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Genetic Basis and Molecular Mechanisms of Uveal Melanomas

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 46278

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Dr. Karen Sisley

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Guest Editor

The Medical School, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK
Interests: rare cancers genetics; stem cells microenvironment
Special Issues, Collections and Topics in MDPI journals

Dr. Emma Chilton

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Guest Editor

Weston Park Cancer Centre, Department of Oncology & Metabolism, University of Sheffield, Sheffield, S10 2RX and Sheffield Ocular Oncology Service, Royal Hallamshire Hosptial, UK
Interests: uveal melanoma; sarcoma; genetics; biomarkers; stem cells; targeted therapies

Special Issue Information

Dear Colleagues,

Uveal melanoma (UM) is the most common primary eye tumour of adults. For most patients the primary tumour is effectively controlled with surgical or radio-therapeutic approaches. Unfortunately, about 50% of patients will later present with metastases, usually affecting the liver. The time between treatment of the primary tumour and metastasis ranges from simultaneous presentation to decades later. For many patients however, treatment of the primary tumour is analogous to “closing the door after the horse has bolted”, since the tumour has already spread prior to the removal of the eye.

It is now 30 years since the first publications reported UM as having recurrent abnormalities of chromosomes 1, 3, 6 and 8. These changes are reliable genetic biomarkers of aggressive UM. Their presence detected by a number of methods, and the use of other genetic tests, contribute to the prognostic assessment of UM. In the intervening 30 years however, little headway has been made in understanding the mechanistic control these changes exert. The target genes in the large areas affected have not been fully identified. Even for targets, such as BAP1 there is still much to learn regarding its role in UM. Other mutations, such as those of GNAQ and GNA11, are ubiquitous amongst UM and in combination with additional mutations point to dysregulation of key pathways. UM however remain at odds with many solid tumours, and specifically unlike their cutaneous counterpart, they mainly do not demonstrate high levels of genetic instability. Recent studies combining bioinformatics with additional investigations have contributed to the identification of new targets for exploration and revealed that epigenetic modulation of UM maybe a key driver in their development. The consequences of molecular / cytogenetic changes to the mechanistic regulation of UM is not clearly understood. Equally, studies have shown the perversion in UM of regulatory pathways but the mechanism instigating these changes is again poorly detailed. As a cancer of unmet need, a better understanding of its genetic basis and sequences is essential to improving the treatment of patients with disseminated disease.

This special issue will cover all aspects of the genetic background to UM and the mechanistic consequences. Areas of focus include, but are not limited to, tumour heterogeneity and targeted treatment based on genetic alterations, a better understanding of the DNA Damage response (DDR), and the effect of changes on the mechanisms and control of UM.

Dr. Karen Sisley
Guest Editor

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Keywords

genetic
regulatory mechanisms
heterogeneity
biomarkers
DNA repair
chromosomes
mutational analysis
epigenetic
synthetic lethality

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Research

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21 pages, 11170 KiB

Open AccessArticle

Monosomy 3 Is Linked to Resistance to MEK Inhibitors in Uveal Melanoma

by Svenja Mergener, Jens T. Siveke and Samuel Peña-Llopis

Int. J. Mol. Sci. 2021, 22(13), 6727; https://doi.org/10.3390/ijms22136727 - 23 Jun 2021

Cited by 13 | Viewed by 3886

Abstract

The use of MEK inhibitors in the therapy of uveal melanoma (UM) has been investigated widely but has failed to show benefits in clinical trials due to fast acquisition of resistance. In this study, we investigated a variety of therapeutic compounds in primary-derived uveal melanoma cell lines and found monosomy of chromosome 3 (M3) and mutations in BAP1 to be associated with higher resistance to MEK inhibition. However, reconstitution of BAP1 in a BAP1-deficient UM cell line was unable to restore sensitivity to MEK inhibition. We then compared UM tumors from The Cancer Genome Atlas (TCGA) with mutations in BAP1 with tumors with wild-type BAP1. Principal component analysis (PCA) clearly differentiated both groups of tumors, which displayed disparate overall and progression-free survival data. Further analysis provided insight into differential expression of genes involved in signaling pathways, suggesting that the downregulation of the eukaryotic translation initiation factor 2A (EIF2A) observed in UM tumors with BAP1 mutations and M3 UM cell lines might lead to a decrease in ribosome biogenesis while inducing an adaptive response to stress. Taken together, our study links loss of chromosome 3 with decreased sensitivity to MEK inhibition and gives insight into possible related mechanisms, whose understanding is fundamental to overcome resistance in this aggressive tumor. Full article

(This article belongs to the Special Issue Genetic Basis and Molecular Mechanisms of Uveal Melanomas)

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17 pages, 2621 KiB

Open AccessArticle

Additive Role of Immune System Infiltration and Angiogenesis in Uveal Melanoma Progression

by Sandra García-Mulero, Maria Henar Alonso, Luis P. del Carpio, Rebeca Sanz-Pamplona and Josep M. Piulats

Int. J. Mol. Sci. 2021, 22(5), 2669; https://doi.org/10.3390/ijms22052669 - 6 Mar 2021

