Genomic Applications in Melanoma

  • Carlos N. Prieto-GranadaEmail author
  • John Van Arnam
  • Kabeer K. Shah
  • Aleodor A. Andea
  • Alexander J. Lazar


Advances in molecular techniques have confirmed that melanoma encompasses several neural crest-derived malignancies that cluster in groups with shared features including exposure to known risk factors, histomorphology, mutational/molecular profiles, and clinical behavior. Multiple targeted therapy and immunotherapeutic approaches have advanced the field of melanoma therapy. The growing understanding of the mutational and molecular underpinnings of both benign and malignant melanocytic lesions, including the identification of driver mutations such as BRAF p.V600E/K and others, has not only opened multiple opportunities for intervention and revolutionized melanoma therapy but also provided tools for diagnosis and prognostication. In this chapter, we comprehensively review the molecular landscape of melanocytic tumors including the most frequently affected pathways, epigenetic changes, and chromosomal aberrations. Examples of practical application of this knowledge are represented by chromosomal copy number evaluation techniques such as fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH) for diagnosis of problematic lesions, gene expression profile for prognostication, and evaluation of tumor neoantigens that could facilitate complete responses with immunotherapy. The applicability of testing will likely continue to grow as targeted therapies are increasingly tested and employed in the adjuvant setting in earlier-stage disease. This chapter represents a brief snapshot of our current understanding of melanoma and some of the approaches currently in use or likely to be deployed in the near future.


Melanoma BRAF Epigenetics FISH CGH NGS Anti-CTLA4 Anti-PD1 Immunotherapy Neoantigens Microbiome 



The authors would like to acknowledge Katheryn Pearce3 and the Division of Cytogenetics for their help with procuring FISH images.


  1. 1.
    Goldgeier MH, Klein LE, Klein-Angerer S, Moellmann G, Nordlund JJ. The distribution of melanocytes in the leptomeninges of the human brain. J Invest Dermatol. 1984;82(3):235–8.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Clemmensen OJ. Fenger C melanocytes in the anal canal epithelium. Histopathology. 1991;18(3):237–41.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Lin JY. Fisher DE melanocyte biology and skin pigmentation. Nature. 2007;445(7130):843–50.CrossRefGoogle Scholar
  4. 4.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30.CrossRefGoogle Scholar
  5. 5.
    Gershenwald JE, Scolyer RA, Hess KR, Sondak VK, Long GV, Ross MI, Lazar AJ, Faries MB, et al. Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(6):472–92.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Zhang M, Qureshi AA, Geller AC, Frazier L, Hunter DJ, Han J. Use of tanning beds and incidence of skin cancer. J Clin Oncol. 2012;30(14):1588–93.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Harrington CR, Beswick TC, Leitenberger J, Minhajuddin A, Jacobe HT, Adinoff B. Addictive-like behaviours to ultraviolet light among frequent indoor tanners. Clin Exp Dermatol. 2011;36(1):33–8.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Soura E, Eliades PJ, Shannon K, Stratigos AJ, Tsao H. Hereditary melanoma: update on syndromes and management: genetics of familial atypical multiple mole melanoma syndrome. J Am Acad Dermatol. 2016;74(3):395–407. quiz 408-310.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Soufir N, Avril MF, Chompret A, Demenais F, Bombled J, Spatz A, Stoppa-Lyonnet D, Benard J, 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(2):209–16.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Molven A, Grimstvedt MB, Steine SJ, Harland M, Avril MF, Hayward NK, Akslen LA. A large Norwegian family with inherited malignant melanoma, multiple atypical nevi, and CDK4 mutation. Genes Chromosomes Cancer. 2005;44(1):10–8.CrossRefGoogle Scholar
  11. 11.
    Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E, Cox NJ, Dogan AU, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet. 2011;43(10):1022–5.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Wiesner T, Obenauf AC, Murali R, Fried I, Griewank KG, Ulz P, Windpassinger C, Wackernagel W, et al. Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet. 2011;43(10):1018–21.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Carbone M, Yang H, Pass HI, Krausz T, Testa JR, Gaudino G. BAP1 and cancer. Nat Rev Cancer. 2013;13(3):153–9.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Curiel-Lewandrowski C, Speetzen LS, Cranmer L, Warneke JA, Loescher LJ. Multiple primary cutaneous melanomas in Li-Fraumeni syndrome. Arch Dermatol. 2011;147(2):248–50.CrossRefGoogle Scholar
  15. 15.
    Giavedoni P, Ririe M, Carrera C, Puig S, Malvehy J. Familial melanoma associated with Li-Fraumeni syndrome and atypical mole syndrome: total-body digital photography, dermoscopy and confocal microscopy. Acta Derm Venereol. 2017;97(6):720–3.CrossRefGoogle Scholar
  16. 16.
    Tan MH, Mester JL, Ngeow J, Rybicki LA, Orloff MS, Eng C. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012;18(2):400–7.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    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(2):277–80.CrossRefGoogle Scholar
  18. 18.
    Eng C, Li FP, Abramson DH, Ellsworth RM, Wong FL, Goldman MB, Seddon J, Tarbell N, et al. Mortality from second tumors among long-term survivors of retinoblastoma. J Natl Cancer Inst. 1993;85(14):1121–8.CrossRefGoogle Scholar
  19. 19.
    Bataille V, Hiles R, Bishop JA. Retinoblastoma, melanoma and the atypical mole syndrome. Br J Dermatol. 1995;132(1):134–8.CrossRefGoogle Scholar
  20. 20.
    Kleinerman RA, Tucker MA, Tarone RE, Abramson DH, Seddon JM, Stovall M, Li FP, Fraumeni JF Jr. Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol. 2005;23(10):2272–9.CrossRefGoogle Scholar
  21. 21.
    Bertolotto C, Lesueur F, Giuliano S, Strub T, de Lichy M, Bille K, Dessen P, d'Hayer B, et al. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature. 2011;480(7375):94–8.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Yokoyama S, Woods SL, Boyle GM, Aoude LG, MacGregor S, Zismann V, Gartside M, Cust AE, et al. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature. 2011;480(7375):99–103.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Cocciolone RA, Crotty KA, Andrews L, Haass NK, Moloney FJ. Multiple desmoplastic melanomas in Birt-Hogg-Dube syndrome and a proposed signaling link between folliculin, the mTOR pathway, and melanoma susceptibility. Arch Dermatol. 2010;146(11):1316–8.CrossRefGoogle Scholar
  24. 24.
    Fontcuberta IC, Salomao DR, Quiram PA, Pulido JS. Choroidal melanoma and lid fibrofolliculomas in Birt-Hogg-Dube syndrome. Ophthalmic Genet. 2011;32(3):143–6.CrossRefGoogle Scholar
  25. 25.
    Mota-Burgos A, Acosta EH, Marquez FV, Mendiola M, Herrera-Ceballos E. Birt-Hogg-Dube syndrome in a patient with melanoma and a novel mutation in the FCLN gene. Int J Dermatol. 2013;52(3):323–6.CrossRefGoogle Scholar
  26. 26.
    Kraemer KH, Lee MM, Andrews AD, Lambert WC. The role of sunlight and DNA repair in melanoma and nonmelanoma skin cancer. The xeroderma pigmentosum paradigm. Arch Dermatol. 1994;130(8):1018–21.CrossRefGoogle Scholar
  27. 27.
    Wang Y, Digiovanna JJ, Stern JB, Hornyak TJ, Raffeld M, Khan SG, Oh KS, Hollander MC, et al. Evidence of ultraviolet type mutations in xeroderma pigmentosum melanomas. Proc Natl Acad Sci U S A. 2009;106(15):6279–84.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Wang Y, Tan XH, DiGiovanna JJ, Lee CC, Stern JB, Raffeld M, Jaffe ES, Kraemer KH. Genetic diversity in melanoma metastases from a patient with xeroderma pigmentosum. J Invest Dermatol. 2010;130(4):1188–91.CrossRefGoogle Scholar
  29. 29.
    Shibuya H, Kato A, Kai N, Fujiwara S, Goto M. A case of Werner syndrome with three primary lesions of malignant melanoma. J Dermatol. 2005;32(9):737–44.CrossRefGoogle Scholar
  30. 30.
    Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst. 1999;91(15):1310–6.CrossRefGoogle Scholar
  31. 31.
    Robles-Espinoza CD, Harland M, Ramsay AJ, Aoude LG, Quesada V, Ding Z, Pooley KA, Pritchard AL, et al. POT1 loss-of-function variants predispose to familial melanoma. Nat Genet. 2014;46(5):478–81.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Shi J, Yang XR, Ballew B, Rotunno M, Calista D, Fargnoli MC, Ghiorzo P, Bressac-de Paillerets B, et al. Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nat Genet. 2014;46(5):482–6.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Landi MT, Bauer J, Pfeiffer RM, Elder DE, Hulley B, Minghetti P, Calista D, Kanetsky PA, et al. MC1R germline variants confer risk for BRAF-mutant melanoma. Science. 2006;313(5786):521–2.CrossRefGoogle Scholar
  34. 34.
    Bishop DT, Demenais F, Iles MM, Harland M, Taylor JC, Corda E, Randerson-Moor J, Aitken JF, et al. Genome-wide association study identifies three loci associated with melanoma risk. Nat Genet. 2009;41(8):920–5.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    LeBoit P. WHO classification of tumours of skin. Lyon: IARC Press; 2006.Google Scholar
  36. 36.
    Chung AF, Woodruff JM, Lewis JL Jr. Malignant melanoma of the vulva: a report of 44 cases. Obstet Gynecol. 1975;45(6):638–46.CrossRefGoogle Scholar
  37. 37.
    Chattopadhyay C, Kim DW, Gombos DS, Oba J, Qin Y, Williams MD, Esmaeli B, Grimm EA, et al. Uveal melanoma: from diagnosis to treatment and the science in between. Cancer. 2016;122(15):2299–312.CrossRefGoogle Scholar
  38. 38.
    Cummins DL, Cummins JM, Pantle H, Silverman MA, Leonard AL, Chanmugam A. Cutaneous malignant melanoma. Mayo Clin Proc. 2006;81(4):500–7.CrossRefGoogle Scholar
  39. 39.
    Barnhill RL, Fine JA, Roush GC, Berwick M. Predicting five-year outcome for patients with cutaneous melanoma in a population-based study. Cancer. 1996;78(3):427–32.CrossRefGoogle Scholar
  40. 40.
    Hayward NK, Wilmott JS, Waddell N, Johansson PA, Field MA, Nones K, Patch AM, Kakavand H, et al. Whole-genome landscapes of major melanoma subtypes. Nature. 2017;545(7653):175–80.CrossRefGoogle Scholar
  41. 41.
    Akbani RAK, Aksoy BA, Albert M, et al. Genomic classification of cutaneous melanoma. Cell. 2015;161(7):1681–96.CrossRefGoogle Scholar
  42. 42.
    Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, Cho KH, Aiba S, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353(20):2135–47.CrossRefGoogle Scholar
  43. 43.
    Bauer J, Curtin JA, Pinkel D, Bastian BC. Congenital melanocytic nevi frequently harbor NRAS mutations but no BRAF mutations. J Invest Dermatol. 2007;127(1):179–82.CrossRefGoogle Scholar
  44. 44.
    Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins CM, Moses TY, Hostetter G, et al. High frequency of BRAF mutations in nevi. Nat Genet. 2003;33(1):19–20.CrossRefGoogle Scholar
  45. 45.
    Yeh I, von Deimling A, Bastian BC. Clonal BRAF mutations in melanocytic nevi and initiating role of BRAF in melanocytic neoplasia. J Natl Cancer Inst. 2013;105(12):917–9.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Wiesner T, Murali R, Fried I, Cerroni L, Busam K, Kutzner H, Bastian BC. A distinct subset of atypical Spitz tumors is characterized by BRAF mutation and loss of BAP1 expression. Am J Surg Pathol. 2012;36(6):818–30.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Krauthammer M, Kong Y, Bacchiocchi A, Evans P, Pornputtapong N, Wu C, McCusker JP, Ma S, et al. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas. Nat Genet. 2015;47(9):996–1002.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Wiesner T, Kiuru M, Scott SN, Arcila M, Halpern AC, Hollmann T, Berger MF, Busam KJ NF1 Mutations Are Common in Desmoplastic Melanoma. Am J Surg Pathol. 2015;39(10):1357–62.Google Scholar
  49. 49.
    Jahn SW, Kashofer K, Halbwedl I, Winter G, El-Shabrawi-Caelen L, Mentzel T, Hoefler G, Liegl-Atzwanger B. Mutational dichotomy in desmoplastic malignant melanoma corroborated by multigene panel analysis. Mod Pathol. 2015;28(7):895–903.CrossRefGoogle Scholar
  50. 50.
    Turner J, Couts K, Sheren J, Saichaemchan S, Ariyawutyakorn W, Avolio I, Cabral E, Glogowska M, et al. Kinase gene fusions in defined subsets of melanoma. Pigment Cell Melanoma Res. 2017;30(1):53–62.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Moon KR, Choi YD, Kim JM, Jin S, Shin MH, Shim HJ, Lee JB, Yun SJ. Genetic alterations in primary acral melanoma and acral melanocytic nevus in Korea: common mutated genes show distinct cytomorphological features. J Invest Dermatol. 2018;138(4):933–45.CrossRefGoogle Scholar
  52. 52.
    Hintzsche JD, Gorden NT, Amato CM, Kim J, Wuensch KE, Robinson SE, Applegate AJ, Couts KL, et al. Whole-exome sequencing identifies recurrent SF3B1 R625 mutation and comutation of NF1 and KIT in mucosal melanoma. Melanoma Res. 2017;27(3):189–99.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Hou JY, Baptiste C, Hombalegowda RB, Tergas AI, Feldman R, Jones NL, Chatterjee-Paer S, Bus-Kwolfski A, et al. Vulvar and vaginal melanoma: a unique subclass of mucosal melanoma based on a comprehensive molecular analysis of 51 cases compared with 2253 cases of nongynecologic melanoma. Cancer. 2017;123(8):1333–44.CrossRefGoogle Scholar
  54. 54.
    Tseng D, Kim J, Warrick A, Nelson D, Pukay M, Beadling C, Heinrich M, Selim MA, et al. Oncogenic mutations in melanomas and benign melanocytic nevi of the female genital tract. J Am Acad Dermatol. 2014;71(2):229–36.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Bastian BC, LeBoit PE, Pinkel D. Mutations and copy number increase of HRAS in Spitz nevi with distinctive histopathological features. Am J Pathol. 2000;157(3):967–72.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Wiesner T, He J, Yelensky R, Esteve-Puig R, Botton T, Yeh I, Lipson D, Otto G, et al. Kinase fusions are frequent in Spitz tumours and spitzoid melanomas. Nat Commun. 2014;5:3116.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Tetzlaff MT, Reuben A, Billings SD, Prieto VG, Curry JL. Toward a molecular-genetic classification of Spitzoid neoplasms. Clin Lab Med. 2017;37(3):431–48.CrossRefGoogle Scholar
  58. 58.
    Yeh I, Lang UE, Durieux E, Tee MK, Jorapur A, Shain AH, Haddad V, Pissaloux D, et al. Combined activation of MAP kinase pathway and beta-catenin signaling cause deep penetrating nevi. Nat Commun. 2017;8(1):644.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Yelamos O, Arva NC, Obregon R, Yazdan P, Wagner A, Guitart J, Gerami P. A comparative study of proliferative nodules and lethal melanomas in congenital nevi from children. Am J Surg Pathol. 2015;39(3):405–15.Google Scholar
  60. 60.
    Moller I, Murali R, Muller H, Wiesner T, Jackett LA, Scholz SL, Cosgarea I, van de Nes JA, et al. Activating cysteinyl leukotriene receptor 2 (CYSLTR2) mutations in blue nevi. Mod Pathol. 2017;30(3):350–6.Google Scholar
  61. 61.
    Griewank KG, Muller H, Jackett LA, Emberger M, Moller I, van de Nes JA, Zimmer L, Livingstone E, et al. SF3B1 and BAP1 mutations in blue nevus-like melanoma. Mod Pathol. 2017;30(7):928–39.Google Scholar
  62. 62.
    Costa S, Byrne M, Pissaloux D, Haddad V, Paindavoine S, Thomas L, Aubin F, Lesimple T, et al. Melanomas associated with blue nevi or mimicking cellular blue nevi: clinical, pathologic, and molecular study of 11 cases displaying a high frequency of GNA11 mutations, BAP1 expression loss, and a predilection for the scalp. Am J Surg Pathol. 2016;40(3):368–77.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Van Raamsdonk CD, Bezrookove V, Green G, Bauer J, Gaugler L, O'Brien JM, Simpson EM, Barsh GS, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009;457(7229):599–602.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Van Raamsdonk CD, Griewank KG, Crosby MB, Garrido MC, Vemula S, Wiesner T, Obenauf AC, Wackernagel W, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med. 2010;363(23):2191–9.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Murali R, Wiesner T, Rosenblum MK, Bastian BC. GNAQ and GNA11 mutations in melanocytomas of the central nervous system. Acta Neuropathol. 2012;123(3):457–9.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Robertson AG, Shih J, Yau C, Gibb EA, Oba J, Mungall KL, Hess JM, Uzunangelov V, et al. Integrative analysis identifies four molecular and clinical subsets in uveal melanoma. Cancer Cell. 2017;32(2):204–20. e215.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Cohen JN, Joseph NM, North JP, Onodera C, Zembowicz A, LeBoit PE. Genomic analysis of pigmented epithelioid Melanocytomas reveals recurrent alterations in PRKAR1A, and PRKCA genes. Am J Surg Pathol. 2017;41(10):1333–46.CrossRefGoogle Scholar
  68. 68.
    Zembowicz A, Knoepp SM, Bei T, Stergiopoulos S, Eng C, Mihm MC, Stratakis CA. Loss of expression of protein kinase a regulatory subunit 1alpha in pigmented epithelioid melanocytoma but not in melanoma or other melanocytic lesions. Am J Surg Pathol. 2007;31(11):1764–75.CrossRefGoogle Scholar
  69. 69.
    Antonescu CR, Nafa K, Segal NH, Dal Cin P, Ladanyi M. EWS-CREB1: a recurrent variant fusion in clear cell sarcoma--association with gastrointestinal location and absence of melanocytic differentiation. Clin Cancer Res. 2006;12(18):5356–62.CrossRefGoogle Scholar
  70. 70.
    Hisaoka M, Ishida T, Kuo TT, Matsuyama A, Imamura T, Nishida K, Kuroda H, Inayama Y, et al. Clear cell sarcoma of soft tissue: a clinicopathologic, immunohistochemical, and molecular analysis of 33 cases. Am J Surg Pathol. 2008;32(3):452–60.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Wang WL, Mayordomo E, Zhang W, Hernandez VS, Tuvin D, Garcia L, Lev DC, Lazar AJ, et al. Detection and characterization of EWSR1/ATF1 and EWSR1/CREB1 chimeric transcripts in clear cell sarcoma (melanoma of soft parts). Mod Pathol. 2009;22(9):1201–9.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Lewis TB, Robison JE, Bastien R, Milash B, Boucher K, Samlowski WE, Leachman SA, Dirk Noyes R, et al. Molecular classification of melanoma using real-time quantitative reverse transcriptase-polymerase chain reaction. Cancer. 2005;104(8):1678–86.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Von Hoff DD, LoRusso PM, Rudin CM, Reddy JC, Yauch RL, Tibes R, Weiss GJ, Borad MJ, et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med. 2009;361(12):1164–72.CrossRefGoogle Scholar
  74. 74.
    Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, Nickerson E, Auclair D, et al. A landscape of driver mutations in melanoma. Cell. 2012;150(2):251–63.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A, McCusker JP, Cheng E, Davis MJ, et al. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet. 2012;44(9):1006–14.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Mahalingam M. NF1 and neurofibromin: emerging players in the genetic landscape of desmoplastic melanoma. Adv Anat Pathol. 2017;24(1):1–14.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    van Engen-van Grunsven AC, van Dijk MC, Ruiter DJ, Klaasen A, Mooi WJ, Blokx WA. HRAS-mutated Spitz tumors: a subtype of Spitz tumors with distinct features. Am J Surg Pathol. 2010;34(10):1436–41.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Da Forno PD, Pringle JH, Fletcher A, Bamford M, Su L, Potter L, Saldanha G. BRAF, NRAS and HRAS mutations in spitzoid tumours and their possible pathogenetic significance. Br J Dermatol. 2009;161(2):364–72.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    van Dijk MC, Bernsen MR, Ruiter DJ. Analysis of mutations in B-RAF, N-RAS, and H-RAS genes in the differential diagnosis of Spitz nevus and spitzoid melanoma. Am J Surg Pathol. 2005;29(9):1145–51.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Cirenajwis H, Lauss M, Ekedahl H, Torngren T, Kvist A, Saal LH, Olsson H, Staaf J, et al. NF1-mutated melanoma tumors harbor distinct clinical and biological characteristics. Mol Oncol. 2017;11(4):438–51.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Bastian BC. The molecular pathology of melanoma: an integrated taxonomy of melanocytic neoplasia. Annu Rev Pathol. 2014;9:239–71.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Viros A, Fridlyand J, Bauer J, Lasithiotakis K, Garbe C, Pinkel D, Bastian BC. Improving melanoma classification by integrating genetic and morphologic features. PLoS Med. 2008;5(6):e120.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Narita N, Tanemura A, Murali R, Scolyer RA, Huang S, Arigami T, Yanagita S, Chong KK, et al. Functional RET G691S polymorphism in cutaneous malignant melanoma. Oncogene. 2009;28(34):3058–68.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Ostrem JM, Shokat KM. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat Rev Drug Discov. 2016;15(11):771–85.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Fedorenko IV, Gibney GT, Smalley KS. NRAS mutant melanoma: biological behavior and future strategies for therapeutic management. Oncogene. 2013;32(25):3009–18.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Gajewski TF, Salama AK, Niedzwiecki D, Johnson J, Linette G, Bucher C, Blaskovich MA, Sebti SM, et al. Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma (CALGB 500104). J Transl Med. 2012;10:246.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Kwong LN, Costello JC, Liu H, Jiang S, Helms TL, Langsdorf AE, Jakubosky D, Genovese G, et al. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat Med. 2012;18(10):1503–10.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Li J, Xu M, Yang Z, Li A, Dong J. Simultaneous inhibition of MEK and CDK4 leads to potent apoptosis in human melanoma cells. Cancer Investig. 2010;28(4):350–6.CrossRefGoogle Scholar
  89. 89.
