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Uveal Melanoma: Molecular Pathology

  • Sarah E. CouplandEmail author
  • Helen Kalirai
  • Sophie Thornton
  • Bertil E. Damato
Chapter

Abstract

Research into the molecular genetics of uveal melanomas (UM) has identified several predictors of metastatic disease as well as signaling pathways and molecules that can be targeted using systemic therapies. Most UM have GNAQ/11 initiating mutations, which activate the MAPK pathway, with dysregulation of the PI3K/AKT and other signaling pathways. Some patients develop UM because they have inherited the BAP-1 tumor predisposition syndrome, which also causes malignant mesothelioma and renal cell carcinoma. Metastasis is associated with many genetic aberrations, particularly chromosome 3 deletion, chromosome 8q gain, and somatic BAP1 mutation, whereas SF3B1 mutation predicts late metastasis, while chromosome 6p gain, and EIF1AX and CNKSR3 mutations are associated with a good prognosis. Recent data from The Cancer Genome Atlas (TCGA) indicate four prognostic groups of UM, categorized according to chromosome copy number variations, mutations and DNA methylation profiles. Other abnormalities include PTEN inactivation, inhibition of the retinoblastoma and p53 pathways, cyclin D1 overexpression, and CDKN2a promoter hypermethylation. Several potential MAPK/MEK, PI3K/AKT targets for UM therapy have been identified, using mTOR inhibitors, tyrosine kinase inhibitors, c-Met pathway inhibitors, CXCR4 small molecule inhibitors, histone deacetylase inhibitors, and others.

Keywords

GNAQ/11 MAPK pathway TCGA BAP1 SF3B1 EIF1AX CNKSR3 PRAME 

References

  1. 1.
    Canning CR, Hungerford J. Familial uveal melanoma. Br J Ophthalmol. 1988;72(4):241–3.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Turner BJ, Siatkowski RM, Augsburger JJ, et al. Other cancers in uveal melanoma patients and their families. Am J Ophthalmol. 1989;107(6):601–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Singh AD. Familial uveal melanoma. Arch Ophthalmol. 1996;114(4):392.PubMedCrossRefGoogle Scholar
  4. 4.
    COMS. Second primary cancers after enrollment in the COMS trials for treatment of choroidal melanoma. Archives of Ophthalmology. 2005;123(5):601.CrossRefGoogle Scholar
  5. 5.
    Abdel-Rahman MH, Pilarski R, Ezzat S, et al. Cancer family history characterization in an unselected cohort of 121 patients with uveal melanoma. Familial Cancer. 2010;9(3):431–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Abdel-Rahman MH, Pilarski R, Cebulla CM, et al. Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J Med Genet. 2011;48(12):856–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Carbone M, Ferris LK, Baumann F, et al. BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs. J Transl Med. 2012;10(1):179.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Murali R, Wiesner T, Scolyer RA. Tumours associated with BAP1 mutations. Pathology. 2013;45(2):116–26.PubMedCrossRefGoogle Scholar
  9. 9.
    Rai K, Pilarski R, Boru G, et al. GermlineBAP1alterations in familial uveal melanoma. Genes Chromosom Cancer. 2016;56(2):168–74.PubMedCrossRefGoogle Scholar
  10. 10.
    Masoomian B, Shields JA, Shields CL. Overview of BAP1 cancer predisposition syndrome and the relationship to uveal melanoma. Journal of Current Ophthalmology. 2018;30(2):102–9.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Harbour JW, Onken MD, Roberson EDO, et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science. 2010;330(6009):1410–3.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Koopmans AE, Verdijk RM, Brouwer RWW, et al. Clinical significance of immunohistochemistry for detection of BAP1 mutations in uveal melanoma. Mod Pathol. 2014;27(10):1321–30.PubMedCrossRefGoogle Scholar
  13. 13.
    Harbour JW, Roberson EDO, Anbunathan H, et al. Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma. Nat Genet. 2013;45(2):133–5.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Martin M, Maßhöfer L, Temming P, et al. Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3. Nat Genet. 2013;45(8):933–6.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Onken MD, Worley LA, Harbour JW. A metastasis modifier locus on human chromosome 8p in uveal melanoma identified by integrative genomic analysis. Clin Cancer Res. 2008;14(12):3737–45.PubMedCrossRefGoogle Scholar
  16. 16.
    Ehlers JP. DDEF1 is located in an amplified region of chromosome 8q and is overexpressed in uveal melanoma. Clin Cancer Res. 2005;11(10):3609–13.PubMedCrossRefGoogle Scholar
  17. 17.
