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Review

Unpacking the genetic etiology of uveal melanoma

, , &
Pages 211-220 | Received 20 Mar 2020, Accepted 18 Jun 2020, Published online: 30 Jun 2020

References

  • Kaliki S, Shields CL. Uveal melanoma: relatively rare but deadly cancer. Eye (Lond). 2017;31(2):241–257.
  • Krantz BA, Dave N, Komatsubara KM, et al. Uveal melanoma: epidemiology, etiology, and treatment of primary disease. Clin Ophthalmol. 2017;11:279–289.
  • Singh AD, Turell ME, Topham AK. Uveal melanoma: trends in incidence, treatment, and survival. Ophthalmology. 2011;118(9):1881–1885.
  • Damato BE, Coupland SE. Ocular melanoma. Saudi J Ophthalmol. 2012;26(2):137–144.
  • Brewington BY, Shao YF, Davidorf FH, et al. Brachytherapy for patients with uveal melanoma: historical perspectives and future treatment directions. Clin Ophthalmol. 2018;12:925–934.
  • Damato B. Ocular treatment of choroidal melanoma in relation to the prevention of metastatic death - A personal view. Prog Retin Eye Res. 2018;66:187–199.
  • Damato BE. Local resection of uveal melanoma. Dev Ophthalmol. 2012;49:66–80.
  • Desjardins L, Lumbroso-Le Rouic L, Levy-Gabriel C, et al. Treatment of uveal melanoma by accelerated proton beam. Dev Ophthalmol. 2012;49:41–57.
  • Groenewald C, Konstantinidis L, Damato B. Effects of radiotherapy on uveal melanomas and adjacent tissues. Eye (Lond). 2013;27(2):163–171.
  • Reichstein D, Karan K. Plaque brachytherapy for posterior uveal melanoma in 2018: improved techniques and expanded indications. Curr Opin Ophthalmol. 2018;29(3):191–198.
  • Chang MY, McCannel TA. Local treatment failure after globe-conserving therapy for choroidal melanoma. Br J Ophthalmol. 2013;97(7):804–811.
  • Dithmar S, Diaz CE, Grossniklaus HE. Intraocular melanoma spread to regional lymph nodes: report of two cases. Retina (Philadelphia, Pa). 2000;20(1):76–79.
  • Kath R, Hayungs J, Bornfeld N, et al. Prognosis and treatment of disseminated uveal melanoma. Cancer. 1993;72(7):2219–2223.
  • Yang J, Manson DK, Marr BP, et al. Treatment of uveal melanoma: where are we now? Ther Adv Med Oncol. 2018;10:1758834018757175.
  • Komatsubara KM, Carvajal RD. Immunotherapy for the treatment of uveal melanoma: current status and emerging therapies. Curr Oncol Rep. 2017;19(7):45.
  • Luke JJ. The newest treatments for uveal melanoma. Clin Adv Hematol Oncol. 2019;17(9):490–493.
  • Luke JJ, Triozzi PL, McKenna KC, et al. Biology of advanced uveal melanoma and next steps for clinical therapeutics. Pigment Cell Melanoma Res. 2015;28(2):135–147.
  • Angi M, Damato B, Kalirai H, et al. Immunohistochemical assessment of mitotic count in uveal melanoma. Acta Ophthalmol. 2011;89(2):e155–60.
  • Bronkhorst IH, Vu TH, Jordanova ES, et al. Different subsets of tumor-infiltrating lymphocytes correlate with macrophage influx and monosomy 3 in uveal melanoma. Invest Ophthalmol Vis Sci. 2012;53(9):5370–5378.
  • Coupland SE, Campbell I, Damato B. Routes of extraocular extension of uveal melanoma: risk factors and influence on survival probability. Ophthalmology. 2008;115(10):1778–1785.
  • Damato B, Coupland SE. A reappraisal of the significance of largest basal diameter of posterior uveal melanoma. Eye (Lond). 2009;23(12):2152–2160. quiz 61-2.
  • Makitie T, Summanen P, Tarkkanen A, et al. Microvascular loops and networks as prognostic indicators in choroidal and ciliary body melanomas. J Natl Cancer Inst. 1999;91(4):359–367.
