Iris Colour and the Risk of Developing Uveal Melanoma.

Uveal melanoma (UM) is a global disease which especially occurs in elderly people. Its incidence varies widely between populations, with the highest incidence among Caucasians, and a South-to-North increase in Europe. As northern Europeans often have blond hair and light eyes, we wondered whether iris colour may be a predisposing factor for UM and if so, why. We compared the distribution of iris colour between Dutch UM patients and healthy Dutch controls, using data from the Rotterdam Study (RS), and reviewed the literature regarding iris colour. We describe molecular mechanisms that might explain the observed associations. When comparing a group of Dutch UM patients with controls, we observed that individuals from Caucasian ancestry with a green/hazel iris colour (Odds Ratio (OR) = 3.64, 95% Confidence Interval (CI) 2.57-5.14) and individuals with a blue/grey iris colour (OR = 1.38, 95% CI 1.04-1.82) had a significantly higher crude risk of UM than those with brown eyes. According to the literature, this may be due to a difference in the function of pheomelanin (associated with a light iris colour) and eumelanin (associated with a brown iris colour). The combination of light-induced stress and aging may affect pheomelanin-carrying melanocytes in a different way than eumelanin-carrying melanocytes, increasing the risk of developing a malignancy.

Evaluation of oncogenic cysteinyl leukotriene receptor 2 as a therapeutic target for uveal melanoma.

Uveal melanoma is a rare, but deadly, form of eye cancer that arises from melanocytes within the uveal tract. Although advances have emerged in treatment of the primary tumour, patients are still faced with vision loss, eye enucleation and lethal metastatic spread of the disease. Approximately 50% of uveal melanoma patients develop metastases, which occur most frequently in the liver. Metastatic patients encounter an extremely poor prognosis; as few as 8% survive beyond 2 years. Understanding of the genetic underpinnings of this fatal disease evolved in recent years with the identification of new oncogenic mutations that drive uveal melanoma pathogenesis. Despite this progress, the lack of successful therapies or a proven standard-of-care for uveal melanoma highlights the need for new targeted therapies. This review focuses on the recently identified CYSLTR2 oncogenic mutation in uveal melanoma. Here, we evaluate the current status of uveal melanoma and investigate how to better understand the role of this CYSLTR2 mutation in the disease and implications for patients harbouring this mutation.

Uveal melanoma: From diagnosis to treatment and the science in between.

Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United States, and their age-adjusted risk is 5 per 1 million population. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomic spread, molecular changes, and responses to systemic therapy. Once uveal melanoma becomes metastatic, therapy options are limited and are often extrapolated from cutaneous melanoma therapies despite the routine exclusion of patients with uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress, and data from these well designed investigations will help guide future directions in this orphan disease. Cancer 2016;122:2299-2312. © 2016 American Cancer Society.

Sunlamp use is a risk factor for uveal melanoma: a meta-analysis.

OBJECTIVE: Advancements in the treatment of uveal melanoma have not improved survival; therefore, identifying modifiable risk factors is critical to improving outcomes. This study aims to investigate the association between sunlamp use and the development of uveal melanoma. DESIGN: This study is designed as a meta-analysis. METHODS: Literature was searched and reviewed through the MEDLINE (with both OVID and PubMed), EMBASE, MD Consult, and Web of Science databases. These databases were searched from 1966 to 2019 using the following keywords to identify articles examining risk factors for uveal melanoma: ultraviolet, sun, sunlight, uveal melanoma, eye cancer, eye melanoma, nevus, and risk factor. All articles were evaluated for inclusion based on methodology and data reporting association between sunlamp use and uveal melanoma. The Meta-analysis of Observational Studies in Epidemiology guidelines and the Newcastle-Ottawa Scale were used to assess data quality and validity. A random effects model was employed. RESULTS: A total of 5 studies, enrolling a total of 1753 uveal melanoma cases and 3399 controls were included in this meta-analysis. The results of this study showed a positive association between sunlamp use and uveal melanoma (odds ratio = 2.15; 95% confidence interval 1.27-3.64). Meta-regression of between study heterogeneity did not reveal a statistically significant association when publication year, site latitude, melanoma tissue location (specifically, inclusion of iris tumors), or control type (population versus clinic) were evaluated. CONCLUSION: This meta-analysis identified a statistically significant association between sunlamp use and uveal melanoma, supporting sunlamp use as a modifiable risk factor for uveal melanoma.

Immune classification and identification of prognostic genes for uveal melanoma based on six immune cell signatures.

