Genetics of Uveal Melanoma


Uveal melanoma (UM) is the most common primary intraocular malignancy in adults and is associated with high rates of metastasis and death. Unlike many other solid cancers, UM harbours a relatively small number of conserved genetic alterations, which lead to oncogenesis and metastatic progression. Chromosomal alterations are largely restricted to chromosomes 1, 3, 6 and 8. Progression from melanocyte to nevus is characterised by acquisition of specific pathogenic genetic variants in either GNAQ or GNA11, followed by pathogenic genetic variants in either SF3B1/EIF1AX to form low metastatic risk UMs or in BAP1 to form high metastatic risk UMs. Gene expression profiling and multiplex ligation‐dependent probe amplification offer excellent prognostic accuracy regarding metastatic risk and mortality. Despite this extensive knowledge of UM genetics, the mechanisms by which these specific genetic variants lead to melanomagenesis and metastatic progression are only beginning to be understood and have yet to lead to the development of effective targeted therapies for metastatic UM.

Key Concepts

  • Primary uveal melanoma is characterised by a relatively small number of conserved genetic alterations that lead to oncogenesis and metastatic progression.
  • Melanocytes acquire initial pathogenic variants in either GNAQ or GNA11 to activate the ARF6‐Hippo‐YAP pathway and form a uveal melanocytic nevus, then in either SF3B1/EIF1AX or in BAP1 during the course of their subsequent progression to primary uveal melanoma.
  • Common chromosome derangements include gains and losses in chromosomes 1, 3, 6 and 8.
  • The most significant chromosomal derangement is complete or partial loss of chromosome 3, which leads to highly metastatic tumours.
  • Prognostic testing is highly accurate and currently relies on gene expression profiling (GEP) or multiplex ligand probe amplification (MLPA) to assess for microscopic chromosomal deletions. While clinical and pathologic features are incorporated into the prognostic algorithm for some of these techniques, these clinical features now play a relatively minor role compared to molecular phenotyping with GEP or MLPA.
  • Primary uveal melanoma tumours generally fall into two prognostic classes: GEP class 1 tumours have a low (0–21% 5‐year) risk of metastatic progression, are associated with disomy of chromosome 3, gain of chromosome 6p, presence of mutations in SF3B1 or EIF1AX, and no loss of BAP1. GEP class 2 tumours have a high (72% 5‐year) risk of metastatic progression, are associated with monosomy of chromosome 3, loss of chromosome 1p or 8q, and loss of BAP1.

Keywords: uveal melanoma; genetics; epigenetics; prognostic testing; gene expression profile (GEP); multiplex ligation‐dependent probe amplification (MLPA); GNAQ; GNA11; BAP1; SF3B1; EIF1AX; monosomy 3

Figure 1. GNAQ/11 cellular pathway in the oncogenesis of uveal melanoma. GNAQ and GNA11 (GNAQ/11) are proteins that belong to a subfamily of G‐protein‐related alpha subunits. By far, the most common pathogenic variant observed is an inactivating mutation within the GTPase catalytic domain at codon 209 (Q209) in exon 5. An inactivating mutation at this site prevents the hydrolysis of GTP associated with the larger G‐protein complex. As a result, the protein complex cannot release a phosphate group from GTP and is locked in its active conformation. Consequently, many downstream pathways are constitutively activated, including the RHO/ROCK pathway, which then eventually leads to constitutive activation of YAP/TAZ through dephosphorylation. The dephosphorylated YAP protein is now able to localise into the nucleus where it binds TEAD and leads to transcriptional activation of cell cycle genes.
Figure 2. BAP1 tumour suppressor cellular pathways. BAP1 gene is located on chromosome 3p21 and has several important protein binding domains, including BARD1, BRCA1, HCFC1, YY1 and ASXL1. Pathogenic variants in any of these domains may result in reduced tumour suppressor activity (a–c). There is also a bipartite nuclear localising signal (NLS), which if may also be a target for pathogenic variants, leading to inability of BAP1 protein product to localise to the nucleus where it exhibits its tumour suppressor activity (d). (a) Role of BAP1 in chromatin activation and transcription regulation. BAP1 has two major binding partners in HCFC1 and YY1, which are involved in promoting normal upregulation of gene expression. A pathogenic variant in either the HCFC1 or YY1 domain of BAP1 may lead to aberrant transcription factor regulation. (b) Role of BAP1 in chromatin regulation. In normal cellular function, ubiquitination and deubiquitination of histone complexes is balanced. This balance is needed to appropriately turn on and off expression of various genes responsible for normal cellular function. BAP1 contains a binding site for ASXL1, which leads to deubiquitination of chromatin histone complexes, leading to subsequent chromatin opening and increased accessibility of cell function genes. A mutation in this binding domain may alter the balance of chromatin suppression and activation. (c) Role of BAP1 in double‐stranded DNA repair. BRCA1 and BARD1 are other binding partners of BAP1 that have important roles in repairing double‐stranded DNA breaks. Pathogenic variants in BAP1 that prevent complexes from forming with target binding partners may therefore inhibit double‐stranded DNA repair. (d) BAP1 localises to the nucleus via NLS. Pathogenic variants in the bipartite NLS may prevent the BAP1 protein from appropriately localising to the nucleus, thus affecting transcription of BAP1 downstream target genes.
Figure 3. Uveal melanoma genetic pathway. Genetic development of primary uveal melanoma starts with a uveal melanocyte acquiring a mutation in either GNAQ or GNA11, which appears to be a critical step in initial nevogenesis. In forming a uveal melanoma, the nevus appears to embark on one of two mutually exclusive fates. For some tumours, there is chromosome 3 loss (monosomy 3) with loss of BAP1, leading to a high metastatic risk melanoma with a class 2 gene expression profile (GEP). Alternatively, tumours may remain with disomoy 3 and no BAP1 mutation, and instead acquire a mutation in either SF3B1 or EIF1AX, leading to a low metastatic risk, GEP class 1 tumour. After the initial fate‐determining class 1/class 2 step, tumours may acquire subsequent chromosomal derangements, especially in chromosomes 1, 6 and 8, which are independent modifiers of metastatic risk.


Abdel‐Rahman MH, Yang Y, Zhou XP, et al. (2006) High frequency of submicroscopic hemizygous deletion is a major mechanism of loss of expression of PTEN in uveal melanoma. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 24 (2): 288–295.

Augsburger JJ, Correa ZM and Augsburger BD (2015) Frequency and implications of discordant gene expression profile class in posterior uveal melanomas sampled by fine needle aspiration biopsy. American Journal of Ophthalmology 159 (2): 248–256.

Bauer J, Kilic E, Vaarwater J, et al. (2009) Oncogenic GNAQ mutations are not correlated with disease‐free survival in uveal melanoma. British Journal of Cancer 101 (5): 813–815.

Brantley MA and Harbour JW (2000a) Deregulation of the rb and p53 pathways in uveal melanoma. The American Journal of Pathology 157 (6): 1795–1801.

Brantley MA and Harbour JW (2000b) Inactivation of retinoblastoma protein in uveal melanoma by phosphorylation of sites in the COOH‐terminal region. Cancer Research 60 (16): 4320–4323.

Carbone M, Ferris LK, Baumann F, et al. (2012) BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs. Journal of Translational Medicine 10 (179): 1–7.

Chang AE, Karnell LH and Menck HR (1998) The national cancer data base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American college of surgeons commission on cancer and the American cancer society. Cancer 83 (8): 1664–1678.

Chang SH, Worley LA, Onken MD, et al. (2008) Prognostic biomarkers in uveal melanoma: evidence for a stem cell‐like phenotype associated with metastasis. Melanoma Research 18 (3): 191–200.

Coupland SE, Anastassiou G, Stang A, et al. (2000) The prognostic value of cyclin D1, p53, and MDM2 protein expression in uveal melanoma. The Journal of Pathology 191 (2): 120–126.

Coupland SE, Lake SL, Zeschnigk M, et al. (2013) Molecular pathology of uveal melanoma. Eye (London, England) 27 (2): 230–242.

Damato B, Dopierala J, Klaasen A, et al. (2009) Multiplex ligation‐dependent probe amplification of uveal melanoma: correlation with metastatic death. Investigative Ophthalmology & Visual Science 50 (7): 3048–3055.

Damato B, Dopierala JA and Coupland SE (2010) Genotypic profiling of 452 choroidal melanomas with multiplex ligation‐dependent probe amplification. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 16 (24): 6083–6092.

Daniels AB and Abramson DH (2009) C‐KIT in uveal melanoma: big fish or red herring? Archives of Ophthalmology (Chicago, Ill.: 1960) 127 (5): 695–697.

Daniels AB, Lee JE, MacConaill LE, et al. (2012) High throughput mass spectrometry‐based mutation profiling of primary uveal melanoma. Investigative Ophthalmology & Visual Science 53 (11): 6991–6996.

Decatur CL, Ong E, Garg N, et al. (2016) Driver mutations in uveal melanoma: associations with gene expression profile and patient outcomes. JAMA Ophthalmology 134 (7): 728–733.