    Johnpulle RA, Johnson DB, Sosman JA. Molecular targeted therapy approaches for BRAF wild-type melanoma. Curr Oncol Rep. 2016;18(1):6.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Dhomen N, Reis-Filho JS, da Rocha Dias S, Hayward R, Savage K, Delmas V, Larue L, Pritchard C, et al. Oncogenic Braf induces melanocyte senescence and melanoma in mice. Cancer Cell. 2009;15(4):294–303.CrossRefGoogle Scholar
  92. 92.
    Kiel C, Benisty H, Llorens-Rico V, Serrano L. The yin-yang of kinase activation and unfolding explains the peculiarity of Val600 in the activation segment of BRAF. elife. 2016;5:e12814.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Holderfield M, Merritt H, Chan J, Wallroth M, Tandeske L, Zhai H, Tellew J, Hardy S, et al. RAF inhibitors activate the MAPK pathway by relieving inhibitory autophosphorylation. Cancer Cell. 2013;23(5):594–602.CrossRefPubMedGoogle Scholar
  94. 94.
    Siroy AE, Boland GM, Milton DR, Roszik J, Frankian S, Malke J, Haydu L, Prieto VG, et al. Beyond BRAF(V600): clinical mutation panel testing by next-generation sequencing in advanced melanoma. J Invest Dermatol. 2015;135(2):508–15.CrossRefPubMedGoogle Scholar
  95. 95.
    Hutchinson KE, Lipson D, Stephens PJ, Otto G, Lehmann BD, Lyle PL, Vnencak-Jones CL, Ross JS, et al. BRAF fusions define a distinct molecular subset of melanomas with potential sensitivity to MEK inhibition. Clin Cancer Res. 2013;19(24):6696–702.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Kim HS, Jung M, Kang HN, Kim H, Park CW, Kim SM, Shin SJ, Kim SH, et al. Oncogenic BRAF fusions in mucosal melanomas activate the MAPK pathway and are sensitive to MEK/PI3K inhibition or MEK/CDK4/6 inhibition. Oncogene. 2017;36(23):3334–45.CrossRefPubMedGoogle Scholar
  97. 97.
    Shitara D, Tell-Marti G, Badenas C, Enokihara MM, Alos L, Larque AB, Michalany N, Puig-Butille JA, et al. Mutational status of naevus-associated melanomas. Br J Dermatol. 2015;173(3):671–80.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Poynter JN, Elder JT, Fullen DR, Nair RP, Soengas MS, Johnson TM, Redman B, Thomas NE, et al. BRAF and NRAS mutations in melanoma and melanocytic nevi. Melanoma Res. 2006;16(4):267–73.CrossRefPubMedGoogle Scholar
  99. 99.
    Blokx WA, van Dijk MC, Ruiter DJ. Molecular cytogenetics of cutaneous melanocytic lesions – diagnostic, prognostic and therapeutic aspects. Histopathology. 2010;56(1):121–32.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Shain AH, Yeh I, Kovalyshyn I, Sriharan A, Talevich E, Gagnon A, Dummer R, North J, et al. The genetic evolution of melanoma from precursor lesions. N Engl J Med. 2015;373(20):1926–36.CrossRefGoogle Scholar
  101. 101.
    Menzies AM, Haydu LE, Visintin L, Carlino MS, Howle JR, Thompson JF, Kefford RF, Scolyer RA, et al. Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res. 2012;18(12):3242–9.CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Stadelmeyer E, Heitzer E, Resel M, Cerroni L, Wolf P, Dandachi N. The BRAF V600K mutation is more frequent than the BRAF V600E mutation in melanoma in situ of lentigo maligna type. J Invest Dermatol. 2014;134(2):548–50.CrossRefGoogle Scholar
  103. 103.
    Ladstein RG, Bachmann IM, Straume O, Akslen LA. Tumor necrosis is a prognostic factor in thick cutaneous melanoma. Am J Surg Pathol. 2012;36(10):1477–82.CrossRefGoogle Scholar
  104. 104.
    Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, McArthur GA, Hutson TE, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366(8):707–14.CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O’Dwyer PJ, Lee RJ, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809–19.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP, Hamid O, Infante JR, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet. 2012;379(9829):1893–901.CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Williams TE, Subramanian S, Verhagen J, McBride CM, Costales A, Sung L, Antonios-McCrea W, McKenna M, et al. Discovery of RAF265: a potent mut-B-RAF inhibitor for the treatment of metastatic melanoma. ACS Med Chem Lett. 2015;6(9):961–5.CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Su Y, Vilgelm AE, Kelley MC, Hawkins OE, Liu Y, Boyd KL, Kantrow S, Splittgerber RC, et al. RAF265 inhibits the growth of advanced human melanoma tumors. Clin Cancer Res. 2012;18(8):2184–98.CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Arkenau HT, Kefford R, Long GV. Targeting BRAF for patients with melanoma. Br J Cancer. 2011;104(3):392–8.CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Dickson MA, Gordon MS, Edelman G, Bendell JC, Kudchadkar RR, LoRusso PM, Johnston SH, Clary DO, et al. Phase I study of XL281 (BMS-908662), a potent oral RAF kinase inhibitor, in patients with advanced solid tumors. Investig New Drugs. 2015;33(2):349–56.CrossRefGoogle Scholar
  111. 111.
    Das Thakur M, Salangsang F, Landman AS, Sellers WR, Pryer NK, Levesque MP, Dummer R, McMahon M, et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature. 2013;494(7436):251–5.CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Nikolaev SI, Rimoldi D, Iseli C, Valsesia A, Robyr D, Gehrig C, Harshman K, Guipponi M, et al. Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma. Nat Genet. 2011;44(2):133–9.CrossRefGoogle Scholar
  113. 113.
    Solit DB, Garraway LA, Pratilas CA, Sawai A, Getz G, Basso A, Ye Q, Lobo JM, et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature. 2006;439(7074):358–62.CrossRefGoogle Scholar
  114. 114.
    Hatzivassiliou G, Haling JR, Chen H, Song K, Price S, Heald R, Hewitt JF, Zak M, et al. Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers. Nature. 2013;501(7466):232–6.CrossRefGoogle Scholar
  115. 115.
    Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367(2):107–14.CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30–9.CrossRefGoogle Scholar
  117. 117.
    Larkin J, Ascierto PA, Dreno B, Atkinson V, Liszkay G, Maio M, Mandala M, Demidov L, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867–76.CrossRefGoogle Scholar
  118. 118.
    Lu H, Liu S, Zhang G, Bin W, Zhu Y, Frederick DT, Hu Y, Zhong W, et al. PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas. Nature. 2017;550(7674):133–6.CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Ambrosini G, Pratilas CA, Qin LX, Tadi M, Surriga O, Carvajal RD, Schwartz GK. Identification of unique MEK-dependent genes in GNAQ mutant uveal melanoma involved in cell growth, tumor cell invasion, and MEK resistance. Clin Cancer Res. 2012;18(13):3552–61.CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Chan MP, Andea AA, Harms PW, Durham AB, Patel RM, Wang M, Robichaud P, Fisher GJ, et al. Genomic copy number analysis of a spectrum of blue nevi identifies recurrent aberrations of entire chromosomal arms in melanoma ex blue nevus. Mod Pathol. 2016;29(3):227–39.CrossRefGoogle Scholar
  121. 121.
    Carvajal RD, Sosman JA, Quevedo JF, Milhem MM, Joshua AM, Kudchadkar RR, Linette GP, Gajewski TF, et al. Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. JAMA. 2014;311(23):2397–405.CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Russo AE, Torrisi E, Bevelacqua Y, Perrotta R, Libra M, McCubrey JA, Spandidos DA, Stivala F, et al. Melanoma: molecular pathogenesis and emerging target therapies (review). Int J Oncol. 2009;34(6):1481–9.PubMedGoogle Scholar
  123. 123.
    Robertson GP. Functional and therapeutic significance of Akt deregulation in malignant melanoma. Cancer Metastasis Rev. 2005;24(2):273–85.CrossRefGoogle Scholar
  124. 124.
    Stahl JM, Sharma A, Cheung M, Zimmerman M, Cheng JQ, Bosenberg MW, Kester M, Sandirasegarane L, et al. Deregulated Akt3 activity promotes development of malignant melanoma. Cancer Res. 2004;64(19):7002–10.CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Omholt K, Krockel D, Ringborg U, Hansson J. Mutations of PIK3CA are rare in cutaneous melanoma. Melanoma Res. 2006;16(2):197–200.CrossRefGoogle Scholar
  126. 126.
    Shi H, Hugo W, Kong X, Hong A, Koya RC, Moriceau G, Chodon T, Guo R, et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 2014;4(1):80–93.CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Chen G, Chakravarti N, Aardalen K, Lazar AJ, Tetzlaff MT, Wubbenhorst B, Kim SB, Kopetz S, et al. Molecular profiling of patient-matched brain and extracranial melanoma metastases implicates the PI3K pathway as a therapeutic target. Clin Cancer Res. 2014;20(21):5537–46.CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Bucheit AD, Chen G, Siroy A, Tetzlaff M, Broaddus R, Milton D, Fox P, Bassett R, et al. Complete loss of PTEN protein expression correlates with shorter time to brain metastasis and survival in stage IIIB/C melanoma patients with BRAFV600 mutations. Clin Cancer Res. 2014;20(21):5527–36.CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Davies MA, Stemke-Hale K, Lin E, Tellez C, Deng W, Gopal YN, Woodman SE, Calderone TC, et al. Integrated molecular and clinical analysis of AKT activation in metastatic melanoma. Clin Cancer Res. 2009;15(24):7538–46.CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Peng W, Chen JQ, Liu C, Malu S, Creasy C, Tetzlaff MT, Xu C, McKenzie JA, et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 2016;6(2):202–16.CrossRefGoogle Scholar
  131. 131.
    Trunzer K, Pavlick AC, Schuchter L, Gonzalez R, McArthur GA, Hutson TE, Moschos SJ, Flaherty KT, et al. Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma. J Clin Oncol. 2013;31(14):1767–74.CrossRefGoogle Scholar
  132. 132.
    Nathanson KL, Martin AM, Wubbenhorst B, Greshock J, Letrero R, D'Andrea K, O'Day S, Infante JR, et al. Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor dabrafenib (GSK2118436). Clin Cancer Res. 2013;19(17):4868–78.CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Van Allen EM, Wagle N, Sucker A, Treacy DJ, Johannessen CM, Goetz EM, Place CS, Taylor-Weiner A, et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 2014;4(1):94–109.CrossRefGoogle Scholar
  134. 134.
    Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468(7326):973–7.CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Lin J, Sampath D, Nannini MA, Lee BB, Degtyarev M, Oeh J, Savage H, Guan Z, et al. Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models. Clin Cancer Res. 2013;19(7):1760–72.CrossRefGoogle Scholar
  136. 136.
