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Tumor Biology

, Volume 35, Issue 12, pp 11711–11717 | Cite as

Genetic determinants of uveal melanoma

  • Jasbir Kaur
  • Manzoor Ahmad Malik
  • Rishabh Gulati
  • Shorya Vardhan Azad
  • Sandeep Goswami
Review

Abstract

Melanoma of the uveal tract is the most common primary intraocular tumor in adults. With advances in genetic research and the open source access of genetic databases, new insights are emerging into the molecular changes of this cancer. As with most other tumors, the driving force behind such research is the hope of finding and developing new modalities for therapeutic purposes, prognosticating disease and understanding risk factors for metastasis. With advances in proteomics, cytogenetics and gene profiling, the stage is set to unearth the underlying genetic basis which can in the future be a target of therapeutic modalities. This article describes the cytogenetic, molecular pathogenesis, and prognostic factors along with the most important findings and their attribution to current and future management of uveal melanoma.

Keywords

Uveal melanoma Genetics Metastasis 

Notes

Conflicts of interest

None

References

  1. 1.
    Swerdlow AJ. Epidemiology of melanoma of the eye in the Oxford Region, 1952–78. Br J Cancer. 1983;47:311–3.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Pach JM, Robertson DM. Metastasis from untreated uveal melanomas. Arch Ophthalmol. 1986;104:1624–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Rajpal S, Moore R, Karakousis CP. Survival in metastatic ocular melanoma. Cancer. 1983;52:334–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Brantley Jr MA, Harbour JW. Inactivation of retinoblastoma protein in uveal melanoma by phosphorylation of sites in the COOH-terminal region. Cancer Res. 2000;16:4320–3.Google Scholar
  5. 5.
    Delston RB, Harbour JW. Rb at the interface between cell cycle and apoptotic decisions. Curr Mol Med. 2006;7:713–8.Google Scholar
  6. 6.
    Das SK, Hashimoto T, Shimizu K, Yoshida T, Sakai T, Sowa Y, et al. Fucoxanthin induces cell cycle arrest at G0/G1 phase in human colon carcinoma cells through up-regulation of p21WAF1/Cip1. Biochim Biophys Acta. 2005;1726:328–35.PubMedCrossRefGoogle Scholar
  7. 7.
    Landreville S, Agapova OA, Harbour JW. Emerging insights into the molecular pathogenesis of uveal melanoma. Future Oncol. 2008;4:629–36.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    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;23:2191–9.CrossRefGoogle Scholar
  9. 9.
    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;457:599–602.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Ehlers JP, Harbour JW. NBS1 expression as a prognostic marker in uveal melanoma. Clin Cancer Res. 2005;11:849–53.Google Scholar
  11. 11.
    van den Bosch T, Kilic E, Paridaens D, de Klein A. Genetics of uveal melanoma and cutaneous melanoma: two of a kind? Dermatol Res Pract. 2010;2010:360136.PubMedCentralPubMedGoogle Scholar
  12. 12.
    Ehlers JP, Worley L, Onken MD, Harbour JW. DDEF1 is located in an amplified region of chromosome 8q and is overexpressed in uveal melanoma. Clin Cancer Res. 2005;11:3609–13.PubMedCrossRefGoogle Scholar
  13. 13.
    Coupland SE, Anastassiou G, Stang A, Schilling H, Anagnostopoulos I, Bornfeld N, et al. The prognostic value of cyclin D1, p53, and MDM2 protein expression in uveal melanoma. J Pathol. 2000;191:120–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Harbour JW, Worley L, Ma D, Cohen M. Transducible peptide therapy for uveal melanoma and retinoblastoma. Arch Ophthalmol. 2002;120:1341–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Sulkowska M, Famulski W, Bakunowicz-Lazarczyk A, Chyczewski L, Sulkowski S. Bcl-2 expression in primary uveal melanoma. Tumori. 2001;87:54–7.PubMedGoogle Scholar