Cutaneous melanoma could be treated by immunotherapy, which only has limited efficacy on uveal melanoma (UM). UM immunotyping for predicting immunotherapeutic responses and guiding immunotherapy should be better understood. This study identified molecular subtypes and key genetic markers associated with immunotherapy through immunosignature analysis. We screened a 6-immune cell signature simultaneously correlated with UM prognosis. Three immune subtypes (IS) were determined based on the 6-immune cell signature. Overall survival (OS) of IS3 was the longest. Significant differences of linear discriminant analysis (LDA) score were detected among the three IS types. IS3 with the highest LDA score showed a low immunosuppression. IS1 with the lowest LDA score was more immunosuppressive. LDA score was significantly negatively correlated with most immune checkpoint-related genes, and could reflect UM patients' response to anti-PD1 immunotherapy. Weighted correlation network analysis (WGCNA) identified that salmon, purple, yellow modules were related to IS and screened 6 prognostic genes. Patients with high-expressed NME1 and TMEM255A developed poor prognosis, while those with high-expressed BEX5 and ROPN1 had better prognosis. There was no notable difference in OS between patients with high-expressed LRRN1 and ST13 and those with low-expressed LRRN1 and ST13. NME1, TMEM255A, Bex5 and ROPN1 showed potential prognostic significance in UM.

Rapid growth of primary uveal melanoma following intravitreal bevacizumab injection: a case report and review of the literature.

Uveal melanoma size is a significant predictor of tumor metastasis. Although the relationship between antivascular endothelial growth factors (VEGF) and uveal melanoma growth has been studied, results are paradoxical, and the relationship remains controversial. We report the case of a 65-year-old man who presented with elevated intraocular pressure in his right eye, neovascularization of his iris, and significant corneal edema, which obscured the view of the angle. Given his history of proliferative diabetic retinopathy, he was diagnosed with neovascular glaucoma and subsequently received an intravitreal injection of bevacizumab and underwent Ahmed valve insertion. This was complicated by postoperative hyphema. Two and a half months postoperatively, a mass involving the inferior iris and ciliary body became visible, and fine-needle aspiration biopsy confirmed uveal melanoma. Seven weeks after diagnosis, the tumor's largest basal diameter had increased from 2.51 mm to 18.0 mm, and apical height increased from 6.23 mm to 11.0 mm. His right eye was enucleated. Histopathological analysis showed discontinuous invasion next to the Ahmed valve. Tumor progression after injection raises the possibility that in some untreated uveal melanomas, accelerated growth may occur following exposure to anti-VEGF agents.

Extracutaneous Melanoma.

Extracutaneous melanomas (ECMs) represent a heterogeneous group of melanoma subtypes characterized by distinct clinical and biological features from cutaneous melanoma. These subtypes share an aggressive natural history with high mortalities compared with nonacral cutaneous melanoma (NACM). Although recent advances in NACM have made significant improvements in morbidity and mortality, ECMs continue to lag behind. As the pathogenesis and molecular features of these rare subtypes continue to emerge, therapeutic research has aimed to closing the gap.

Hormonal exposures and the risk of uveal melanoma.

OBJECTIVES: Several studies suggest that hormonal mechanisms may be associated with the development of uveal melanoma. Therefore, the association between the risk of uveal melanoma and exposure to hormonal exposures was investigated in a case-control study from nine European countries. METHODS: Incident cases of uveal melanoma were frequency-matched to population and hospital controls by country, age, and sex. Female subjects were asked about their reproductive history, use of menopausal hormone replacement therapy and oral contraceptives. Among men, occupational handling of oils while working with transformers or capacitors which contain polychlorinated biphenyls (PCB) was solicited. Unconditional logistic regression analyses were calculated, adjusting for several potential confounders. Analyses were stratified by sex. RESULTS: Two hundred and ninety-three cases (165 men, 128 women) and 3,198 control subjects (2,121 men, 1,077 women) were interviewed. Among women, no associations were observed with hormonal status variables, intake of hormonal therapy or intake of oral contraceptives. Men showed an increased risk with occupational exposure to transformer/capacitor oils (OR = 2.74; Bonferroni-corrected 99.3% CI 1.07-7.02). However, these results were based on few exposed subjects only. CONCLUSION: The results of this study do not support the hypothesis of a hormonal influence in the carcinogenesis of uveal melanoma. Our finding of a potentially increased risk with PCB-containing oils requires further research.

Occupational exposure to electromagnetic fields and sex-differential risk of uveal melanoma.