    Vasudevan KM, Barbie DA, Davies MA, Rabinovsky R, McNear CJ, Kim JJ, Hennessy BT, Tseng H, et al. AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell. 2009;16(1):21–32.CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Margolin K, Longmate J, Baratta T, Synold T, Christensen S, Weber J, Gajewski T, Quirt I, et al. CCI-779 in metastatic melanoma: a phase II trial of the California Cancer Consortium. Cancer. 2005;104(5):1045–8.CrossRefGoogle Scholar
  138. 138.
    Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, Sasaki AT, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest. 2008;118(9):3065–74.PubMedPubMedCentralGoogle Scholar
  139. 139.
    Chresta CM, Davies BR, Hickson I, Harding T, Cosulich S, Critchlow SE, Vincent JP, Ellston R, et al. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res. 2010;70(1):288–98.CrossRefGoogle Scholar
  140. 140.
    Deng W, Gopal YN, Scott A, Chen G, Woodman SE, Davies MA. Role and therapeutic potential of PI3K-mTOR signaling in de novo resistance to BRAF inhibition. Pigment Cell Melanoma Res. 2012;25(2):248–58.CrossRefGoogle Scholar
  141. 141.
    Aziz SA, Jilaveanu LB, Zito C, Camp RL, Rimm DL, Conrad P, Kluger HM. Vertical targeting of the phosphatidylinositol-3 kinase pathway as a strategy for treating melanoma. Clin Cancer Res. 2010;16(24):6029–39.CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Tolcher AW, Patnaik A, Papadopoulos KP, Rasco DW, Becerra CR, Allred AJ, Orford K, Aktan G, et al. Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma. Cancer Chemother Pharmacol. 2015;75(1):183–9.CrossRefGoogle Scholar
  143. 143.
    Rakosy Z, Vizkeleti L, Ecsedi S, Voko Z, Begany A, Barok M, Krekk Z, Gallai M, et al. EGFR gene copy number alterations in primary cutaneous malignant melanomas are associated with poor prognosis. Int J Cancer. 2007;121(8):1729–37.CrossRefGoogle Scholar
  144. 144.
    Wu XC, Eide MJ, King J, Saraiya M, Huang Y, Wiggins C, Barnholtz-Sloan JS, Martin N, et al. Racial and ethnic variations in incidence and survival of cutaneous melanoma in the United States, 1999-2006. J Am Acad Dermatol. 2011;65(5 Suppl 1):S26–37.PubMedGoogle Scholar
  145. 145.
    Vizoso M, Ferreira HJ, Lopez-Serra P, Carmona FJ, Martinez-Cardus A, Girotti MR, Villanueva A, Guil S, et al. Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR. Nat Med. 2015;21(7):741–50.CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol. 2006;24(26):4340–6.CrossRefGoogle Scholar
  147. 147.
    Handolias D, Salemi R, Murray W, Tan A, Liu W, Viros A, Dobrovic A, Kelly J, et al. Mutations in KIT occur at low frequency in melanomas arising from anatomical sites associated with chronic and intermittent sun exposure. Pigment Cell Melanoma Res. 2010;23(2):210–5.CrossRefGoogle Scholar
  148. 148.
    Park E, Yang S, Emley A, DeCarlo K, Richards J, Mahalingam M. Lack of correlation between immunohistochemical expression of CKIT and KIT mutations in atypical acral nevi. Am J Dermatopathol. 2012;34(1):41–6.CrossRefGoogle Scholar
  149. 149.
    Bastian BC, Kashani-Sabet M, Hamm H, Godfrey T, Moore DH 2nd, Brocker EB, LeBoit PE. Pinkel D gene amplifications characterize acral melanoma and permit the detection of occult tumor cells in the surrounding skin. Cancer Res. 2000;60(7):1968–73.PubMedGoogle Scholar
  150. 150.
    Ugurel S, Hildenbrand R, Zimpfer A, La Rosee P, Paschka P, Sucker A, Keikavoussi P, Becker JC, et al. Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer. 2005;92(8):1398–405.CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Wyman K, Atkins MB, Prieto V, Eton O, McDermott DF, Hubbard F, Byrnes C, Sanders K, et al. Multicenter phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy. Cancer. 2006;106(9):2005–11.CrossRefGoogle Scholar
  152. 152.
    Kim KB, Eton O, Davis DW, Frazier ML, McConkey DJ, Diwan AH, Papadopoulos NE, Bedikian AY, et al. Phase II trial of imatinib mesylate in patients with metastatic melanoma. Br J Cancer. 2008;99(5):734–40.CrossRefPubMedPubMedCentralGoogle Scholar
  153. 153.
    Kluger HM, Dudek AZ, McCann C, Ritacco J, Southard N, Jilaveanu LB, Molinaro A, Sznol M. A phase 2 trial of dasatinib in advanced melanoma. Cancer. 2011;117(10):2202–8.CrossRefGoogle Scholar
  154. 154.
    Hofmann UB, Kauczok-Vetter CS, Houben R, Becker JC. Overexpression of the KIT/SCF in uveal melanoma does not translate into clinical efficacy of imatinib mesylate. Clin Cancer Res. 2009;15(1):324–9.CrossRefGoogle Scholar
  155. 155.
    Carvajal RD, Antonescu CR, Wolchok JD, Chapman PB, Roman RA, Teitcher J, Panageas KS, Busam KJ, et al. KIT as a therapeutic target in metastatic melanoma. JAMA. 2011;305(22):2327–34.CrossRefPubMedPubMedCentralGoogle Scholar
  156. 156.
    Guo J, Si L, Kong Y, Flaherty KT, Xu X, Zhu Y, Corless CL, Li L, et al. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol. 2011;29(21):2904–9.CrossRefGoogle Scholar
  157. 157.
    Lee SJ, Kim TM, Kim YJ, Jang KT, Lee HJ, Lee SN, Ahn MS, Hwang IG, et al. Phase II trial of nilotinib in patients with metastatic malignant melanoma harboring KIT gene aberration: a multicenter trial of Korean Cancer Study Group (UN10-06). Oncologist. 2015;20(11):1312–9.CrossRefPubMedPubMedCentralGoogle Scholar
  158. 158.
    Hodi FS, Corless CL, Giobbie-Hurder A, Fletcher JA, Zhu M, Marino-Enriquez A, Friedlander P, Gonzalez R, et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol. 2013;31(26):3182–90.CrossRefPubMedPubMedCentralGoogle Scholar
  159. 159.
    Carvajal RD, Lawrence DP, Weber JS, Gajewski TF, Gonzalez R, Lutzky J, O’Day SJ, Hamid O, et al. Phase II study of nilotinib in melanoma harboring KIT alterations following progression to prior KIT inhibition. Clin Cancer Res. 2015;21(10):2289–96.CrossRefPubMedPubMedCentralGoogle Scholar
  160. 160.
    Lee CK, Goldstein D, Gibbs E, Joensuu H, Zalcberg J, Verweij J, Casali PG, Maki RG, et al. Development and validation of prognostic nomograms for metastatic gastrointestinal stromal tumour treated with imatinib. Eur J Cancer. 2015;51(7):852–60.CrossRefGoogle Scholar
  161. 161.
    O’Connell MP, Weeraratna AT. Hear the Wnt Ror: how melanoma cells adjust to changes in Wnt. Pigment Cell Melanoma Res. 2009;22(6):724–39.CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Vibert L, Aquino G, Gehring I, Subkankulova T, Schilling TF, Rocco A, Kelsh RN. An ongoing role for Wnt signaling in differentiating melanocytes in vivo. Pigment Cell Melanoma Res. 2017;30(2):219–32.CrossRefPubMedPubMedCentralGoogle Scholar
  163. 163.
    Xue G, Romano E, Massi D, Mandala M. Wnt/beta-catenin signaling in melanoma: preclinical rationale and novel therapeutic insights. Cancer Treat Rev. 2016;49:1–12.CrossRefGoogle Scholar
  164. 164.
    Anastas JN, Kulikauskas RM, Tamir T, Rizos H, Long GV, von Euw EM, Yang PT, Chen HW, et al. WNT5A enhances resistance of melanoma cells to targeted BRAF inhibitors. J Clin Invest. 2014;124(7):2877–90.CrossRefPubMedPubMedCentralGoogle Scholar
  165. 165.
    Chien AJ, Haydu LE, Biechele TL, Kulikauskas RM, Rizos H, Kefford RF, Scolyer RA, Moon RT, et al. Targeted BRAF inhibition impacts survival in melanoma patients with high levels of Wnt/beta-catenin signaling. PLoS One. 2014;9(4):e94748.CrossRefPubMedPubMedCentralGoogle Scholar
  166. 166.
    Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature. 2015;523(7559):231–5.CrossRefGoogle Scholar
  167. 167.
    Spranger S, Gajewski TF. Impact of oncogenic pathways on evasion of antitumour immune responses. Nat Rev Cancer. 2018;18(3):139–47.CrossRefGoogle Scholar
  168. 168.
    Bell RJ, Rube HT, Xavier-Magalhaes A, Costa BM, Mancini A, Song JS, Costello JF. Understanding TERT promoter mutations: a common path to immortality. Mol Cancer Res. 2016;14(4):315–23.CrossRefPubMedPubMedCentralGoogle Scholar
  169. 169.
    Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, et al. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994;266(5193):2011–5.CrossRefPubMedPubMedCentralGoogle Scholar
  170. 170.
    Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA. Highly recurrent TERT promoter mutations in human melanoma. Science. 2013;339(6122):957–9.CrossRefPubMedPubMedCentralGoogle Scholar
  171. 171.
    Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A, Gast A, Kadel S, Moll I, et al. TERT promoter mutations in familial and sporadic melanoma. Science. 2013;339(6122):959–61.CrossRefGoogle Scholar
  172. 172.
    Chiba K, Lorbeer FK, Shain AH, McSwiggen DT, Schruf E, Oh A, Ryu J, Darzacq X, et al. Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism. Science. 2017;357(6358):1416–20.CrossRefPubMedPubMedCentralGoogle Scholar
  173. 173.
    Heidenreich B, Nagore E, Rachakonda PS, Garcia-Casado Z, Requena C, Traves V, Becker J, Soufir N, et al. Telomerase reverse transcriptase promoter mutations in primary cutaneous melanoma. Nat Commun. 2014;5:3401.CrossRefGoogle Scholar
  174. 174.
    Liang WS, Hendricks W, Kiefer J, Schmidt J, Sekar S, Carpten J, Craig DW, Adkins J, et al. Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma. Genome Res. 2017;27(4):524–32.CrossRefPubMedPubMedCentralGoogle Scholar
  175. 175.
    Griewank KG, Murali R, Puig-Butille JA, Schilling B, Livingstone E, Potrony M, Carrera C, Schimming T et al. TERT promoter mutation status as an independent prognostic factor in cutaneous melanoma. J Natl Cancer Inst. 2014;106(9).Google Scholar
  176. 176.
    Lee S, Barnhill RL, Dummer R, Dalton J, Wu J, Pappo A, Bahrami A. TERT promoter mutations are predictive of aggressive clinical behavior in patients with spitzoid melanocytic neoplasms. Sci Rep. 2015;5:11200.CrossRefPubMedPubMedCentralGoogle Scholar
  177. 177.
