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Melanoma Genetics and Genomics

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Melanoma Development

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Abstract

Recent work has expanded our knowledge in somatic genetic events related to melanoma progression. It has become increasingly clear that multiple genetic events are required for melanoma to develop and that melanoma is a vastly heterogeneous disease. Signaling pathways that are essential for tumor progression have been pinpointed due to recent technological developments, which has led to the vigorous pursuit of small molecule kinase inhibitors and the eventual FDA approval of novel MAPK pathway inhibitors for the treatment of advanced melanoma (see Chaps. 7 and 16). As has been implicated in many other malignancies, molecular profiling is further anticipated to reveal prognostic, diagnostic, and predictive tools in the clinical setting of melanoma.

Additionally, tumor genetic data have been interconnected with epidemiology of melanoma (see Chap. 3). Two etiological pathways have been postulated to trigger the formation of melanoma. The first pathway involves relatively young individuals with large numbers of nevi and who develop melanomas on locations (e.g., trunk) that are intermittently UV exposed. This pathway is further corroborated by the fact that BRAF mutations, which frequently occur in nevi, are also more common in melanomas of younger patients with larger number of moles. A second pathway, which is probably related to chronic UV exposure, leads to melanomas that develop among older individuals and on chronically sun-exposed sites. Additionally, genetic analyses have uncovered a previously undisclosed hidden molecular structure between subtypes of melanoma.

Along translational lines, tumor genetic information has recently shown to be of enormous significance for personalizing therapeutic choice, e.g., Braf inhibitors that selectively target BrafV600E mutated melanomas and Mek inhibitors that target the MAPK pathway in metastatic melanoma; thus tumor genetic information is required prior to treatment. Moreover, molecular studies have also begun to shed light onto mechanisms of resistance that develop in the context of treatment with Braf and/or Mek inhibitors.

In this chapter, we have screened current literature for an update of genetics and genomics within the field of melanoma tumor biology.

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References

  • Ambrosini G, Musi E, Ho AL, de Stanchina E, Schwartz GK (2013) Inhibition of mutant GNAQ signaling in uveal melanoma induces AMPK-dependent autophagic cell death. Mol Cancer Ther 12(5):768–776

    Article  CAS  PubMed  Google Scholar 

  • Aoude LG, Pritchard AL, Robles-Espinoza CD, Wadt K, Harland M, Choi J, Gartside M, Quesada V, Johansson P, Palmer JM, Ramsay AJ, Zhang X, Jones K, Symmons J, Holland EA, Schmid H, Bonazzi V, Woods S, Dutton-Regester K, Stark MS, Snowden H, van Doorn R, Montgomery GW, Martin NG, Keane TM, López-Otín C, Gerdes AM, Olsson H, Ingvar C, Borg A, Gruis NA, Trent JM, Jönsson G, Bishop DT, Mann GJ, Newton-Bishop JA, Brown KM, Adams DJ, Hayward NK (2015) Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma. J Natl Cancer Inst 107(2). pii: dju408

    Google Scholar 

  • April C, Klotzle B, Royce T, Wickham-Garcia E, Boyaniwsky T, Izzo J, Cox D, Jones W, Rubio R, Holton K, Matulonis U, Quackenbush J, Fan JB (2009) Whole-genome gene expression profiling of formalin-fixed, paraffin-embedded tissue samples. PLoS One 4:e8162

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Atefi M, von Euw E, Attar N, Ng C, Chu C, Guo D, Nazarian R, Chmielowski B, Glaspy JA, Comin-Anduix B, Mischel PS, Lo RS, Ribas A (2011) Reversing melanoma cross-resistance to BRAF and MEK inhibitors by co-targeting the AKT/mTOR pathway. PLoS One 6(12):e28973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bastian BC (2014) The molecular pathology of melanoma: an integrated taxonomy of melanocytic neoplasia. Annu Rev Pathol 9:239–271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bastian BC, LeBoit PE, Pinkel D (2000) Mutations and copy number increase of HRAS in Spitz nevi with distinctive histopathological features. Am J Pathol 157:967–972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beadling C, Jacobson-Dunlop E, Hodi FS, Le C, Warrick A, Patterson J, Town A, Harlow A, Cruz F 3rd, Azar S, Rubin BP, Muller S, West R, Heinrich MC, Corless CL (2008) KIT gene mutations and copy number in melanoma subtypes. Clin Cancer Res 14(21):6821–6828

    Article  CAS  PubMed  Google Scholar 

  • Bennett DC (2003) Human melanocyte senescence and melanoma susceptibility genes. Oncogene 22:3063–3069

    Article  CAS  PubMed  Google Scholar 

  • Berger MF, Levin JZ, Vijayendran K, Sivachenko A, Adiconis X, Maguire J, Johnson LA, Robinson J, Verhaak RG, Sougnez C, Onofrio RC, Ziaugra L, Cibulskis K, Laine E, Barretina J, Winckler W, Fisher DE, Getz G, Meyerson M, Jaffe DB, Gabriel SB, Lander ES, Dummer R, Gnirke A, Nusbaum C, Garraway LA (2010) Integrative analysis of the melanoma transcriptome. Genome Res 20:413–427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berger MF, Hodis E, Heffernan TP, Deribe YL, Lawrence MS, Protopopov A, Ivanova E, Watson IR, Nickerson E, Ghosh P, Zhang H, Zeid R, Ren X, Cibulskis K, Sivachenko AY, Wagle N, Sucker A, Sougnez C, Onofrio R, Ambrogio L, Auclair D, Fennell T, Carter SL, Drier Y, Stojanov P, Singer MA, Voet D, Jing R, Saksena G, Barretina J, Ramos AH, Pugh TJ, Stransky N, Parkin M, Winckler W, Mahan S, Ardlie K, Baldwin J, Wargo J, Schadendorf D, Meyerson M, Gabriel SB, Golub TR, Wagner SN, Lander ES, Getz G, Chin L, Garraway LA (2012) Melanoma genome sequencing reveals frequent PREX2 mutations. Nature 485(7399):502–506

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bertolotto C, Lesueur F, Giuliano S, Strub T, de Lichy M, Bille K, Dessen P, d’Hayer B, Mohamdi H, Remenieras A, Maubec E, de la Fouchardière A, Molinié V, Vabres P, Dalle S, Poulalhon N, Martin-Denavit T, Thomas L, Andry-Benzaquen P, Dupin N, Boitier F, Rossi A, Perrot JL, Labeille B, Robert C, Escudier B, Caron O, Brugières L, Saule S, Gardie B, Gad S, Richard S, Couturier J, Teh BT, Ghiorzo P, Pastorino L, Puig S, Badenas C, Olsson H, Ingvar C, Rouleau E, Lidereau R, Bahadoran P, Vielh P, Corda E, Blanché H, Zelenika D, Galan P, Group FFMS, Aubin F, Bachollet B, Becuwe C, Berthet P, Bignon YJ, Bonadona V, Bonafe JL, Bonnet-Dupeyron MN, Cambazard F, Chevrant-Breton J, Coupier I, Dalac S, Demange L, d’Incan M, Dugast C, Faivre L, Vincent-Fétita L, Gauthier-Villars M, Gilbert B, Grange F, Grob JJ, Humbert P, Janin N, Joly P, Kerob D, Lasset C, Leroux D, Levang J, Limacher JM, Livideanu C, Longy M, Lortholary A, Stoppa-Lyonnet D, Mansard S, Mansuy L, Marrou K, Matéus C, Maugard C, Meyer N, Nogues C, Souteyrand P, Venat-Bouvet L, Zattara H, Chaudru V, Lenoir GM, Lathrop M, Davidson I, Avril MF, Demenais F, Ballotti R, Bressac-de Paillerets B (2011) A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature 480(7375):94–98