    Laurent C, Valet F, Planque N, et al. High PTP4A3 phosphatase expression correlates with metastatic risk in uveal melanoma patients. Cancer Res. 2010;71(3):666–74.PubMedCrossRefGoogle Scholar
  18. 18.
    Lake SL, Damato BE, Kalirai H, et al. Single nucleotide polymorphism Array analysis of uveal melanomas reveals that amplification of CNKSR3 is correlated with improved patient survival. Am J Pathol. 2013;182(3):678–87.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Yu H, Fang D, Kumar SM, et al. Isolation of a novel population of multipotent adult stem cells from human hair follicles. Am J Pathol. 2006;168(6):1879–88.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Bergeron MA, Champagne S, Gaudreault M, et al. Repression of genes involved in melanocyte differentiation in uveal melanoma. Mol Vis. 2012;18:1813–22.PubMedPubMedCentralGoogle Scholar
  21. 21.
    An J, Wan H, Zhou X, et al. A comparative Transcriptomic analysis of uveal melanoma and normal uveal melanocyte. PLoS One. 2011;6(1):e16516.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Onken MD, Ehlers JP, Worley LA, et al. Functional gene expression analysis uncovers phenotypic switch in aggressive uveal melanomas. Cancer Res. 2006;66(9):4602–9.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Aleksidze N, Medina CA, Singh AD. De novo evolution of a small choroidal melanoma. Ocul Oncol Pathol. 2015;1(2):83–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Singh AD, Kalyani P, Topham A. Estimating the risk of malignant transformation of a choroidal nevus. Ophthalmology. 2005;112(10):1784–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.CrossRefGoogle Scholar
  27. 27.
    Coupland SE, Bechrakis N, Schuler A, et al. Expression patterns of cyclin D1 and related proteins regulating G1-S phase transition in uveal melanoma and retinoblastoma. Br J Ophthalmol. 1998;82(8):961–70.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Brantley MA Jr, Harbour JW. Deregulation of the Rb and p53 pathways in uveal melanoma. Am J Pathol. 2000;157(6):1795–801.PubMedCrossRefGoogle Scholar
  29. 29.
    Coupland SE, Anastassiou G, Stang A, et al. The prognostic value of cyclin D1, p53, and MDM2 protein expression in uveal melanoma. J Pathol. 2000;191(2):120–6.PubMedCrossRefGoogle Scholar
  30. 30.
    van der Velden PA, Metzelaar-Blok JA, Bergman W, et al. Promoter hypermethylation: a common cause of reduced p16(INK4a) expression in uveal melanoma. Cancer Res. 2001;61(13):5303–6.PubMedGoogle Scholar
  31. 31.
    Naus NC, Zuidervaart W, Rayman N, et al. Mutation analysis of the PTEN gene in uveal melanoma cell lines. Int J Cancer. 2000;87(1):151–3.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Zuidervaart W, van Nieuwpoort F, Stark M, et al. Activation of the MAPK pathway is a common event in uveal melanomas although it rarely occurs through mutation of BRAF or RAS. Br J Cancer. 2005;92(11):2032–8.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Onken MD, Worley LA, Long MD, et al. Oncogenic mutations inGNAQOccur early in uveal melanoma. Invest Opthalmol Vis Sci. 2008;49(12):5230.CrossRefGoogle Scholar
  34. 34.
    Shoushtari AN, Carvajal RD. GNAQ and GNA11 mutations in uveal melanoma. Melanoma Res. 2014;24(6):525–34.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Brantley MA, Worley L, Harbour JW. Altered expression of rb and p53 in uveal melanomas following plaque radiotherapy11The author has no proprietary interest in this study. Am J Ophthalmol. 2002;133(2):242–8.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    All-Ericsson C, Girnita L, Müller-Brunotte A, et al. c-Kit–dependent growth of uveal melanoma cells: a potential therapeutic target? Invest Opthalmol Vis Sci. 2004;45(7):2075.CrossRefGoogle Scholar
  37. 37.
    Economou MA, All-Ericsson C, Bykov V, et al. Receptors for the liver synthesized growth factors IGF-1 and HGF/SF in uveal melanoma: intercorrelation and prognostic implications. Invest Opthalmol Vis Sci. 2005;46(12):4372.CrossRefGoogle Scholar
  38. 38.
