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      Uveal Melanoma

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          Abstract

          Uveal melanoma is the most common primary intraocular malignancy and the leading primary intraocular disease which can be fatal in adults. In this paper epidemiologic, pathogenetic, and clinical aspects of uveal melanoma are discussed. Despite the advance in local ocular treatments, there has been no change in patient survival for three decades. Development of metastases affects prognosis significantly. Current survival rates, factors predictive of metastatic potential and metastatic screening algorithms are discussed. Proposed and emerging treatments for uveal melanoma metastases are also overviewed. Current advances in genetics and cytogenetics have provided a significant insight in tumours with high metastatic potential and the molecular mechanisms that underlie their development. Biopsy of those lesions may prove to be important for prognostication and to allow further research into genetic mutations and potential new therapeutic targets in the future.

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          Mutations in GNA11 in uveal melanoma.

          Uveal melanoma is the most common intraocular cancer. There are no effective therapies for metastatic disease. Mutations in GNAQ, the gene encoding an alpha subunit of heterotrimeric G proteins, are found in 40% of uveal melanomas. We sequenced exon 5 of GNAQ and GNA11, a paralogue of GNAQ, in 713 melanocytic neoplasms of different types (186 uveal melanomas, 139 blue nevi, 106 other nevi, and 282 other melanomas). We sequenced exon 4 of GNAQ and GNA11 in 453 of these samples and in all coding exons of GNAQ and GNA11 in 97 uveal melanomas and 45 blue nevi. We found somatic mutations in exon 5 (affecting Q209) and in exon 4 (affecting R183) in both GNA11 and GNAQ, in a mutually exclusive pattern. Mutations affecting Q209 in GNA11 were present in 7% of blue nevi, 32% of primary uveal melanomas, and 57% of uveal melanoma metastases. In contrast, we observed Q209 mutations in GNAQ in 55% of blue nevi, 45% of uveal melanomas, and 22% of uveal melanoma metastases. Mutations affecting R183 in either GNAQ or GNA11 were less prevalent (2% of blue nevi and 6% of uveal melanomas) than the Q209 mutations. Mutations in GNA11 induced spontaneously metastasizing tumors in a mouse model and activated the mitogen-activated protein kinase pathway. Of the uveal melanomas we analyzed, 83% had somatic mutations in GNAQ or GNA11. Constitutive activation of the pathway involving these two genes appears to be a major contributor to the development of uveal melanoma. (Funded by the National Institutes of Health and others.).
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            Incidence of uveal melanoma in Europe.

            To estimate incidence rates of uveal melanoma in Europe from 1983 to 1994. Incidence analysis of data from cancer registries adhering to the European Cancer Registry-based study on survival and care of cancer patients (EUROCARE) (cases diagnosed from 1983 to 1994). Data of 6673 patients with ocular melanoma (as defined by International Classification of Diseases for Oncology morphology codes 8720 to 8780 [melanoma] and International Classification of Diseases 9 (ICD9) codes 190.0 [iris and ciliary body], 190.5 [retina], 190.6 [choroid], and 190.9 [unspecified ocular location]) from 33 cancer registries of 16 European countries. Incidence rate ratios (IRRs) were obtained from a multilevel Poisson regression model. Incidence rates and IRRs associated with demographic and geographic variables. Standardized incidence rates increased from south to north across registries, from a minimum of 8 per million in Norway and Denmark. The inclusion of tumors with unspecified ocular location (code 190.9) increased incidence rates in most United Kingdom registries, but not in the other geographic areas, where this code was seldom used for uveal melanomas. Incidence increased noticeably up to age 55 (IRR, 1.46 per 5 years; 95% confidence interval [CI], 1.36-1.57) but leveled off after age 75 (IRR, 0.99 per 5 years; 95% CI, 0.93-1.05), with intermediate levels midway (IRR, 1.18 per 5 years; 95% CI, 1.12-1.23). It was also higher in males (IRR, 1.22; 95% CI, 1.16-1.28). Rates were stable during the study period, but a cohort effect was evidenced, accounting for higher incidence rates in people born during the period 1910 to 1935 (P = 0.005). Incidence increased with latitude (P = 0.008), which explained most differences in rates among areas. In this large series of uveal melanomas, we found stable incidence during the years 1983 to 1994. The north-to-south decreasing gradient supports the protective role of ocular pigmentation. European ophthalmologists should develop guidelines to standardize the coding of tumors treated conservatively using the ICD classification to improve the registration and surveillance of uveal melanoma by cancer registries.
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              Prognostic implications of monosomy 3 in uveal melanoma.

              A high proportion of patients with uveal melanoma die of metastatic disease. In a subgroup of uveal melanomas there is the loss of one chromosome 3. To assess the prognostic implications of this genetic anomaly, we studied 54 patients for a median of 3.4 years. 180 patients underwent primary enucleation for malignant uveal melanoma at the Ophthalmology Department of the Universitätsklinikum Essen between 1987 and 1993. Tumour material was available for chromosome analysis and DNA preparation from 69 of these patients (for logistic reasons unlikely, we believe, to introduce bias). 15 patients were excluded from our study: nine because the methods for assessment of monosomy 3 were unsuccessful; five because of insufficient information about their relapse status; one because histopathological data were incomplete. Of the 54 remaining patients, the tumours of 16 were assessed for copy number of chromosome 3 by karyotype analysis, of 30 by comparative genomic hybridisation, and of eight by both techniques. Clinical status was assessed by contact with family doctor or a clinical check up. Statistical analysis was by the log-rank test and Cox proportional-hazard regression. The tumours of 30 patients had monosomy 3. 17 (57%) of these patients relapsed with metastatic disease, and the 3-year relapse-free survival rate was 50%. By contrast, of the 24 patients whose tumours had retained both chromosomes 3, none developed metastatic disease. In univariate analysis monosomy 3 was the most significant (p < 0.0001) predictor of poor prognosis in uveal melanoma, followed by tumour location (p < 0.0007) and tumour diameter (p < 0.0021). Histopathological subtype, age, sex, extrascleral growth, and tumour thickness had no additional predictive value. In uveal melanoma, monosomy 3 is a significant predictor of both relapse-free and overall survival.
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                Author and article information

                Journal
                J Skin Cancer
                JSC
                Journal of Skin Cancer
                Hindawi Publishing Corporation
                2090-2905
                2090-2913
                2011
                30 June 2011
                : 2011
                : 573974
                Affiliations
                1Ocular Oncology Service, Moorfields Eye Hospital, London EC1V 2PD, UK
                2Ocular Oncology Service, St Bartholomew's Hospital, London EC1A 7BE, UK
                Author notes

                Academic Editor: Paolo A. Ascierto

                Article
                10.1155/2011/573974
                3135138
                21773036
                998dbdde-b144-4c04-b9dc-d15e1cc75676
                Copyright © 2011 V. P. Papastefanou and V. M. L. Cohen.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 2 March 2011
                : 20 April 2011
                : 28 April 2011
                Categories
                Review Article

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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