The genome and epigenome of malignant melanoma

APMIS

Volumn 115, Issue 10, 2007, Pages 1161-1176

  Dahl, Christina ^a   Guldberg, Per ^a  

^a DANISH CANCER SOCIETY RESEARCH CENTER   (Denmark)

Author keywords

Epigenetics; Genomics; Melanoma progression; Mutations; Promoter hypermethylation; Signaling transduction

Indexed keywords

CYCLIN DEPENDENT KINASE 4; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE KINASE; PROTEIN P16INK4A; RAF PROTEIN; RAS PROTEIN; RETINOBLASTOMA PROTEIN; WNT PROTEIN;

ARF GENE; BRAF GENE; CDK4 GENE; CELL FUNCTION; CTNNB1 GENE; DNA METHYLATION; EPIGENETICS; GENE; GENE CONTROL; GENE MUTATION; GENOME; GENOMICS; HUMAN; INK4A GENE; KIT GENES; KNOWLEDGE; MELANOCYTE; MELANOMA; ONCOGENE N RAS; PIK3CA GENE; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN FUNCTION; PROTO ONCOGENE; PTEN GENE; REVIEW; SIGNAL TRANSDUCTION; TP53 GENE; TUMOR SUPPRESSOR GENE;

DNA METHYLATION; EPIGENESIS, GENETIC; EXTRACELLULAR SIGNAL-REGULATED MAP KINASES; GENE AMPLIFICATION; GENES, RAS; GENOME, HUMAN; HUMANS; MAP KINASE KINASE KINASES; MELANOMA; MUTATION; PROTO-ONCOGENE PROTEINS B-RAF;

EID: 36549085004     PISSN: 09034641     EISSN: 16000463     Source Type: Journal    
DOI: 10.1111/j.1600-0463.2007.apm_855.xml.x     Document Type: Review

References (136)