    Heine B. Telomerase expression in uveal melanoma. Br J Ophthalmol. 2000;84(2):217–23.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Rohrbach JM, Riedinger C, Wild M, et al. Telomeraseaktivität in uvealen Melanomen. Ophthalmologe. 2000;97(5):359–63.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Abdel-Rahman MH, Craig EL, Davidorf FH, et al. Expression of vascular endothelial growth factor in uveal melanoma is independent of 6p21-region copy number. Clin Cancer Res. 2005;11(1):73–8.PubMedGoogle Scholar
  41. 41.
    Kirschmann DA, Seftor EA, Hardy KM, et al. Molecular pathways: vasculogenic mimicry in tumor cells: diagnostic and therapeutic implications. Clin Cancer Res. 2012;18(10):2726–32.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Cools-Lartigue J, Marshall JC, Caissie AL, et al. Secretion of hepatocyte growth factor and vascular endothelial growth factor during uveal melanoma-monocyte in vitro interactions. Melanoma Res. 2005;15(3):141–5.PubMedCrossRefGoogle Scholar
  43. 43.
    Wu X, Zhou J, Rogers AM, et al. c-Met, epidermal growth factor receptor, and insulin-like growth factor-1 receptor are important for growth in uveal melanoma and independently contribute to migration and metastatic potential. Melanoma Res. 2012;22(2):123–32.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Anastassiou G, Tschentscher F, Zeschnigk M, et al. Cadherin expression in uveal melanoma. Exp Eye Res. 2002;74(3):423–5.PubMedCrossRefGoogle Scholar
  45. 45.
    Zuidervaart W, Pavey S, van Nieuwpoort FA, et al. Expression of Wnt5a and its downstream effector β-catenin in uveal melanoma. Melanoma Res. 2007;17(6):380–6.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Harbour JW. The genetics of uveal melanoma: an emerging framework for targeted therapy. Pigment Cell Melanoma Res. 2012;25(2):171–81.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    de Waard-Siebinga I, Hilders CGJM, Hansen BE, et al. HLA expression and tumor-infiltrating immune cells in uveal melanoma. Graefes Arch Clin Exp Ophthalmol. 1996;234(1):34–42.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Hurks HMH, Metzelaar-Blok JAW, Mulder A, et al. High frequency of allele-specific down-regulation of HLA class I expression in uveal melanoma cell lines. Int J Cancer. 2000;85(5):697–702.PubMedCrossRefGoogle Scholar
  49. 49.
    Yang W, Chen PW, Li H, et al. PD-L1: PD-1 interaction contributes to the functional suppression of T-cell responses to human uveal melanoma cells in vitro. Invest Opthalmol Vis Sci. 2008;49(6):2518.CrossRefGoogle Scholar
  50. 50.
    Whelchel JC, Farah SE, McLean IW, et al. Immunohistochemistry of infiltrating lymphocytes in uveal malignant melanoma. Invest Ophthalmol Vis Sci. 1993;34(8):2603–6.PubMedGoogle Scholar
  51. 51.
    Makitie T, Summanen P, Tarkkanen A, et al. Tumor-infiltrating macrophages (CD68(+) cells) and prognosis in malignant uveal melanoma. Invest Ophthalmol Vis Sci. 2001;42(7):1414–21.PubMedGoogle Scholar
  52. 52.
    Pi T, Mäkitie T, Kujala E, et al. Microcirculation and tumor-infiltrating macrophages in choroidal and ciliary body melanoma and corresponding metastases. Invest Opthalmol Vis Sci. 2004;45(1):1.CrossRefGoogle Scholar
  53. 53.
    Sharma A, Stei MM, Frohlich H, et al. Genetic and epigenetic insights into uveal melanoma. Clin Genet. 2018;93(5):952–61.PubMedCrossRefGoogle Scholar
  54. 54.