    Article  CAS  PubMed  Google Scholar 

  • Bishop DT, Demenais F, Iles MM, Harland M, Taylor JC, Corda E, Randerson-Moor J, Aitken JF, Avril MF, Azizi E, Bakker B, Bianchi-Scarra G, Bressac-de Paillerets B, Calista D, Cannon-Albright LA, Chin AWT, Debniak T, Galore-Haskel G, Ghiorzo P, Gut I, Hansson J, Hocevar M, Hoiom V, Hopper JL, Ingvar C, Kanetsky PA, Kefford RF, Landi MT, Lang J, Lubinski J, Mackie R, Malvehy J, Mann GJ, Martin NG, Montgomery GW, van Nieuwpoort FA, Novakovic S, Olsson H, Puig S, Weiss M, van Workum W, Zelenika D, Brown KM, Goldstein AM, Gillanders EM, Boland A, Galan P, Elder DE, Gruis NA, Hayward NK, Lathrop GM, Barrett JH, Bishop JA (2009) Genome-wide association study identifies three loci associated with melanoma risk. Nat Genet 41:920–925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bogunovic D, O’Neill DW, Belitskaya-Levy I, Vacic V, Yu YL, Adams S, Darvishian F, Berman R, Shapiro R, Pavlick AC, Lonardi S, Zavadil J, Osman I, Bhardwaj N (2009) Immune profile and mitotic index of metastatic melanoma lesions enhance clinical staging in predicting patient survival. Proc Natl Acad Sci U S A 106:20429–20434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R, Einhorn E, Herlyn M, Minna J, Nicholson A, Roth JA, Albelda SM, Davies H, Cox C, Brignell G, Stephens P, Futreal PA, Wooster R, Stratton MR, Weber BL (2002) BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res 62:6997–7000

    CAS  PubMed  Google Scholar 

  • Brown KM, Macgregor S, Montgomery GW, Craig DW, Zhao ZZ, Iyadurai K, Henders AK, Homer N, Campbell MJ, Stark M, Thomas S, Schmid H, Holland EA, Gillanders EM, Duffy DL, Maskiell JA, Jetann J, Ferguson M, Stephan DA, Cust AE, Whiteman D, Green A, Olsson H, Puig S, Ghiorzo P, Hansson J, Demenais F, Goldstein AM, Gruis NA, Elder DE, Bishop JN, Kefford RF, Giles GG, Armstrong BK, Aitken JF, Hopper JL, Martin NG, Trent JM, Mann GJ, Hayward NK (2008) Common sequence variants on 20q11.22 confer melanoma susceptibility. Nat Genet 40:838–840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cancer Genome Atlas Network (2015) Genomic classification of cutaneous melanoma. Cell 161(7):1681–1696

    Article  CAS  Google Scholar 

  • Cardenas-Navia LI, Cruz P, Lin JC, Rosenberg SA, Samuels Y (2010) Novel somatic mutations in heterotrimeric G proteins in melanoma. Cancer Biol Ther 10:33–37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, Sasaki AT, Thomas G, Kozma SC, Papa A, Nardella C, Cantley LC, Baselga J, Pandolfi PP (2008) Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 118(9):3065–3074

    CAS  PubMed  PubMed Central  Google Scholar 

  • Carreira S, Liu B, Goding CR (2000) The gene encoding the T-box factor Tbx2 is a target for the microphthalmia-associated transcription factor in melanocytes. J Biol Chem 275:21920–21927

    Article  CAS  PubMed  Google Scholar 

  • Carvajal RD, Antonescu CR, Wolchok JD, Chapman PB, Roman RA, Teitcher J, Panageas KS, Busam KJ, Chmielowski B, Lutzky J, Pavlick AC, Fusco A, Cane L, Takebe N, Vemula S, Bouvier N, Bastian BC, Schwartz GK (2011) KIT as a therapeutic target in metastatic melanoma. JAMA 305(22):2327–2334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Casula M, Colombino M, Satta MP, Cossu A, Ascierto PA, Bianchi-Scarra G, Castiglia D, Budroni M, Rozzo C, Manca A, Lissia A, Carboni A, Petretto E, Satriano SM, Botti G, Mantelli M, Ghiorzo P, Stratton MR, Tanda F, Palmieri G (2004) BRAF gene is somatically mutated but does not make a major contribution to malignant melanoma susceptibility: the Italian Melanoma Intergroup Study. J Clin Oncol 22:286–292

    Article  CAS  PubMed  Google Scholar 

  • Chang X, Sun Y, Han S, Zhu W, Zhang H, Lian S (2015) MiR-203 inhibits melanoma invasive and proliferative abilities by targeting the polycomb group gene BMI1. Biochem Biophys Res Commun 456(1):361–366

    Article  CAS  PubMed  Google Scholar 

  • Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O’Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA, BRIM-3 Study Group (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364(26):2507–2516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chin L, Pomerantz J, Polsky D, Jacobson M, Cohen C, Cordon-Cardo C, Horner JW 2nd, DePinho RA (1997) Cooperative effects of INK4a and ras in melanoma susceptibility in vivo. Genes Dev 11:2822–2834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cho E, Rosner BA, Colditz GA (2005) Risk factors for melanoma by body site. Cancer Epidemiol Biomarkers Prev 14:1241–1244

    Article  PubMed  Google Scholar 

  • Cirenajwis H, Ekedahl H, Lauss M, Harbst K, Carneiro A, Enoksson J, Rosengren F, Werner-Hartman L, Törngren T, Kvist A, Fredlund E, Bendahl PO, Jirström K, Lundgren L, Howlin J, Borg Å, Gruvberger-Saal SK, Saal LH, Nielsen K, Ringnér M, Tsao H, Olsson H, Ingvar C, Staaf J, Jönsson G (2015) Molecular stratification of metastatic melanoma using gene expression profiling: prediction of survival outcome and benefit from molecular targeted therapy. Oncotarget 6(14):12297–12309