  • 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):1414–1421.
  • McLean IW, Ainbinder DJ, Gamel JW, et al. Choroidal-ciliary body melanoma. A multivariate survival analysis of tumor location. Ophthalmology. 1995;102(7):1060–1064.
  • Smit KN, Jager MJ, de Klein A, et al. Uveal melanoma: towards a molecular understanding. Prog Retin Eye Res. 2020 Mar;75:100800.
  • Prescher G, Bornfeld N, Becher R. Nonrandom chromosomal abnormalities in primary uveal melanoma. J Natl Cancer Inst. 1990;82(22):1765–1769.
  • Prescher G, Bornfeld N. Prognostic implications of monosomy 3 in uveal melanoma. Lancet. 1996;347(9010):1222.
  • Abdel-Rahman MH, Cebulla CM, Verma V, et al. Monosomy 3 status of uveal melanoma metastases is associated with rapidly progressive tumors and short survival. Exp Eye Res. 2012;100:26–31.
  • Damato B, Duke C, Douglas A, et al. Cytogenetics of uveal melanoma. A 7-year clinical experience. Ophthalmology. 2007;114(10):1925–31.e1.
  • Dogrusoz M, Jager MJ. Genetic prognostication in uveal melanoma. Acta Ophthalmol. 2018;96(4):331–347.
  • Sisley K, Rennie IG, Parsons MA, et al. Abnormalities of chromosomes 3 and 8 in posterior uveal melanoma correlate with prognosis. Genes Chromosomes Cancer. 1997;19(1):22–28.
  • Thomas S, Putter 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):1171–1176.
  • van de Nes JA, Nelles J, Kreis S, et al. Comparing the prognostic value of BAP1 mutation pattern, chromosome 3 status, and BAP1 immunohistochemistry in uveal melanoma. Am J Surg Pathol. 2016;40(6):796–805.
  • White VA, Chambers JD, Courtright PD, et al. Correlation of cytogenetic abnormalities with the outcome of patients with uveal melanoma. Cancer. 1998;83(2):354–359.
  • Cassoux N, Rodrigues MJ, Plancher C, et al. Genome-wide profiling is a clinically relevant and affordable prognostic test in posterior uveal melanoma. Br J Ophthalmol. 2014;98(6):769–774.
  • Versluis M, de Lange MJ, van Pelt SI, et al. Digital PCR validates 8q dosage as prognostic tool in uveal melanoma. PloS One. 2015;10(3):e0116371.
  • 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):110–114.
  • Parrella P, Caballero OL, Sidransky D, et al. Detection of c-myc amplification in uveal melanoma by fluorescent in situ hybridization. Invest Ophthalmol Vis Sci. 2001;42(8):1679–1684.
  • Robertson AG, Shih J, Yau C, et al. Integrative analysis identifies four molecular and clinical subsets in uveal melanoma. Cancer Cell. 2017;32(2):204–20.e15.
  • Aalto Y, Eriksson L, Seregard S, et al. Concomitant loss of chromosome 3 and whole arm losses and gains of chromosome 1, 6, or 8 in metastasizing primary uveal melanoma. Invest Ophthalmol Vis Sci. 2001;42(2):313–317.
  • Anbunathan H, Verstraten R, Singh AD, et al. Integrative copy number analysis of uveal melanoma reveals novel candidate genes involved in tumorigenesis including a tumor suppressor role for PHF10/BAF45a. Clin Cancer Res off J Am Assoc Cancer Res. 2019;25(16):5156–5166.
  • Bonaldi L, Midena E, Filippi B, et al. FISH analysis of chromosomes 3 and 6 on fine needle aspiration biopsy samples identifies distinct subgroups of uveal melanomas. J Cancer Res Clin Oncol. 2008;134(10):1123–1127.
  • Kilic E, Naus NC, van Gils W, et al. Concurrent loss of chromosome arm 1p and chromosome 3 predicts a decreased disease-free survival in uveal melanoma patients. Invest Ophthalmol Vis Sci. 2005;46(7):2253–2257.
  • Coupland SE, Lake SL, Zeschnigk M, et al. Molecular pathology of uveal melanoma. Eye. 2013;27(2):230–242.
  • 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):1190–1198.