    Helgadottir H, Hoiom V. The genetics of uveal melanoma: current insights. Appl Clin Genet. 2016;9:147–55.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Werdich XQ, Jakobiec FA, Singh AD, et al. A review of advanced genetic testing for clinical prognostication in uveal melanoma. Semin Ophthalmol. 2013;28(5–6):361–71.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Li Y, Jia R, Ge S. Role of epigenetics in uveal melanoma. Int J Biol Sci. 2017;13(4):426–33.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Russo A, Caltabiano R, Longo A, et al. Increased levels of miRNA-146a in serum and histologic samples of patients with uveal melanoma. Front Pharmacol. 2016;7:424.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Ragusa M, Barbagallo C, Statello L, et al. miRNA profiling in vitreous humor, vitreal exosomes and serum from uveal melanoma patients: pathological and diagnostic implications. Cancer Biol Ther. 2015;16(9):1387–96.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Zhou J, Jiang J, Wang S, et al. Oncogenic role of microRNA20a in human uveal melanoma. Mol Med Rep. 2016;14(2):1560–6.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Li Y, Huang Q, Shi X, et al. MicroRNA 145 may play an important role in uveal melanoma cell growth by potentially targeting insulin receptor substrate-1. Chin Med J. 2014;127(8):1410–6.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Chen X, Wang J, Shen H, et al. Epigenetics, microRNAs, and carcinogenesis: functional role of microRNA-137 in uveal melanoma. Invest Ophthalmol Vis Sci. 2011;52(3):1193–9.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Yan D, Dong XD, Chen X, et al. Role of microRNA-182 in posterior uveal melanoma: regulation of tumor development through MITF, BCL2 and cyclin D2. PLoS One. 2012;7(7):e40967.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Yan D, Zhou X, Chen X, et al. MicroRNA-34a inhibits uveal melanoma cell proliferation and migration through downregulation of c-Met. Invest Ophthalmol Vis Sci. 2009;50(4):1559–65.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Höglund M, Gisselsson D, Hansen GB, et al. Dissecting karyotypic patterns in malignant melanomas: temporal clustering of losses and gains in melanoma karyotypic evolution. Int J Cancer. 2003;108(1):57–65.CrossRefGoogle Scholar
  65. 65.
    Parrella P, Sidransky D, Merbs SL. Allelotype of posterior uveal melanoma: implications for a bifurcated tumor progression pathway. Cancer Res. 1999;59(13):3032–7.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Tschentscher F, Husing J, Holter T, et al. Tumor classification based on gene expression profiling shows that uveal melanomas with and without monosomy 3 represent two distinct entities. Cancer Res. 2003;63(10):2578–84.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Field MG, Durante MA, Anbunathan H, et al. Punctuated evolution of canonical genomic aberrations in uveal melanoma. Nat Commun 2018;9(1).Google Scholar
  68. 68.
    Singh N, Singh AD, Hide W. Inferring an evolutionary tree of uveal melanoma from genomic copy number aberrations. Invest Ophthalmol Vis Sci. 2015;56(11):6801–9.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Damato B, Dopierala JA, Coupland SE. Genotypic profiling of 452 Choroidal melanomas with multiplex ligation-dependent probe amplification. Clin Cancer Res. 2010;16(24):6083–92.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Mensink HW, Vaarwater J, Kilic E, et al. Chromosome 3 intratumor heterogeneity in uveal melanoma. Invest Opthalmol Vis Sci. 2009;50(2):500.CrossRefGoogle Scholar
  71. 71.
    Dopierala J, Damato BE, Lake SL, et al. Genetic heterogeneity in uveal melanoma assessed by multiplex ligation-dependent probe amplification. Invest Opthalmol Vis Sci. 2010;51(10):4898.CrossRefGoogle Scholar
  72. 72.
    Bronkhorst IHG, Maat W, Jordanova ES, et al. Effect of heterogeneous distribution of monosomy 3 on prognosis in uveal melanoma. Arch Pathol Lab Med. 2011;135(8):1042–7.PubMedCrossRefGoogle Scholar
  73. 73.
    Callejo SA. Sudden growth of a choroidal melanoma and multiplex ligation-dependent probe amplification findings suggesting late transformation to monosomy 3 type. Arch Ophthalmol. 2011;129(7):958.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Swanton C. Intratumor heterogeneity: evolution through space and time. Cancer Res. 2012;72(19):4875–82.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Royer-Bertrand B, Torsello M, Rimoldi D, et al. Comprehensive genetic landscape of uveal melanoma by whole-genome sequencing. Am J Hum Genet. 2016;99(5):1190–8.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Robertson AG, Shih J, Yau C, et al. Integrative analysis identifies four molecular and clinical subsets in uveal melanoma. Cancer Cell. 2018;33(1):151.PubMedCrossRefGoogle Scholar
  77. 77.
    Denhardt DT. Signal-transducing protein phosphorylation cascades mediated by Ras/Rho proteins in the mammalian cell: the potential for multiplex signalling. Biochem J. 1996;318(3):729–47.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Weber A, Hengge UR, Urbanik D, et al. Absence of mutations of the BRAF gene and constitutive activation of extracellular-regulated kinase in malignant melanomas of the uvea. Lab Investig. 2003;83(12):1771–6.PubMedCrossRefGoogle Scholar
  79. 79.