    Kang HJ, Cui Y, Yin H, Scheid A, Hendricks WP, Schmidt J, Sekulic A, Kong D et al. A pharmacological chaperone molecule induces Cancer cell death by restoring tertiary DNA structures in mutant hTERT promoters. J. Am. Chem. Soc. 2016;138(41):13673–92.Google Scholar
  178. 178.
    Moran B, Silva R, Perry AS, Gallagher WM Epigenetics of malignant melanoma. Semin Cancer Biol. 2018;51:80–88.Google Scholar
  179. 179.
    Cannuyer J, Van Tongelen A, Loriot A, De Smet C. A gene expression signature identifying transient DNMT1 depletion as a causal factor of cancer-germline gene activation in melanoma. Clin Epigenetics. 2015;7:114.CrossRefPubMedPubMedCentralGoogle Scholar
  180. 180.
    Lian CG, Xu Y, Ceol C, Wu F, Larson A, Dresser K, Xu W, Tan L, et al. Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma. Cell. 2012;150(6):1135–46.CrossRefPubMedPubMedCentralGoogle Scholar
  181. 181.
    Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012;150(1):12–27.CrossRefGoogle Scholar
  182. 182.
    Woods DM, Sodre AL, Villagra A, Sarnaik A, Sotomayor EM, Weber J. HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade. Cancer Immunol Res. 2015;3(12):1375–85.CrossRefPubMedPubMedCentralGoogle Scholar
  183. 183.
    Verfaillie A, Imrichova H, Atak ZK, Dewaele M, Rambow F, Hulselmans G, Christiaens V, Svetlichnyy D, et al. Decoding the regulatory landscape of melanoma reveals TEADS as regulators of the invasive cell state. Nat Commun. 2015;6:6683.CrossRefPubMedPubMedCentralGoogle Scholar
  184. 184.
    Sengupta D, Byrum SD, Avaritt NL, Davis L, Shields B, Mahmoud F, Reynolds M, Orr LM, et al. Quantitative histone mass spectrometry identifies elevated histone H3 lysine 27 (Lys27) trimethylation in melanoma. Mol Cell Proteomics. 2016;15(3):765–75.CrossRefPubMedGoogle Scholar
  185. 185.
    Souroullas GP, Jeck WR, Parker JS, Simon JM, Liu JY, Paulk J, Xiong J, Clark KS, et al. An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation. Nat Med. 2016;22(6):632–40.CrossRefPubMedPubMedCentralGoogle Scholar
  186. 186.
    Shields BD, Mahmoud F, Taylor EM, Byrum SD, Sengupta D, Koss B, Baldini G, Ransom S, et al. Indicators of responsiveness to immune checkpoint inhibitors. Sci Rep. 2017;7(1):807.CrossRefPubMedPubMedCentralGoogle Scholar
  187. 187.
    Tiffen J, Gallagher SJ, Hersey P. EZH2: an emerging role in melanoma biology and strategies for targeted therapy. Pigment Cell Melanoma Res. 2015;28(1):21–30.CrossRefPubMedGoogle Scholar
  188. 188.
    Lee W, Teckie S, Wiesner T, Ran L, Prieto Granada CN, Lin M, Zhu S, Cao Z, et al. PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nat Genet. 2014;46(11):1227–32.CrossRefPubMedPubMedCentralGoogle Scholar
  189. 189.
    De Raedt T, Beert E, Pasmant E, Luscan A, Brems H, Ortonne N, Helin K, Hornick JL, et al. PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014;514(7521):247–51.CrossRefPubMedGoogle Scholar
  190. 190.
    Goding CR. Targeting the lncRNA SAMMSON reveals metabolic vulnerability in melanoma. Cancer Cell. 2016;29(5):619–21.CrossRefPubMedGoogle Scholar
  191. 191.
    Leucci E, Vendramin R, Spinazzi M, Laurette P, Fiers M, Wouters J, Radaelli E, Eyckerman S, et al. Melanoma addiction to the long non-coding RNA SAMMSON. Nature. 2016;531(7595):518–22.CrossRefPubMedGoogle Scholar
  192. 192.
    Hanniford D, Zhong J, Koetz L, Gaziel-Sovran A, Lackaye DJ, Shang S, Pavlick A, Shapiro R, et al. A miRNA-based signature detected in primary melanoma tissue predicts development of brain metastasis. Clin Cancer Res. 2015;21(21):4903–12.CrossRefPubMedPubMedCentralGoogle Scholar
  193. 193.
    Tembe V, Schramm SJ, Stark MS, Patrick E, Jayaswal V, Tang YH, Barbour A, Hayward NK, et al. MicroRNA and mRNA expression profiling in metastatic melanoma reveal associations with BRAF mutation and patient prognosis. Pigment Cell Melanoma Res. 2015;28(3):254–66.CrossRefPubMedGoogle Scholar
  194. 194.
    Pfeffer SR, Grossmann KF, Cassidy PB, Yang CH, Fan M, Kopelovich L, Leachman SA, Pfeffer LM. Detection of exosomal miRNAs in the plasma of melanoma patients. J Clin Med. 2015;4(12):2012–27.CrossRefPubMedPubMedCentralGoogle Scholar
  195. 195.
    Alegre E, Sanmamed MF, Rodriguez C, Carranza O, Martin-Algarra S, Gonzalez A. Study of circulating microRNA-125b levels in serum exosomes in advanced melanoma. Arch Pathol Lab Med. 2014;138(6):828–32.CrossRefPubMedGoogle Scholar
  196. 196.
    Busam KJ, Hedvat C, Pulitzer M, von Deimling A, Jungbluth AA. Immunohistochemical analysis of BRAF(V600E) expression of primary and metastatic melanoma and comparison with mutation status and melanocyte differentiation antigens of metastatic lesions. Am J Surg Pathol. 2013;37(3):413–20.CrossRefPubMedGoogle Scholar
  197. 197.
    Long GV, Wilmott JS, Capper D, Preusser M, Zhang YE, Thompson JF, Kefford RF, von Deimling A, et al. Immunohistochemistry is highly sensitive and specific for the detection of V600E BRAF mutation in melanoma. Am J Surg Pathol. 2013;37(1):61–5.CrossRefPubMedPubMedCentralGoogle Scholar
  198. 198.
    Tetzlaff MT, Pattanaprichakul P, Wargo J, Fox PS, Patel KP, Estrella JS, Broaddus RR, Williams MD, et al. Utility of BRAF V600E immunohistochemistry expression pattern as a surrogate of BRAF mutation status in 154 patients with advanced melanoma. Hum Pathol. 2015;46(8):1101–10.CrossRefPubMedPubMedCentralGoogle Scholar
  199. 199.
    Rapisuwon S, Busam KJ, Parks K, Chapman PB, Lee E, Atkins MB. Discordance between Cobas BRAF V600 testing and VE1 immunohistochemistry in a melanoma patient with bone marrow metastases. Am J Dermatopathol. 2016;38(9):687–9.CrossRefPubMedPubMedCentralGoogle Scholar
  200. 200.
    Ponti G, Tomasi A, Maiorana A, Ruini C, Maccaferri M, Cesinaro AM, Depenni R, Manni P, et al. BRAFp.V600E, p.V600K, and p.V600R mutations in malignant melanoma: do they also differ in Immunohistochemical assessment and clinical features? Appl Immunohistochem Mol Morphol. 2016;24(1):30–4.CrossRefGoogle Scholar
  201. 201.
    Heinzerling L, Kuhnapfel S, Meckbach D, Baiter M, Kaempgen E, Keikavoussi P, Schuler G, Agaimy A, et al. Rare BRAF mutations in melanoma patients: implications for molecular testing in clinical practice. Br J Cancer. 2013;108(10):2164–71.CrossRefPubMedPubMedCentralGoogle Scholar
  202. 202.
    Kakavand H, Walker E, Lum T, Wilmott JS, Selinger CI, Smith E, Saw RP, Yu B, et al. BRAF(V600E) and NRAS(Q61L/Q61R) mutation analysis in metastatic melanoma using immunohistochemistry: a study of 754 cases highlighting potential pitfalls and guidelines for interpretation and reporting. Histopathology. 2016;69(4):680–6.CrossRefGoogle Scholar
  203. 203.
    Massi D, Simi L, Sensi E, Baroni G, Xue G, Scatena C, Caldarella A, Pinzani P, et al. Immunohistochemistry is highly sensitive and specific for the detection of NRASQ61R mutation in melanoma. Mod Pathol. 2015;28(4):487–97.CrossRefGoogle Scholar
  204. 204.
    Harms PW, Hocker TL, Zhao L, Chan MP, Andea AA, Wang M, Harms KL, Wang ML, et al. Loss of p16 expression and copy number changes of CDKN2A in a spectrum of spitzoid melanocytic lesions. Hum Pathol. 2016;58:152–60.CrossRefGoogle Scholar
  205. 205.
    Al Dhaybi R, Agoumi M, Gagne I, McCuaig C, Powell J, Kokta V. p16 expression: a marker of differentiation between childhood malignant melanomas and spitz nevi. J Am Acad Dermatol. 2011;65(2):357–63.CrossRefGoogle Scholar
  206. 206.
    Hilliard NJ, Krahl D, Sellheyer K. p16 expression differentiates between desmoplastic spitz nevus and desmoplastic melanoma. J Cutan Pathol. 2009;36(7):753–9.CrossRefGoogle Scholar
  207. 207.
    Lade-Keller J, Riber-Hansen R, Guldberg P, Schmidt H, Hamilton-Dutoit SJ, Steiniche T. Immunohistochemical analysis of molecular drivers in melanoma identifies p16 as an independent prognostic biomarker. J Clin Pathol. 2014;67(6):520–8.CrossRefGoogle Scholar
  208. 208.
    Rowe CJ, Tang F, Hughes MC, Rodero MP, Malt M, Lambie D, Barbour A, Hayward NK, et al. Molecular markers to complement sentinel node status in predicting survival in patients with high-risk locally invasive melanoma. Int J Cancer. 2016;139(3):664–72.CrossRefGoogle Scholar
  209. 209.
    Uguen A, Uguen M, Guibourg B, Talagas M, Marcorelles P, De Braekeleer M The p16-Ki-67-HMB45 Immunohistochemistry Scoring System is Highly Concordant With the Fluorescent In Situ Hybridization Test to Differentiate Between Melanocytic Nevi and Melanomas. Appl Immunohistochem Mol Morphol. 2018;26 (6):361–7.Google Scholar
  210. 210.
    Strickler AG, Schaefer JT, Slingluff CL Jr, Wick MR. Immunolabeling for p16, WT1, and Fli-1 in the assignment of growth phase for cutaneous melanomas. Am J Dermatopathol. 2014;36(9):718–22.CrossRefGoogle Scholar
  211. 211.
    de la Fouchardiere A, Cabaret O, Savin L, Combemale P, Schvartz H, Penet C, Bonadona V, Soufir N et al. Germline BAP1 mutations predispose also to multiple basal cell carcinomas. Clin Genet. 2015; 88 (3):273–77.Google Scholar
  212. 212.
    Murali R, Wiesner T, Scolyer RA. Tumours associated with BAP1 mutations. Pathology. 2013;45(2):116–26.CrossRefGoogle Scholar
  213. 213.
