Skip to main content

Molecular Basis of Uveal Melanoma and Emerging Therapeutic Targets

  • Chapter
  • First Online:
Uveal Melanoma

Abstract

Key genetic events and their relationship to prognosis in uveal melanoma (UM) have been elucidated recently. While not predictive of metastasis, Gαq pathway mutations are initiating events that are present in almost all UM. Molecular classification based on gene expression profile (GEP) has been found to be more accurate than clinical, histopathologic, and chromosomal prognostic factors, and it has been prospectively validated as a clinical test that is now widely used for routine patient prognostication. The two most important predictors of metastasis in UM are (1) the class 2 GEP caused by loss of BAP1 and (2) aberrant expression of the cancer-testis-antigen PRAME. Driver mutations have received extensive attention in UM to address the need for systemic targeted therapy through the inhibition of downstream signaling pathways.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 69.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 89.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Diener-West M, Reynolds SM, Agugliaro DJ, Caldwell R, Cumming K, Earle JD, et al. Development of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma: Collaborative Ocular Melanoma Study Group Report No. 26. Arch Ophthalmol. 2005;123(12):1639–43.

    Article  PubMed  Google Scholar 

  2. Augsburger JJ, Gamel JW. Clinical prognostic factors in patients with posterior uveal malignant melanoma. Cancer. 1990;66(7):1596–600.

    Article  CAS  PubMed  Google Scholar 

  3. Mooy CM, De Jong PT. Prognostic parameters in uveal melanoma: a review. Surv Ophthalmol. 1996;41(3):215–28.

    Article  CAS  PubMed  Google Scholar 

  4. 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;64:7205–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Worley LA, Onken MD, Person E, Robirds D, Branson J, Char DH, et al. Transcriptomic versus chromosomal prognostic markers and clinical outcome in uveal melanoma. Clin Cancer Res. 2007;13(5):1466–71.

    Article  CAS  PubMed  Google Scholar 

  6. Onken MD, Worley LA, Tuscan MD, Harbour JW. An accurate, clinically feasible multi-gene expression assay for predicting metastasis in uveal melanoma. J Mol Diagn. 2010;12(4):461–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Onken MD, Worley LA, Char DH, Augsburger JJ, Correa ZM, Nudleman E, et al. Collaborative ocular oncology group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology. 2012;119(8):1596–603.

    Article  PubMed  Google Scholar 

  8. Harbour JW, Chen R. The DecisionDx-UM gene expression profile test provides risk stratification and individualized patient care in uveal melanoma. PLoS Curr. 2013;5:1–7.

    Google Scholar 

  9. Aaberg TM Jr, Cook RW, Oelschlager K, Maetzold D, Rao PK, Mason JO 3rd. Current clinical practice: differential management of uveal melanoma in the era of molecular tumor analyses. Clin Ophthalmol. 2014;8:2449–60.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Aaberg TM, Covington KR, Tsai T, Shildkrot Y, Plasseraud KM, Alsina KM, et al. Gene expression profiling in uveal melanoma: five-year prospective outcomes and meta-analysis. Ocul Oncol Pathol. 2020;6(5):360–7.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA, et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science. 2010;330(6009):1410–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Onken MD, Ehlers JP, Worley LA, Makita J, Yokota Y, Harbour JW. Functional gene expression analysis uncovers phenotypic switch in aggressive uveal melanomas. Cancer Res. 2006;66(9):4602–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Matatall KA, Agapova OA, Onken MD, Worley LA, Bowcock AM, Harbour JW. BAP1 deficiency causes loss of melanocytic cell identity in uveal melanoma. BMC Cancer. 2013;13(1):371.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Harbour JW, Roberson ED, Anbunathan H, Onken MD, Worley LA, Bowcock AM. Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma. Nat Genet. 2013;45(2):133–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Martin M, Masshofer L, Temming P, Rahmann S, Metz C, Bornfeld N, et al. Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3. Nat Genet. 2013;45:933–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Decatur CL, Ong E, Garg N, Anbunathan H, Bowcock AM, Field MG, et al. Driver mutations in uveal melanoma: associations with gene expression profile and patient outcomes. JAMA Ophthalmol. 2016;134(7):728–33.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Field MG, Decatur CL, Kurtenbach S, Gezgin G, van der Velden PA, Jager MJ, et al. PRAME as an independent biomarker for metastasis in uveal melanoma. Clin Cancer Res. 2016;22(5):1234–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Field MG, Durante MA, Decatur CL, Tarlan B, Oelschlager KM, Stone JF, 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):59209–19.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Epping MT, Wang L, Edel MJ, Carlee L, Hernandez M, Bernards R. The human tumor antigen PRAME is a dominant repressor of retinoic acid receptor signaling. Cell. 2005;122(6):835–47.