1. Chin L, Merlino G, DePinho RA,. Malignant melanoma: modern black plague and genetic black box. Genes Dev 1998 12 : 3467 81.
2. Miller AJ, Mihm MC, Jr.,. Melanoma. N Engl J Med 2006 355 : 51 65.
3. Tsao H, Atkins MB, Sober AJ,. Management of cutaneous melanoma. N Engl J Med 2004 351 : 998 1012.
4. Tucker MA, Goldstein AM,. Melanoma etiology: where are we? Oncogene 2003 22 : 3042 52.
5. Houghton AN, Viola MV,. Solar radiation and malignant melanoma of the skin. J Am Acad Dermatol 1981 5 : 477 83.
6. Valverde P, Healy E, Jackson I, Rees JL, Thody AJ,. Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans. Nat Genet 1995 11 : 328 30.
7. Palmer JS, Duffy DL, Box NF, Aitken JF, O'Gorman LE, Green AC, et al. Melanocortin-1 receptor polymorphisms and risk of melanoma: is the association explained solely by pigmentation phenotype? Am J Hum Genet 2000 66 : 176 86.
8. Bennett DC. Genetics, development, and malignancy of melanocytes. Int Rev Cytol 1993 146 : 191 260.
9. Clark WH, Jr. Human cutaneous malignant melanoma as a model for cancer. Cancer Metastasis Rev 1991 10 : 83 8.
10. Demunter A, Stas M, Degreef H, De Wolf-Peeters C, van den Oord JJ,. Analysis of N- and K-ras mutations in the distinctive tumor progression phases of melanoma. J Invest Dermatol 2001 117 : 1483 9.
11. Albino AP, Nanus DM, Mentle IR, Cordon-Cardo C, McNutt NS, Bressler J, et al. Analysis of ras oncogenes in malignant melanoma and precursor lesions: correlation of point mutations with differentiation phenotype. Oncogene 1989 4 : 1363 74.
12. Jafari M, Papp T, Kirchner S, Diener U, Henschler D, Burg G, et al. Analysis of ras mutations in human melanocytic lesions: activation of the ras gene seems to be associated with the nodular type of human malignant melanoma. J Cancer Res Clin Oncol 1995 121 : 23 30.
13. Daniotti M, Oggionni M, Ranzani T, Vallacchi V, Campi V, Di SD, et al. BRAF alterations are associated with complex mutational profiles in malignant melanoma. Oncogene 2004 23 : 5968 77.
14. Christensen C, Guldberg P,. Growth factors rescue cutaneous melanoma cells from apoptosis induced by knock-down of mutated (V600E) B-RAF. Oncogene 2005 24 : 6292 302.
15. 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.
16. Tsao H, Goel V, Wu H, Yang G, Haluska FG,. Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma. J Invest Dermatol 2004 122 : 337 41.
17. Giehl K. Oncogenic Ras in tumour progression and metastasis. Biol Chem 2005 386 : 193 205.
18. Eskandarpour M, Kiaii S, Zhu C, Castro J, Sakko AJ, Hansson J,. Suppression of oncogenic NRAS by RNA interference induces apoptosis of human melanoma cells. Int J Cancer 2005 115 : 65 73.
19. Whitwam T, Vanbrocklin MW, Russo ME, Haak PT, Bilgili D, Resau JH, et al. Differential oncogenic potential of activated RAS isoforms in melanocytes. Oncogene 2007 26 : 4563 70.
20. Wellbrock C, Karasarides M, Marais R,. The RAF proteins take centre stage. Nat Rev Mol Cell Biol 2004 5 : 875 85.
21. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature 2002 417 : 949 54.
22. Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R, et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res 2002 62 : 6997 7000.
23. Gorden A, Osman I, Gai W, He D, Huang W, Davidson A, et al. Analysis of BRAF and N-RAS mutations in metastatic melanoma tissues. Cancer Res 2003 63 : 3955 7.
24. Dong J, Phelps RG, Qiao R, Yao S, Benard O, Ronai Z, et al. BRAF oncogenic mutations correlate with progression rather than initiation of human melanoma. Cancer Res 2003 63 : 3883 5.
25. Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 2004 116 : 855 67.
26. Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins CM, et al. High frequency of BRAF mutations in nevi. Nat Genet 2003 33 : 19 20.
27. 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 : 154 60.
28. Hingorani SR, Jacobetz MA, Robertson GP, Herlyn M, Tuveson DA,. Suppression of BRAF (V599E) in human melanoma abrogates transformation. Cancer Res 2003 63 : 5198 202.
29. Hoeflich KP, Gray DC, Eby MT, Tien JY, Wong L, Bower J, et al. Oncogenic BRAF is required for tumor growth and maintenance in melanoma models. Cancer Res 2006 66 : 999 1006.