    Murali R, Wilmott JS, Jakrot V, Al-Ahmadie HA, Wiesner T, McCarthy SW, Thompson JF, Scolyer RA. BAP1 expression in cutaneous melanoma: a pilot study. Pathology. 2013;45(6):606–9.CrossRefGoogle Scholar
  214. 214.
    Massi D, Romano E, Rulli E, Merelli B, Nassini R, De Logu F, Bieche I, Baroni G, et al. Baseline beta-catenin, programmed death-ligand 1 expression and tumour-infiltrating lymphocytes predict response and poor prognosis in BRAF inhibitor-treated melanoma patients. Eur J Cancer. 2017;78:70–81.CrossRefGoogle Scholar
  215. 215.
    Larson AR, Dresser KA, Zhan Q, Lezcano C, Woda BA, Yosufi B, Thompson JF, Scolyer RA, et al. Loss of 5-hydroxymethylcytosine correlates with increasing morphologic dysplasia in melanocytic tumors. Mod Pathol. 2014;27(7):936–44.CrossRefPubMedPubMedCentralGoogle Scholar
  216. 216.
    Lee JJ, Cook M, Mihm MC, Xu S, Zhan Q, Wang TJ, Murphy GF, Lian CG. Loss of the epigenetic mark, 5-Hydroxymethylcytosine, correlates with small cell/nevoid subpopulations and assists in microstaging of human melanoma. Oncotarget. 2015;6(35):37995–8004.PubMedPubMedCentralGoogle Scholar
  217. 217.
    Lee JJ, Granter SR, Laga AC, Saavedra AP, Zhan Q, Guo W, Xu S, Murphy GF, et al. 5-Hydroxymethylcytosine expression in metastatic melanoma versus nodal nevus in sentinel lymph node biopsies. Mod Pathol. 2015;28(2):218–29.CrossRefGoogle Scholar
  218. 218.
    Pavlova O, Fraitag S, Hohl D 5-Hydroxymethylcytosine Expression in Proliferative Nodules Arising within Congenital Nevi Allows Differentiation from Malignant Melanoma. J Invest Dermatol. 2016;136(12):2453–61.Google Scholar
  219. 219.
    Busam KJ, Shah KN, Gerami P, Sitzman T, Jungbluth AA, Kinsler V. Reduced H3K27me3 expression is common in nodular melanomas of childhood associated with congenital melanocytic nevi but not in proliferative nodules. Am J Surg Pathol. 2017;41(3):396–404.CrossRefPubMedPubMedCentralGoogle Scholar
  220. 220.
    Kampilafkos P, Melachrinou M, Kefalopoulou Z, Lakoumentas J, Sotiropoulou-Bonikou G. Epigenetic modifications in cutaneous malignant melanoma: EZH2, H3K4me2, and H3K27me3 immunohistochemical expression is enhanced at the invasion front of the tumor. Am J Dermatopathol. 2015;37(2):138–44.CrossRefGoogle Scholar
  221. 221.
    Le Guellec S, Macagno N, Velasco V, Lamant L, Lae M, Filleron T, Malissen N, Cassagnau E, et al. Loss of H3K27 trimethylation is not suitable for distinguishing malignant peripheral nerve sheath tumor from melanoma: a study of 387 cases including mimicking lesions. Mod Pathol. 2017;30(12):1677–87.CrossRefGoogle Scholar
  222. 222.
    Lazova R, Seeley EH. Proteomic mass spectrometry imaging for skin cancer diagnosis. Dermatol Clin. 2017;35(4):513–9.CrossRefGoogle Scholar
  223. 223.
    Alomari AK, Klump V, Neumeister V, Ariyan S, Narayan D, Lazova R. Comparison of the expression of vimentin and actin in spitz nevi and spitzoid malignant melanomas. Am J Dermatopathol. 2015;37(1):46–51.CrossRefGoogle Scholar
  224. 224.
    Lazova R, Seeley EH, Keenan M, Gueorguieva R, Caprioli RM. Imaging mass spectrometry – a new and promising method to differentiate Spitz nevi from Spitzoid malignant melanomas. Am J Dermatopathol. 2012;34(1):82–90.CrossRefPubMedPubMedCentralGoogle Scholar
  225. 225.
    Lazova R, Seeley EH, Kutzner H, Scolyer RA, Scott G, Cerroni L, Fried I, Kozovska ME, et al. Imaging mass spectrometry assists in the classification of diagnostically challenging atypical spitzoid neoplasms. J Am Acad Dermatol. 2016;75(6):1176–86. e1174.CrossRefPubMedPubMedCentralGoogle Scholar
  226. 226.
    Alomari AK, Glusac EJ, Choi J, Hui P, Seeley EH, Caprioli RM, Watsky KL, Urban J, et al. Congenital nevi versus metastatic melanoma in a newborn to a mother with malignant melanoma – diagnosis supported by sex chromosome analysis and imaging mass spectrometry. J Cutan Pathol. 2015;42(10):757–64.CrossRefGoogle Scholar
  227. 227.
    Lazova R, Yang Z, El Habr C, Lim Y, Choate KA, Seeley EH, Caprioli RM, Yangqun L. Mass spectrometry imaging can distinguish on a proteomic level between proliferative nodules within a benign congenital nevus and malignant melanoma. Am J Dermatopathol. 2017;39(9):689–95.CrossRefPubMedPubMedCentralGoogle Scholar
  228. 228.
    Balaban G, Herlyn M, Guerry D IV, Bartolo R, Koprowski H, Clark WH, Nowell PC. Cytogenetics of human malignant melanoma and premalignant lesions. Cancer Genet Cytogenet. 1984;11(4):429–39.CrossRefGoogle Scholar
  229. 229.
    Sisley K, Cottam DW, Rennie IG, Parsons MA, Potter AM, Potter CW, Rees RC. Non-random abnormalities of chromosomes 3, 6, and 8 associated with posterior uveal melanoma. Genes Chromosomes Cancer. 1992;5(3):197–200.CrossRefGoogle Scholar
  230. 230.
    Mertens F, Johansson B, Hoglund M, Mitelman F. Chromosomal imbalance maps of malignant solid tumors: a cytogenetic survey of 3185 neoplasms. Cancer Res. 1997;57(13):2765–80.PubMedGoogle Scholar
  231. 231.
    Speicher MR, Prescher G, du Manoir S, Jauch A, Horsthemke B, Bornfeld N, Becher R, Cremer T. Chromosomal gains and losses in uveal melanomas detected by comparative genomic hybridization. Cancer Res. 1994;54(14):3817–23.PubMedGoogle Scholar
  232. 232.
    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(10):2170–5.PubMedGoogle Scholar
  233. 233.
    Bastian BC, Wesselmann U, Pinkel D, Leboit PE. Molecular cytogenetic analysis of Spitz nevi shows clear differences to melanoma. J Invest Dermatol. 1999;113(6):1065–9.CrossRefGoogle Scholar
  234. 234.
    Bastian BC, Olshen AB, LeBoit PE, Pinkel D. Classifying melanocytic tumors based on DNA copy number changes. Am J Pathol. 2003;163(5):1765–70.CrossRefPubMedPubMedCentralGoogle Scholar
  235. 235.
    Maize JC Jr, McCalmont TH, Carlson JA, Busam KJ, Kutzner H, Bastian BC. Genomic analysis of blue nevi and related dermal melanocytic proliferations. Am J Surg Pathol. 2005;29(9):1214–20.CrossRefGoogle Scholar
  236. 236.
    Raskin L, Ludgate M, Iyer RK, Ackley TE, Bradford CR, Johnson TM, Fullen DR. Copy number variations and clinical outcome in atypical spitz tumors. Am J Surg Pathol. 2011;35(2):243–52.CrossRefGoogle Scholar
  237. 237.
    Chandler WM, Rowe LR, Florell SR, Jahromi MS, Schiffman JD, South ST. Differentiation of malignant melanoma from benign nevus using a novel genomic microarray with low specimen requirements. Arch Pathol Lab Med. 2012;136(8):947–55.CrossRefGoogle Scholar
  238. 238.
    Wang L, Rao M, Fang Y, Hameed M, Viale A, Busam K, Jhanwar SC. A genome-wide high-resolution array-CGH analysis of cutaneous melanoma and comparison of array-CGH to FISH in diagnostic evaluation. J Mol Diagn. 2013;15(5):581–91.CrossRefGoogle Scholar
  239. 239.
    Hirsch D, Kemmerling R, Davis S, Camps J, Meltzer PS, Ried T, Gaiser T. Chromothripsis and focal copy number alterations determine poor outcome in malignant melanoma. Cancer Res. 2013;73(5):1454–60.CrossRefGoogle Scholar
  240. 240.
    Gerami P, Jewell SS, Morrison LE, Blondin B, Schulz J, Ruffalo T, Matushek P IV, Legator M, et al. Fluorescence in situ hybridization (FISH) as an ancillary diagnostic tool in the diagnosis of melanoma. Am J Surg Pathol. 2009;33(8):1146–56.CrossRefGoogle Scholar
  241. 241.
    Gammon B, Beilfuss B, Guitart J, Gerami P. Enhanced detection of spitzoid melanomas using fluorescence in situ hybridization with 9p21 as an adjunctive probe. Am J Surg Pathol. 2012;36(1):81–8.CrossRefGoogle Scholar
  242. 242.
    Gerami P, Wass A, Mafee M, Fang Y, Pulitzer MP, Busam KJ. Fluorescence in situ hybridization for distinguishing nevoid melanomas from mitotically active nevi. Am J Surg Pathol. 2009;33(12):1783–8.CrossRefGoogle Scholar
  243. 243.
    Pouryazdanparast P, Newman M, Mafee M, Haghighat Z, Guitart J, Gerami P. Distinguishing epithelioid blue nevus from blue nevus-like cutaneous melanoma metastasis using fluorescence in situ hybridization. Am J Surg Pathol. 2009;33(9):1396–400.CrossRefGoogle Scholar
  244. 244.
    Gerami P, Mafee M, Lurtsbarapa T, Guitart J, Haghighat Z, Newman M. Sensitivity of fluorescence in situ hybridization for melanoma diagnosis using RREB1, MYB, Cep6, and 11q13 probes in melanoma subtypes. Arch Dermatol. 2010;146(3):273–8.CrossRefGoogle Scholar
  245. 245.
    Isaac AK, Lertsburapa T, Pathria Mundi J, Martini M, Guitart J, Gerami P. Polyploidy in spitz nevi: a not uncommon karyotypic abnormality identifiable by fluorescence in situ hybridization. Am J Dermatopathol. 2010;32(2):144–8.CrossRefGoogle Scholar
  246. 246.
    Gammon B, Beilfuss B, Guitart J, Busam KJ, Gerami P. Fluorescence in situ hybridization for distinguishing cellular blue nevi from blue nevus-like melanoma. J Cutan Pathol. 2011;38(4):335–41.PubMedGoogle Scholar
  247. 247.
    Gerami P, Beilfuss B, Haghighat Z, Fang Y, Jhanwar S, Busam KJ. Fluorescence in situ hybridization as an ancillary method for the distinction of desmoplastic melanomas from sclerosing melanocytic nevi. J Cutan Pathol. 2011;38(4):329–34.CrossRefGoogle Scholar
  248. 248.
