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Molecular Pathology of Uveal Melanoma SE Coupland Et Al 231

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Molecular Pathology of Uveal Melanoma SE Coupland Et Al 231 Eye (2013) 27, 230–242 & 2013 Macmillan Publishers Limited All rights reserved 0950-222X/13 www.nature.com/eye 1 1 2 CAMBRIDGE OPHTHALMOLOGICAL SYMPOSIUM Molecular SE Coupland , SL Lake , M Zeschnigk and BE Damato3 pathology of uveal melanoma Abstract Introduction Like other cancers, uveal melanomas (UM) Uveal melanoma (UM) is the most common are characterised by an uncontrolled, clonal, primary adult intraocular cancer. More than cellular proliferation, occurring as a result 90% involve the choroid, the remainder being of numerous genetic, and epigenetic confined to iris and ciliary body. UM affects aberrations. Signalling pathways known approximately six individuals per million per to be disrupted in UM include: (1) the year in the United Kingdom, with the age at retinoblastoma pathway, probably as a result diagnosis peaking at 50–60 years. It is markedly of cyclin D1 overexpression; p53 signalling, different to cutaneous melanoma in its clinical possibly as a consequence of MDM2 and molecular genetic features. Concerning overexpression; and the P13K/AKT and predisposition to UM, rare reports of families mitogen-activated protein kinase/extracellular with an excess of UM cases have been signal-related kinase pathway pathways that published.1–3 Recent evidence suggests that are disturbed as a result of PTEN and patients with a cancer susceptibility may have GNAQ/11 mutations, respectively. higher frequencies of UM compared with the Characteristic chromosomal abnormalities are normal population.4 Other risk factors are 1Pathology, Department of common and include 6p gain, associated with congenital ocular melanocytosis, Molecular and Clinical a good prognosis, as well as 1p loss, 3 loss, melanocytoma, and neurofibromatosis. Cancer Medicine, University and 8q gain, which correlate with high There is a wide range of therapeutic options of Liverpool, Liverpool, UK mortality. These are identified by techniques for the treatment of primary UM. These include 2Institute for Human such as fluorescence in situ hybridisation, various forms of radiotherapy, surgical Genetics, comparative genomic hybridisation, resection, and phototherapy.5 The 5-year local- Universita¨ tsklinikum Essen, microsatellite analysis, multiplex ligation- tumour control rates in most specialised Essen, Germany dependent probe amplification, and single- treatment centres exceed 90%. Despite this, nucleotide polymorphisms. UM can also be almost 50% of patients with UM will develop 3Department of Molecular and Clinical Cancer categorised by their gene expression profiles disseminated disease, predominantly in the Medicine, Liverpool Ocular as class 1 or class 2, the latter correlating liver, but also in the lungs (24% of patients) and Oncology Centre, University with poor survival, as do BRCA1-associated bone (16%).6 Early surgical removal of of Liverpool, Liverpool, UK protein-1 (BAP1) inactivating mutations. metastases has improved patient survival in Genetic testing of UM has enhanced some cases;7,8 however, in general, the Correspondence: prognostication, especially when results are prognosis of UM patients with metastatic SE Coupland, Pathology, Department of Molecular integrated with histological and clinical data. disease is currently poor because of the lack of and Clinical Cancer The identification of abnormal signalling effective chemotherapeutic agents. Medicine, University of pathways, genes and proteins in UM opens Intense efforts have been made in the last Liverpool, 6th Floor Duncan the way for target-based therapies, improving decades to understand the molecular genetics Building, Daulby Street, prospects for conserving vision and involved in the development and the Liverpool L69 3GA, UK Tel: þ 44 (0)151 706 5885; prolonging life. progression of UM, to recognise those that are Fax: þ 44 (0)151 706 5859. Eye (2013) 27, 230–242; doi:10.1038/eye.2012.255; likely to metastasise, and to identify signalling E-mail: s.e.coupland@ published online 7 December 2012 pathways and possible ‘druggable’ molecules in liverpool.ac.uk the neoplastic melanocytes, which can be Keywords: uveal melanoma; cytogenetics; targeted using systemic therapies. Some of the Received: 5 November 2012 molecular alterations; signalling pathways; early genetic events causing disruption of the Accepted: 5 November 2012 Published online: MLPA; GEP cell cycle and apoptotic control in uveal 7 December 2012 melanocytes have been determined, as well as Update in the molecular pathology of uveal melanoma SE Coupland et al 231 those leading to their malignant transformation and transformation and propensity to spread. It is unclear metastasis promotion. whether the ‘melanoma-initiating’ or ‘cancer