OBJECTIVES: The association between occupational exposure to electromagnetic fields (EMF) and the risk of uveal melanoma was investigated in a case-control study in nine European countries. METHODS: Incident cases of uveal melanoma and population as well as hospital controls were included and frequency matched by country, 5-year birth cohort and sex. Subjects were asked whether they had worked close to high-voltage electrical transmission installations, computer screens and various electrical machines, or in complex electrical environments. Measurements of two Scandinavian job-exposure matrices were applied to estimate lifelong cumulative EMF exposure. Unconditional logistic regression analyses, stratified by sex and eye colour were calculated, adjusting for several potential confounders. RESULTS: 293 patients with uveal melanoma and 3198 control subjects were interviewed. Women exposed to electrical transmission installations showed elevated risks (OR 5.81, 95% CI 1.72 to 19.66). Positive associations with exposure to control rooms were seen among men and women, but most risk increases were restricted to subjects with dark iris colour. Application of published EMF measurements revealed stronger risk increases among women compared to men. Again, elevated risks were restricted to subjects with dark eye colour. CONCLUSION: Although based on a low prevalence of exposure to potential occupational sources of EMF, our data indicate that exposed dark-eyed women may be at particular risk for uveal melanoma.

A case-control study: occupational cooking and the risk of uveal melanoma.

BACKGROUND: A European-wide population based case-control study (European rare cancer study) undertaken in nine European countries examined risk factors for uveal melanoma. They found a positive association between cooks and the risk of uveal melanoma. In our study we examine whether cooks or people who worked in cook related jobs have an increased uveal melanoma risk. METHODS: We conducted a case-control study during 2002 and 2005. Overall, 1653 eligible subjects (age range: 20-74 years, living in Germany) participated. Interviews were conducted with 459 incident uveal melanoma cases, 827 population controls, 180 ophthalmologist controls and 187 sibling controls. Data on occupational exposure were obtained from a self-administered postal questionnaire and a computer-assisted telephone interview. We used conditional logistic regression to estimate odds ratios adjusting for the matching factors. RESULTS: Overall, we did not observe an increased risk of uveal melanoma among people who worked as cooks or who worked in cook related jobs. When we restricted the source population of our study to the population of the Federal State of Northrhine-Westphalia, we observed an increased risk among subjects who were categorized as cooks in the cases-control analysis. CONCLUSION: Our results are in conflict with former results of the European rare cancer study. Considering the rarity of the disease laboratory in vitro studies of human uveal melanoma cell lines should be done to analyze potential exposure risk factors like radiation from microwaves, strong light from incandescent ovens, or infrared radiation.

Update on uveal melanoma: Translational research from biology to clinical practice (Review).

Uveal melanoma is the most common type of intraocular cancer with a low mean annual incidence of 5­10 cases per million. Tumours are located in the choroid (90%), ciliary body (6%) or iris (4%) and of 85% are primary tumours. As in cutaneous melanoma, tumours arise in melanocytes; however, the characteristics of uveal melanoma differ, accounting for 3­5% of melanocytic cancers. Among the numerous risk factors are age, sex, genetic and phenotypic predisposition, the work environment and dermatological conditions. Management is usually multidisciplinary, including several specialists such as ophthalmologists, oncologists and maxillofacial surgeons, who participate in the diagnosis, treatment and complex follow­up of these patients, without excluding the management of the immense emotional burden. Clinically, uveal melanoma generates symptoms that depend as much on the affected ocular globe site as on the tumour size. The anatomopathological study of uveal melanoma has recently benefited from developments in molecular biology. In effect, disease classification or staging according to molecular profile is proving useful for the assessment of this type of tumour. Further, the improved knowledge of tumour biology is giving rise to a more targeted approach to diagnosis, prognosis and treatment development; for example, epigenetics driven by microRNAs as a target for disease control. In the present study, the main epidemiological, clinical, physiopathological and molecular features of this disease are reviewed, and the associations among all these factors are discussed.

Positive interaction between light iris color and ultraviolet radiation in relation to the risk of uveal melanoma: a case-control study.