    Mooy CM, Van der Helm MJ, Van der Kwast TH, et al. No N-ras mutations in human uveal melanoma: the role of ultraviolet light revisited. Br J Cancer. 1991;64(2):411–3.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Soparker CN, O'Brien JM, Albert DM. Investigation of the role of the ras protooncogene point mutation in human uveal melanomas. Invest Ophthalmol Vis Sci. 1993;34(7):2203–9.PubMedGoogle Scholar
  81. 81.
    Cruz F 3rd, Rubin BP, Wilson D, et al. Absence of BRAF and NRAS mutations in uveal melanoma. Cancer Res. 2003;63(18):5761–6.PubMedGoogle Scholar
  82. 82.
    Pache M, Glatz K, Bosch D, et al. Sequence analysis and high-throughput immunhistochemical profiling of KIT (CD 117) expression in uveal melanoma using tissue microarrays. Virchows Arch. 2003;443(6):741–4.PubMedCrossRefGoogle Scholar
  83. 83.
    Cohen Y, Goldenberg-Cohen N, Parrella P, et al. Lack of BRAF mutation in primary uveal melanoma. Invest Opthalmol Vis Sci. 2003;44(7):2876.CrossRefGoogle Scholar
  84. 84.
    Rimoldi D, Salvi S, Lienard D, et al. Lack of BRAF mutations in uveal melanoma. Cancer Res. 2003;63(18):5712–5.PubMedGoogle Scholar
  85. 85.
    Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Mutations in GNA11in uveal melanoma. N Engl J Med. 2010;363(23):2191–9.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Johansson P, Aoude LG, Wadt K, et al. Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4. Oncotarget. 2015;7(4):4624–31.PubMedCentralPubMedGoogle Scholar
  87. 87.
    Moore AR, Ceraudo E, Sher JJ, et al. Recurrent activating mutations of G-protein-coupled receptor CYSLTR2 in uveal melanoma. Nat Genet. 2016;48(6):675–80.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Bauer J, Kilic E, Vaarwater J, et al. Oncogenic GNAQ mutations are not correlated with disease-free survival in uveal melanoma. Br J Cancer. 2009;101(5):813–5.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Van Raamsdonk CD, Bezrookove V, Green G, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2008;457(7229):599–602.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Babchia N, Calipel A, Mouriaux F, et al. The PI3K/Akt and mTOR/P70S6K signaling pathways in human uveal melanoma cells: interaction with B-Raf/ERK. Invest Opthalmol Vis Sci. 2010;51(1):421.CrossRefGoogle Scholar
  91. 91.
    Saraiva VS, Caissie AL, Segal L, et al. Immunohistochemical expression of phospho-Akt in uveal melanoma. Melanoma Res. 2005;15(4):245–50.PubMedCrossRefGoogle Scholar
  92. 92.
    Abdel-Rahman MH, Yang Y, Zhou X-P, et al. High frequency of submicroscopic hemizygous deletion is a major mechanism of loss of expression of PTEN in uveal melanoma. J Clin Oncol. 2006;24(2):288–95.PubMedCrossRefGoogle Scholar
  93. 93.
    Ehlers JP, Worley L, Onken MD, Harbour JW. Integrative genomic analysis of aneuploidy in uveal melanoma. Clin Cancer Res. 2008;14(1):115–22.PubMedCrossRefGoogle Scholar
  94. 94.
    Bronkhorst IHG, Jager MJ. Uveal melanoma: the inflammatory microenvironment. J Innate Immun. 2012;4(5–6):454–62.PubMedCrossRefGoogle Scholar
  95. 95.
    Chana JS, Wilson GD, Cree IA, et al. c-myc, p53, and Bcl-2 expression and clinical outcome in uveal melanoma. Br J Ophthalmol. 1999;83(1):110–4.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Sun Y, Tran BN, Worley LA, et al. Functional analysis of the p53 pathway in response to ionizing radiation in uveal melanoma. Invest Opthalmol Vis Sci. 2005;46(5):1561.CrossRefGoogle Scholar
  97. 97.
    Scholes AG, Liloglou T, Maloney P, et al. Loss of heterozygosity on chromosomes 3, 9, 13, and 17, including the retinoblastoma locus, in uveal melanoma. Invest Ophthalmol Vis Sci. 2001;42(11):2472–7.PubMedGoogle Scholar
  98. 98.
    Brantley MA Jr, Harbour JW. Inactivation of retinoblastoma protein in uveal melanoma by phosphorylation of sites in the COOH-terminal region. Cancer Res. 2000;60(16):4320–3.PubMedPubMedCentralGoogle Scholar
  99. 99.
    Prescher G, Bornfeld N, Becher R. Nonrandom chromosomal abnormalities in primary uveal melanoma. JNCI J Natl Cancer Instit. 1990;82(22):1765–9.CrossRefGoogle Scholar
  100. 100.
    Sisley K, Rennie IG, Cottam DW, et al. Cytogenetic findings in six posterior uveal melanomas: involvement of chromosomes 3, 6, and 8. Genes Chromosom Cancer. 1990;2(3):205–9.PubMedCrossRefGoogle Scholar
  101. 101.
    Horsman DE, Sroka H, Rootman J, et al. Monosomy 3 and isochromosome 8q in a uveal melanoma. Cancer Genet Cytogenet. 1990;45(2):249–53.PubMedCrossRefGoogle Scholar
  102. 102.
    Sisley K, Rennie IG, Parsons MA, et al. Abnormalities of chromosomes 3 and 8 in posterior uveal melanoma correlate with prognosis. Genes Chromosom Cancer. 1997;19(1):22–8.PubMedCrossRefGoogle Scholar
  103. 103.
    McNamara M, Felix C, Val Davison E, et al. Assessment of chromosome 3 copy number in ocular melanoma using fluorescence in situ hybridization. Cancer Genet Cytogenet. 1997;98(1):4–8.PubMedCrossRefGoogle Scholar
  104. 104.
    Damato B, Duke C, Coupland SE, et al. Cytogenetics of uveal melanoma. Ophthalmology. 2007;114(10):1925–31.e1.PubMedCrossRefGoogle Scholar
  105. 105.
    Aronow M, Sun Y, Saunthararajah Y, et al. Monosomy 3 by FISH in uveal melanoma: variability in techniques and results. Surv Ophthalmol. 2012;57(5):463–73.PubMedCrossRefGoogle Scholar
  106. 106.
    Hughes S, Damato BE, Giddings I, et al. Microarray comparative genomic hybridisation analysis of intraocular uveal melanomas identifies distinctive imbalances associated with loss of chromosome 3. Br J Cancer. 2005;93(10):1191–6.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Ghazvini S, Char DH, Kroll S, et al. Comparative genomic hybridization analysis of archival formalin-fixed paraffin-embedded uveal melanomas. Cancer Genet Cytogenet. 1996;90(2):95–101.PubMedCrossRefGoogle Scholar
  108. 108.
    Kilic E, van Gils W, Lodder E, et al. Clinical and cytogenetic analyses in uveal melanoma. Invest Opthalmol Vis Sci. 2006;47(9):3703.CrossRefGoogle Scholar
  109. 109.
    Petrausch U, Martus P, Tönnies H, et al. Significance of gene expression analysis in uveal melanoma in comparison to standard risk factors for risk assessment of subsequent metastases. Eye. 2007;22(8):997–1007.PubMedCrossRefGoogle Scholar
  110. 110.
    Naus NC, van Drunen E, de Klein A, et al. Characterization of complex chromosomal abnormalities in uveal melanoma by fluorescence in situ hybridization, spectral karyotyping, and comparative genomic hybridization. Genes Chromosom Cancer. 2001;30(3):267–73.PubMedCrossRefGoogle Scholar
  111. 111.
    White JS, Becker RL, McLean IW, et al. Molecular cytogenetic evaluation of 10 uveal melanoma cell lines. Cancer Genet Cytogenet. 2006;168(1):11–21.PubMedCrossRefGoogle Scholar
  112. 112.
    Tschentscher F, Prescher G, Zeschnigk M, et al. Identification of chromosomes 3, 6, and 8 aberrations in uveal melanoma by microsatellite analysis in comparison to comparative genomic hybridization. Cancer Genet Cytogenet. 2000;122(1):13–7.PubMedCrossRefGoogle Scholar
  113. 113.
    Scholes AGM, Damato BE, Nunn J, et al. Monosomy 3 in uveal melanoma: correlation with clinical and histologic predictors of survival. Invest Opthalmol Vis Sci. 2003;44(3):1008.CrossRefGoogle Scholar
  114. 114.
    Thomas S, Pütter C, Weber S, et al. Prognostic significance of chromosome 3 alterations determined by microsatellite analysis in uveal melanoma: a long-term follow-up study. Br J Cancer. 2012;106(6):1171–6.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Häusler T, Stang A, Anastassiou G, et al. Loss of heterozygosity of 1p in uveal melanomas with monosomy 3. Int J Cancer. 2005;116(6):909–13.PubMedCrossRefGoogle Scholar
  116. 116.