    Article  CAS  PubMed  Google Scholar 

  20. Schefler AC, Koca E, Bernicker EH, Correa ZM. Relationship between clinical features, GEP class, and PRAME expression in uveal melanoma. Graefes Arch Clin Exp Ophthalmol. 2019;257(7):1541–5.

    Article  CAS  PubMed  Google Scholar 

  21. Field MG, Durante MA, Anbunathan H, Cai LZ, Decatur CL, Bowcock AM, et al. Punctuated evolution of canonical genomic aberrations in uveal melanoma. Nat Commun. 2018;9(1):116.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Onken MD, Worley LA, Long MD, Duan S, Council ML, Bowcock AM, et al. Oncogenic mutations in GNAQ occur early in uveal melanoma. Invest Ophthalmol Vis Sci. 2008;49(12):5230–4.

    Article  PubMed  Google Scholar 

  23. Van Raamsdonk CD, Bezrookove V, Green G, Bauer J, Gaugler L, O’Brien JM, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009;457(7229):599–602.

    Article  PubMed  CAS  Google Scholar 

  24. Van Raamsdonk CD, Griewank KG, Crosby MB, Garrido MC, Vemula S, Wiesner T, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med. 2010;363(23):2191–9.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Johansson P, Aoude LG, Wadt K, Glasson WJ, Warrier SK, Hewitt AW, et al. Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4. Oncotarget. 2016;7(4):4624–31.

    Article  PubMed  Google Scholar 

  26. Moore AR, Ceraudo E, Sher JJ, Guan Y, Shoushtari AN, Chang MT, et al. Recurrent activating mutations of G-protein-coupled receptor CYSLTR2 in uveal melanoma. Nat Genet. 2016;48(6):675–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Greenstein MB, Myers CE, Meuer SM, Klein BE, Cotch MF, Wong TY, et al. Prevalence and characteristics of choroidal nevi: the multi-ethnic study of atherosclerosis. Ophthalmology. 2011;118(12):2468–73.

    Article  PubMed  Google Scholar 

  28. Sumich P, Mitchell P, Wang JJ. Choroidal nevi in a white population: the Blue Mountains eye study. Arch Ophthalmol. 1998;116(5):645–50.

    Article  CAS  PubMed  Google Scholar 

  29. White VA, McNeil BK, Thiberville L, Horsman DE. Acquired homozygosity (isodisomy) of chromosome 3 during clonal evolution of a uveal melanoma: association with morphologic heterogeneity. Genes Chromosomes Cancer. 1996;15(2):138–43.

    Article  CAS  PubMed  Google Scholar 

  30. Onken MD, Worley LA, Person E, Char DH, Bowcock AM, Harbour JW. 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.

    Article  CAS  PubMed  Google Scholar 

  31. Robertson AG, Shih J, Yau C, Gibb EA, Oba J, Mungall KL, et al. Integrative analysis identifies four molecular and clinical subsets in uveal melanoma. Cancer Cell. 2017;32(2):204–20 e15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yavuzyigitoglu S, Koopmans AE, Verdijk RM, Vaarwater J, Eussen B, van Bodegom A, et al. Uveal melanomas with SF3B1 mutations: a distinct subclass associated with late-onset metastases. Ophthalmology. 2016;123(5):1118–28.

    Article  PubMed  Google Scholar 

  33. Nik-Zainal S, Van Loo P, Wedge DC, Alexandrov LB, Greenman CD, Lau KW, et al. The life history of 21 breast cancers. Cell. 2012;149(5):994–1007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Shain AH, Bagger MM, Yu R, Chang D, Liu S, Vemula S, et al. The genetic evolution of metastatic uveal melanoma. Nat Genet. 2019;51(7):1123–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Annala S, Feng X, Shridhar N, Eryilmaz F, Patt J, Yang J, et al. Direct targeting of Galphaq and Galpha11 oncoproteins in cancer cells. Sci Signal. 2019;12(573):eaau5948.

