimoto, R. A, et al. (2004). Activating mutations in the epidermal growth factor receptor underlying responsive‐

[42] Curtin, J. A, Busam, K, Pinkel, D, & Bastian, B. C. (2006). Somatic activation of KIT in

[43] Albino, A. P. Le Strange R, Oliff AI, Furth ME, Old LJ ((1984). Transforming ras genes from human melanoma: a manifestation of tumour heterogeneity? Nature ,

[44] Davies, H, Bignell, G. R, Cox, C, Stephens, P, Edkins, S, et al. (2002). Mutations of the

[45] Lopez-bergami, P, Fitchman, B, & Ronai, Z. (2008). Understanding signaling cascades

[46] Pollock, P. M, Harper, U. L, Hansen, K. S, Yudt, L. M, Stark, M, et al. (2003). High

[47] Gorden, A, Osman, I, Gai, W, He, D, Huang, W, et al. (2003). Analysis of BRAF and N-RAS mutations in metastatic melanoma tissues. Cancer Res , 63, 3955-3957.

[48] Kumar, R, Angelini, S, Czene, K, Sauroja, I, Hahka-kemppinen, M, et al. (2003). BRAF mutations in metastatic melanoma: a possible association with clinical outcome. Clin

[49] Carr, J, & Mackie, R. M. (1994). Point mutations in the N-ras oncogene in malignant

[50] Van Elsas, A, Zerp, S, Van Der Flier, S, Kruse-wolters, M, Vacca, A, et al. (1995). Analysis of N-ras mutations in human cutaneous melanoma: tumor heterogeneity detected by polymerase chain reaction/single-stranded conformation polymorphism

[51] Kortylewski, M, Heinrich, P. C, Kauffmann, M. E, & Bohm, M. MacKiewicz A, et al. ((2001). Mitogen-activated protein kinases control Kip1 expression and growth of hu‐

ness of non-small-cell lung cancer to gefitinib. N Engl J Med , 350, 2129-2139.

distinct subtypes of melanoma. J Clin Oncol , 24, 4340-4346.

BRAF gene in human cancer. Nature , 417, 949-954.

in melanoma. Photochem Photobiol , 84, 289-306.

frequency of BRAF mutations in nevi. Nat Genet , 33, 19-20.

melanoma and congenital naevi. Br J Dermatol , 131, 72-77.

analysis. Recent Results Cancer Res , 139, 57-67.

man melanoma cells. Biochem J 357: 297-303., 27.

kemia. N Engl J Med , 344, 1031-1037.

mal tumors. N Engl J Med , 347, 472-480.

308, 69-72.

58 Highlights in Skin Cancer

Cancer Res , 9, 3362-3368.


[64] Simpson, L, & Parsons, R. (2001). PTEN: life as a tumor suppressor. Exp Cell Res , 264, 29-41.

[78] Datta, S. R, Dudek, H, Tao, X, Masters, S, Fu, H, et al. (1997). Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell , 91, 231-241.

An Overview of Important Genetic Aspects in Melanoma

http://dx.doi.org/10.5772/55257

61

[79] Giles, R. H, Van Es, J. H, & Clevers, H. (2003). Caught up in a Wnt storm: Wnt signal‐

[80] Veeman, M. T, Axelrod, J. D, & Moon, R. T. (2003). A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling. Dev Cell , 5, 367-377.

[81] Elcheva, I, Tarapore, R. S, Bhatia, N, & Spiegelman, V. S. (2008). Overexpression of mRNA-binding protein CRD-BP in malignant melanomas. Oncogene , 27, 5069-5074.

[82] Rimm, D. L, Caca, K, Hu, G, Harrison, F. B, & Fearon, E. R. (1999). Frequent nuclear/ cytoplasmic localization of beta-catenin without exon 3 mutations in malignant mela‐

[83] Demunter, A, Libbrecht, L, Degreef, H, & De Wolf-peeters, C. van den Oord JJ ((2002). Loss of membranous expression of beta-catenin is associated with tumor pro‐ gression in cutaneous melanoma and rarely caused by exon 3 mutations. Mod Path‐

[84] Omholt, K, Platz, A, Ringborg, U, & Hansson, J. (2001). Cytoplasmic and nuclear ac‐ cumulation of beta-catenin is rarely caused by CTNNB1 exon 3 mutations in cutane‐

[85] Rubinfeld, B, Robbins, P, Gamil, M, Albert, I, Porfiri, E, et al. (1997). Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science , 275, 1790-1792.