  16. 16.
    Krvavica A, Talan-Hranilović J, Belicza M. Expression of bcl-2, Ki-67 and p-53 in uveal melanoma. Acta Med Croatica. 2008;62:267–71.PubMedGoogle Scholar
  17. 17.
    Brantley Jr MA, Harbour JW. Deregulation of the Rb and p53 pathways in uveal melanoma. Am J Pathol. 2000;157:1795–801.PubMedCrossRefGoogle Scholar
  18. 18.
    Abdel-Rahman MH, Yang Y, Zhou XP, Craig EL, Davidorf FH, Eng C. High frequency of submicroscopic hemizygous deletion is a major mechanism of loss of expression of PTEN in uveal melanoma. J Clin Onco. 2006;24:288–95.CrossRefGoogle Scholar
  19. 19.
    Economou MA, Andersson S, Vasilcanu D, All-Ericsson C, Menu E, Girnita A, et al. Oral picropodophyllin (PPP) is well tolerated in vivo and inhibits IGF-1R expression and growth of uveal melanoma. Invest Ophthalmol Vis Sci. 2008;49:2337–42.PubMedCrossRefGoogle Scholar
  20. 20.
    Chen X, Wang J, Shen H, Lu J, Li C, Hu DN, et al. Epigenetics, microRNAs, and carcinogenesis: functional role of microRNA-137 in uveal melanoma. Invest Ophthalmol Vis Sci. 2011;52:1193–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Williams AE. Functional aspects of animal microRNAs. Cell Mol Life Sci. 2008;65:545–62.PubMedCrossRefGoogle Scholar
  22. 22.
    Eulalio A, Huntzinger E, Nishihara T, Rehwinkel J, Fauser M, Izaurralde E. Deadenylation is a widespread effect of miRNA regulation. RNA. 2009;15:21–32.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Radhakrishnan A, Badhrinarayanan N, Biswas J, Krishnakumar S. Analysis of chromosomal aberration (1, 3 and 8) and association of microRNAs in uveal melanoma. Mol Vis. 2009;15:2146–54.PubMedCentralPubMedGoogle Scholar
  24. 24.
    Maat W, van der Velden PA, Out-Luiting C, Plug M, Dirks-Mulder A, Jager MJ, et al. Epigenetic inactivation of RASSF1a in uveal melanoma. Invest Ophthalmol Vis Sci. 2007;48:486–90.PubMedCrossRefGoogle Scholar
  25. 25.
    Naus NC, van Drunen E, de Klein A, Luyten GP, Paridaens DA, Alers JC, et al. Characterization of complex chromosomal abnormalities in uveal melanoma by fluorescence in situ hybridization, spectral karyotyping, and comparative genomic hybridization. Genes Chromosomes Cancer. 2001;30:267–73.PubMedCrossRefGoogle Scholar
  26. 26.
    Lake SL, Damato BE, Dopierala J, Baudo MM, Taktak AF, Coupland SE. Multiplex ligation-dependent probe amplification analysis of uveal melanoma with extraocular extension demonstrates heterogeneity of gross chromosomal abnormalities. Invest Ophthalmol Vis Sci. 2011;52:5559–64.PubMedCrossRefGoogle Scholar
  27. 27.
    Häusler T, Stang A, Anastassiou G, Jöckel KH, Mrzyk S, Horsthemke B, et al. Loss of heterozygosity of 1p in uveal melanomas with monosomy 3. Int J Cancer. 2005;116:909–13.PubMedCrossRefGoogle Scholar
  28. 28.
    Aalto Y, Eriksson L, Seregard S, Larsson O, Knuutila S. 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;42:313–7.PubMedGoogle Scholar
  29. 29.
    van den Bosch T, van Beek JG, Vaarwater J, Verdijk RM, Naus NC, Paridaens D, et al. Higher percentage of FISH-determined monosomy 3 and 8q amplification in uveal melanoma cells relate to poor patient prognosis. Invest Ophthalmol Vis Sci. 2012;53:2668–74.PubMedCrossRefGoogle Scholar
  30. 30.
    Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA, et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science. 2010;330:1410–3.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Wiesner T, Obenauf AC, Murali R, Fried I, Griewank KG, Ulz P, et al. Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet. 2011;43:1018–21.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    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;14:3737–45.PubMedCrossRefGoogle Scholar
  33. 33.
    Merbs SL, Sidransky D. Analysis of p16 (CDKN2/MTS-1/INK4A) alterations in primary sporadic uveal melanoma. Invest Ophthalmol Vis Sci. 1999;40:779–83.PubMedGoogle Scholar