    Article  PubMed  CAS  Google Scholar 

  36. Feng X, Degese MS, Iglesias-Bartolome R, Vaque JP, Molinolo AA, Rodrigues M, 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):831–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yu FX, Luo J, Mo JS, Liu G, Kim YC, Meng Z, et al. Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP. Cancer Cell. 2014;25(6):822–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yoo JH, Shi DS, Grossmann AH, Sorensen LK, Tong Z, Mleynek TM, et al. ARF6 is an actionable node that orchestrates oncogenic GNAQ signaling in uveal melanoma. Cancer Cell. 2016;29(6):889–904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Feng X, Arang N, Rigiracciolo DC, Lee JS, Yeerna H, Wang Z, et al. A platform of synthetic lethal gene interaction networks reveals that the GNAQ Uveal melanoma oncogene controls the hippo pathway through FAK. Cancer Cell. 2019;35(3):457–472.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Carvajal RD, Sosman JA, Quevedo JF, Milhem MM, Joshua AM, Kudchadkar RR, et al. Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. JAMA. 2014;311(23):2397–405.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Amirouchene-Angelozzi N, Frisch-Dit-Leitz E, Carita G, Dahmani A, Raymondie C, Liot 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):23633–46.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Khalili JS, Yu X, Wang J, Hayes BC, Davies MA, Lizee G, et al. Combination small molecule MEK and PI3K inhibition enhances uveal melanoma cell death in a mutant GNAQ- and GNA11-dependent manner. Clin Cancer Res. 2012;18(16):4345–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. de Koning L, Decaudin D, El Botty R, Nicolas A, Carita G, Schuller M, et al. PARP inhibition increases the response to chemotherapy in uveal melanoma. Cancers (Basel). 2019;11(6):751.

    Article  CAS  Google Scholar 

  44. George TJ, DeRemer DL, Parekh HD, Lee J-H, Markham MJ, Daily KC, et al. Phase II trial of the PARP inhibitor, niraparib, in BAP1 and other DNA damage response (DDR) pathway deficient neoplasms including cholangiocarcinoma. J Clin Oncol. 2020;38(4_suppl):TPS591.

    Article  Google Scholar 

  45. Kuznetsov JN, Aguero TH, Owens DA, Kurtenbach S, Field MG, Durante MA, et al. BAP1 regulates epigenetic switch from pluripotency to differentiation in developmental lineages giving rise to BAP1-mutant cancers. Sci Adv. 2019;5(9):eaax1738.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Landreville S, Agapova OA, Matatall KA, Kneass ZT, Onken MD, Lee RS, et al. Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma. Clin Cancer Res. 2012;18(2):408–16.

    Article  CAS  PubMed  Google Scholar 

  47. Kuznetsoff JN, Owens DA, Lopez A, Rodriguez DA, Chee NT, Kurtenbach S, et al. Dual screen for efficacy and toxicity identifies HDAC inhibitor with distinctive activity spectrum for BAP1-mutant uveal melanoma. Mol Cancer Res. 2020;19(2):215–22.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Ikeda H, Lethe B, Lehmann F, van Baren N, Baurain JF, de Smet C, et al. Characterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor. Immunity. 1997;6(2):199–208.

    Article  CAS  PubMed  Google Scholar 

  49. Gezgin G, Luk SJ, Cao J, Dogrusoz M, van der Steen DM, Hagedoorn RS, et al. PRAME as a potential target for immunotherapy in metastatic Uveal melanoma. JAMA Ophthalmol. 2017;135(6):541–9.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Kwon J, Bakhoum SF. The cytosolic DNA-sensing cGAS-STING pathway in cancer. Cancer Discov. 2020;10(1):26–39.

    Article  CAS  PubMed  Google Scholar 

  51. Flood BA, Higgs EF, Li S, Luke JJ, Gajewski TF. STING pathway agonism as a cancer therapeutic. Immunol Rev. 2019;290(1):24–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Pelster MS, Gruschkus SK, Bassett R, Gombos DS, Shephard M, Posada L, et al. Nivolumab and Ipilimumab in metastatic uveal melanoma: results from a single-arm phase II study. J Clin Oncol. 2021;39(6):599–607.