[86] Reifenberger, J, Knobbe, C. B, Wolter, M, Blaschke, B, Schulte, K. W, et al. (2002). Mo‐ lecular genetic analysis of malignant melanomas for aberrations of the WNT signal‐ ing pathway genes CTNNB1, APC, ICAT and BTRC. Int J Cancer , 100, 549-556. [87] Pollock, P. M, & Hayward, N. (2002). Mutations in exon 3 of the beta-catenin gene

[88] Worm, J, Christensen, C, Gronbaek, K, Tulchinsky, E, & Guldberg, P. (2004). Genetic and epigenetic alterations of the APC gene in malignant melanoma. Oncogene , 23,

[89] Tago, K, Nakamura, T, Nishita, M, Hyodo, J, Nagai, S, et al. (2000). Inhibition of Wnt signaling by ICAT, a novel beta-catenin-interacting protein. Genes Dev , 14,

[90] Goodall, J, Martinozzi, S, Dexter, T. J, Champeval, D, Carreira, S, et al. (2004). Brn-2 expression controls melanoma proliferation and is directly regulated by beta-catenin.

[91] Thomson, J. A, Murphy, K, Baker, E, Sutherland, G. R, Parsons, P. G, et al. (1995). The brn-2 gene regulates the melanocytic phenotype and tumorigenic potential of human

ing in cancer. Biochim Biophys Acta , 1653, 1-24.

ous malignant melanoma. Int J Cancer , 92, 839-842.

are rare in melanoma cell lines. Melanoma Res , 12, 183-186.

noma. Am J Pathol , 154, 325-329.

ol , 15, 454-461.

5215-5226.

1741-1749.

Mol Cell Biol , 24, 2915-2922.

melanoma cells. Oncogene , 11, 691-700.


[78] Datta, S. R, Dudek, H, Tao, X, Masters, S, Fu, H, et al. (1997). Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell , 91, 231-241.

[64] Simpson, L, & Parsons, R. (2001). PTEN: life as a tumor suppressor. Exp Cell Res ,

[65] Wu, H, Goel, V, & Haluska, F. G. (2003). PTEN signaling pathways in melanoma. On‐

[66] Herbst, R. A, Weiss, J, Ehnis, A, Cavenee, W. K, & Arden, K. C. (1994). Loss of hetero‐ zygosity for 10q22-10qter in malignant melanoma progression. Cancer Res , 54,

[67] Healy, E, Rehman, I, Angus, B, & Rees, J. L. (1995). Loss of heterozygosity in sporadic primary cutaneous melanoma. Genes Chromosomes Cancer , 12, 152-156.

[68] Harlan, J. E, Yoon, H. S, Hajduk, P. J, & Fesik, S. W. (1995). Structural characteriza‐ tion of the interaction between a pleckstrin homology domain and phosphatidylino‐

[69] Nicholson, K. M, & Anderson, N. G. (2002). The protein kinase B/Akt signalling path‐

[70] Stahl, J. M, Sharma, A, Cheung, M, Zimmerman, M, Cheng, J. Q, et al. (2004). De‐ regulated Akt3 activity promotes development of malignant melanoma. Cancer Res ,

[71] Robertson, G. P. (2005). Functional and therapeutic significance of Akt deregulation

[72] Dhawan, P, Singh, A. B, Ellis, D. L, & Richmond, A. (2002). Constitutive activation of Akt/protein kinase B in melanoma leads to up-regulation of nuclear factor-kappaB

[73] Li, G, Kalabis, J, Xu, X, Meier, F, Oka, M, et al. (2003). Reciprocal regulation of Mel‐

[74] Johnson, J. P. (1999). Cell adhesion molecules in the development and progression of

[75] Kim, D, Kim, S, Koh, H, Yoon, S. O, Chung, A. S, et al. (2001). Akt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production. FASEB

[76] Park, B. K, Zeng, X, & Glazer, R. I. (2001). Akt1 induces extracellular matrix invasion and matrix metalloproteinase-2 activity in mouse mammary epithelial cells. Cancer

[77] Cardone, M. H, Roy, N, Stennicke, H. R, Salvesen, G. S, Franke, T. F, et al. (1998). Regulation of cell death protease caspase-9 by phosphorylation. Science , 282,

sitol 4,5-bisphosphate. Biochemistry , 34, 9859-9864.

way in human malignancy. Cell Signal , 14, 381-395.

and tumor progression. Cancer Res , 62, 7335-7342.

in malignant melanoma. Cancer Metastasis Rev , 24, 273-285.