    Shields CL, Ganguly A, Bianciotto CG, et al. Prognosis of uveal melanoma in 500 cases using genetic testing of fine-needle aspiration biopsy specimens. Ophthalmology. 2011;118(2):396–401.PubMedCrossRefGoogle Scholar
  117. 117.
    Shields CL. Chromosome 3 analysis of uveal melanoma using fine-needle aspiration biopsy at the time of plaque radiotherapy in 140 consecutive cases. Arch Ophthalmol. 2007;125(8):1017.PubMedCrossRefGoogle Scholar
  118. 118.
    Damato B, Dopierala J, Klaasen A, et al. Multiplex ligation-dependent probe amplification of uveal melanoma: correlation with metastatic death. Invest Opthalmol Vis Sci. 2009;50(7):3048.CrossRefGoogle Scholar
  119. 119.
    Damato B. Progress in the management of patients with uveal melanoma. The 2012 Ashton lecture. Eye. 2012;26(9):1157–72.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Onken MD, Worley LA, Person E, et al. Loss of heterozygosity of chromosome 3 detected with single nucleotide polymorphisms is superior to monosomy 3 for predicting metastasis in uveal melanoma. Clin Cancer Res. 2007;13(10):2923–7.PubMedCrossRefGoogle Scholar
  121. 121.
    Singh AD, Aronow ME, Sun Y, et al. Chromosome 3 status in uveal melanoma: a comparison of fluorescence in situ hybridization and single-nucleotide polymorphism array. Invest Opthalmol Vis Sci. 2012;53(7):3331.CrossRefGoogle Scholar
  122. 122.
    Trolet J, Hupé P, Huon I, et al. Genomic profiling and identification of high-risk uveal melanoma by array CGH analysis of primary tumors and liver metastases. Invest Opthalmol Vis Sci. 2009;50(6):2572.CrossRefGoogle Scholar
  123. 123.
    Lake SL, Coupland SE, Taktak AFG, et al. Whole-genome microarray detects deletions and loss of heterozygosity of chromosome 3 occurring exclusively in metastasizing uveal melanoma. Invest Opthalmol Vis Sci. 2010;51(10):4884.CrossRefGoogle Scholar
  124. 124.
    McCannel TA, Burgess BL, Nelson SF, et al. Genomic identification of significant targets in ciliochoroidal melanoma. Invest Opthalmol Vis Sci. 2011;52(6):3018.CrossRefGoogle Scholar
  125. 125.
    Abi-Ayad N, Kodjikian L, Couturier J. Techniques d’analyse génomique du mélanome uvéal: une revue bibliographique. J Fr Ophtalmol. 2011;34(4):259–64.PubMedCrossRefGoogle Scholar
  126. 126.
    Prescher G, Bornfeld N, Horsthemke B, et al. Chromosomal aberrations defining uveal melanoma of poor prognosis. Lancet. 1992;339(8794):691–2.PubMedCrossRefGoogle Scholar
  127. 127.
    Prescher G, Bornfeld N, Hirche H, et al. Prognostic implications of monosomy 3 in uveal melanoma. Lancet. 1996;347(9010):1222–5.PubMedCrossRefGoogle Scholar
  128. 128.
    White VA, Chambers JD, Courtright PD, et al. Correlation of cytogenetic abnormalities with the outcome of patients with uveal melanoma. Cancer. 1998;83(2):354–9.PubMedCrossRefGoogle Scholar
  129. 129.
    Onken MD, Worley LA, Ehlers JP, et al. Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death. Cancer Res. 2004;64(20):7205–9.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Decatur CL, Ong E, Garg N, et al. Driver mutations in uveal melanoma: associations with gene expression profile and patient outcomes. JAMA Ophthalmol. 2016;134(7):728–33.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Asnaghi L, Ebrahimi KB, Schreck KC, et al. Notch signaling promotes growth and invasion in uveal melanoma. Clin Cancer Res. 2012;18(3):654–65.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Jensen DE, Proctor M, Marquis ST, et al. BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene. 1998;16(9):1097–112.PubMedCrossRefGoogle Scholar
  133. 133.