    Article  PubMed  PubMed Central  Google Scholar 

  • Conway C, Mitra A, Jewell R, Randerson-Moor J, Lobo S, Nsengimana J, Edward S, Sanders DS, Cook M, Powell B, Boon A, Elliott F, de Kort F, Knowles MA, Bishop DT, Newton-Bishop J (2009) Gene expression profiling of paraffin-embedded primary melanoma using the DASL assay identifies increased osteopontin expression as predictive of reduced relapse-free survival. Clin Cancer Res 15:6939–6946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Córdoba-Lanús E, Hernández-Jiménez JG, Medina-Coello C, Espinoza-Jiménez A, González A, Rodríguez-Pérez MD, Carretero-Hernández G, Almeida P, Suárez-Hernández J, Perera-Molinero A, Fernández-de-Misa R (2014) MC1R gene variants and sporadic malignant melanoma susceptibility in the Canary Islands population. Arch Dermatol Res 306(1):51–58

    Article  PubMed  CAS  Google Scholar 

  • Cronin JC, Wunderlich J, Loftus SK, Prickett TD, Wei X, Ridd K, Vemula S, Burrell AS, Agrawal NS, Lin JC, Banister CE, Buckhaults P, Rosenberg SA, Bastian BC, Pavan WJ, Samuels Y (2009) Frequent mutations in the MITF pathway in melanoma. Pigment Cell Melanoma Res 22:435–444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, Cho KH, Aiba S, Brocker EB, LeBoit PE, Pinkel D, Bastian BC (2005) Distinct sets of genetic alterations in melanoma. N Engl J Med 353:2135–2147

    Article  CAS  PubMed  Google Scholar 

  • Curtin JA, Busam K, Pinkel D, Bastian BC (2006) Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 24:4340–4346

    Article  CAS  PubMed  Google Scholar 

  • Damsky W, Micevic G, Meeth K, Muthusamy V, Curley DP, Santhanakrishnan M, Erdelyi I, Platt JT, Huang L, Theodosakis N, Zaidi MR, Tighe S, Davies MA, Dankort D, McMahon M, Merlino G, Bardeesy N, Bosenberg M (2015) mTORC1 activation blocks BrafV600E-induced growth arrest but is insufficient for melanoma formation. Cancer Cell 27(1):41–56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dankort D, Curley DP, Cartlidge RA, Nelson B, Karnezis AN, Damsky WE Jr, You MJ, DePinho RA, McMahon M, Bosenberg M (2009) Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet 41:544–552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Das Thakur M, Salangsang F, Landman AS, Sellers WR, Pryer NK, Levesque MP, Dummer R, McMahon M, Stuart DD (2013) Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature 494(7436):251–255

    Article  CAS  PubMed  Google Scholar 

  • Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954

    Article  CAS  PubMed  Google Scholar 

  • Davies MA, Stemke-Hale K, Tellez C, Calderone TL, Deng W, Prieto VG, Lazar AJ, Gershenwald JE, Mills GB (2008) A novel AKT3 mutation in melanoma tumours and cell lines. Br J Cancer 99:1265–1268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Delmas V, Beermann F, Martinozzi S, Carreira S, Ackermann J, Kumasaka M, Denat L, Goodall J, Luciani F, Viros A, Demirkan N, Bastian BC, Goding CR, Larue L (2007) Beta-catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development. Genes Dev 21:2923–2935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dorsky RI, Moon RT, Raible DW (1998) Control of neural crest cell fate by the Wnt signalling pathway. Nature 396(6709):370–373

    Article  CAS  PubMed  Google Scholar 

  • Dronca RS, Allred JB, Perez DG, Nevala WK, Lieser EA, Thompson M, Maples WJ, Creagan ET, Pockaj BA, Kaur JS, Moore TD, Marchello BT, Markovic SN (2014) Phase II study of temozolomide (TMZ) and everolimus (RAD001) therapy for metastatic melanoma: a North Central Cancer Treatment Group study, N0675. Am J Clin Oncol 37(4):369–376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Du J, Widlund HR, Horstmann MA, Ramaswamy S, Ross K, Huber WE, Nishimura EK, Golub TR, Fisher DE (2004) Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF. Cancer Cell 6:565–576

    Article  CAS  PubMed  Google Scholar 

  • Eisen T, Ahmad T, Flaherty KT, Gore M, Kaye S, Marais R, Gibbens I, Hackett S, James M, Schuchter LM, Nathanson KL, Xia C, Simantov R, Schwartz B, Poulin-Costello M, O’Dwyer PJ, Ratain MJ (2006) Sorafenib in advanced melanoma: a phase II randomised discontinuation trial analysis. Br J Cancer 95:581–586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ellerhorst JA, Greene VR, Ekmekcioglu S, Warneke CL, Johnson MM, Cooke CP, Wang LE, Prieto VG, Gershenwald JE, Wei Q, Grimm EA (2011) Clinical correlates of NRAS and BRAF mutations in primary human melanoma. Clin Cancer Res 17:229–235

    Article  CAS  PubMed  Google Scholar 

  • Emery CM, Vijayendran KG, Zipser MC, Sawyer AM, Niu L, Kim JJ, Hatton C, Chopra R, Oberholzer PA, Karpova MB, MacConaill LE, Zhang J, Gray NS, Sellers WR, Dummer R, Garraway LA (2009) MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci U S A 106:20411–20416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fargnoli MC, Gandini S, Peris K, Maisonneuve P, Raimondi S (2010) MC1R variants increase melanoma risk in families with CDKN2A mutations: a meta-analysis. Eur J Cancer 46(8):1413–1420

    Article  CAS  PubMed  Google Scholar 

  • Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D, METRIC Study Group (2012a) Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367(2):107–114

    Article  CAS  PubMed  Google Scholar 

  • Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA 3rd, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J (2012b) Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367(18):1694–1703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garraway LA, Widlund HR, Rubin MA, Getz G, Berger AJ, Ramaswamy S, Beroukhim R, Milner DA, Granter SR, Du J, Lee C, Wagner SN, Li C, Golub TR, Rimm DL, Meyerson ML, Fisher DE, Sellers WR (2005) Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436:117–122

    Article  CAS  PubMed  Google Scholar 

  • Gast A, Scherer D, Chen B, Bloethner S, Melchert S, Sucker A, Hemminki K, Schadendorf D, Kumar R (2010) Somatic alterations in the melanoma genome: a high-resolution array-based comparative genomic hybridization study. Genes Chromosomes Cancer 49:733–745

    Article  CAS  PubMed  Google Scholar 

  • Greenberg ES, Chong KK, Huynh KT, Tanaka R, Hoon DS (2014) Epigenetic biomarkers in skin cancer. Cancer Lett 342(2):170–177

    Article  CAS  PubMed  Google Scholar 

  • Greger JG, Eastman SD, Zhang V, Bleam MR, Hughes AM, Smitheman KN, Dickerson SH, Laquerre SG, Liu L, Gilmer TM (2012) Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations. Mol Cancer Ther 11(4):909–920

    Article  CAS  PubMed  Google Scholar 

  • Gudbjartsson DF, Sulem P, Stacey SN, Goldstein AM, Rafnar T, Sigurgeirsson B, Benediktsdottir KR, Thorisdottir K, Ragnarsson R, Sveinsdottir SG, Magnusson V, Lindblom A, Kostulas K, Botella-Estrada R, Soriano V, Juberias P, Grasa M, Saez B, Andres R, Scherer D, Rudnai P, Gurzau E, Koppova K, Kiemeney LA, Jakobsdottir M, Steinberg S, Helgason A, Gretarsdottir S, Tucker MA, Mayordomo JI, Nagore E, Kumar R, Hansson J, Olafsson JH, Gulcher J, Kong A, Thorsteinsdottir U, Stefansson K (2008) ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma. Nat Genet 40:886–891