CAM and AKT in human melanoma. Oncogene , 22, 6891-6899.

malignant melanoma. Cancer Metastasis Rev , 18, 345-357.

264, 29-41.

60 Highlights in Skin Cancer

3111-3114.

64, 7002-7010.

J , 15, 1953-1962.

Res , 61, 7647-7653.

1318-1321.

cogene , 22, 3113-3122.


[92] Hodgkinson, C. A, Moore, K. J, Nakayama, A, Steingrimsson, E, Copeland, N. G, et al. (1993). Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-helix-zipper protein. Cell , 74, 395-404.

[106] Khatlani, T. S, Wislez, M, Sun, M, Srinivas, H, Iwanaga, K, et al. (2007). c-Jun N-ter‐ minal kinase is activated in non-small-cell lung cancer and promotes neoplastic

An Overview of Important Genetic Aspects in Melanoma

http://dx.doi.org/10.5772/55257

63

transformation in human bronchial epithelial cells. Oncogene , 26, 2658-2666.

[107] Adler, V, Schaffer, A, Kim, J, Dolan, L, & Ronai, Z. (1995). UV Irradiation and heat shock mediate JNK activation via alternate pathways. J Biol Chem , 270, 26071-26077.

[108] Mariani, O, Brennetot, C, Coindre, J. M, Gruel, N, Ganem, C, et al. (2007). JUN onco‐ gene amplification and overexpression block adipocytic differentiation in highly ag‐

[109] Vleugel, M. M, Greijer, A. E, Bos, R, Van Der Wall, E, & Van Diest, P. J. (2006). c-Jun activation is associated with proliferation and angiogenesis in invasive breast cancer.

[110] Maeno, K, Masuda, A, Yanagisawa, K, Konishi, H, Osada, H, et al. (2006). Altered regulation of c-jun and its involvement in anchorage-independent growth of human

[111] Yamanishi, D. T, Buckmeier, J. A, & Meyskens, F. L. Jr. ((1991). Expression of c-jun, jun-B, and c-fos proto-oncogenes in human primary melanocytes and metastatic mel‐

[112] Rutberg, S. E, Goldstein, I. M, Yang, Y. M, Stackpole, C. W, & Ronai, Z. (1994). Ex‐ pression and transcriptional activity of AP-1, CRE, and URE binding proteins in B16

[113] Mingo-sion, A. M, Marietta, P. M, Koller, E, & Wolf, D. M. Van Den Berg CL ((2004). Inhibition of JNK reduces G2/M transit independent of leading to endoreduplication, decreased proliferation, and apoptosis in breast cancer cells. Oncogene 23: 596-604.,

[114] Uzgare, A. R, & Isaacs, J. T. (2004). Enhanced redundancy in Akt and mitogen-acti‐ vated protein kinase-induced survival of malignant versus normal prostate epithelial

[115] Gurzov, E. N, Bakiri, L, Alfaro, J. M, Wagner, E. F, & Izquierdo, M. (2008). Targeting c-Jun and JunB proteins as potential anticancer cell therapy. Oncogene , 27, 641-652.

[116] Dixit, V, & Mak, T. W. (2002). NF-kappaB Signaling Many roads lead to madrid.

[117] Ghosh, S, & Karin, M. (2002). Missing pieces in the NF-kappaB puzzle. Cell 109

[118] Chen, X, Kandasamy, K, & Srivastava, R. K. (2003). Differential roles of RelA (and c-Rel subunits of nuclear factor kappa B in tumor necrosis factor-related apoptosis-in‐

gressive sarcomas. Cancer Cell , 11, 361-374.

lung cancers. Oncogene , 25, 271-277.

anomas. J Invest Dermatol , 97, 349-353.

cells. Cancer Res , 64, 6190-6199.

Cell , 111, 615-619.