    Pouryazdanparast P, Haghighat Z, Beilfuss BA, Guitart J, Gerami P. Melanocytic nevi with an atypical epithelioid cell component: clinical, histopathologic, and fluorescence in situ hybridization findings. Am J Surg Pathol. 2011;35(9):1405–12.CrossRefGoogle Scholar
  249. 249.
    Yelamos O, Busam KJ, Lee C, Meldi Sholl L, Amin SM, Merkel EA, Obregon R, Guitart J, et al. Morphologic clues and utility of fluorescence in situ hybridization for the diagnosis of nevoid melanoma. J Cutan Pathol. 2015;42(11):796–806.CrossRefGoogle Scholar
  250. 250.
    Gerami P, Li G, Pouryazdanparast P, Blondin B, Beilfuss B, Slenk C, Du J, Guitart J, et al. A highly specific and discriminatory FISH assay for distinguishing between benign and malignant melanocytic neoplasms. Am J Surg Pathol. 2012;36(6):808–17.CrossRefGoogle Scholar
  251. 251.
    Morey AL, Murali R, McCarthy SW, Mann GJ, Scolyer RA. Diagnosis of cutaneous melanocytic tumours by four-colour fluorescence in situ hybridisation. Pathology. 2009;41(4):383–7.CrossRefGoogle Scholar
  252. 252.
    Vergier B, Prochazkova-Carlotti M, de la Fouchardiere A, Cerroni L, Massi D, De Giorgi V, Bailly C, Wesselmann U, et al. Fluorescence in situ hybridization, a diagnostic aid in ambiguous melanocytic tumors: European study of 113 cases. Mod Pathol. 2011;24(5):613–23.Google Scholar
  253. 253.
    North JP, Garrido MC, Kolaitis NA, LeBoit PE, McCalmont TH, Bastian BC. Fluorescence in situ hybridization as an ancillary tool in the diagnosis of ambiguous melanocytic neoplasms: a review of 804 cases. Am J Surg Pathol. 2014;38(6):824–31.CrossRefGoogle Scholar
  254. 254.
    Requena C, Rubio L, Traves V, Sanmartin O, Nagore E, Llombart B, Serra C, Fernandez-Serra A, et al. Fluorescence in situ hybridization for the differential diagnosis between Spitz naevus and spitzoid melanoma. Histopathology. 2012;61(5):899–909.CrossRefGoogle Scholar
  255. 255.
    Gerami P, Scolyer RA, Xu X, Elder DE, Abraham RM, Fullen D, Prieto VG, Leboit PE, et al. Risk assessment for atypical spitzoid melanocytic neoplasms using FISH to identify chromosomal copy number aberrations. Am J Surg Pathol. 2013;37(5):676–84.CrossRefGoogle Scholar
  256. 256.
    Shen L, Cooper C, Bajaj S, Liu P, Pestova E, Guitart J, Gerami P. Atypical spitz tumors with 6q23 deletions: a clinical, histological, and molecular study. Am J Dermatopathol. 2013;35(8):804–12.CrossRefGoogle Scholar
  257. 257.
    Newman MD, Lertsburapa T, Mirzabeigi M, Mafee M, Guitart J, Gerami P. Fluorescence in situ hybridization as a tool for microstaging in malignant melanoma. Mod Pathol. 2009;22(8):989–95.CrossRefGoogle Scholar
  258. 258.
    Newman MD, Mirzabeigi M, Gerami P. Chromosomal copy number changes supporting the classification of lentiginous junctional melanoma of the elderly as a subtype of melanoma. Mod Pathol. 2009;22(9):1258–62.CrossRefGoogle Scholar
  259. 259.
    Su J, Yu W, Liu J, Zheng J, Huang S, Wang Y, Qi S, Ma X, et al. Fluorescence in situ hybridisation as an ancillary tool in the diagnosis of acral melanoma: a review of 44 cases. Pathology. 2017;49(7):740–9.CrossRefGoogle Scholar
  260. 260.
    Busam KJ, Fang Y, Jhanwar SC, Pulitzer MP, Marr B, Abramson DH. Distinction of conjunctival melanocytic nevi from melanomas by fluorescence in situ hybridization. J Cutan Pathol. 2010;37(2):196–203.CrossRefGoogle Scholar
  261. 261.
    Bastian BC, Xiong J, Frieden IJ, Williams ML, Chou P, Busam K, Pinkel D, LeBoit PE. Genetic changes in neoplasms arising in congenital melanocytic nevi: differences between nodular proliferations and melanomas. Am J Pathol. 2002;161(4):1163–9.CrossRefPubMedPubMedCentralGoogle Scholar
  262. 262.
    Boi S, Leonardi E, Fasanella S, Cantaloni C, Micciolo R. The four-color FISH probe in the diagnosis of melanocytic lesions. J Eur Acad Dermatol Venereol: JEADV. 2010;24(10):1235–6.CrossRefGoogle Scholar
  263. 263.
    Ferrara G, Misciali C, Brenn T, Cerroni L, Kazakov DW, Perasole A, Russo R, Ricci R, et al. The impact of molecular morphology techniques on the expert diagnosis in melanocytic skin neoplasms. Int J Surg Pathol. 2013;21(5):483–92.CrossRefGoogle Scholar
  264. 264.
    Ferrara G, De Vanna AC. Fluorescence in situ hybridization for melanoma diagnosis: a review and a reappraisal. Am J Dermatopathol. 2016;38(4):253–69.CrossRefGoogle Scholar
  265. 265.
    Onken MD, Worley LA, Ehlers JP, Harbour JW. Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death. Cancer Res. 2004;64(20):7205–9.CrossRefPubMedPubMedCentralGoogle Scholar
  266. 266.
    Haqq C, Nosrati M, Sudilovsky D, Crothers J, Khodabakhsh D, Pulliam BL, Federman S, Miller JR 3rd, et al. The gene expression signatures of melanoma progression. Proc Natl Acad Sci U S A. 2005;102(17):6092–7.CrossRefPubMedPubMedCentralGoogle Scholar
  267. 267.
    Smith AP, Hoek K, Becker D. Whole-genome expression profiling of the melanoma progression pathway reveals marked molecular differences between nevi/melanoma in situ and advanced-stage melanomas. Cancer Biol Ther. 2005;4(9):1018–29.CrossRefGoogle Scholar
  268. 268.
    Jaeger J, Koczan D, Thiesen HJ, Ibrahim SM, Gross G, Spang R, Kunz M. Gene expression signatures for tumor progression, tumor subtype, and tumor thickness in laser-microdissected melanoma tissues. Clin Cancer Res. 2007;13(3):806–15.CrossRefGoogle Scholar
  269. 269.
    Koh SS, Opel ML, Wei JP, Yau K, Shah R, Gorre ME, Whitman E, Shitabata PK, et al. Molecular classification of melanomas and nevi using gene expression microarray signatures and formalin-fixed and paraffin-embedded tissue. Mod Pathol. 2009;22(4):538–46.CrossRefGoogle Scholar
  270. 270.
    Jonsson G, Busch C, Knappskog S, Geisler J, Miletic H, Ringner M, Lillehaug JR, Borg A, et al. Gene expression profiling-based identification of molecular subtypes in stage IV melanomas with different clinical outcome. Clin Cancer Res. 2010;16(13):3356–67.CrossRefGoogle Scholar
  271. 271.
    Scatolini M, Grand MM, Grosso E, Venesio T, Pisacane A, Balsamo A, Sirovich R, Risio M, et al. Altered molecular pathways in melanocytic lesions. Int J Cancer. 2010;126(8):1869–81.CrossRefGoogle Scholar
  272. 272.
    Mauerer A, Roesch A, Hafner C, Stempfl T, Wild P, Meyer S, Landthaler M, Vogt T. Identification of new genes associated with melanoma. Exp Dermatol. 2011;20(6):502–7.CrossRefGoogle Scholar
  273. 273.
    Harbst K, Staaf J, Lauss M, Karlsson A, Masback A, Johansson I, Bendahl PO, Vallon-Christersson J, et al. Molecular profiling reveals low- and high-grade forms of primary melanoma. Clin Cancer Res. 2012;18(15):4026–36.CrossRefPubMedPubMedCentralGoogle Scholar
  274. 274.
    Clarke LE, Warf MB, Flake DD 2nd, Hartman AR, Tahan S, Shea CR, Gerami P, Messina J, et al. Clinical validation of a gene expression signature that differentiates benign nevi from malignant melanoma. J Cutan Pathol. 2015;42(4):244–52.CrossRefGoogle Scholar
  275. 275.
    Gerami P, Cook RW, Russell MC, Wilkinson J, Amaria RN, Gonzalez R, Lyle S, Jackson GL, et al. Gene expression profiling for molecular staging of cutaneous melanoma in patients undergoing sentinel lymph node biopsy. J Am Acad Dermatol. 2015;72(5):780–5. e783.CrossRefGoogle Scholar
  276. 276.
    Gerami P, Cook RW, Wilkinson J, Russell MC, Dhillon N, Amaria RN, Gonzalez R, Lyle S, et al. Development of a prognostic genetic signature to predict the metastatic risk associated with cutaneous melanoma. Clin Cancer Res. 2015;21(1):175–83.CrossRefGoogle Scholar
  277. 277.
    Meves A, Nikolova E, Heim JB, Squirewell EJ, Cappel MA, Pittelkow MR, Otley CC, Behrendt N, et al. Tumor cell adhesion as a risk factor for sentinel lymph node metastasis in primary cutaneous melanoma. J Clin Oncol. 2015;33(23):2509–15.CrossRefPubMedPubMedCentralGoogle Scholar
  278. 278.
    Nsengimana J, Laye J, Filia A, Walker C, Jewell R, Van den Oord JJ, Wolter P, Patel P, et al. Independent replication of a melanoma subtype gene signature and evaluation of its prognostic value and biological correlates in a population cohort. Oncotarget. 2015;6(13):11683–93.CrossRefPubMedPubMedCentralGoogle Scholar
  279. 279.
    Warf MB, Flake DD 2nd, Adams D, Gutin A, Kolquist KA, Wenstrup RJ, Roa BB. Analytical validation of a melanoma diagnostic gene signature using formalin-fixed paraffin-embedded melanocytic lesions. Biomark Med. 2015;9(5):407–16.CrossRefGoogle Scholar
  280. 280.
    Cockerell CJ, Tschen J, Evans B, Bess E, Kidd J, Kolquist KA, Rock C, Clarke LE. The influence of a gene expression signature on the diagnosis and recommended treatment of melanocytic tumors by dermatopathologists. Medicine (Baltimore). 2016;95(40):e4887.CrossRefGoogle Scholar
  281. 281.
    Tirosh I, Izar B, Prakadan SM, Wadsworth MH 2nd, Treacy D, Trombetta JJ, Rotem A, Rodman C, et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science. 2016;352(6282):189–96.CrossRefPubMedPubMedCentralGoogle Scholar
  282. 282.
    Clarke LE, Flake DD 2nd, Busam K, Cockerell C, Helm K, McNiff J, Reed J, Tschen J, et al. An independent validation of a gene expression signature to differentiate malignant melanoma from benign melanocytic nevi. Cancer. 2017;123(4):617–28.CrossRefGoogle Scholar
  283. 283.