    Article  CAS  PubMed  Google Scholar 

  • Guldberg P, thor Straten P, Birck A, Ahrenkiel V, Kirkin AF, Zeuthen J (1997) Disruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma. Cancer Res 57:3660–3663

    CAS  PubMed  Google Scholar 

  • Haqq C, Nosrati M, Sudilovsky D, Crothers J, Khodabakhsh D, Pulliam BL, Federman S, Miller JR 3rd, Allen RE, Singer MI, Leong SP, Ljung BM, Sagebiel RW, Kashani-Sabet M (2005) The gene expression signatures of melanoma progression. Proc Natl Acad Sci U S A 102:6092–6097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harbst K, Staaf J, Masback A, Olsson H, Ingvar C, Vallon-Christersson J, Ringner M, Borg A, Jonsson G (2010) Multiple metastases from cutaneous malignant melanoma patients may display heterogeneous genomic and epigenomic patterns. Melanoma Res 20:381–391

    CAS  PubMed  Google Scholar 

  • Harbst K, Staaf J, Lauss M, Karlsson A, Måsbäck A, Johansson I, Bendahl PO, Vallon-Christersson J, Törngren T, Ekedahl H, Geisler J, Höglund M, Ringnér M, Lundgren L, Jirström K, Olsson H, Ingvar C, Borg Å, Tsao H, Jönsson G (2012) Molecular profiling reveals low- and high-grade forms of primary melanoma. Clin Cancer Res 18(15):4026–4036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hari L, Brault V, Kléber M, Lee HY, Ille F, Leimeroth R, Paratore C, Suter U, Kemler R, Sommer L (2002) Lineage-specific requirements of beta-catenin in neural crest development. J Cell Biol 159(5):867–880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, Martín-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380(9839):358–365

    Article  CAS  PubMed  Google Scholar 

  • Hayward NK (2003) Genetics of melanoma predisposition. Oncogene 22:3053–3062

    Article  CAS  PubMed  Google Scholar 

  • Hocker T, Tsao H (2007) Ultraviolet radiation and melanoma: a systematic review and analysis of reported sequence variants. Hum Mutat 28:578–588

    Article  CAS  PubMed  Google Scholar 

  • Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, Nickerson E, Auclair D, Li L, Place C, Dicara D, Ramos AH, Lawrence MS, Cibulskis K, Sivachenko A, Voet D, Saksena G, Stransky N, Onofrio RC, Winckler W, Ardlie K, Wagle N, Wargo J, Chong K, Morton DL, Stemke-Hale K, Chen G, Noble M, Meyerson M, Ladbury JE, Davies MA, Gershenwald JE, Wagner SN, Hoon DS, Schadendorf D, Lander ES, Gabriel SB, Getz G, Garraway LA, Chin L (2012) A landscape of driver mutations in melanoma. Cell 150(2):251–263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Höiom V, Edsgärd D, Helgadottir H, Eriksson H, All-Ericsson C, Tuominen R, Ivanova I, Lundeberg J, Emanuelsson O, Hansson J (2013) Hereditary uveal melanoma: a report of a germline mutation in BAP1. Genes Chromosomes Cancer 52(4):378–384

    Article  PubMed  CAS  Google Scholar 

  • Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A, Gast A, Kadel S, Moll I, Nagore E, Hemminki K, Schadendorf D, Kumar R (2013) TERT promoter mutations in familial and sporadic melanoma. Science 339(6122):959–961

    Article  CAS  PubMed  Google Scholar 

  • Hunter Shain A, Ye I, Kovalyshyn I, Sriharan A, Talevich E, Gagnon A, Dummer R, North J, Pincus L, Ruben B, Rickaby W, D’Arrigo C, Robson A, Bastian B (2015) The genetic evolution of melanoma from precursor lesions. N Engl J Med 373:1926–1936

    Article  PubMed  CAS  Google Scholar 

  • Jackson S, Harland M, Turner F, Taylor C, Chambers PA, Dos Randerson-Moor J, Swerdlow AJ, Santos Silva I, Beswick S, Bishop DT, Newton Bishop JA (2005) No evidence for BRAF as a melanoma/nevus susceptibility gene. Cancer Epidemiol Biomarkers Prev 14:913–918

    Article  CAS  PubMed  Google Scholar 

  • Jane-Valbuena J, Widlund HR, Perner S, Johnson LA, Dibner AC, Lin WM, Baker AC, Nazarian RM, Vijayendran KG, Sellers WR, Hahn WC, Duncan LM, Rubin MA, Fisher DE, Garraway LA (2010) An oncogenic role for ETV1 in melanoma. Cancer Res 70:2075–2084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jewell R, Conway C, Mitra A, Randerson-Moor J, Lobo S, Nsengimana J, Harland M, Marples M, Edward S, Cook M, Powell B, Boon A, de Kort F, Parker KA, Cree IA, Barrett JH, Knowles MA, Bishop DT, Newton-Bishop J (2010) Patterns of expression of DNA repair genes and relapse from melanoma. Clin Cancer Res 16:5211–5221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA, Emery CM, Stransky N, Cogdill AP, Barretina J, Caponigro G, Hieronymus H, Murray RR, Salehi-Ashtiani K, Hill DE, Vidal M, Zhao JJ, Yang X, Alkan O, Kim S, Harris JL, Wilson CJ, Myer VE, Finan PM, Root DE, Roberts TM, Golub T, Flaherty KT, Dummer R, Weber BL, Sellers WR, Schlegel R, Wargo JA, Hahn WC, Garraway LA (2010) COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468(7326):968–972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johansson P, Pavey S, Hayward N (2007) Confirmation of a BRAF mutation-associated gene expression signature in melanoma. Pigment Cell Res 20:216–221

    Article  CAS  PubMed  Google Scholar 

  • Jonsson G, Dahl C, Staaf J, Sandberg T, Bendahl PO, Ringner M, Guldberg P, Borg A (2007) Genomic profiling of malignant melanoma using tiling-resolution arrayCGH. Oncogene 26:4738–4748

    Article  CAS  PubMed  Google Scholar 

  • Jonsson G, Busch C, Knappskog S, Geisler J, Miletic H, Ringner M, Lillehaug JR, Borg A, Lonning PE (2010) Gene expression profiling-based identification of molecular subtypes in stage IV melanomas with different clinical outcome. Clin Cancer Res 16:3356–3367

    Article  PubMed  Google Scholar 

  • Kabbarah O, Nogueira C, Feng B, Nazarian RM, Bosenberg M, Wu M, Scott KL, Kwong LN, Xiao Y, Cordon-Cardo C, Granter SR, Ramaswamy S, Golub T, Duncan LM, Wagner SN, Brennan C, Chin L (2010) Integrative genome comparison of primary and metastatic melanomas. PLoS One 5:e10770

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kamb A, Shattuck-Eidens D, Eeles R, Liu Q, Gruis NA, Ding W, Hussey C, Tran T, Miki Y, Weaver-Feldhaus J et al (1994) Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nat Genet 8:23–26

    Article  CAS  PubMed  Google Scholar 

  • Kauffmann A, Rosselli F, Lazar V, Winnepenninckx V, Mansuet-Lupo A, Dessen P, van den Oord JJ, Spatz A, Sarasin A (2008) High expression of DNA repair pathways is associated with metastasis in melanoma patients. Oncogene 27:565–573

    Article  CAS  PubMed  Google Scholar 

  • Kielhorn E, Provost E, Olsen D, D’Aquila TG, Smith BL, Camp RL, Rimm DL (2003) Tissue microarray-based analysis shows phospho-beta-catenin expression in malignant melanoma is associated with poor outcome. Int J Cancer 103:652–656

    Article  CAS  PubMed  Google Scholar 

  • Kim M, Gans JD, Nogueira C, Wang A, Paik JH, Feng B, Brennan C, Hahn WC, Cordon-Cardo C, Wagner SN, Flotte TJ, Duncan LM, Granter SR, Chin L (2006) Comparative oncogenomics identifies NEDD9 as a melanoma metastasis gene. Cell 125:1269–1281

    Article  CAS  PubMed  Google Scholar 

  • Kim RD, Curtin JA, Bastian BC (2008) Lack of somatic alterations of MC1R in primary melanoma. Pigment Cell Melanoma Res 21:579–582

    Article  CAS  PubMed  Google Scholar 

  • Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A, McCusker JP, Cheng E, Davis MJ, Goh G, Choi M, Ariyan S, Narayan D, Dutton-Regester K, Capatana A, Holman EC, Bosenberg M, Sznol M, Kluger HM, Brash DE, Stern DF, Materin MA, Lo RS, Mane S, Ma S, Kidd KK, Hayward NK, Lifton RP, Schlessinger J, Boggon TJ, Halaban R (2012) Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet 44(9):1006–1014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kumar R, Taylor M, Miao B, Ji Z, Njauw JC, Jönsson G, Frederick DT, Tsao H (2015) BAP1 has a survival role in cutaneous melanoma. J Invest Dermatol 135(4):1089–1097

    Article  CAS  PubMed  Google Scholar 

  • Kuźbicki L, Lange D, Strączyńska-Niemiec A, Chwirot BW (2013) JARID1B expression in human melanoma and benign melanocytic skin lesions. Melanoma Res 23(1):8–12

    Article  PubMed  CAS  Google Scholar 

  • Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M, Mandalà M, Demidov L, Stroyakovskiy D, Thomas L, de la Cruz-Merino L, Dutriaux C, Garbe C, Sovak MA, Chang I, Choong N, Hack SP, McArthur GA, Ribas A (2014) Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 371(20):1867–1876

    Article  PubMed  CAS  Google Scholar 

  • Laud K, Kannengiesser C, Avril MF, Chompret A, Stoppa-Lyonnet D, Desjardins L, Eychene A, Demenais F, Lenoir GM, Bressac-de Paillerets B (2003) BRAF as a melanoma susceptibility candidate gene? Cancer Res 63:3061–3065

    CAS  PubMed  Google Scholar 

  • Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA, Kiezun A, Hammerman PS, McKenna A, Drier Y, Zou L, Ramos AH, Pugh TJ, Stransky N, Helman E, Kim J, Sougnez C, Ambrogio L, Nickerson E, Shefler E, Cortés ML, Auclair D, Saksena G, Voet D, Noble M, DiCara D, Lin P, Lichtenstein L, Heiman DI, Fennell T, Imielinski M, Hernandez B, Hodis E, Baca S, Dulak AM, Lohr J, Landau DA, Wu CJ, Melendez-Zajgla J, Hidalgo-Miranda A, Koren A, McCarroll SA, Mora J, Lee RS, Crompton B, Onofrio R, Parkin M, Winckler W, Ardlie K, Gabriel SB, Roberts CW, Biegel JA, Stegmaier K, Bass AJ, Garraway LA, Meyerson M, Golub TR, Gordenin DA, Sunyaev S, Lander ES, Getz G (2013) Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499(7457):214–218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin J, Hocker TL, Singh M, Tsao H (2008) Genetics of melanoma predisposition. Br J Dermatol 159:286–291

    Article  CAS  PubMed  Google Scholar 

  • Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion Sileni V, Lebbe C, Mandalà M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Casey M, Ouellet D, Martin AM, Le N, Patel K, Flaherty K (2014) Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 371(20):1877–1888

    Article  PubMed  CAS  Google Scholar 

  • Lopez-Otin C, Palavalli LH, Samuels Y (2009) Protective roles of matrix metalloproteinases: from mouse models to human cancer. Cell Cycle 8:3657–3662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maldonado JL, Fridlyand J, Patel H, Jain AN, Busam K, Kageshita T, Ono T, Albertson DG, Pinkel D, Bastian BC (2003) Determinants of BRAF mutations in primary melanomas. J Natl Cancer Inst 95:1878–1890

    Article  CAS  PubMed  Google Scholar 

  • Margolin KA, Moon J, Flaherty LE, Lao CD, Akerley WL 3rd, Othus M, Sosman JA, Kirkwood JM, Sondak VK (2012) Randomized phase II trial of sorafenib with temsirolimus or tipifarnib in untreated metastatic melanoma (S0438). Clin Cancer Res 18(4):1129–1137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martincorena I, Roshan A, Gerstung M, Ellis P, Van Loo P, McLaren S, Wedge DC, Fullam A, Alexandrov LB, Tubio JM, Stebbings L, Menzies A, Widaa S, Stratton MR, Jones PH, Campbell PJ (2015) Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348(6237):880–886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McGill GG, Horstmann M, Widlund HR, Du J, Motyckova G, Nishimura EK, Lin YL, Ramaswamy S, Avery W, Ding HF, Jordan SA, Jackson IJ, Korsmeyer SJ, Golub TR, Fisher DE (2002) Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability. Cell 109:707–718

    Article  CAS  PubMed  Google Scholar 

  • McGill GG, Haq R, Nishimura EK, Fisher DE (2006) c-Met expression is regulated by Mitf in the melanocyte lineage. J Biol Chem 281:10365–10373

    Article  CAS  PubMed  Google Scholar 

  • Mitra A, Conway C, Walker C, Cook M, Powell B, Lobo S, Chan M, Kissin M, Layer G, Smallwood J, Ottensmeier C, Stanley P, Peach H, Chong H, Elliott F, Iles MM, Nsengimana J, Barrett JH, Bishop DT, Newton-Bishop JA (2010) Melanoma sentinel node biopsy and prediction models for relapse and overall survival. Br J Cancer 103:1229–1236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Momand J, Zambetti GP, Olson DC, George D, Levine AJ (1992) The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69:1237–1245