  • Shoushtari AN, Carvajal RD. GNAQ and GNA11 mutations in uveal melanoma. Melanoma Res. 2014;24(6):525–534.
  • Van Raamsdonk CD, Bezrookove V, Green G, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009;457(7229):599–602.
  • Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med. 2010;363(23):2191–2199.
  • 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):813–815.
  • Koopmans AE, Vaarwater J, Paridaens D, et al. Patient survival in uveal melanoma is not affected by oncogenic mutations in GNAQ and GNA11. Br J Cancer. 2013;109(2):493–496.
  • Staby KM, Gravdal K, Mork SJ, et al. Prognostic impact of chromosomal aberrations and GNAQ, GNA11 and BAP1 mutations in uveal melanoma. Acta Ophthalmol. 2018;96(1):31–38.
  • Onken MD, Worley LA, Long MD, et al. Oncogenic mutations in GNAQ occur early in uveal melanoma. Invest Ophthalmol Vis Sci. 2008;49(12):5230–5234.
  • 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):675–680.
  • Johansson P, Aoude LG, Wadt K, et al. Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4. Oncotarget. 2015;7(4):4624–4631.
  • Park JJ, Diefenbach RJ, Joshua AM, et al. Oncogenic signaling in uveal melanoma. Pigment Cell Melanoma Res. 2018;31(6):661–672.
  • Durante MA, Field MG, Sanchez MI, et al. Genomic evolution of uveal melanoma arising in ocular melanocytosis. Cold Spring Harb Mol Case Stud. 2019;5:4.
  • Thornton S, Coupland SE, Olohan L, et al. Targeted next-generation sequencing of 117 routine clinical samples provides further insights into the molecular landscape of uveal melanoma. Cancers (Basel). 2020;12:4.
  • Piaggio F, Tozzo V, Bernardi C, et al. Secondary somatic mutations in G-protein-related pathways and mutation signatures in uveal melanoma. Cancers (Basel). 2019;11:11.
  • Chua V, Lapadula D, Randolph C, et al. Dysregulated GPCR signaling and therapeutic options in uveal melanoma. Mol Cancer Res. 2017;15(5):501–506.
  • Feng X, Degese MS, Iglesias-Bartolome R, et al. Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry. Cancer Cell. 2014;25(6):831–845.
  • Populo H, Vinagre J, Lopes JM, et al. Analysis of GNAQ mutations, proliferation and MAPK pathway activation in uveal melanomas. Br J Ophthalmol. 2011;95(5):715–719.
  • Urtatiz O, Van Raamsdonk CD. Gnaq and Gna11 in the endothelin signaling pathway and melanoma. Front Genet. 2016;7:59.
  • Yu FX, Luo J, Mo JS, et al. Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP. Cancer Cell. 2014;25(6):822–830.
  • Chen X, Wu Q, Tan L, et al. Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations. Oncogene. 2014;33(39):4724–4734.
  • Carvajal RD, Schwartz GK, Tezel T, et al. Metastatic disease from uveal melanoma: treatment options and future prospects. Br J Ophthalmol. 2017;101(1):38–44.
  • Amirouchene-Angelozzi N, Frisch-Dit-Leitz E, Carita G, et al. The mTOR inhibitor Everolimus synergizes with the PI3K inhibitor GDC0941 to enhance anti-tumor efficacy in uveal melanoma. Oncotarget. 2016;7(17):23633–23646.
  • 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 Ophthalmol Vis Sci. 2010;51(1):421–429.
  • Croce M, Ferrini S, Pfeffer U, et al. Targeted therapy of uveal melanoma: recent failures and new perspectives. Cancers (Basel). 2019;11:6.
  • Ho AL, Musi E, Ambrosini G, et al. Impact of combined mTOR and MEK inhibition in uveal melanoma is driven by tumor genotype. PloS One. 2012;7(7):e40439.
  • Masoomian B, Shields JA, Shields CL. Overview of BAP1 cancer predisposition syndrome and the relationship to uveal melanoma. J Curr Ophthalmol. 2018;30(2):102–109.
  • Murali R, Wiesner T, Scolyer RA. Tumours associated with BAP1 mutations. Pathology. 2013;45(2):116–126.