  34. 34.
    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.PubMedCrossRefGoogle Scholar
  35. 35.
    Kujala E, Mäkitie T, Kivelä T. Very long-term prognosis of patients with malignant uveal melanoma. Invest Ophthalmol Vis Sci. 2003;44:4651–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Lorigan JG, Wallace S, Mavligit GM. The prevalence and location of metastases from ocular melanoma: imaging study in 110 patients. AJR Am J Roentgenol. 1991;157:1279–81.PubMedCrossRefGoogle Scholar
  37. 37.
    Eskelin S, Pyrhönen S, Summanen P, Hahka-Kemppinen M, Kivelä T. Tumor doubling times in metastatic malignant melanoma of the uvea: tumor progression before and after treatment. Ophthalmology. 2000;107:1443–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Bakalian S, Marshall JC, Logan P, Faingold D, Maloney S, Di Cesare S, et al. Molecular pathways mediating liver metastasis in patients with uveal melanoma. Clin Cancer Res. 2008;14:951–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Di Cesare S, Marshall JC, Logan P, Antecka E, Faingold D, Maloney SC, et al. Expression and migratory analysis of 5 human uveal melanoma cell lines for CXCL12, CXCL8, CXCL1, and HGF. J Carcinog. 2007;6:2–8.PubMedCentralPubMedGoogle Scholar
  40. 40.
    All-Ericsson C, Girnita L, Seregard S, Bartolazzi A, Jager MJ, Larsson O. Insulin-like growth factor-1 receptor in uveal melanoma: a predictor for metastatic disease and a potential therapeutic target. Invest Ophthalmol Vis Sci. 2002;43:1–8.PubMedGoogle Scholar
  41. 41.
    Scala S, Ieranò C, Ottaiano A, Franco R, La Mura A, Liguori G, et al. CXC chemokine receptor 4 is expressed in uveal malignant melanoma and correlates with the epithelioid-mixed cell type. Cancer Immunol Immunother. 2007;56:1589–95.PubMedCrossRefGoogle Scholar
  42. 42.
    Di Cesare S, Marshall JC, Fernandes BF, Logan P, Antecka E, Filho VB, et al. In vitro characterization and inhibition of the CXCR4/CXCL12 chemokine axis in human uveal melanoma cell lines. Cancer Cell Int. 2007;7:17.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Jannie KM, Stipp CS, Weiner JA. ALCAM regulates motility, invasiveness, and adherens junction formation in uveal melanoma cells. PLoS One. 2012;7:e39330.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Gangemi R, Mirisola V, Barisione G, Fabbi M, Brizzolara A, Lanza F, et al. Mda-9/syntenin is expressed in uveal melanoma and correlates with metastatic progression. PLoS One. 2012;7:e29989.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Pavey S, Zuidervaart W, van Nieuwpoort F, Packer L, Jager M, Gruis N, et al. Increased p21-activated kinase-1 expression is associated with invasive potential in uveal melanoma. Melanoma Res. 2006;16:285–96.PubMedCrossRefGoogle Scholar
  46. 46.
    Patel M, Smyth E, Chapman PB, Wolchok JD, Schwartz GK, Abramson DH, et al. Therapeutic implications of the emerging molecular biology of uveal melanoma. Clin Cancer Res. 2011;17:2087–100.PubMedCrossRefGoogle Scholar
  47. 47.
    Yang H, Jager MJ, Grossniklaus HE. Bevacizumab suppression of establishment of micrometastases in experimental ocular melanoma. Invest Ophthalmol Vis Sci. 2010;51:2835–42.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Jasbir Kaur
    • 1
  • Manzoor Ahmad Malik
    • 1
  • Rishabh Gulati
    • 1
  • Shorya Vardhan Azad
    • 2
  • Sandeep Goswami
    • 1
  1. 1.Department of Ocular Biochemistry, Dr. Rajendra Prasad Centre for Ophthalmic SciencesAll India Institute of Medical SciencesNew DelhiIndia
  2. 2.Vitreo-Retina, Ocular Trauma and Retinopathy of Prematurity Services, Dr. Rajendra Prasad Centre for Ophthalmic SciencesAll India Institute of Medical SciencesNew DelhiIndia

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