    Article  CAS  PubMed  Google Scholar 

  • Muthusamy V, Hobbs C, Nogueira C, Cordon-Cardo C, McKee PH, Chin L, Bosenberg MW (2006) Amplification of CDK4 and MDM2 in malignant melanoma. Genes Chromosomes Cancer 45:447–454

    Article  CAS  PubMed  Google Scholar 

  • Nathanson KL, Martin AM, Wubbenhorst B, Greshock J, Letrero R, D’Andrea K, O’Day S, Infante JR, Falchook GS, Arkenau HT, Millward M, Brown MP, Pavlick A, Davies MA, Ma B, Gagnon R, Curtis M, Lebowitz PF, Kefford R, Long GV (2013) Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor dabrafenib (GSK2118436). Clin Cancer Res 19(17):4868–4878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H, Chodon T, Nelson SF, McArthur G, Sosman JA, Ribas A, Lo RS (2010) Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468(7326):973–977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nelson AA, Tsao H (2009) Melanoma and genetics. Clin Dermatol 27:46–52

    Article  PubMed  Google Scholar 

  • Niederleithner H, Heinz M, Tauber S, Bilban M, Pehamberger H, Sonderegger S, Knöfler M, Bracher A, Berger W, Loewe R, Petzelbauer P (2012) Wnt1 is anti-lymphangiogenic in a melanoma mouse model. J Invest Dermatol 132(9):2235–2244

    Article  CAS  PubMed  Google Scholar 

  • Nikolaev SI, Rimoldi D, Iseli C, Valsesia A, Robyr D, Gehrig C, Harshman K, Guipponi M, Bukach O, Zoete V, Michielin O, Muehlethaler K, Speiser D, Beckmann JS, Xenarios I, Halazonetis TD, Jongeneel CV, Stevenson BJ, Antonarakis SE (2011) Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma. Nat Genet 44(2):133–139

    Article  PubMed  CAS  Google Scholar 

  • Njauw CN, Kim I, Piris A, Gabree M, Taylor M, Lane AM, DeAngelis MM, Gragoudas E, Duncan LM, Tsao H (2012) Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families. PLoS One 7(4):e35295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ogino S, Nosho K, Kirkner GJ, Shima K, Irahara N, Kure S, Chan AT, Engelman JA, Kraft P, Cantley LC, Giovannucci EL, Fuchs CS (2009) PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. J Clin Oncol 27:1477–1484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Omholt K, Krockel D, Ringborg U, Hansson J (2006) Mutations of PIK3CA are rare in cutaneous melanoma. Melanoma Res 16:197–200

    Article  CAS  PubMed  Google Scholar 

  • Onken MD, Worley LA, Long MD, Duan S, Council ML, Bowcock AM, Harbour JW (2008) Oncogenic mutations in GNAQ occur early in uveal melanoma. Invest Ophthalmol Vis Sci 49:5230–5234

    Article  PubMed  PubMed Central  Google Scholar 

  • Padua RA, Barrass N, Currie GA (1984) A novel transforming gene in a human malignant melanoma cell line. Nature 311:671–673

    Article  CAS  PubMed  Google Scholar 

  • Palanisamy N, Ateeq B, Kalyana-Sundaram S, Pflueger D, Ramnarayanan K, Shankar S, Han B, Cao Q, Cao X, Suleman K, Kumar-Sinha C, Dhanasekaran SM, Chen YB, Esgueva R, Banerjee S, LaFargue CJ, Siddiqui J, Demichelis F, Moeller P, Bismar TA, Kuefer R, Fullen DR, Johnson TM, Greenson JK, Giordano TJ, Tan P, Tomlins SA, Varambally S, Rubin MA, Maher CA, Chinnaiyan AM (2010) Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma. Nat Med 16:793–798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Palavalli LH, Prickett TD, Wunderlich JR, Wei X, Burrell AS, Porter-Gill P, Davis S, Wang C, Cronin JC, Agrawal NS, Lin JC, Westbroek W, Hoogstraten-Miller S, Molinolo AA, Fetsch P, Filie AC, O’Connell MP, Banister CE, Howard JD, Buckhaults P, Weeraratna AT, Brody LC, Rosenberg SA, Samuels Y (2009) Analysis of the matrix metalloproteinase family reveals that MMP8 is often mutated in melanoma. Nat Genet 41:518–520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paraiso KH, Xiang Y, Rebecca VW, Abel EV, Chen YA, Munko AC, Wood E, Fedorenko IV, Sondak VK, Anderson AR, Ribas A, Palma MD, Nathanson KL, Koomen JM, Messina JL, Smalley KS (2011) PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res 71(7):2750–2760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pavey S, Johansson P, Packer L, Taylor J, Stark M, Pollock PM, Walker GJ, Boyle GM, Harper U, Cozzi SJ, Hansen K, Yudt L, Schmidt C, Hersey P, Ellem KA, O’Rourke MG, Parsons PG, Meltzer P, Ringner M, Hayward NK (2004) Microarray expression profiling in melanoma reveals a BRAF mutation signature. Oncogene 23:4060–4067

    Article  CAS  PubMed  Google Scholar 

  • Pleasance ED, Cheetham RK, Stephens PJ, McBride DJ, Humphray SJ, Greenman CD, Varela I, Lin ML, Ordonez GR, Bignell GR, Ye K, Alipaz J, Bauer MJ, Beare D, Butler A, Carter RJ, Chen L, Cox AJ, Edkins S, Kokko-Gonzales PI, Gormley NA, Grocock RJ, Haudenschild CD, Hims MM, James T, Jia M, Kingsbury Z, Leroy C, Marshall J, Menzies A, Mudie LJ, Ning Z, Royce T, Schulz-Trieglaff OB, Spiridou A, Stebbings LA, Szajkowski L, Teague J, Williamson D, Chin L, Ross MT, Campbell PJ, Bentley DR, Futreal PA, Stratton MR (2010) A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 463:191–196

    Article  CAS  PubMed  Google Scholar 

  • Pollock PM, Walker GJ, Glendening JM, Que Noy T, Bloch NC, Fountain JW, Hayward NK (2002) PTEN inactivation is rare in melanoma tumours but occurs frequently in melanoma cell lines. Melanoma Res 12:565–575

    Article  CAS  PubMed  Google Scholar 

  • Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins CM, Moses TY, Hostetter G, Wagner U, Kakareka J, Salem G, Pohida T, Heenan P, Duray P, Kallioniemi O, Hayward NK, Trent JM, Meltzer PS (2003) High frequency of BRAF mutations in nevi. Nat Genet 33:19–20

    Article  CAS  PubMed  Google Scholar 

  • Potterf SB, Furumura M, Dunn KJ, Arnheiter H, Pavan WJ (2000) Transcription factor hierarchy in Waardenburg syndrome: regulation of MITF expression by SOX10 and PAX3. Hum Genet 107:1–6