    Sominidi-Damodaran S, Guo R, Meves A, Bridges AG. Expanded traditional melanoma FISH testing versus CAP-QPCR to identify high-risk melanocytic lesions. Int J Dermatol. 2017;56(9):e182–4.CrossRefGoogle Scholar
  284. 284.
    Cserni G, Chmielik E, Cserni B, Tot T The new TNM-based staging of breast cancer. Virchows Arch. 2018;472(5):697–703.Google Scholar
  285. 285.
    Plasseraud KM, Wilkinson JK, Oelschlager KM, Poteet TM, Cook RW, Stone JF, Monzon FA. Gene expression profiling in uveal melanoma: technical reliability and correlation of molecular class with pathologic characteristics. Diagn Pathol. 2017;12(1):59.CrossRefPubMedPubMedCentralGoogle Scholar
  286. 286.
    Clemente CG, Mihm MC Jr, Bufalino R, Zurrida S, Collini P, Cascinelli N. Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer. 1996;77(7):1303–10.CrossRefGoogle Scholar
  287. 287.
    Kubica AW, Brewer JD. Melanoma in immunosuppressed patients. Mayo Clin Proc. 2012;87(10):991–1003.CrossRefPubMedPubMedCentralGoogle Scholar
  288. 288.
    Kalialis LV, Drzewiecki KT, Klyver H. Spontaneous regression of metastases from melanoma: review of the literature. Melanoma Res. 2009;19(5):275–82.CrossRefGoogle Scholar
  289. 289.
    Menzies SW, McCarthy WH. Complete regression of primary cutaneous malignant melanoma. Arch Surg. 1997;132(5):553–6.CrossRefGoogle Scholar
  290. 290.
    Harlin H, Meng Y, Peterson AC, Zha Y, Tretiakova M, Slingluff C, McKee M, Gajewski TF. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 2009;69(7):3077–85.CrossRefGoogle Scholar
  291. 291.
    Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, Gajewski TF. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med. 2013;5(200):200ra116.CrossRefPubMedPubMedCentralGoogle Scholar
  292. 292.
    Kerkar SP, Restifo NP. Cellular constituents of immune escape within the tumor microenvironment. Cancer Res. 2012;72(13):3125–30.CrossRefPubMedPubMedCentralGoogle Scholar
  293. 293.
    Jacobs JF, Nierkens S, Figdor CG, de Vries IJ, Adema GJ. Regulatory T cells in melanoma: the final hurdle towards effective immunotherapy? Lancet Oncol. 2012;13(1):e32–42.CrossRefGoogle Scholar
  294. 294.
    Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the eastern cooperative oncology group trial EST 1684. J Clin Oncol. 1996;14(1):7–17.CrossRefGoogle Scholar
  295. 295.
    Kirkwood JM, Ibrahim JG, Sondak VK, Richards J, Flaherty LE, Ernstoff MS, Smith TJ, Rao U, et al. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol. 2000;18(12):2444–58.CrossRefGoogle Scholar
  296. 296.
    Wheatley K, Ives N, Hancock B, Gore M, Eggermont A, Suciu S. Does adjuvant interferon-alpha for high-risk melanoma provide a worthwhile benefit? A meta-analysis of the randomised trials. Cancer Treat Rev. 2003;29(4):241–52.CrossRefPubMedGoogle Scholar
  297. 297.
    Mocellin S, Pasquali S, Rossi CR, Nitti D. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst. 2010;102(7):493–501.CrossRefPubMedGoogle Scholar
  298. 298.
    Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol. 2014;192(12):5451–8.CrossRefPubMedPubMedCentralGoogle Scholar
  299. 299.
    Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17(7):2105–16.CrossRefPubMedPubMedCentralGoogle Scholar
  300. 300.
    Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.CrossRefPubMedPubMedCentralGoogle Scholar
  301. 301.
    Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, Lebbe C, Baurain JF, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517–26.CrossRefPubMedPubMedCentralGoogle Scholar
  302. 302.
    Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, Patt D, Chen TT, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol. 2015;33(17):1889–94.CrossRefPubMedPubMedCentralGoogle Scholar
  303. 303.
    Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16(5):522–30.CrossRefGoogle Scholar
  304. 304.
    Flies DB, Sandler BJ, Sznol M, Chen L. Blockade of the B7-H1/PD-1 pathway for cancer immunotherapy. Yale J Biol Med. 2011;84(4):409–21.PubMedPubMedCentralGoogle Scholar
  305. 305.
    Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331(6024):1565–70.CrossRefGoogle Scholar
  306. 306.
    Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, Brahmer JR, Lawrence DP, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32(10):1020–30.CrossRefPubMedPubMedCentralGoogle Scholar
  307. 307.
    Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16(4):375–84.CrossRefPubMedPubMedCentralGoogle Scholar
  308. 308.
    Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30.CrossRefPubMedPubMedCentralGoogle Scholar
  309. 309.
    Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006–17.CrossRefPubMedPubMedCentralGoogle Scholar
  310. 310.
    Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016;17(11):1558–68.CrossRefPubMedPubMedCentralGoogle Scholar
  311. 311.
    Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345–56.CrossRefPubMedPubMedCentralGoogle Scholar
  312. 312.
    Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH, Hu-Lieskovan S, Berent-Maoz B, Pang J, et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell. 2016;165(1):35–44.CrossRefPubMedPubMedCentralGoogle Scholar
  313. 313.
    Roh W, Chen PL, Reuben A, Spencer CN, Prieto PA, Miller JP, Gopalakrishnan V, Wang F et al. Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance. Sci Transl Med. 2017;9(379) pii: eaah3560.
  314. 314.
    Hugo W, Shi H, Sun L, Piva M, Song C, Kong X, Moriceau G, Hong A, et al. Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. Cell. 2015;162(6):1271–85.CrossRefPubMedPubMedCentralGoogle Scholar
  315. 315.
    Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S, Torrejon DY, Abril-Rodriguez G, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med. 2016;375(9):819–29.CrossRefPubMedPubMedCentralGoogle Scholar
  316. 316.
    Shin DS, Zaretsky JM, Escuin-Ordinas H, Garcia-Diaz A, Hu-Lieskovan S, Kalbasi A, Grasso CS, Hugo W, et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov. 2017;7(2):188–201.CrossRefGoogle Scholar
  317. 317.
    Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST, Simon P, Lotze MT, et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med. 1988;319(25):1676–80.CrossRefGoogle Scholar
  318. 318.
    Wu R, Forget MA, Chacon J, Bernatchez C, Haymaker C, Chen JQ, Hwu P, Radvanyi LG. Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes for metastatic melanoma: current status and future outlook. Cancer J. 2012;18(2):160–75.CrossRefPubMedPubMedCentralGoogle Scholar
  319. 319.
    Deniger DC, Kwong ML, Pasetto A, Dudley ME, Wunderlich JR, Langhan MM, Lee CR, Rosenberg SA. A pilot trial of the combination of vemurafenib with adoptive cell therapy in patients with metastatic melanoma. Clin Cancer Res. 2017;23(2):351–62.CrossRefGoogle Scholar
  320. 320.
    Cooper ZA, Frederick DT, Juneja VR, Sullivan RJ, Lawrence DP, Piris A, Sharpe AH, Fisher DE, et al. BRAF inhibition is associated with increased clonality in tumor-infiltrating lymphocytes. Oncoimmunology. 2013;2(10):e26615.CrossRefPubMedPubMedCentralGoogle Scholar
  321. 321.
    Frederick DT, Piris A, Cogdill AP, Cooper ZA, Lezcano C, Ferrone CR, Mitra D, Boni A, et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res. 2013;19(5):1225–31.CrossRefPubMedPubMedCentralGoogle Scholar
  322. 322.
    Ott PA, Fritsch EF, Wu CJ, Dranoff G. Vaccines and melanoma. Hematol Oncol Clin North Am. 2014;28(3):559–69.CrossRefGoogle Scholar
  323. 323.
    Lennerz V, Fatho M, Gentilini C, Frye RA, Lifke A, Ferel D, Wolfel C, Huber C, et al. The response of autologous T cells to a human melanoma is dominated by mutated neoantigens. Proc Natl Acad Sci U S A. 2005;102(44):16013–8.CrossRefPubMedPubMedCentralGoogle Scholar
  324. 324.
    Gros A, Parkhurst MR, Tran E, Pasetto A, Robbins PF, Ilyas S, Prickett TD, Gartner JJ, et al. Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat Med. 2016;22(4):433–8.CrossRefGoogle Scholar
  325. 325.
    Cohen CJ, Gartner JJ, Horovitz-Fried M, Shamalov K, Trebska-McGowan K, Bliskovsky VV, Parkhurst MR, Ankri C, et al. Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes. J Clin Invest. 2015;125(10):3981–91.CrossRefPubMedPubMedCentralGoogle Scholar
  326. 326.
    Prickett TD, Crystal JS, Cohen CJ, Pasetto A, Parkhurst MR, Gartner JJ, Yao X, Wang R, et al. Durable complete response from metastatic melanoma after transfer of autologous T cells recognizing 10 mutated tumor antigens. Cancer Immunol Res. 2016;4(8):669–78.CrossRefPubMedPubMedCentralGoogle Scholar
  327. 327.
    Pritchard AL, Burel JG, Neller MA, Hayward NK, Lopez JA, Fatho M, Lennerz V, Wolfel T, et al. Exome sequencing to predict neoantigens in melanoma. Cancer Immunol Res. 2015;3(9):992–8.CrossRefGoogle Scholar
  328. 328.
    Ott PA, Hu Z, Keskin DB, Shukla SA, Sun J, Bozym DJ, Zhang W, Luoma A, et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature. 2017;547(7662):217–21.CrossRefPubMedPubMedCentralGoogle Scholar
  329. 329.
    Sahin U, Derhovanessian E, Miller M, Kloke BP, Simon P, Lower M, Bukur V, Tadmor AD, et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature. 2017;547(7662):222–6.CrossRefGoogle Scholar
  330. 330.
    Palm NW, de Zoete MR, Flavell RA. Immune-microbiota interactions in health and disease. Clin Immunol. 2015;159(2):122–7.CrossRefPubMedPubMedCentralGoogle Scholar
  331. 331.
    Vetizou M, Pitt JM, Daillere R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350(6264):1079–84.CrossRefPubMedPubMedCentralGoogle Scholar
  332. 332.
    Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018;359(6371):97–103.CrossRefGoogle Scholar
  333. 333.
    Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre ML, Luke JJ, Gajewski TF. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 2018;359(6371):104–8.CrossRefGoogle Scholar
  334. 334.
    Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillere R, Fluckiger A, Messaoudene M, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359(6371):91–7.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  • Carlos N. Prieto-Granada
    • 1
    Email author
  • John Van Arnam
    • 2
  • Kabeer K. Shah
    • 3
  • Aleodor A. Andea
    • 4
  • Alexander J. Lazar
    • 2
    • 5
  1. 1.Department of PathologyUniversity of Alabama at BirminghamBirminghamUSA
  2. 2.Translational Molecular PathologyMD Anderson Cancer CenterHoustonUSA
  3. 3.Department of Laboratory Medicine and PathologyMayo ClinicRochesterUSA
  4. 4.Departments of Pathology and DermatologyUniversity of MichiganAnn ArborUSA
  5. 5.Departments of Genomic Medicine & DermatologyThe University of Texas MD Anderson Cancer CenterHoustonUSA

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