Dopierala J, Damato BE, Lake SL, et al. (2010) Genetic heterogeneity in uveal melanoma assessed by multiplex ligation‐dependent probe amplification. Investigative Ophthalmology & Visual Science 51 (10): 4898–4905.

van Essen TH, van Pelt SI, Versluis M, et al. (2014) Prognostic parameters in uveal melanoma and their association with BAP1 expression. The British Journal of Ophthalmology 98 (12): 1738–1743.

Field MG and Harbour JW (2014a) GNAQ/11 mutations in uveal melanoma: is YAP the key to targeted therapy? Cancer Cell 25 (6): 714–715.

Field MG and Harbour JW (2014b) Recent developments in prognostic and predictive testing in uveal melanoma. Current Opinion in Ophthalmology 25 (3): 234–239.

Field MG, Decatur CL, Kurtenbach S, et al. (2016) PRAME as an independent biomarker for metastasis in uveal melanoma. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 22 (5): 1234–1242.

Gupta MP, Lane AM, DeAngelis MM, et al. (2015) Clinical characteristics of uveal melanoma in patients with germline BAP1 mutations. JAMA Ophthalmology 133 (8): 881–887.

Harbour JW and Chen R (2013). The DecisionDx‐UM Gene Expression Profile Test Provides Risk Stratification and Individualized Patient Care in Uveal Melanoma. PLoS Currents, 5, ecurrents.eogt.af8ba80fc776c8f1ce8f5dc485d4a618.

Hawkins BS and Group COMS (2004) The collaborative ocular melanoma study (COMS) randomized trial of pre‐enucleation radiation of large choroidal melanoma: IV. Ten‐year mortality findings and prognostic factors. COMS report number 24. American Journal of Ophthalmology 138 (6): 936–951.

Herlihy N, Dogrusoz M, van Essen TH, et al. (2015) Skewed expression of the genes encoding epigenetic modifiers in high‐risk uveal melanoma. Investigative Ophthalmology & Visual Science 56 (3): 1447–1458.

Landreville S, Agapova OA, Matatall KA, et al. (2012) Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 18 (2): 408–416.

Maat W, Ly LV, Jordanova ES, et al. (2008) Monosomy of chromosome 3 and an inflammatory phenotype occur together in uveal melanoma. Investigative Ophthalmology & Visual Science 49 (2): 505–510.

Maciejewski JP and Padgett RA (2012) Defects in spliceosomal machinery: a new pathway of leukaemogenesis. British Journal of Haematology 158 (2): 165–173.

Martin M, Masshofer L, Temming P, et al. (2013) Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3. Nature Genetics 45 (8): 933–936.

Matatall KA, Agapova OA, Onken MD, et al. (2013) BAP1 deficiency causes loss of melanocytic cell identity in uveal melanoma. BMC Cancer 13 (371): 1–12.

Nichols EE, Richmond A and Daniels AB (2016) Tumor characteristics, genetics, management, and the risk of metastasis in uveal melanoma. Seminars in Ophthalmology 31 (4): 304–309.

Onken MD, Worley LA, Ehlers JP, et al. (2004) Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death. Cancer Research 64 (20): 7205–7209.

Onken MD, Ehlers JP, Worley LA, et al. (2006) Functional gene expression analysis uncovers phenotypic switch in aggressive uveal melanomas. Cancer Research 66 (9): 4602–4609.

Onken MD, Worley LA, Long MD, et al. (2008) Oncogenic mutations in GNAQ occur early in uveal melanoma. Investigative Ophthalmology & Visual Science 49 (12): 5230–5234.

Onken MD, Worley LA, Char DH, et al. (2012) Collaborative ocular oncology group report number 1: prospective validation of a multi‐gene prognostic assay in uveal melanoma. Ophthalmology 119 (8): 1596–1603.

Parrella P, Sidransky D and Merbs SL (1999) Allelotype of posterior uveal melanoma: implications for a bifurcated tumor progression pathway. Cancer Research 59 (13): 3032–3037.

Pilarski R, Rai K, Cebulla C, et al. (1993) BAP1 tumor predisposition syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al. (eds) GeneReviews (internet).. Seattle, WA: University of Washington, Seattle.

Prescher G, Bornfeld N, Horsthemke B, et al. (1992) Chromosomal aberrations defining uveal melanoma of poor prognosis. Lancet 339 (8794): 691–692.

Rai K, Pilarski R, Boru G, et al. (2017) Germline BAP1 alterations in familial uveal melanoma. Genes, Chromosomes & Cancer 56 (2): 168–174.