    Article  PubMed  Google Scholar 

  53. Middleton MR, McAlpine C, Woodcock VK, Corrie P, Infante JR, Steven NM, et al. Tebentafusp, a TCR/anti-CD3 bispecific fusion protein targeting gp100, potently activated antitumor immune responses in patients with metastatic melanoma. Clin Cancer Res. 2020;26(22):5869–78.

    Article  CAS  PubMed  Google Scholar 

  54. Chandran SS, Somerville RPT, Yang JC, Sherry RM, Klebanoff CA, Goff SL, et al. Treatment of metastatic uveal melanoma with adoptive transfer of tumour-infiltrating lymphocytes: a single-centre, two-stage, single-arm, phase 2 study. Lancet Oncol. 2017;18(6):792–802.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Durante MA, Rodriguez DA, Kurtenbach S, Kuznetsov JN, Sanchez MI, Decatur CL, et al. Single-cell analysis reveals new evolutionary complexity in uveal melanoma. Nat Commun. 2020;11(1):496.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Karlsson J, Nilsson LM, Mitra S, Alsen S, Shelke GV, Sah VR, et al. Molecular profiling of driver events in metastatic uveal melanoma. Nat Commun. 2020;11(1):1894.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Aoude LG, Wadt K, Bojesen A, Cruger D, Borg A, Trent JM, et al. A BAP1 mutation in a Danish family predisposes to uveal melanoma and other cancers. PLoS One. 2013;8(8):e72144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Aoude LG, Vajdic CM, Kricker A, Armstrong B, Hayward NK. Prevalence of germline BAP1 mutation in a population-based sample of uveal melanoma cases. Pigment Cell Melanoma Res. 2013;26(2):278–9.

    Article  PubMed  Google Scholar 

  59. Krishna Y, Acha-Sagredo A, Sabat-Pospiech D, Kipling N, Clarke K, Figueiredo CR, et al. Transcriptome profiling reveals new insights into the immune microenvironment and upregulation of novel biomarkers in metastatic uveal melanoma. Cancers (Basel). 2020;12(10):2832.

    Article  CAS  Google Scholar 

  60. Bauer J, Kilic E, Vaarwater J, Bastian BC, Garbe C, de Klein A. Oncogenic GNAQ mutations are not correlated with disease-free survival in uveal melanoma. Br J Cancer. 2009;101(5):813–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ambrosini G, Pratilas CA, Qin LX, Tadi M, Surriga O, Carvajal RD, et al. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ho AL, Musi E, Ambrosini G, Nair JS, Deraje Vasudeva S, de Stanchina E, et al. Impact of combined mTOR and MEK inhibition in uveal melanoma is driven by tumor genotype. PLoS One. 2012;7(7):e40439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Khan S, Lutzky J, Shoushtari AN, Jeter JM, Chiuzan C, Sender N, et al. Adjuvant crizotinib in high-risk uveal melanoma following definitive therapy. J Clin Oncol. 2020;38(15_suppl):10075.

    Article  Google Scholar 

  64. Gonsalves CF, Eschelman DJ, Adamo RD, Anne PR, Orloff MM, Terai M, et al. A prospective phase II trial of radioembolization for treatment of uveal melanoma hepatic metastasis. Radiology. 2019;293(1):223–31.

    Article  PubMed  Google Scholar 

  65. Valsecchi ME, Orloff M, Sato R, Chervoneva I, Shields CL, Shields JA, et al. Adjuvant Sunitinib in high-risk patients with uveal melanoma: comparison with institutional controls. Ophthalmology. 2018;125(2):210–7.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J. William Harbour .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2021 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Harbour, J.W., Correa, Z.M. (2021). Molecular Basis of Uveal Melanoma and Emerging Therapeutic Targets. In: Bernicker, E.H. (eds) Uveal Melanoma. Springer, Cham. https://doi.org/10.1007/978-3-030-78117-0_1

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-78117-0_1

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-78116-3

  • Online ISBN: 978-3-030-78117-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics