The Genetics of Uveal Melanoma: Overview and Clinical Relevance

Aline Isabel Riechardt; Emine Kilic; Antonia M. Joussen

doi:10.1055/a-1513-0789

Klinische Monatsblätter für Augenheilkunde, Table of Contents

Klin Monbl Augenheilkd 2021; 238(07): 773-780
DOI: 10.1055/a-1513-0789

Übersicht

The Genetics of Uveal Melanoma: Overview and Clinical Relevance

Article in several languages: English | deutsch

Authors

Aline Isabel Riechardt

¹Klinik für Augenheilkunde, Charité – Universitätsmedizin Berlin, Deutschland
Emine Kilic

²Department of Ophthalmology, Erasmus Medical Center, Rotterdam, Niederlande
Antonia M. Joussen

¹Klinik für Augenheilkunde, Charité – Universitätsmedizin Berlin, Deutschland

Abstract

Over the last ten years, much has been learnt about the genetic characteristics and genetic evolution of uveal melanoma. It has been shown that uveal melanoma differs fundamentally from non-uveal melanoma and is an independent genetic subtype. Compared to other tumours, uveal melanoma has a low mutational burden. There are recurring chromosomal aberrations with losses of 1p, 6q, 8p and 16q, gains of 6p and 8q, and the presence of monosomy 3. GNAQ, GNA11, PLCB4, CYSLTR2, MAPKAPK5, as well as mutations in BAP1, SF3B1, SRSF2 and EIF1AX, the latter being linked to a higher risk of metastasis, have been identified as significantly mutated genes. In rare cases, a BAP1 germline mutation may also be present. In addition to higher risk of uveal melanoma, this variant is also linked with other tumours. In this case, additional work-up, genetic counselling and screening of family members should be offered. While the knowledge about the genetic characteristics of uveal melanoma is already routinely used for diagnostic and prognostic purposes, targeted genotype-dependent therapy of uveal melanoma is currently still missing.

Key words

genetics - uveal melanoma - chromosomal aberration - somatic mutation - genetic evolution - BAP1 tumour predisposition syndrome