    Wiesner T, Obenauf AC, Murali R, et al. Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet. 2011;43(10):1018–21.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Testa JR, Cheung M, Pei J, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet. 2011;43(10):1022–5.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Njauw C-NJ, Kim I, Piris A, et al. Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families. PLoS One. 2012;7(4):e35295.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Komeno Y, Huang Y-J, Qiu J, et al. SRSF2 is essential for hematopoiesis, and its myelodysplastic syndrome-related mutations dysregulate alternative pre-mRNA splicing. Mol Cell Biol. 2015;35(17):3071–82.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Luscan A, Just PA, Briand A, et al. Uveal melanoma hepatic metastases mutation spectrum analysis using targeted next-generation sequencing of 400 cancer genes. Br J Ophthalmol. 2014;99(4):437–9.PubMedCrossRefGoogle Scholar
  138. 138.
    Field MG, Decatur CL, Kurtenbach S, et al. PRAME as an independent biomarker for metastasis in uveal melanoma. Clin Cancer Res. 2016;22(5):1234–42.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Gezgin G, Luk SJ, Cao J, et al. PRAME as a potential target for immunotherapy in metastatic uveal melanoma. JAMA Ophthalmol. 2017;135(6):541–9.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    McCarthy C, Kalirai H, Lake SL, et al. Insights into genetic alterations of liver metastases from uveal melanoma. Pigment Cell Melanoma Res. 2015;29(1):60–7.CrossRefGoogle Scholar
  141. 141.
    Griewank KG, van de Nes J, Schilling B, et al. Genetic and clinico-pathologic analysis of metastatic uveal melanoma. Mod Pathol. 2013;27(2):175–83.PubMedCrossRefGoogle Scholar
  142. 142.
    Fuchs E. Das Sarkom des Uvealtractus. Graefe’s Archiv für Ophthalmologie. 1882;12(2):233.Google Scholar
  143. 143.
    Scala S, Ieranò C, Ottaiano A, et al. CXC chemokine receptor 4 is expressed in uveal malignant melanoma and correlates with the epithelioid-mixed cell type. Cancer Immunol Immunother. 2007;56(10):1589–95.PubMedCrossRefPubMedCentralGoogle Scholar
  144. 144.
    Anastassiou G, Coupland SE, Stang A, et al. Expression of Fas and Fas ligand in uveal melanoma: biological implication and prognostic value. J Pathol. 2001;194(4):466–72.PubMedCrossRefPubMedCentralGoogle Scholar
  145. 145.
    Bakalian S, Marshall JC, Logan P, et al. Molecular pathways mediating liver metastasis in patients with uveal melanoma. Clin Cancer Res. 2008;14(4):951–6.PubMedCrossRefPubMedCentralGoogle Scholar
  146. 146.
    Triozzi PL, Eng C, Singh AD. Targeted therapy for uveal melanoma. Cancer Treat Rev. 2008;34(3):247–58.PubMedCrossRefPubMedCentralGoogle Scholar
  147. 147.
    Yang J, Manson DK, Marr BP, et al. Treatment of uveal melanoma: where are we now? Ther Adv Med Oncol. 2018;10:1758834018757175.PubMedPubMedCentralGoogle Scholar
  148. 148.
    Triozzi PL, Singh AD. Adjuvant therapy of uveal melanoma: current status. Ocul Oncol Pathol. 2014;1(1):54–62.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Bailey FP, Clarke K, Kalirai H, Kenyani J, Shahidipour H, Falciani F, Coulson JM, Sacco JJ, Coupland SE, Eyers PA. Kinome-wide transcriptional profiling of uveal melanoma reveals new vulnerabilities to targeted therapeutics. Pigment Cell Melanoma Res. 2018;31(2):253–66. https://doi.org/10.1111/pcmr.12650. Epub 2017 Oct 15.CrossRefGoogle Scholar
  150. 150.
    Ambrosini G, Do C, Tycko B, Realubit RB, Karan C, Musi E, Carvajal RD, Chua V, Aplin AE, Schwartz GK. Inhibition of NF-κB-dependent signaling enhances sensitivity and overcomes resistance to BET inhibition in uveal melanoma. Cancer Res. 2019;79(9):2415–25. https://doi.org/10.1158/0008-5472.CAN-18-3177. Epub 2019 Mar 18.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Sarah E. Coupland
    • 1
    Email author
  • Helen Kalirai
    • 1
  • Sophie Thornton
    • 1
  • Bertil E. Damato
    • 2
  1. 1.Department of Molecular and Clinical Cancer Medicine, Institute of Translational MedicineUniversity of LiverpoolLiverpool, MerseysideUK
  2. 2.Nuffield Department of Clinical NeurosciencesUniversity of Oxford, John Radcliffe HospitalOxfordUK

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