  • Harbour JW, Onken MD, Roberson ED, et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science. 2010;330(6009):1410–1413.
  • Ewens KG, Lalonde E, Richards-Yutz J, et al. Comparison of germline versus somatic BAP1 mutations for risk of metastasis in uveal melanoma. BMC Cancer. 2018;18(1):1172.
  • Farquhar N, Thornton S, Coupland SE, et al. Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma. J Pathol Clin Res. 2017;4(1):26–38.
  • Kalirai H, Dodson A, Faqir S, et al. Lack of BAP1 protein expression in uveal melanoma is associated with increased metastatic risk and has utility in routine prognostic testing. Br J Cancer. 2014 Sep 23;111(7):1373–1380. DOI:10.1038/bjc.2014.417. Epub 2014 Jul 24.
  • Patrone S, Maric I, Rutigliani M, et al. Prognostic value of chromosomal imbalances, gene mutations, and BAP1 expression in uveal melanoma. Genes Chromosomes Cancer. 2018;57(8):387–400.
  • van Essen TH, van Pelt SI, Versluis M, et al. Prognostic parameters in uveal melanoma and their association with BAP1 expression. Br J Ophthalmol. 2014;98(12):1738–1743.
  • Yavuzyigitoglu S, Mensink HW, Smit KN, et al. Metastatic disease in polyploid uveal melanoma patients is associated with BAP1 mutations. Invest Ophthalmol Vis Sci. 2016;57(4):2232–2239.
  • Bononi A, Giorgi C, Patergnani S, et al. BAP1 regulates IP3R3-mediated Ca(2+) flux to mitochondria suppressing cell transformation. Nature. 2017;546(7659):549–553.
  • Daou S, Hammond-Martel I, Mashtalir N, et al. The BAP1/ASXL2 histone H2A deubiquitinase complex regulates cell proliferation and is disrupted in cancer. J Biol Chem. 2015;290(48):28643–28663.
  • Fukuda T, Tsuruga T, Kuroda T, et al. Functional link between BRCA1 and BAP1 through histone H2A, heterochromatin and DNA damage response. Curr Cancer Drug Targets. 2016;16(2):101–109.
  • Yu H, Pak H, Hammond-Martel I, et al. Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair. Proc Natl Acad Sci U S A. 2014;111(1):285–290.
  • 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):856–859.
  • Carbone M, Baumann F, Napolitano A, et al. BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs. J Transl Med. 2012;10:1.
  • Rai K, Pilarski R, Boru G, et al. Germline BAP1 alterations in familial uveal melanoma. Genes Chromosomes Cancer. 2017;56(2):168–174.
  • Furney SJ, Marais R, Pedersen M, et al. SF3B1 mutations are associated with alternative splicing in uveal melanoma. Cancer Discov. 2013;3(10):1122–1129.
  • Afshar AR, Damato BE, Stewart JM, et al. Next-generation sequencing of uveal melanoma for detection of genetic alterations predicting metastasis. Trans Vision Sci Technol. 2019;8(2):18.
  • 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):933–936.
  • Smit KN, van Poppelen NM, Vaarwater J, et al. Combined mutation and copy-number variation detection by targeted next-generation sequencing in uveal melanoma. Mod Pathol. 2018;31(5):763–771.
  • Yavuzyigitoglu S, Koopmans AE, Verdijk RM, et al. Uveal melanomas with SF3B1 mutations: a distinct subclass associated with late-onset metastases. Ophthalmology. 2016;123(5):1118–1128.
  • Harbour JW, Onken MD, Worley LA, et al. Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma. Nat Genet. 2013;45(2):133–135.
  • Ewens KG, Richards-Yutz J, Purrazzella J, et al. Chromosome 3 status combined with BAP1 and EIF1AX mutation profiles are associated with metastasis in uveal melanoma. Invest Ophthalmol Visual Sci. 2014;55(8):5160–5167.
  • Dono M, Angelini G, Cecconi M, et al. Mutation frequencies of GNAQ, GNA11, BAP1, SF3B1, EIF1AX and TERT in uveal melanoma: detection of an activating mutation in the TERT gene promoter in a single case of uveal melanoma. Br J Cancer. 2014;110(4):1058–1065.