Suppl: S, 81-96.

mouse melanoma subclones. Mol Carcinog , 10, 82-87.

ducing ligand signaling. Cancer Res 63: 1059-1066., 65.

Hum Pathol , 37, 668-674.

53.


[106] Khatlani, T. S, Wislez, M, Sun, M, Srinivas, H, Iwanaga, K, et al. (2007). c-Jun N-ter‐ minal kinase is activated in non-small-cell lung cancer and promotes neoplastic transformation in human bronchial epithelial cells. Oncogene , 26, 2658-2666.

[92] Hodgkinson, C. A, Moore, K. J, Nakayama, A, Steingrimsson, E, Copeland, N. G, et al. (1993). Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-helix-zipper protein. Cell , 74, 395-404.

[93] Hughes, M. J, Lingrel, J. B, Krakowsky, J. M, & Anderson, K. P. (1993). A Helix-loop helix transcription factor-like gene is located at the mi locus. J Biol Chem , 268,

[94] Widlund, H. R, Horstmann, M. A, Price, E. R, Cui, J, Lessnick, S. L, et al. (2002). Betacatenin-induced melanoma growth requires the downstream target Microphthalmia-

[95] Schepsky, A, Bruser, K, Gunnarsson, G. J, Goodall, J, Hallsson, J. H, et al. (2006). The microphthalmia-associated transcription factor Mitf interacts with beta-catenin to de‐

[96] Kawano, Y, & Kypta, R. (2003). Secreted antagonists of the Wnt signalling pathway. J

[97] Forget, M. A, Turcotte, S, Beauseigle, D, Godin-ethier, J, Pelletier, S, et al. (2007). The Wnt pathway regulator DKK1 is preferentially expressed in hormone-resistant breast

[98] Kuphal, S, Lodermeyer, S, Bataille, F, Schuierer, M, Hoang, B. H, et al. (2006). Expres‐ sion of Dickkopf genes is strongly reduced in malignant melanoma. Oncogene , 25,

[99] Mikheev, A. M, Mikheeva, S. A, Rostomily, R, & Zarbl, H. (2007). Dickkopf-1 acti‐ vates cell death in MDA-MB435 melanoma cells. Biochem Biophys Res Commun ,

[100] Lin, Y. C, You, L, Xu, Z, He, B, Yang, C. T, et al. (2007). Wnt inhibitory factor-1 gene

[101] Weston, C. R, & Davis, R. J. (2007). The JNK signal transduction pathway. Curr Opin

[102] Karin, M. (1995). The regulation of AP-1 activity by mitogen-activated protein kinas‐

[103] Kennedy, N. J, & Davis, R. J. (2003). Role of JNK in tumor development. Cell Cycle ,

[104] Yang, Y. M, Bost, F, Charbono, W, Dean, N, Mckay, R, et al. (2003). C-Jun NH(2)-ter‐ minal kinase mediates proliferation and tumor growth of human prostate carcinoma.

[105] Cui, J, Han, S. Y, Wang, C, Su, W, Harshyne, L, et al. (2006). c-Jun NH(2)-terminal kinase 2alpha2 promotes the tumorigenicity of human glioblastoma cells. Cancer

transfer inhibits melanoma cell growth. Hum Gene Ther , 18, 379-386.

tumours and in some common cancer types. Br J Cancer , 96, 646-653.

associated transcription factor. J Cell Biol , 158, 1079-1087.

termine target gene expression. Mol Cell Biol , 26, 8914-8927.

20687-20690.

62 Highlights in Skin Cancer

Cell Sci , 116, 2627-2634.

5027-5036.

352, 675-680.

2, 199-201.

Cell Biol , 19, 142-149.

es. J Biol Chem , 270, 16483-16486.

Clin Cancer Res , 9, 391-401.

Res , 66, 10024-10031.


[119] Poser, I, Dominguez, D, De Herreros, A. G, Varnai, A, Buettner, R, et al. (2001). Loss of E-cadherin expression in melanoma cells involves up-regulation of the transcrip‐ tional repressor Snail. J Biol Chem , 276, 24661-24666.