30. Sumimoto H, Miyagishi M, Miyoshi H, Yamagata S, Shimizu A, Taira K, et al. Inhibition of growth and invasive ability of melanoma by inactivation of mutated BRAF with lentivirus-mediated RNA interference. Oncogene 2004 23 : 6031 9.
31. Sharma A, Tran MA, Liang S, Sharma AK, Amin S, Smith CD, et al. Targeting mitogen-activated protein kinase/extracellular signal-regulated kinase kinase in the mutant (V600E) B-Raf signaling cascade effectively inhibits melanoma lung metastases. Cancer Res 2006 66 : 8200 9.
32. Solit DB, Garraway LA, Pratilas CA, Sawai A, Getz G, Basso A, et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature 2006 439 : 358 62.
33. Halaban R. The regulation of normal melanocyte proliferation. Pigment Cell Res 2000 13 : 4 14.
34. 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 : 939 44.
35. Easty DJ, Bennett DC,. Protein tyrosine kinases in malignant melanoma. Melanoma Res 2000 10 : 401 11.
36. Huang S, Luca M, Gutman M, McConkey DJ, Langley KE, Lyman SD, 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 13 : 2339 47.
37. Willmore-Payne C, Holden JA, Tripp S, Layfield LJ,. Human malignant melanoma: detection of BRAF- and c-kit-activating mutations by high-resolution amplicon melting analysis. Hum Pathol 2005 36 : 486 93.
38. Curtin JA, Busam K, Pinkel D, Bastian BC,. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 2006 24 : 4340 6.
39. Fletcher JA, Rubin BP,. KIT mutations in GIST. Curr Opin Genet Dev 2007 17 : 3 7.
40. Mooi WJ, Peeper DS,. Oncogene-induced cell senescence-halting on the road to cancer. N Engl J Med 2006 355 : 1037 46.
41. Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM, et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 2005 436 : 720 4.
42. Braig M, Lee S, Loddenkemper C, Rudolph C, Peters AH, Schlegelberger B, et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 2005 436 : 660 5.
43. Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 2006 444 : 633 7.
44. Bennett DC. Human melanocyte senescence and melanoma susceptibility genes. Oncogene 2003 22 : 3063 9.
45. Bennett DC, Medrano EE,. Molecular regulation of melanocyte senescence. Pigment Cell Res 2002 15 : 242 50.
46. Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A 1995 92 : 9363 7.
47. Bartkova J, Lukas J, Guldberg P, Alsner J, Kirkin AF, Zeuthen J, et al. The p16-cyclin D/Cdk4-pRB pathway as a functional unit frequently altered in melanoma pathogenesis. Cancer Res 1996 56 : 5475 83.
48. 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 : 157 63.
49. Kamb A, Shattuck-Eidens D, Eeles R, Liu Q, Gruis NA, Ding W, et al. Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nature Genet 1994 8 : 22 6.
50. Hussussian CJ, Struewing JP, Goldstein AM, Higgins PAT, Ally DS, Sheahan MD, et al. Germline p16 mutations in familial melanoma. Nature Genet 1994 8 : 15 21.
51. Goldstein AM, Chan M, Harland M, Gillanders EM, Hayward NK, Avril MF, et al. High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res 2006 66 : 9818 28.
52. Sviderskaya EV, Gray-Schopfer VC, Hill SP, Smit NP, Evans-Whipp TJ, Bond J, et al. p16/cyclin-dependent kinase inhibitor 2A deficiency in human melanocyte senescence, apoptosis, and immortalization: possible implications for melanoma progression. J Natl Cancer Inst 2003 95 : 723 32.
53. Wölfel T, Hauer M, Schneider J, Serrano M, Wölfel C, Klehman-Hieb E, et al. A p16INK4a-insensitive CDK4 mutant targeted by cytologic T lymphocytes in a human melanoma. Science 1995 269 : 1281 4.
54. Ceha HM, Nasser I, Medema RH, Slebos RJ,. Several noncontiguous domains of CDK4 are involved in binding to the P16 tumor suppressor protein. Biochem Biophys Res Commun 1998 249 : 550 5.
55. Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005 353 : 2135 47.
56. Muthusamy V, Hobbs C, Nogueira C, Cordon-Cardo C, McKee PH, Chin L, et al. Amplification of CDK4 and MDM2 in malignant melanoma. Genes Chromosomes Cancer 2006 45 : 447 54.
57. Zuo L, Weger J, Yang Q, Goldstein AM, Tucker MA, Walker GJ, et al. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nature Genet 1996 12 : 97 9.
58. Soufir N, Avril MF, Chompret A, Demenais F, Bombled J, Spatz A, et al. Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France. The French Familial Melanoma Study Group. Hum Mol Genet 1998 7 : 209 16.