  • van Poppelen NM, Drabarek W, Smit KN, et al. SRSF2 mutations in uveal melanoma: a preference for in-frame deletions? Cancers (Basel). 2019;11:8.
  • Kim E, Ilagan JO, Liang Y, et al. srsf2 mutations contribute to myelodysplasia by mutant-specific effects on exon recognition. Cancer Cell. 2015;27(5):617–630.
  • Field MG, Durante MA, Anbunathan H, et al. Punctuated evolution of canonical genomic aberrations in uveal melanoma. Nat Commun. 2018;9(1):116.
  • Komeno Y, Huang YJ, 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):3071–3082.
  • 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):2578–2584.
  • 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):7205–7209.
  • Harbour JW. Molecular prognostic testing and individualized patient care in uveal melanoma. Am J Ophthalmol. 2009;148(6):823–9.e1.
  • Onken MD, Worley LA, Char DH, et al. Collaborative ocular oncology group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology. 2012;119(8):1596–1603.
  • Klufas MA, McCannel TA. Response to “comparison of gene expression profiling and chromosome 3 analysis by fluorescent in situ hybridization and multiplex ligation probe amplification in fine-needle aspiration biopsy specimens of uveal melanoma”. Ocul Oncol Pathol. 2018;4(3):191.
  • Seider MI, Stewart PJ, Mishra KK, et al. Uveal melanoma gene expression profile test result provided for uveal metastasis. Ophthalmic Surg Lasers Imaging Retina. 2014;45(5):441–442.
  • Mulero-Navarro S, Esteller M. Epigenetic biomarkers for human cancer: the time is now. Crit Rev Oncol Hematol. 2008;68(1):1–11.
  • Fearon ER. Molecular genetics of colorectal cancer. Annu Rev Pathol. 2011;6:479–507.
  • Neumann LC, Weinhausel A, Thomas S, et al. EFS shows biallelic methylation in uveal melanoma with poor prognosis as well as tissue-specific methylation. BMC Cancer. 2011;11:380.
  • Zeschnigk M, Tschentscher F, Lich C, et al. Methylation analysis of several tumour suppressor genes shows a low frequency of methylation of CDKN2A and RARB in uveal melanomas. Comp Funct Genomics. 2003;4(3):329–336.
  • Moulin AP, Clement G, Bosman FT, et al. Methylation of CpG island promoters in uveal melanoma. Br J Ophthalmol. 2008;92(2):281–285.
  • Maat W, Beiboer SH, Jager MJ, et al. van der Velden PA. Epigenetic regulation identifies RASEF as a tumor-suppressor gene in uveal melanoma. Invest Ophthalmol Vis Sci. 2008;49(4):1291–1298.
  • van der Velden PA, Zuidervaart W, Hurks MH, et al. Expression profiling reveals that methylation of TIMP3 is involved in uveal melanoma development. Int J Cancer. 2003;106(4):472–479.
  • 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):5303–5306.
  • Merbs SL, Sidransky D. Analysis of p16 (CDKN2/MTS-1/INK4A) alterations in primary sporadic uveal melanoma. Invest Ophthalmol Vis Sci. 1999;40(3):779–783.
  • Venza M, Visalli M, Biondo C, et al. Epigenetic regulation of p14ARF and p16INK4A expression in cutaneous and uveal melanoma. Biochim Biophys Acta. 2015;1849(3):247–256.
  • Maat W, van der Velden PA, Out-Luiting C, et al. Epigenetic inactivation of RASSF1a in uveal melanoma. Invest Ophthalmol Vis Sci. 2007;48(2):486–490.
  • Calipel A, Abonnet V, Nicole O, et al. Status of RASSF1A in uveal melanocytes and melanoma cells. Mol Cancer Res. 2011;9(9):1187–1198.
  • Merhavi E, Cohen Y, Avraham BC, et al. Promoter methylation status of multiple genes in uveal melanoma. Invest Ophthalmol Vis Sci. 2007;48(10):4403–4406.
  • Dratviman-Storobinsky O, Cohen Y, Frenkel S, et al. The role of RASSF1A in uveal melanoma. Invest Ophthalmol Vis Sci. 2012;53(6):2611–2619.