    Article  CAS  PubMed  Google Scholar 

  • Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, Shi H, Atefi M, Titz B, Gabay MT, Salton M, Dahlman KB, Tadi M, Wargo JA, Flaherty KT, Kelley MC, Misteli T, Chapman PB, Sosman JA, Graeber TG, Ribas A, Lo RS, Rosen N, Solit DB (2011) RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 480(7377):387–390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Puig S, Malvehy J, Badenas C, Ruiz A, Jimenez D, Cuellar F, Azon A, Gonzàlez U, Castel T, Campoy A, Herrero J, Martí R, Brunet-Vidal J, Milà M (2005) Role of the CDKN2A locus in patients with multiple primary melanomas. J Clin Oncol 23(13):3043–3051

    Article  CAS  PubMed  Google Scholar 

  • Ragnarsson-Olding BK, Karsberg S, Platz A, Ringborg UK (2002) Mutations in the TP53 gene in human malignant melanomas derived from sun-exposed skin and unexposed mucosal membranes. Melanoma Res 12:453–463

    Article  CAS  PubMed  Google Scholar 

  • Reifenberger J, Knobbe CB, Sterzinger AA, Blaschke B, Schulte KW, Ruzicka T, Reifenberger G (2004) Frequent alterations of Ras signaling pathway genes in sporadic malignant melanomas. Int J Cancer 109:377–384

    Article  CAS  PubMed  Google Scholar 

  • Rizos H, Menzies AM, Pupo GM, Carlino MS, Fung C, Hyman J, Haydu LE, Mijatov B, Becker TM, Boyd SC, Howle J, Saw R, Thompson JF, Kefford RF, Scolyer RA, Long GV (2014) BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin Cancer Res 20(7):1965–1977

    Article  CAS  PubMed  Google Scholar 

  • Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K, Krajsova I, Hauschild A, Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P, Ribas A, Martin AM, Sun P, Crist W, Legos J, Rubin SD, Little SM, Schadendorf D (2015) Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 372(1):30–39

    Article  PubMed  CAS  Google Scholar 

  • Robles-Espinoza CD, Harland M, Ramsay AJ, Aoude LG, Quesada V, Ding Z, Pooley KA, Pritchard AL, Tiffen JC, Petljak M, Palmer JM, Symmons J, Johansson P, Stark MS, Gartside MG, Snowden H, Montgomery GW, Martin NG, Liu JZ, Choi J, Makowski M, Brown KM, Dunning AM, Keane TM, López-Otín C, Gruis NA, Hayward NK, Bishop DT, Newton-Bishop JA, Adams DJ (2014) POT1 loss-of-function variants predispose to familial melanoma. Nat Genet 46(5):478–481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rouzaud F, Kadekaro AL, Abdel-Malek ZA, Hearing VJ (2005) MC1R and the response of melanocytes to ultraviolet radiation. Mutat Res 571:133–152

    Article  CAS  PubMed  Google Scholar 

  • Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, Yu JS, Malmstrom PO, Mansukhani M, Enoksson J, Hibshoosh H, Borg A, Parsons R (2005) PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res 65:2554–2559

    Article  CAS  PubMed  Google Scholar 

  • Sabatino M, Zhao Y, Voiculescu S, Monaco A, Robbins P, Karai L, Nickoloff BJ, Maio M, Selleri S, Marincola FM, Wang E (2008) Conservation of genetic alterations in recurrent melanoma supports the melanoma stem cell hypothesis. Cancer Res 68:122–131

    Article  CAS  PubMed  Google Scholar 

  • Sánchez-Hernández I, Baquero P, Calleros L, Chiloeches A (2012) Dual inhibition of (V600E)BRAF and the PI3K/AKT/mTOR pathway cooperates to induce apoptosis in melanoma cells through a MEK-independent mechanism. Cancer Lett 314(2):244–255

    Article  PubMed  CAS  Google Scholar 

  • Sarris M, Nikolaou K, Talianidis I (2014) Context-specific regulation of cancer epigenomes by histone and transcription factor methylation. Oncogene 33(10):1207–1217

    Article  CAS  PubMed  Google Scholar 

  • Shi H, Moriceau G, Kong X, Lee MK, Lee H, Koya RC, Ng C, Chodon T, Scolyer RA, Dahlman KB, Sosman JA, Kefford RF, Long GV, Nelson SF, Ribas A, Lo RS (2012) Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat Commun 3:724

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Shi J, Yang XR, Ballew B, Rotunno M, Calista D, Fargnoli MC, Ghiorzo P, Bressac-de Paillerets B, Nagore E, Avril MF, Caporaso NE, McMaster ML, Cullen M, Wang Z, Zhang X, NCI DCEG Cancer Sequencing Working Group, NCI DCEG Cancer Genomics Research Laboratory, French Familial Melanoma Study Group, Bruno W, Pastorino L, Queirolo P, Banuls-Roca J, Garcia-Casado Z, Vaysse A, Mohamdi H, Riazalhosseini Y, Foglio M, Jouenne F, Hua X, Hyland PL, Yin J, Vallabhaneni H, Chai W, Minghetti P, Pellegrini C, Ravichandran S, Eggermont A, Lathrop M, Peris K, Scarra GB, Landi G, Savage SA, Sampson JN, He J, Yeager M, Goldin LR, Demenais F, Chanock SJ, Tucker MA, Goldstein AM, Liu Y, Landi MT (2014) Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nat Genet 46(5):482–486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shull AY, Latham-Schwark A, Ramasamy P, Leskoske K, Oroian D, Birtwistle MR, Buckhaults PJ (2012) Novel somatic mutations to PI3K pathway genes in metastatic melanoma. PLoS One 7(8):e43369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smalley KS, Lioni M, Dalla Palma M, Xiao M, Desai B, Egyhazi S, Hansson J, Wu H, King AJ, Van Belle P, Elder DE, Flaherty KT, Herlyn M, Nathanson KL (2008) Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas. Mol Cancer Ther 7(9):2876–2883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS, Hollmann TJ, Bruggeman C, Kannan K, Li Y, Elipenahli C, Liu C, Harbison CT, Wang L, Ribas A, Wolchok JD, Chan TA (2014) Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371(23):2189–2199

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Spranger S, Bao R, Gajewski TF (2015) Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 523(7559):231–235

    Article  CAS  PubMed  Google Scholar 

  • Staaf J, Harbst K, Lauss M, Ringnér M, Måsbäck A, Howlin J, Jirström K, Harland M, Zebary A, Palmer JM, Ingvar C, Olsson H, Newton-Bishop J, Hansson J, Hayward N, Gruis N, Jönsson G, Melanoma Genetics Consortium (2014) Primary melanoma tumors from CDKN2A mutation carriers do not belong to a distinct molecular subclass. J Invest Dermatol 134(12):3000–3003

    Article  CAS  PubMed  Google Scholar 

  • Stark M, Hayward N (2007) Genome-wide loss of heterozygosity and copy number analysis in melanoma using high-density single-nucleotide polymorphism arrays. Cancer Res 67:2632–2642

    Article  CAS  PubMed  Google Scholar 

  • Sun C, Wang L, Huang S, Heynen GJ, Prahallad A, Robert C, Haanen J, Blank C, Wesseling J, Willems SM, Zecchin D, Hobor S, Bajpe PK, Lieftink C, Mateus C, Vagner S, Grernrum W, Hofland I, Schlicker A, Wessels LF, Beijersbergen RL, Bardelli A, Di Nicolantonio F, Eggermont AM, Bernards R (2014) Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature 508(7494):118–122