stem-like’ This review summarises the current insights into the cells, recently shown to be present in UM cell lines,61 molecular mechanisms underlying UM pathogenesis, are derived directly from ocular melanocyte progenitors prognostic tests, and potential therapeutic strategies. or from more mature melanocytes that have de- differentiated. Recent analysis of gene expression data of UM would suggest that de-differentiation indeed does The hallmarks of cancer occur during UM development, but this requires further Cancer is defined as an uncontrolled, clonal proliferation investigation.11,39 It is also unclear whether the naevus of cells, which progressively acquire most if not all of the stage is a prerequisite in UM development: it has been six ‘hallmarks’ of neoplasia, as defined by Hanahan and estimated that o1 in 8000 naevi undergo malignant Weinberg in 2000, and then updated in 2011.9,10 These transformation to form UM.62 Histologically, it is hallmarks are considered to be absolute biological exceptionally rare for a residual naevus to be evident prerequisites of neoplastic cells for their survival and adjacent to or within a choroidal melanoma, supporting proliferation capacity at the primary site, and for their this observation. ability to invade and metastasise (Table 1). These features Despite this large gap in our knowledge regarding are acquired by a multistep process and include: (1) initial UM development, it has been demonstrated by insensitivity to anti-growth signals; (2) self-sufficiency in several groups that most (if not all) of the ‘hallmarks of growth signals; (3) avoiding apoptosis; (4) limitless cancer’ can be applied to UM pathogenesis (Table 1). replicative potential; (5) sustained angiogenesis; and (6) The genetic and epigenetic events involved in UM tissue invasion and metastasis. development and dissemination enable malignant uveal These six core characteristics of the malignant cell are melanocytes to proliferate and survive autonomously. acquired in different tumour types via distinct These events include: mutation or amplification of mechanisms and at various times during the course of proto-oncogenes; inactivating mutations or deletions of multistep tumourigenesis. An increasing body of tumour (and metastasis) suppressor genes; and evidence suggests that two additional ‘emerging’ chromosomal aberrations (Tables 1, 2 and 3).11 Some of hallmarks of cancer and two ‘enabling characteristics’ are these genetic alterations are considered to occur in the involved in the pathogenesis of some and perhaps all early stages of UM development; others, at later stages cancers. These were added in the revised article of (ie, prior to or at haematogeneous dissemination). It has Hanahan and Weinberg in 2011, and include: (1) been proposed that the genetic developmental pathway deregulating cellular energetics; (2) avoidance of immune of UM bifurcates at an early stage to result in two very destruction; (3) tumour-promoting inflammation and (4) distinct genetic signatures: (1) disomy 3 with genome instability and mutation (Table 1). As these chromosome 6p gain and class 1 gene expression capabilities have yet to be generalised to all tumour types profile, and (2) monosomy 3 with class 2 molecular and yet to be fully validated, they are still considered to signature and a high metastatic propensity.40,78,80,81 be provisional.10 Later genetic events in UM development are suggested to be increasing aneuploidy and alterations in chromosome 8 (eg, gains in 8q and loss of 8p; see below How do these hallmarks of cancer relate to UM? for further details). UM is considered to be a cancer arising from uveal Although this dichotomous model is helpful in melanocytes. The precursors of melanocytes are non- ‘classifying’ UM into two risk groups with respect to the pigmented melanoblasts derived from the neural crest, development of metastasis, it essentially discounts any which bypass natural tissue barriers and basement concept of clonal heterogeneity within UM, which has membranes of the eye when migrating during been demonstrated by several groups using differing embryogenesis. As with processes occurring in the skin, methods.82–86 Furthermore, it does not fit well with the the melanoblasts mature into melanocytes within the concept of clonal evolution.87,88 Recent evidence does uvea, and/or give rise to melanocytic stem cells, which indeed suggest that this model may be too simple, and maintain the ocular melanocytic ‘system’. Although it is that different clones of malignant melanocytes may known that melanocytic stem cells reside in the hair evolve and co-exist within UM, with some having the bulge in the skin,60 the location of uveal melanocytic potential to override or dominate others.79 This has been stem cells is still unknown. observed in longitudinal studies using next-generation It is hypothesised
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