  • Field MG, Durante MA, Decatur CL, et al. Epigenetic reprogramming and aberrant expression of PRAME are associated with increased metastatic risk in class 1 and class 2 uveal melanomas. Oncotarget. 2016;7(37):59209–59219.
  • Gezgin G, Luk SJ, Cao J, et al. PRAME as a potential target for immunotherapy in metastatic uveal melanoma. JAMA Ophthalmol. 2017;135(6):541–549.
  • Griewank KG, Koelsche C, van de Nes JAP, et al. Integrated genomic classification of melanocytic tumors of the central nervous system using mutation analysis, copy number alterations, and DNA methylation profiling. Clin Cancer Res off J Am Assoc Cancer Res. 2018;24(18):4494–4504.
  • van der Velden PA, Maat W. Methylation in uveal melanoma. Br J Ophthalmol. 2009;93(1):132.
  • Esquela-Kerscher A, Slack FJ. Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer. 2006;6(4):259–269.
  • Liu N, Sun Q, Chen J, et al. MicroRNA-9 suppresses uveal melanoma cell migration and invasion through the NF-kappaB1 pathway. Oncol Rep. 2012;28(3):961–968.
  • Londin E, Magee R, Shields CL, et al. IsomiRs and tRNA-derived fragments are associated with metastasis and patient survival in uveal melanoma. Pigment Cell Melanoma Res. 2020;33(1):52–62.
  • Radhakrishnan A, Badhrinarayanan N, Biswas J, et al. Analysis of chromosomal aberration (1, 3, and 8) and association of microRNAs in uveal melanoma. Mol Vis. 2009;15:2146–2154.
  • Smit KN, Chang J, Derks K, et al. Aberrant microRNA expression and its implications for uveal melanoma metastasis. Cancers (Basel). 2019;11:6.
  • Sun L, Bian G, Meng Z, et al. MiR-144 inhibits uveal melanoma cell proliferation and invasion by regulating c-met expression. PloS One. 2015;10(5):e0124428.
  • Triozzi PL, Achberger S, Aldrich W, et al. Association of tumor and plasma microRNA expression with tumor monosomy-3 in patients with uveal melanoma. Clin Epigenetics. 2016;8:80.
  • Wang YC, Yang X, Wei WB, et al. Role of microRNA-21 in uveal melanoma cell invasion and metastasis by regulating p53 and its downstream protein. Int J Ophthalmol. 2018;11(8):1258–1268.
  • Worley LA, Long MD, Onken MD, et al. Micro-RNAs associated with metastasis in uveal melanoma identified by multiplexed microarray profiling. Melanoma Res. 2008;18(3):184–190.
  • Garzon R, Marcucci G, Croce CM. Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug Discov. 2010;9(10):775–789.
  • Eldh M, Olofsson Bagge R, Lasser C, et al. MicroRNA in exosomes isolated directly from the liver circulation in patients with metastatic uveal melanoma. BMC Cancer. 2014;14:962.
  • Hou Q, Han S, Yang L, et al. The interplay of microRNA-34a, LGR4, EMT-associated factors, and MMP2 in regulating uveal melanoma cells. Invest Ophthalmol Vis Sci. 2019;60(13):4503–4510.
  • 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):1559–1565.
  • Dong F, Lou D. MicroRNA-34b/c suppresses uveal melanoma cell proliferation and migration through multiple targets. Mol Vis. 2012;18:537–546.
  • Liu J, Ma L, Li C, et al. Tumor-targeting TRAIL expression mediated by miRNA response elements suppressed growth of uveal melanoma cells. Mol Oncol. 2013;7(6):1043–1055.
  • Torres R, Lang UE, Hejna M, et al. MicroRNA ratios distinguish melanomas from nevi. J Invest Dermatol. 2020;140(1):164–73.e7.
  • Falzone L, Romano GL, Salemi R, et al. Prognostic significance of deregulated microRNAs in uveal melanomas. Mol Med Rep. 2019;19(4):2599–2610.
  • Stark MS, Gray ES, Isaacs T, et al. A panel of circulating microRNAs detects uveal melanoma with high precision. Trans Vision Sci Technol. 2019;8(6):12.