    Article  CAS  PubMed  Google Scholar 

  • Swerdlow AJ, English J, MacKie RM, O’Doherty CJ, Hunter JA, Clark J, Hole DJ (1986) Benign melanocytic naevi as a risk factor for malignant melanoma. Br Med J (Clin Res Ed) 292:1555–1559

    Article  CAS  Google Scholar 

  • Tiffen J, Gallagher SJ, Hersey P (2015) EZH2: an emerging role in melanoma biology and strategies for targeted therapy. Pigment Cell Melanoma Res 28(1):21–30

    Article  CAS  PubMed  Google Scholar 

  • Tsao H, Zhang X, Fowlkes K, Haluska FG (2000) Relative reciprocity of NRAS and PTEN/MMAC1 alterations in cutaneous melanoma cell lines. Cancer Res 60:1800–1804

    CAS  PubMed  Google Scholar 

  • Tsao H, Goel V, Wu H, Yang G, Haluska FG (2004) Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma. J Invest Dermatol 122:337–341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tschandl P, Berghoff AS, Preusser M, Burgstaller-Muehlbacher S, Pehamberger H, Okamoto I, Kittler H (2013) NRAS and BRAF mutations in melanoma-associated nevi and uninvolved nevi. PLoS One 8(7):e69639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ugurel S, Hildenbrand R, Zimpfer A, La Rosée P, Paschka P, Sucker A, Keikavoussi P, Becker JC, Rittgen W, Hochhaus A, Schadendorf D (2005) Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer 92(8):1398–1405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Van Allen EM, Wagle N, Sucker A, Treacy DJ, Johannessen CM, Goetz EM, Place CS, Taylor-Weiner A, Whittaker S, Kryukov GV, Hodis E, Rosenberg M, McKenna A, Cibulskis K, Farlow D, Zimmer L, Hillen U, Gutzmer R, Goldinger SM, Ugurel S, Gogas HJ, Egberts F, Berking C, Trefzer U, Loquai C, Weide B, Hassel JC, Gabriel SB, Carter SL, Getz G, Garraway LA, Schadendorf D, Dermatologic Cooperative Oncology Group of Germany (DeCOG) (2014) The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov 4(1):94–109

    Article  PubMed  CAS  Google Scholar 

  • Van Allen EM, Miao D, Schilling B, Shukla SA, Blank C, Zimmer L, Sucker A, Hillen U, Foppen MH, Goldinger SM, Utikal J, Hassel JC, Weide B, Kaehler KC, Loquai C, Mohr P, Gutzmer R, Dummer R, Gabriel S, Wu CJ, Schadendorf D, Garraway LA (2015) Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350(6257):207–211

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Van Raamsdonk CD, Bezrookove V, Green G, Bauer J, Gaugler L, O’Brien JM, Simpson EM, Barsh GS, Bastian BC (2009) Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457:599–602

    Article  PubMed  CAS  Google Scholar 

  • Van Raamsdonk CD, Griewank KG, Crosby MB, Garrido MC, Vemula S, Wiesner T, Obenauf AC, Wackernagel W, Green G, Bouvier N, Sozen MM, Baimukanova G, Roy R, Heguy A, Dolgalev I, Khanin R, Busam K, Speicher MR, O’Brien J, Bastian BC (2010) Mutations in GNA11 in uveal melanoma. N Engl J Med 363(23):2191–2199

    Article  PubMed  PubMed Central  Google Scholar 

  • Verastegui C, Bille K, Ortonne JP, Ballotti R (2000) Regulation of the microphthalmia-associated transcription factor gene by the Waardenburg syndrome type 4 gene, SOX10. J Biol Chem 275:30757–30760

    Article  CAS  PubMed  Google Scholar 

  • Viros A, Fridlyand J, Bauer J, Lasithiotakis K, Garbe C, Pinkel D, Bastian BC (2008) Improving melanoma classification by integrating genetic and morphologic features. PLoS Med 5:e120

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Vredeveld LC, Possik PA, Smit MA, Meissl K, Michaloglou C, Horlings HM, Ajouaou A, Kortman PC, Dankort D, McMahon M, Mooi WJ, Peeper DS (2012) Abrogation of BRAFV600E-induced senescence by PI3K pathway activation contributes to melanomagenesis. Genes Dev 26(10):1055–1069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weaver-Feldhaus J, Gruis NA, Neuhausen S, Le Paslier D, Stockert E, Skolnick MH, Kamb A (1994) Localization of a putative tumor suppressor gene by using homozygous deletions in melanomas. Proc Natl Acad Sci U S A 91:7563–7567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xing F, Persaud Y, Pratilas CA, Taylor BS, Janakiraman M, She QB, Gallardo H, Liu C, Merghoub T, Hefter B, Dolgalev I, Viale A, Heguy A, De Stanchina E, Cobrinik D, Bollag G, Wolchok J, Houghton A, Solit DB (2012) Concurrent loss of the PTEN and RB1 tumor suppressors attenuates RAF dependence in melanomas harboring (V600E)BRAF. Oncogene 31(4):446–457

    Article  CAS  PubMed  Google Scholar 

  • Yokoyama S, Woods SL, Boyle GM, Aoude LG, MacGregor S, Zismann V, Gartside M, Cust AE, Haq R, Harland M, Taylor JC, Duffy DL, Holohan K, Dutton-Regester K, Palmer JM, Bonazzi V, Stark MS, Symmons J, Law MH, Schmidt C, Lanagan C, O’Connor L, Holland EA, Schmid H, Maskiell JA, Jetann J, Ferguson M, Jenkins MA, Kefford RF, Giles GG, Armstrong BK, Aitken JF, Hopper JL, Whiteman DC, Pharoah PD, Easton DF, Dunning AM, Newton-Bishop JA, Montgomery GW, Martin NG, Mann GJ, Bishop DT, Tsao H, Trent JM, Fisher DE, Hayward NK, Brown KM (2011) A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature 480(7375):99–103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Xiong Y, Yarbrough WG (1998) ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 92:725–734

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Institute for Biochemistry, Erlangen, Germany

    Allen Ho & Göran Jönsson

  2. Harvard Combined Dermatology Residency Program, Harvard Medical School, Boston, MA, USA

    Allen Ho

  3. Melanoma Genetics Unit, Division of Oncology and Pathology, Lund University, Lund, Sweden

    Göran Jönsson

  4. Wellman Center for Photomedicine, Department of Dermatology, Melanoma and Pigmented Lesion Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Hensin Tsao

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  1. Allen Ho
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  2. Göran Jönsson
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  3. Hensin Tsao
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Correspondence to Hensin Tsao .

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  1. Institute for Biochemistry, Erlangen, Germany

    Anja K. Bosserhoff

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Ho, A., Jönsson, G., Tsao, H. (2017). Melanoma Genetics and Genomics. In: Bosserhoff, A. (eds) Melanoma Development. Springer, Cham. https://doi.org/10.1007/978-3-319-41319-8_4

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