Schopper VJ and Correa ZM (2016) Clinical application of genetic testing for posterior uveal melanoma. International Journal of Retina and Vitreous 2 (4): 1–6.

Schouten JP, McElgunn CJ, Waaijer R, et al. (2002) Relative quantification of 40 nucleic acid sequences by multiplex ligation‐dependent probe amplification. Nucleic Acids Research 30 (12): e57.

Scotto J, Fraumeni JF and Lee JA (1976) Melanomas of the eye and other noncutaneous sites: epidemiologic aspects. Journal of the National Cancer Institute 56 (3): 489–491.

Shields CL, Ganguly A, Bianciotto CG, et al. (2011) Prognosis of uveal melanoma in 500 cases using genetic testing of fine‐needle aspiration biopsy specimens. Ophthalmology 118 (2): 396–401.

Singh AD, Aronow ME, Sun Y, et al. (2012) Chromosome 3 status in uveal melanoma: a comparison of fluorescence in situ hybridization and single‐nucleotide polymorphism array. Investigative Ophthalmology & Visual Science 53 (7): 3331–3339.

Song JS, Kim YS, Kim DK, et al. (2012) Global histone modification pattern associated with recurrence and disease‐free survival in non‐small cell lung cancer patients. Pathology International 62 (3): 182–190.

Thiagalingam S, Cheng KH, Lee HJ, et al. (2003) Histone deacetylases: unique players in shaping the epigenetic histone code. Annals of the New York Academy of Sciences 983: 84–100.

Walter SD, Chao DL, Feuer W, et al. (2016) Prognostic implications of tumor diameter in association with gene expression profile for uveal melanoma. JAMA Ophthalmology 134 (7): 734–740.

White VA, McNeil BK and Horsman DE (1998) Acquired homozygosity (isodisomy) of chromosome 3 in uveal melanoma. Cancer Genetics and Cytogenetics 102 (1): 40–45.

Yavuzyigitoglu S, Koopmans AE, Verdijk RM, et al. (2016) Uveal melanomas with SF3B1 mutations: a distinct subclass associated with late‐onset metastases. Ophthalmology 123 (5): 1118–1128.

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

Yu FX, Luo J, Mo JS, et al. (2014) Mutant gq/11 promote uveal melanoma tumorigenesis by activating YAP. Cancer Cell 25 (6): 822–830.

Further Reading

An J, Wan H, Zhou X, et al. (2011) A comparative transcriptomic analysis of uveal melanoma and normal uveal melanocyte. PLoS One 6 (1): e16516, 1–10.

Correa ZM and Augsburger JJ (2016) Independent prognostic significance of gene expression profile class and largest basal diameter of posterior uveal melanomas. American Journal of Ophthalmology 162: 20–27.

Diener‐West M, Earle JD, Fine SL, et al. and Collaborative Ocular Melanoma Study Group (2001) The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, III: initial mortality findings. COMS report no. 18. Archives of Ophthalmology 119 (7): 969–982.

Earle JD (1999) Results from the collaborative ocular melanoma study (COMS) of enucleation versus preoperative radiation therapy in the management of large ocular melanomas. International Journal of Radiation Oncology, Biology, Physics 43 (5): 1168–1169.

Gill HS and Char DH (2012) Uveal melanoma prognostication: from lesion size and cell type to molecular class. Canadian Journal of Ophthalmology. Journal Canadien D'Ophtalmologie 47 (3): 246–253.

Harbour JW (2012) The genetics of uveal melanoma: an emerging framework for targeted therapy. Pigment Cell & Melanoma Research 25 (2): 171–181.

Hawkins BS and Group COMS (1998) The collaborative ocular melanoma study (COMS) randomized trial of pre‐enucleation radiation of large choroidal melanoma III: local complications and observations following enucleation COMS report no. 11. American Journal of Ophthalmology 126 (3): 362–372.

Jaenisch R and Bird A (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nature Genetics 33: 245–254.

Scholes AG, Damato BE, Nunn J, et al. (2003) Monosomy 3 in uveal melanoma: correlation with clinical and histologic predictors of survival. Investigative Ophthalmology & Visual Science 44 (3): 1008–1011.

Tschentscher F, Husing J, Holter T, et al. (2003) Tumor classification based on gene expression profiling shows that uveal melanomas with and without monosomy 3 represent two distinct entities. Cancer Research 63 (10): 2578–2584.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Milam Jr, Ronald W, and Daniels, Anthony B(Jan 2018) Genetics of Uveal Melanoma. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0027245]