59. Moll AC, Imhof SM, Bouter LM, Tan KE,. Second primary tumors in patients with retinoblastoma. A review of the literature. Ophthalmic Genet 1997 18 : 27 34.
60. Fletcher O, Easton D, Anderson K, Gilham C, Jay M, Peto J,. Lifetime risks of common cancers among retinoblastoma survivors. J Natl Cancer Inst 2004 96 : 357 63.
61. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997 275 : 1943 7.
62. Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 1997 15 : 356 62.
63. Li D-M, Sun H,. TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor β. Cancer Res 1997 57 : 2124 9.
64. 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 : 3660 3.
65. Tsao H, Zhang X, Benoit E, Haluska FG,. Identification of PTEN/MMAC1 alterations in uncultured melanomas and melanoma cell lines. Oncogene 1998 16 : 3397 402.
66. Birck A, Ahrenkiel V, Zeuthen J, Hou-Jensen K, Guldberg P,. Mutation and allelic loss of the PTEN/MMAC1 gene in primary and metastatic melanoma biopsies. J Invest Dermatol 2000 114 : 277 80.
67. Robertson GP, Furnari FB, Miele ME, Glendening MJ, Welch DR, Fountain JW, et al. In vitro loss of heterozygosity targets the PTEN/MMAC1 gene in melanoma. Proc Natl Acad Sci USA 1998 95 : 9418 23.
68. Cully M, You H, Levine AJ, Mak TW,. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 2006 6 : 184 92.
69. Stahl JM, Sharma A, Cheung M, Zimmerman M, Cheng JQ, Bosenberg MW, et al. Deregulated Akt3 activity promotes development of malignant melanoma. Cancer Res 2004 64 : 7002 10.
70. Robertson GP. Functional and therapeutic significance of Akt deregulation in malignant melanoma. Cancer Metastasis Rev 2005 24 : 273 85.
71. Dhawan P, Singh AB, Ellis DL, Richmond A,. Constitutive activation of Akt/protein kinase B in melanoma leads to up-regulation of nuclear factor-kappaB and tumor progression. Cancer Res 2002 62 : 7335 42.
72. Smalley KS, Haass NK, Brafford PA, Lioni M, Flaherty KT, Herlyn M,. Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases. Mol Cancer Ther 2006 5 : 1136 44.
73. Boisvert-Adamo K, Aplin AE,. B-RAF and PI-3 kinase signaling protect melanoma cells from anoikis. Oncogene 2006 25 : 4848 56.
74. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004 304 : 554.
75. Samuels Y, Diaz LA, Jr., Schmidt-Kittler O, Cummins JM, DeLong L, Cheong I, et al. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 2005 7 : 561 73.
76. Omholt K, Krockel D, Ringborg U, Hansson J,. Mutations of PIK3CA are rare in cutaneous melanoma. Melanoma Res 2006 16 : 197 200.
77. Curtin JA, Stark MS, Pinkel D, Hayward NK, Bastian BC,. PI3-kinase subunits are infrequent somatic targets in melanoma. J Invest Dermatol 2006 126 : 1660 3.
78. Gwosdz C, Scheckenbach K, Lieven O, Reifenberger J, Knopf A, Bier H, et al. Comprehensive analysis of the p53 status in mucosal and cutaneous melanomas. Int J Cancer 2006 118 : 577 82.
79. Florenes VA, Oyjord T, Holm R, Skrede M, Borresen AL, Nesland JM, et al. TP53 allele loss, mutations and expression in malignant melanoma. Br J Cancer 1994 69 : 253 9.
80. Albino AP, Vidal MJ, McNutt NS, Shea CR, Prieto VG, Nanus DM, et al. Mutation and expression of the p53 gene in human malignant melanoma. Melanoma Res 1994 4 : 35 45.
81. Sparrow LE, Soong R, Dawkins HJ, Iacopetta BJ, Heenan PJ,. p53 gene mutation and expression in naevi and melanomas. Melanoma Res 1995 5 : 93 100.
82. Hartmann A, Blaszyk H, Cunningham JS, McGovern RM, Schroeder JS, Helander SD, et al. Overexpression and mutations of p53 in metastatic malignant melanomas. Int J Cancer 1996 67 : 313 7.
83. Ragnarsson-Olding BK, Karsberg S, Platz A, Ringborg UK,. Mutations in the TP53 gene in human malignant melanomas derived from sun-exposed skin and unexposed mucosal membranes. Melanoma Res 2002 12 : 453 63.
84. Jönsson G, Dahl C, Staaf J, Sandberg T, Bendahl PO, Ringner M, et al. Genomic profiling of malignant melanoma using tiling-resolution array CGH. Oncogene 2007 26 : 4738 48.
85. Zhang Y, Xiong Y, Yarbrough WG,. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 1998 92 : 725 34.
86. Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF, Sherr CJ,. Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci USA 1998 95 : 8292 7.
87. Yang G, Rajadurai A, Tsao H,. Recurrent patterns of dual RB and p53 pathway inactivation in melanoma. J Invest Dermatol 2005 125 : 1242 51.
88. Rizos H, Darmanian AP, Holland EA, Mann GJ, Kefford RF,. Mutations in the INK4a/ARF melanoma susceptibility locus functionally impair p14ARF. J Biol Chem 2001 276 : 41424 34.
89. Rizos H, Puig S, Badenas C, Malvehy J, Darmanian AP, Jimenez L, et al. A melanoma-associated germline mutation in exon 1beta inactivates p14ARF. Oncogene 2001 20 : 5543 7.
90. Hewitt C, Lee WC, Evans G, Howell A, Elles RG, Jordan R, et al. Germline mutation of ARF in a melanoma kindred. Hum Mol Genet 2002 11 : 1273 9.
91. Harland M, Taylor CF, Chambers PA, Kukalizch K, Randerson-Moor JA, Gruis NA, et al. A mutation hotspot at the p14ARF splice site. Oncogene 2005 24 : 4604 8.
92. Giles RH, van Es JH, Clevers H,. Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta 2003 1653 : 1 24.
93. He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, et al. Identification of c-MYC as a target of the APC pathway. Science 1998 281 : 1509 12.
94. Tetsu O, McCormick F,. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 1999 398 : 422 6.
95. Rimm DL, Caca K, Hu G, Harrison FB, Fearon ER,. Frequent nuclear/cytoplasmic localization of beta-catenin without exon 3 mutations in malignant melanoma. Am J Pathol 1999 154 : 325 9.
96. Demunter A, Libbrecht L, Degreef H, De Wolf-Peeters C, van den Oord JJ,. Loss of membranous expression of beta-catenin is associated with tumor progression in cutaneous melanoma and rarely caused by exon 3 mutations. Mod Pathol 2002 15 : 454 61.
97. Omholt K, Platz A, Ringborg U, Hansson J,. Cytoplasmic and nuclear accumulation of beta-catenin is rarely caused by CTNNB1 exon 3 mutations in cutaneous malignant melanoma. Int J Cancer 2001 92 : 839 42.
98. Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E, Polakis P,. Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science 1997 275 : 1790 2.
99. Reifenberger J, Knobbe CB, Wolter M, Blaschke B, Schulte KW, Pietsch T, et al. Molecular genetic analysis of malignant melanomas for aberrations of the WNT signaling pathway genes CTNNB1, APC, ICAT and BTRC. Int J Cancer 2002 100 : 549 56.
100. Pollock PM, Hayward N,. Mutations in exon 3 of the beta-catenin gene are rare in melanoma cell lines. Melanoma Res 2002 12 : 183 6.
101. Worm J, Christensen C, Grønbæk K, Tulchinsky EM, Guldberg P,. Genetic and epigenetic alterations of the APC gene in malignant melanoma. Oncogene 2004 23 : 5215 26.
102. Fodde R. The APC gene in colorectal cancer. Eur J Cancer 2002 38 : 867 71.
103. Esteller M, Sparks A, Toyota M, Sanchez-Cespedes M, Capella G, Peinado MA, et al. Analysis of adenomatous polyposis coli promoter hypermethylation in human cancer. Cancer Res 2000 60 : 4366 71.
104. Bastian BC, LeBoit PE, Hamm H, Brocker EB, Pinkel D,. Chromosomal gains and losses in primary cutaneous melanomas detected by comparative genomic hybridization. Cancer Res 1998 58 : 2170 5.
105. Garraway LA, Widlund HR, Rubin MA, Getz G, Berger AJ, Ramaswamy S, et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 2005 436 : 117 22.
106. Levy C, Khaled M, Fisher DE,. MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol Med 2006 12 : 406 14.
107. Gray-Schopfer V, Wellbrock C, Marais R,. Melanoma biology and new targeted therapy. Nature 2007 445 : 851 7.
108. Wu M, Hemesath TJ, Takemoto CM, Horstmann MA, Wells AG, Price ER, et al. c-Kit triggers dual phosphorylations, which couple activation and degradation of the essential melanocyte factor Mi. Genes Dev 2000 14 : 301 12.
109. Wellbrock C, Marais R,. Elevated expression of MITF counteracts B-RAF-stimulated melanocyte and melanoma cell proliferation. J Cell Biol 2005 170 : 703 8.
110. Gray-Schopfer V, Wellbrock C, Marais R,. Melanoma biology and new targeted therapy. Nature 2007 445 : 851 7.
111. Grønbæk K, Hother C, Jones PA,. Epigenetic changes in cancer. APMIS 2007 115 : 1038 58.
112. Sansom OJ, Maddison K, Clarke AR,. Mechanisms of disease: methyl-binding domain proteins as potential therapeutic targets in cancer. Nat Clin Pract Oncol 2007 4 : 305 15.