[132] Miller, S. A, Hamilton, S. L, Wester, U. G, & Cyr, W. H. (1998). An analysis of UVA emissions from sunlamps and the potential importance for melanoma. Photochem

An Overview of Important Genetic Aspects in Melanoma

http://dx.doi.org/10.5772/55257

65

[133] Lautenschlager, S, Wulf, H. C, & Pittelkow, M. R. (2007). Photoprotection. Lancet ,

[134] Brenner, M, & Hearing, V. J. (2008). The protective role of melanin against UV dam‐

[135] Bastian, B. C. LeBoit PE, Hamm H, Brocker EB, Pinkel D ((1998). Chromosomal gains and losses in primary cutaneous melanomas detected by comparative genomic hy‐

[136] Curtin, J. A, Fridlyand, J, Kageshita, T, Patel, H. N, Busam, K. J, et al. (2005). Distinct

[137] Balazs, M, Adam, Z, Treszl, A, Begany, A, Hunyadi, J, et al. (2001). Chromosomal im‐ balances in primary and metastatic melanomas revealed by comparative genomic hy‐

[138] Hausler, T, Stang, A, Anastassiou, G, Jockel, K. H, Mrzyk, S, et al. (2005). Loss of het‐ erozygosity of 1p in uveal melanomas with monosomy 3. Int J Cancer , 116, 909-913.

[139] White, J. S, Mclean, I. W, Becker, R. L, Director-myska, A. E, & Nath, J. (2006). Corre‐ lation of comparative genomic hybridization results of 100 archival uveal melanomas

[140] Speicher, M. R, & Prescher, G. du Manoir S, Jauch A, Horsthemke B, et al. ((1994). Chromosomal gains and losses in uveal melanomas detected by comparative genom‐

[141] Vajdic, C. M, Hutchins, A. M, Kricker, A, Aitken, J. F, Armstrong, B. K, et al. (2003). Chromosomal gains and losses in ocular melanoma detected by comparative genom‐ ic hybridization in an Australian population-based study. Cancer Genet Cytogenet ,

[142] Garraway, L. A, Widlund, H. R, Rubin, M. A, Getz, G, Berger, A. J, et al. (2005). Inte‐ grative genomic analyses identify MITF as a lineage survival oncogene amplified in

[143] Jonsson, G, Dahl, C, Staaf, J, Sandberg, T, Bendahl, P. O, et al. (2007). Genomic profil‐ ing of malignant melanoma using tiling-resolution arrayCGH. Oncogene , 26,

[144] Alonso, S. R, Tracey, L, Ortiz, P, Perez-gomez, B, Palacios, J, et al. (2007). A highthroughput study in melanoma identifies epithelial-mesenchymal transition as a ma‐

with patient survival. Cancer Genet Cytogenet , 170, 29-39.

ic hybridization. Cancer Res , 54, 3817-3823.

malignant melanoma. Nature , 436, 117-122.

jor determinant of metastasis. Cancer Res , 67, 3450-3460.

sets of genetic alterations in melanoma. N Engl J Med , 353, 2135-2147.

age in human skin. Photochem Photobiol , 84, 539-549.

bridization. Cancer Res , 58, 2170-2175.

bridization. Cytometry , 46, 222-232.

Photobiol , 68, 63-70.

370, 528-537.

144, 12-17.

4738-4748.


[132] Miller, S. A, Hamilton, S. L, Wester, U. G, & Cyr, W. H. (1998). An analysis of UVA emissions from sunlamps and the potential importance for melanoma. Photochem Photobiol , 68, 63-70.

[119] Poser, I, Dominguez, D, De Herreros, A. G, Varnai, A, Buettner, R, et al. (2001). Loss of E-cadherin expression in melanoma cells involves up-regulation of the transcrip‐

[120] Meyskens, F. L. Jr., Buckmeier JA, McNulty SE, Tohidian NB ((1999). Activation of nuclear factor-kappa B in human metastatic melanomacells and the effect of oxida‐

[121] Boukerche, H, Su, Z. Z, Emdad, L, Sarkar, D, & Fisher, P. B. (2007). mda-9/Syntenin regulates the metastatic phenotype in human melanoma cells by activating nuclear

[122] Philip, S, & Kundu, G. C. (2003). Osteopontin induces nuclear factor kappa B-mediat‐ ed promatrix metalloproteinase-2 activation through I kappa B alpha /IKK signaling pathways, and curcumin (diferulolylmethane) down-regulates these pathways. J Biol

[123] Dupin, E. Le Douarin NM ((2003). Development of melanocyte precursors from the

[124] Hendrix, M. J, Seftor, E. A, Seftor, R. E, Kasemeier-kulesa, J, Kulesa, P. M, et al. (2007). Reprogramming metastatic tumour cells with embryonic microenvironments.