Full Text

References

References/Literatur
1 Xu Y, Lou L, Wang Y. et al. Epidemiological Study of Uveal Melanoma from US Surveillance, Epidemiology, and End Results Program (2010–2015). J Ophthalmol 2020; 2020: 3614039
2 Aronow ME, Topham AK, Singh AD. Uveal Melanoma: 5-Year Update on Incidence, Treatment, and Survival (SEER 1973–2013). Ocul Oncol Pathol 2018; 4: 145-151
3 Hayward NK, Wilmott JS, Waddell N. et al. Whole-genome landscapes of major melanoma subtypes. Nature 2017; 545: 175-180
4 Robertson AG, Shih J, Yau C. et al. Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma. Cancer Cell 2017; 32: 204-220.e15
5 Prescher G, Bornfeld N, Becher R. Nonrandom chromosomal abnormalities in primary uveal melanoma. J Natl Cancer Inst 1990; 82: 1765-1769
6 Horsman DE, Sroka H, Rootman J. et al. Monosomy 3 and isochromosome 8q in a uveal melanoma. Cancer Genet Cytogenet 1990; 45: 249-253
7 Prescher G, Bornfeld N, Hirche H. et al. Prognostic implications of monosomy 3 in uveal melanoma. Lancet 1996; 347: 1222-1225
8 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: 769-774
9 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: 2923-2927
10 Tschentscher F, Hüsing J, Hölter 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: 2578-2584
11 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: 7205-7209
12 Schopper VJ, Correa ZM. Clinical application of genetic testing for posterior uveal melanoma. Int J Retina Vitreous 2016; 2: 4
13 Furney SJ, Pedersen M, Gentien D. et al. SF3B1 mutations are associated with alternative splicing in uveal melanoma. Cancer Discov 2013; 3: 1122-1129
14 Johansson P, Aoude LG, Wadt K. et al. Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4. Oncotarget 2016; 7: 4624-4631
15 Van Raamsdonk CD, Griewank KG, Crosby MB. et al. Mutations in GNA11 in uveal melanoma. N Engl J Med 2010; 363: 2191-2199
16 Onken MD, Worley LA, Long MD. et al. Oncogenic mutations in GNAQ occur early in uveal melanoma. Invest Ophthalmol Vis Sci 2008; 49: 5230-5234
17 Harbour JW, Onken MD, Roberson ED. et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 2010; 330: 1410-1413
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: 933-936
19 Moore AR, Ceraudo E, Sher JJ. et al. Recurrent activating mutations of G-protein-coupled receptor CYSLTR2 in uveal melanoma. Nat Genet 2016; 48: 675-680
20 Harbour JW, Roberson ED, Anbunathan H. et al. Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma. Nat Genet 2013; 45: 133-135
21 Johnson DB, Roszik J, Shoushtari AN. et al. Comparative analysis of the GNAQ, GNA11, SF3B1, and EIF1AX driver mutations in melanoma and across the cancer spectrum. Pigment Cell Melanoma Res 2016; 29: 470-473
22 Shah CP, Weis E, Lajous M. et al. Intermittent and chronic ultraviolet light exposure and uveal melanoma: a meta-analysis. Ophthalmology 2005; 112: 1599-1607
23 van Poppelen NM, Vaarwater J, Mudhar HS. et al. Genetic Background of Iris Melanomas and Iris Melanocytic Tumors of Uncertain Malignant Potential. Ophthalmology 2018; 125: 904-912
24 Johansson PA, Brooks K, Newell F. et al. Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours. Nat Commun 2020; 11: 2408
25 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: 831-845
26 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: 2032-2038
27 Malaponte G, Libra M, Gangemi P. et al. Detection of BRAF gene mutation in primary choroidal melanoma tissue. Cancer Biol Ther 2006; 5: 225-227
28 Van Raamsdonk CD, Bezrookove V, Green G. et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 2009; 457: 599-602
29 Vader MJC, Madigan MC, Versluis M. et al. GNAQ and GNA11 mutations and downstream YAP activation in choroidal nevi. Br J Cancer 2017; 117: 884-887
30 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: 1688
31 Shirley MD, Tang H, Gallione CJ. et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med 2013; 368: 1971-1979
32 Couto JA, Huang L, Vivero MP. et al. Endothelial Cells from Capillary Malformations Are Enriched for Somatic GNAQ Mutations. Plast Reconstr Surg 2016; 137: 77e-82e