PURPOSE: To examine the association among phenotypic characteristics, chronic and intermittent ultraviolet (UV) radiation, and the risk of uveal melanoma. DESIGN: Case-control study. PARTICIPANTS: Overall, between September of 2002 and March of 2005, 1677 eligible subjects (age range: 20-74 years, living in Germany) participated. Interviews were conducted with 459 incident uveal melanoma cases (response proportion 94%), 827 population controls (55%), 180 ophthalmologist controls (52%), and 187 sibling controls (57%). METHODS: Data on phenotypic characteristics and chronic and intermittent UV radiation exposure were obtained from a self-administered postal questionnaire and computer-assisted telephone interview. We used conditional logistic regression to estimate odds ratios adjusting for the matching factors. Furthermore, we studied the presence of synergy (super additive of risk or relative excess risk due to interaction) between light iris color and several UV radiation exposures. MAIN OUTCOME MEASURES: Hair color at age 20 years, eye color, untanned skin color, ability to tan, propensity to burn on exposure, freckling, occupational sun exposure, artificial UV radiation, burns to the eyes. RESULTS: In all 3 control groups, fair skin color, freckling as a child, nevi on the upper arms, burns to the eyes, use of sunlamps, and ever worked outside for 4 or more hours per day were positively associated with uveal melanoma. The association with eye color was apparent only in population controls (odds ratio = 1.9; 95% confidence interval [CI], 1.4-5.2), resulting in a relative excess risk due to interaction of 0.9 (95% CI, -0.6-2.3) for light iris color and more than 5 eye burns (UV-related keratitis) and 0.6 (95% CI, -0.3 to 1.5) for light iris color and eye protection. CONCLUSIONS: Our interaction analyses suggest that there is an etiologic synergism between light iris color and the exposure of UV radiation. People with light iris color may have an especially increased risk for uveal melanoma if they are exposed to UV radiation. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Arylsulfonamide 64B Inhibits Hypoxia/HIF-Induced Expression of c-Met and CXCR4 and Reduces Primary Tumor Growth and Metastasis of Uveal Melanoma.

PURPOSE: Uveal melanoma (UM) is the most prevalent and lethal intraocular malignancy in adults. Here, we examined the importance of hypoxia in UM growth and tested the antitumor effects of arylsulfonamide 64B, an inhibitor of the hypoxia-induced factor (HIF) pathway in animal models of UM and investigated the related mechanisms. EXPERIMENTAL DESIGN: UM cells were implanted in the uvea of mice eyes and mice systemically treated with 64B. Drug effect on primary eye tumor growth, circulating tumor cells, metastasis formation in liver, and survival were examined. 64B effects on UM cell growth, invasion and hypoxia-induced expression of C-X-C chemokine receptor type 4 (CXCR4) and mesenchymal-epithelial transition factor (c-Met) were measured. Luciferase reporter assays, chromatin immunoprecipitation, co-immunoprecipitation, and cellular thermal shift assays were used to determine how 64B interferes with the HIF transcriptional complex. RESULTS: Systemic administration of 64B had potent antitumor effects against UM in several orthotopic mouse models, suppressing UM growth in the eye (∼70% reduction) and spontaneous liver metastasis (∼50% reduction), and extending mice survival (P < 0.001) while being well tolerated. 64B inhibited hypoxia-induced expression of CXCR4 and c-Met, 2 key drivers of tumor invasion and metastasis. 64B disrupted the HIF-1 complex by interfering with HIF-1α binding to p300/CBP co-factors, thus reducing p300 recruitment to the MET and CXCR4 gene promoters. 64B could thermostabilize p300, supporting direct 64B binding to p300. CONCLUSIONS: Our preclinical efficacy studies support the further optimization of the 64B chemical scaffold toward a clinical candidate for the treatment of UM.

Targeted therapy for uveal melanoma.

Uveal melanoma is the most common primary intra-ocular malignancy in adults. Overall mortality rate remains high because of the development of metastatic disease, which is highly resistant to systemic therapy. Improved understanding of the molecular pathogenesis of cancers has led to a new generation of therapeutic agents that interfere with a specific pathway critical in tumor development or progression. Although no specific genes have been linked to the pathogenesis of uveal melanoma, which differs from that of cutaneous melanoma, progress has been made in identifying potential targets involved in uveal melanoma apoptosis, proliferation, invasion, metastasis, and angiogenesis. This review focuses on the prospects for improving the systemic therapy of uveal melanoma using molecularly targeted agents that are currently in clinical use as well as agents being tested in clinical trials. Preclinical studies suggest potential benefit of inhibitors of Bcl-2, ubiquitin-proteasome, histone deactylase, mitogen-activated protein kinase and phosphatidylinositol-3-kinase-AKT pathways, and receptor tyrosine kinases. Modifiers of adhesion molecules, matrix metalloproteinase, and angiogenic factors also have demonstrated potential benefit. Clinical trials of some of these approaches have been initiated in patients with metastatic uveal melanoma as well as in the adjuvant setting after primary therapy.

The hunt for the secrets of uveal melanoma.