113. Gonzalgo ML, Bender CM, You EH, Glendening JM, Flores JF, Walker GJ, et al. Low frequency of p16/CDKN2A methylation in sporadic melanoma: comparative approaches for methylation analysis of primary tumors. Cancer Res 1997 57 : 5336 47.
114. Straume O, Smeds J, Kumar R, Hemminki K, Akslen LA,. Significant impact of promoter hypermethylation and the 540 C>T polymorphism of CDKN2A in cutaneous melanoma of the vertical growth phase. Am J Pathol 2002 161 : 229 37.
115. Laird PW. The power and the promise of DNA methylation markers. Nat Rev Cancer 2003 3 : 253 66.
116. Hoon DS, Spugnardi M, Kuo C, Huang SK, Morton DL, Taback B,. Profiling epigenetic inactivation of tumor suppressor genes in tumors and plasma from cutaneous melanoma patients. Oncogene 2004 23 : 4014 22.
117. Mirmohammadsadegh A, Marini A, Nambiar S, Hassan M, Tannapfel A, Ruzicka T, et al. Epigenetic silencing of the PTEN gene in melanoma. Cancer Res 2006 66 : 6546 52.
118. Li G, Satyamoorthy K, Herlyn M,. Dynamics of cell interactions and communications during melanoma development. Crit Rev Oral Biol Med 2002 13 : 62 70.
119. Merlino G, Noonan FP,. Modeling gene-environment interactions in malignant melanoma. Trends Mol Med 2003 9 : 102 8.
120. Chin L. The genetics of malignant melanoma: lessons from mouse and man. Nat Rev Cancer 2003 3 : 559 70.
121. Kabbarah O, Chin L,. Advances in malignant melanoma: genetic insights from mouse and man. Front Biosci 2006 11 : 928 42.
122. Khavari PA. Modelling cancer in human skin tissue. Nat Rev Cancer 2006 6 : 270 80.
123. Nishimura EK, Jordan SA, Oshima H, Yoshida H, Osawa M, Moriyama M, et al. Dominant role of the niche in melanocyte stem-cell fate determination. Nature 2002 416 : 854 60.
124. Berking C, Takemoto R, Satyamoorthy K, Shirakawa T, Eskandarpour M, Hansson J, et al. Induction of melanoma phenotypes in human skin by growth factors and ultraviolet B. Cancer Res 2004 64 : 807 11.
125. Chudnovsky Y, Adams AE, Robbins PB, Lin Q, Khavari PA,. Use of human tissue to assess the oncogenic activity of melanoma-associated mutations. Nat Genet 2005 37 : 745 9.
126. Guldberg P, Kirkin AF, Grønbæk K, thor Straten P, Ahrenkiel V, Zeuthen J,. Complete scanning of the CDK4 gene by denaturing gradient gel electrophoresis: a novel missense mutation but low overall frequency of mutations in sporadic metastatic malignant melanoma. Int J Cancer 1997 72 : 780 3.
127. Sauter ER, Yeo UC, von SA, Zhu W, Litwin S, Tichansky DS, et al. Cyclin D1 is a candidate oncogene in cutaneous melanoma. Cancer Res 2002 62 : 3200 6.
128. Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science 1994 264 : 436 40.
129. Wu H, Goel V, Haluska FG,. PTEN signaling pathways in melanoma. Oncogene 2003 22 : 3113 22.
130. Spugnardi M, Tommasi S, Dammann R, Pfeifer GP, Hoon DS,. Epigenetic inactivation of RAS association domain family protein 1 (RASSF1A) in malignant cutaneous melanoma. Cancer Res 2003 63 : 1639 43.
131. Furuta J, Umebayashi Y, Miyamoto K, Kikuchi K, Otsuka F, Sugimura T, et al. Promoter methylation profiling of 30 genes in human malignant melanoma. Cancer Sci 2004 95 : 962 8.
132. Guan X, Sagara J, Yokoyama T, Koganehira Y, Oguchi M, Saida T, et al. ASC/TMS1, a caspase-1 activating adaptor, is downregulated by aberrant methylation in human melanoma. Int J Cancer 2003 107 : 202 8.
133. Kohonen-Corish MR, Cooper WA, Saab J, Thompson JF, Trent RJ, Millward MJ,. Promoter hypermethylation of the O(b66)-methylguanine DNA methyltransferase gene and microsatellite instability in metastatic melanoma. J Invest Dermatol 2006 126 : 167 71.
134. Worm J, Bartkova J, Kirkin AF, thor Straten P, Zeuthen J, Bartek J, et al. Aberrant p27kip1 methylation in malignant melanoma. Oncogene 2000 19 : 5111 5.
135. Muthusamy V, Duraisamy S, Bradbury CM, Hobbs C, Curley DP, Nelson B, et al. Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res 2006 66 : 11187 93.
136. Furuta J, Nobeyama Y, Umebayashi Y, Otsuka F, Kikuchi K, Ushijima T,. Silencing of Peroxiredoxin 2 and aberrant methylation of 33 CpG islands in putative promoter regions in human malignant melanomas. Cancer Res 2006 66 : 6080 6.