33 Le Guin CHD, Metz KA, Kreis SH. et al. GNAQ Q209R Mutations Are Highly Specific for Circumscribed Choroidal Hemangioma. Cancers (Basel) 2019; 11: 1031
34 Shain AH, Bagger MM, Yu R. et al. The genetic evolution of metastatic uveal melanoma. Nat Genet 2019; 51: 1123-1130
35 Yavuzyigitoglu S, Koopmans AE, Verdijk RM. et al. Uveal Melanomas with SF3B1 Mutations: A Distinct Subclass Associated with Late-Onset Metastases. Ophthalmology 2016; 123: 1118-1128
36 van Poppelen NM, Drabarek W, Smit KN. et al. SRSF2 Mutations in Uveal Melanoma: A Preference for In-Frame Deletions?. Cancers (Basel) 2019; 11: 1200
37 Yu MD, Masoomian B, Shields JA. et al. BAP1 Germline Mutation Associated with Bilateral Primary Uveal Melanoma. Ocul Oncol Pathol 2020; 6: 10-14
38 Rao R, Pointdujour-Lim R, Ganguly A. et al. Multifocal Choroidal Melanoma in a Patient with Germ Line BRCA-Associated Protein 1 Mutation. Retin Cases Brief Rep 2018; 12: 1-4
39 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: 1172
40 Chau C, van Doorn R, van Poppelen NM. et al. Families with BAP1-Tumor Predisposition Syndrome in The Netherlands: Path to Identification and a Proposal for Genetic Screening Guidelines. Cancers (Basel) 2019; 11: 1114
41 Li Z, Yu X, Shen J. et al. MicroRNA dysregulation in uveal melanoma: a new player enters the game. Oncotarget 2015; 6: 4562-4568
42 Falzone L, Romano GL, Salemi R. et al. Prognostic significance of deregulated microRNAs in uveal melanomas. Mol Med Rep 2019; 19: 2599-2610
43 Stark MS, Gray ES, Isaacs T. et al. A Panel of Circulating MicroRNAs Detects Uveal Melanoma With High Precision. Transl Vis Sci Technol 2019; 8: 12
44 Knudson jr. AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A 1971; 68: 820-823
45 Moolgavkar SH, Knudson jr. AG. Mutation and cancer: a model for human carcinogenesis. J Natl Cancer Inst 1981; 66: 1037-1052
46 Field MG, Durante MA, Anbunathan H. et al. Punctuated evolution of canonical genomic aberrations in uveal melanoma. Nat Commun 2018; 9: 116
47 Davis A, Gao R, Navin N. Tumor evolution: Linear, branching, neutral or punctuated?. Biochim Biophys Acta Rev Cancer 2017; 1867: 151-161
48 Dogrusöz M, Bagger M, van Duinen SG. et al. The Prognostic Value of AJCC Staging in Uveal Melanoma Is Enhanced by Adding Chromosome 3 and 8q Status. Invest Ophthalmol Vis Sci 2017; 58: 833-842
49 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: 1596-1603
50 DeParis SW, Taktak A, Eleuteri A. et al. External Validation of the Liverpool Uveal Melanoma Prognosticator Online. Invest Ophthalmol Vis Sci 2016; 57: 6116-6122
51 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: 763-771
52 Angi M, Kalirai H, Taktak A. et al. Prognostic biopsy of choroidal melanoma: an optimised surgical and laboratory approach. Br J Ophthalmol 2017; 101: 1143-1146
53 Dopierala J, Damato BE, Lake SL. et al. Genetic heterogeneity in uveal melanoma assessed by multiplex ligation-dependent probe amplification. Invest Ophthalmol Vis Sci 2010; 51: 4898-4905
54 Metz CH, Scheulen M, Bornfeld N. et al. Ultradeep sequencing detects GNAQ and GNA11 mutations in cell-free DNA from plasma of patients with uveal melanoma. Cancer Med 2013; 2: 208-215
55 Mitsiades N, Chew SA, He B. et al. Genotype-dependent sensitivity of uveal melanoma cell lines to inhibition of B-Raf, MEK, and Akt kinases: rationale for personalized therapy. Invest Ophthalmol Vis Sci 2011; 52: 7248-7255
56 Ambrosini G, Pratilas CA, Qin LX. 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: 3552-3561
57 Carvajal RD, Sosman JA, Quevedo JF. et al. Effect of selumetinib vs. chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. JAMA 2014; 311: 2397-2405
58 Carvajal RD, Piperno-Neumann S, Kapiteijn E. et al. Selumetinib in Combination With Dacarbazine in Patients With Metastatic Uveal Melanoma: A Phase III, Multicenter, Randomized Trial (SUMIT). J Clin Oncol 2018; 36: 1232-1239
59 Faião-Flores F, Emmons MF, Durante MA. et al. HDAC Inhibition Enhances the In Vivo Efficacy of MEK Inhibitor Therapy in Uveal Melanoma. Clin Cancer Res 2019; 25: 5686-5701
60 Smit KN, Jager MJ, de Klein A. et al. Uveal melanoma: Towards a molecular understanding. Prog Retin Eye Res 2020; 75: 100800