The many secrets of uveal melanoma are being uncovered. Information on host and environmental factors that predispose to uveal melanoma has been published. The most important factors include light eye colour, fair skin, inability to tan and chronic sun exposure. Clinical clues that are visible on ophthalmoscopy have been shown to be significant factors in predicting growth of small borderline tumours and allow for early detection of melanoma. These factors include thickness over 2 mm, subretinal fluid, symptoms, orange pigment overlying the tumour and tumour margin within 3 mm of the disc. Refined methods of cytogenetic analysis have identified several chromosomal mutations associated with uveal melanoma. Currently, the most important mutation proves to be chromosome 3 monosomy, an abnormality associated with greater risk for metastatic disease.

Uveal Melanoma Associated With Myotonic Dystrophy: A Report of 6 Cases.

Importance: Patients with myotonic dystrophy (MD) have an increased risk of malignancy including uveal melanoma. This case series further explores the association between these 2 diseases. Objective: To describe a cohort of patients with uveal melanoma associated with MD, including a case of iris melanoma, and MD-associated uveal melanoma in relatives. Design, Setting, and Participants: Retrospective case series at 3 tertiary referral centers (Wills Eye Hospital, Philadelphia, Pennsylvania; Mayo Clinic, Rochester, Minnesota; and Moorfields Eye Hospital, London, England), between January 1, 2000, and August 31, 2017. The study included 6 patients with MD and uveal melanoma. Main Outcomes and Measures: Melanoma response to treatment and development of metastatic disease. Results: There were 6 patients, 4 men and 2 women, with MD and uveal melanoma. The mean patient age at melanoma diagnosis was 47 years (median, 43 years; range, 30-67 years), and the tumor involved the choroid in 5 patients (83%) and iris in 1 patient (17%). The diagnosis of MD was known since young adulthood in 2 patients (33%) and was discovered in adulthood in 4 patients (67%). The main clinical features of MD included muscle weakness (n = 5; 83%), myotonia (n = 4; 67%), polychromatic cataract (n = 4; 67%), complications with general anesthesia (n = 4; 67%), myalgia (n = 3; 50%), cardiac arrhythmia (n = 2; 33%), and frontal baldness (n = 2; 33%). Genetic testing revealed MD type 1 (4 of 4 tested patients), and 2 patients demonstrated positive family history of MD with classic clinical features and preferred no testing. Melanoma treatment included plaque radiotherapy (n = 4; 67%), photodynamic therapy (n = 1; 17%), and declined treatment (n = 1; 17%). At follow-up of 6, 6, 41, 42, and 87 months (5 patients), findings included melanoma regression (4 of 5 tumors), melanoma recurrence (1 of 5 tumors), and no metastatic disease (5 of 5 patients). Conclusions and Relevance: Six adult patients with MD demonstrated uveal melanoma involving the choroid or iris, emphasizing the association between these 2 diseases. Further research seems warranted to explore the pathogenesis of uveal melanoma in MD. These findings support the consideration of ophthalmic examination for uveal melanoma in patients with MD.

Uveal Melanoma Risk Factors: A Systematic Review of Meta-Analyses.

PURPOSE: There is currently no clinical risk-assessment tool allowing identification of patients at risk for developing uveal melanoma (UM) who might benefit from regular screening. As a first step toward the elaboration of such a tool, we systematically reviewed UM risk factors already established by meta-analysis. METHODS: Two reviewers independently screened Pubmed, Medline, Embase, and Web of Science from their respective inception dates until July 2016 using a combination of keywords and MeSH terms. Eligible studies were meta-analyses or systematic reviews providing pooled odds ratios (ORs) of risk factors for UM development or sufficient information to calculate them. Methodological quality was evaluated using the Assessment of Multiple Systematic Reviews tool. RESULTS: Four meta-analyses with a mean methodological quality score of 65.9% (min: 54.5%; max: 72.7%) were included. The following significant risk factors were identified: atypical cutaneous nevi (OR 2.82, 95% CI 1.10-7.26), welding (OR 2.05, 95% CI 1.20-3.51), occupational cooking (OR 1.81, 95% CI 1.33-2.46), fair skin color (OR 1.80, 95% CI 1.31-2.47), light eye color (OR 1.75, 95% CI 1.31-2.34), common cutaneous nevi (OR 1.74, 95% CI 1.27-2.39), propensity to sunburn (OR 1.64, 95% CI 1.29-2.09), iris nevi (OR 1.53, 95% CI 1.03-2.27), and cutaneous freckles (OR 1.27, 95% CI 1.09-1.49). Non-significant factors included outdoor leisure activity, occupational sunlight exposure, latitude of birth, and hair color. CONCLUSION: Moderate quality of evidence determined nine significant risk factors for developing UM. Knowledge of these variables will assist researchers in the elaboration of a formal risk-assessment tool allowing clinicians to estimate susceptibility to the disease and necessity of regular screening.