[125] Bittner, M, Meltzer, P, Chen, Y, Jiang, Y, Seftor, E, et al. (2000). Molecular classifica‐ tion of cutaneous malignant melanoma by gene expression profiling. Nature , 406,

[126] Hendrix, M. J, Seftor, E. A, Hess, A. R, & Seftor, R. E. (2003). Molecular plasticity of

[127] Coiffier, B, Lepage, E, Briere, J, Herbrecht, R, Tilly, H, et al. (2002). CHOP chemother‐ apy plus rituximab compared with CHOP alone in elderly patients with diffuse

[128] Lee, J. T, & Herlyn, M. (2007). Microenvironmental influences in melanoma progres‐

[129] Paget, S. (1989). The distribution of secondary growths in cancer of the breast. 1889.

[130] Fidler, I. J. (2003). The pathogenesis of cancer metastasis: the'seed and soil' hypothe‐

[131] Topczewska, J. M, Postovit, L. M, Margaryan, N. V, Sam, A, Hess, A. R, et al. (2006). Embryonic and tumorigenic pathways converge via Nodal signaling: role in melano‐

tional repressor Snail. J Biol Chem , 276, 24661-24666.

tive stress. Clin Cancer Res , 5, 1197-1202.

factor-kappaB. Cancer Res , 67, 1812-1822.

vertebrate neural crest. Oncogene , 22, 3016-3023.

human melanoma cells. Oncogene , 22, 3070-3075.

large-B-cell lymphoma. N Engl J Med , 346, 235-242.

sion. J Cell Biochem , 101, 862-872.

Cancer Metastasis Rev , 8, 98-101.

sis revisited. Nat Rev Cancer , 3, 453-458.

ma aggressiveness. Nat Med , 12, 925-932.

Chem , 278, 14487-14497.

Nat Rev Cancer , 7, 246-255.

536-540.

64 Highlights in Skin Cancer


[145] Hoek, K, Rimm, D. L, Williams, K. R, Zhao, H, Ariyan, S, et al. (2004). Expression profiling reveals novel pathways in the transformation of melanocytes to melano‐ mas. Cancer Res , 64, 5270-5282.

**Chapter 4**

**Current Management of Malignant Melanoma:**

The word "melanoma" was first used by *Rene Laennec*, inventor of the stethoscope, in his manuscript reporting a case of disseminated melanoma in 1812 [1]. Cutaneous malignant melanoma (CMM) arises from the malignant transformation of the pigment producing melanocytes, which are located and evenly distributed in the basal epidermal layer of human skin. These pigment-producing cells (melanocytes) are located predominantly in the skin, but also found in the eyes, ears, GI tract, leptomeninges, and oral and genital mucous

The incidence of cutaneous malignant melanoma has increased significantly among all Caucasian populations over the last several decades. The rate of incidence of cutaneous melanoma continues to rise almost inexorably in populations of European origin worldwide. Diagnosis of melanoma at an early stage is almost curable but there is currently no effective treatment for advanced melanoma. Probably a large proportion of melanomas can be ascribed to a single (modifiable) risk factor-sun exposure. It has not been established whether medical intervention of any kind influences the outcome in the case of melanoma. Major initiatives in recent years have concentrated on education about sun avoidance, the importance of skin awareness and skin examination, and the screening of populations at high risk for melanoma. However, it is unclear whether any of the latter measures have had any significant influence on mortality from melanoma. The annual increase in incidence rate varies between popula‐ tions, but in general has been in the order of 3–7% per year for fair-skinned Caucasian populations. CMM represents a significant and growing public health burden because of the

> © 2013 Kutlubay et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

**State of the Art**

Zekayi Kutlubay, Burhan Engin,

http://dx.doi.org/10.5772/55304

**1. Introduction**

membranes [2].

Server Serdaroğlu and Yalçın Tüzün

Additional information is available at the end of the chapter

increase in incidence and the consequent mortality [3].