  • Eleuteri A, Damato B, Coupland SE, et al. Enhancing survival prognostication in patients with choroidal melanoma by integrating pathologic, clinical and genetic predictors of metastasis. Int J Biomed Eng Technol. 2012;8(1):18–35.
  • DeParis SW, Taktak A, Eleuteri A, et al. External validation of the liverpool uveal melanoma prognosticator online. Invest Ophthalmol Vis Sci. 2016;57(14):6116–6122.
  • Rospond-Kubiak I, Wroblewska-Zierhoffer M, Twardosz-Pawlik H, et al. The liverpool uveal melanoma prognosticator online (LUMPO) for prognosing metastasis free survival in the absence of cytogenetic data after ruthenium brachytherapy for uveal melanoma. Acta Ophthalmol. 2015;93:S255.
  • Cunha Rola A, Taktak A, Eleuteri A, et al. Multicenter external validation of the liverpool uveal melanoma prognosticator online: an OOG collaborative study. Cancers (Basel). 2020;12(2):477.
  • Vaquero-Garcia J, Lalonde E, Ewens KG, et al. PRiMeUM: a model for predicting risk of metastasis in uveal melanoma. Invest Ophthalmol Vis Sci. 2017;58(10):4096–4105.
  • Bol KF, Mensink HW, Aarntzen EH, et al. Long overall survival after dendritic cell vaccination in metastatic uveal melanoma patients. Am J Ophthalmol. 2014;158(5):939–947.
  • Bol KF, van den Bosch T, Schreibelt G, et al. Adjuvant dendritic cell vaccination in high-risk uveal melanoma. Ophthalmology. 2016;123(10):2265–2267.
  • Schuler-Thurner B, Bartz-Schmidt KU, Bornfeld N, et al. [Immunotherapy of uveal melanoma: vaccination against cancer. Multicenter adjuvant phase 3 vaccination study using dendritic cells laden with tumor RNA for large newly diagnosed uveal melanoma]. Der Ophthalmologe: Zeitschrift der Deutschen Ophthalmologischen Gesellschaft. 2015;112(12):1017–1021.
  • Zimmer L, Vaubel J, Mohr P, et al. Phase II DeCOG-study of ipilimumab in pretreated and treatment-naive patients with metastatic uveal melanoma. PloS One. 2015;10(3):e0118564.
  • Heppt MV, Heinzerling L, Kahler KC, et al. Prognostic factors and outcomes in metastatic uveal melanoma treated with programmed cell death-1 or combined PD-1/cytotoxic T-lymphocyte antigen-4 inhibition. Eur J Cancer. 1990;2017(82):56–65.
  • Algazi AP, Tsai KK, Shoushtari AN, et al. Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies. Cancer. 2016;122(21):3344–3353.
  • Khoja L, Atenafu EG, Suciu S, et al. Meta-analysis in metastatic uveal melanoma to determine progression free and overall survival benchmarks: an international rare cancers initiative (IRCI) ocular melanoma study. Ann Oncol. 2019;30(8):1370–1380.
  • Spagnolo F, Grosso M, Picasso V, et al. Treatment of metastatic uveal melanoma with intravenous fotemustine. Melanoma Res. 2013;23(3):196–198.
  • Schmittel A, Schmidt-Hieber M, Martus P, et al. A randomized phase II trial of gemcitabine plus treosulfan versus treosulfan alone in patients with metastatic uveal melanoma. Ann Oncol. 2006;17(12):1826–1829.
  • Homsi J, Bedikian AY, Papadopoulos NE, et al. Phase 2 open-label study of weekly docosahexaenoic acid-paclitaxel in patients with metastatic uveal melanoma. Melanoma Res. 2010;20(6):507–510.
  • Steeb T, Wessely A, Ruzicka T, et al. How to MEK the best of uveal melanoma: A systematic review on the efficacy and safety of MEK inhibitors in metastatic or unresectable uveal melanoma. Eur J Cancer. 2018;103:41–51.
  • Piperno-Neumann S, Kapiteijn E, Larkin JMG, et al. Phase I dose-escalation study of the protein kinase C (PKC) inhibitor AEB071 in patients with metastatic uveal melanoma. J Clin Oncol. 2014;32(15_suppl):9030.

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