Cited by 25 | Viewed by 3885

Abstract

Uveal melanoma (UM) is a malignant tumor that arises in the melanocytes of the uveal tract. It is the most frequent eye cancer, and despite new therapeutic approaches, prognosis is still poor, with up to 50% of patients developing metastasis with no efficient treatment options available. In contrast to cutaneous melanoma, UM is considered an “immune-cold” tumor due to the low mutational burden and the unique immunosuppressive microenvironment. To gain insight into the role of the UM microenvironment in regard to prognosis and metastatic progression, we have performed a pool analysis characterizing the UM microenvironment by using a bioinformatic approach. A variety of scores based on gene expression measuring stromal infiltration were calculated and used to assess association with prognosis. As a result, the highest immune and stromal scores were associated with poor prognosis. Specifically, stromal cells (fibroblasts and endothelial cells), T cells CD8+, natural killer (NK) cells, and macrophages M1 and M2 infiltration were associated with poor prognosis. Contrary to other tumors, lymphocytic infiltration is related to poor prognosis. Only B cells were associated with more favorable prognosis. UM samples scoring high in both angiogenesis (Angio) and antigen presentation (AP) pathways showed a poor prognosis suggesting an additive role of both functions. Almost all these tumors exhibited a chromosome 3 monosomy. Finally, an enrichment analysis showed that tumors classified as high Angio-high AP also activated metabolic pathways such as glycolysis or PI3K-AKT-MTOR. In summary, our pool analysis identified a cluster of samples with angiogenic and inflammatory phenotypes exhibiting poor prognosis and metabolic activation. Our analysis showed robust results replicated in a pool analysis merging different datasets from different analytic platforms. Full article

(This article belongs to the Special Issue Genetic Basis and Molecular Mechanisms of Uveal Melanomas)

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24 pages, 11408 KiB

Open AccessArticle

Monosomy 3 Influences Epithelial-Mesenchymal Transition Gene Expression in Uveal Melanoma Patients; Consequences for Liquid Biopsy

by Andrea Soltysova, Tatiana Sedlackova, Dana Dvorska, Karin Jasek, Pooneh Chokhachi Baradaran, Viera Horvathova Kajabova, Lucia Demkova, Verona Buocikova, Terezia Kurucova, Darina Lyskova, Alena Furdova, Gabriel Minarik, Pavel Babal, Zuzana Dankova and Bozena Smolkova

Int. J. Mol. Sci. 2020, 21(24), 9651; https://doi.org/10.3390/ijms21249651 - 17 Dec 2020

Cited by 11 | Viewed by 2922

Abstract

Despite outstanding advances in diagnosis and the treatment of primary uveal melanoma (UM), nearly 50% of UM patients develop metastases via hematogenous dissemination, driven by the epithelial-mesenchymal transition (EMT). Despite the failure in UM to date, a liquid biopsy may offer a feasible non-invasive approach for monitoring metastatic disease progression and addressing protracted dormancy. To detect circulating tumor cells (CTCs) in UM patients, we evaluated the mRNA expression of EMT-associated transcription factors in CD45-depleted blood fraction, using qRT-PCR. ddPCR was employed to assess UM-specific GNA11, GNAQ, PLCβ4, and CYSLTR2 mutations in plasma DNA. Moreover, microarray analysis was performed on total RNA isolated from tumor tissues to estimate the prognostic value of EMT-associated gene expression. In total, 42 primary UM and 11 metastatic patients were enrolled. All CD45-depleted samples were negative for CTC when compared to the peripheral blood fraction of 60 healthy controls. Tumor-specific mutations were detected in the plasma of 21.4% patients, merely, in 9.4% of primary UM, while 54.5% in metastatic patients. Unsupervised hierarchical clustering of differentially expressed EMT genes showed significant differences between monosomy 3 and disomy 3 tumors. Newly identified genes can serve as non-invasive prognostic biomarkers that can support therapeutic decisions. Full article

(This article belongs to the Special Issue Genetic Basis and Molecular Mechanisms of Uveal Melanomas)

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19 pages, 2865 KiB

Open AccessArticle

Monosomy-3 Alters the Expression Profile of the Glucose Transporters GLUT1-3 in Uveal Melanoma

by Tjorge Maaßen, Siranush Vardanyan, Anton Brosig, Hartmut Merz, Mahdy Ranjbar, Vinodh Kakkassery, Salvatore Grisanti and Aysegül Tura

Int. J. Mol. Sci. 2020, 21(24), 9345; https://doi.org/10.3390/ijms21249345 - 8 Dec 2020

Cited by 10 | Viewed by 2600

Abstract

Monosomy-3 in uveal melanoma (UM) cells increases the risk of fatal metastases. The gene encoding the low-affinity glucose transporter GLUT2 resides on chromosome 3q26.2. Here, we analyzed the expression of the glucose transporters GLUT1, GLUT2, and GLUT3 with regard to the histological and clinical factors by performing immunohistochemistry on the primary tumors of n = 33 UM patients. UMs with monosomy-3 exhibited a 57% lower immunoreactivity for GLUT2 and a 1.8×-fold higher ratio of GLUT1 to total GLUT1-3. The combined levels of GLUT1-3 proteins were reduced in the irradiated but not the non-irradiated tumors with monosomy-3. GLUT3 expression was stronger in the irradiated samples with disomy-3 versus monosomy-3, but the ratio of the GLUT3 isoform to total GLUT1-3 did not differ with regard to the monosomy-3 status in the irradiated or non-irradiated subgroups. Systemic metastases were associated with the presence of monosomy-3 in the primary and circulating tumor cells as well as a higher GLUT1 ratio. Upregulation of the high-affinity glucose transporter GLUT1 possibly as a compensation for the low-affinity isoform GLUT2 may be enhancing the basal glucose uptake in the UM cells with monosomy-3. Prevention of hyperglycemia might, therefore, be a valuable approach to delay the lethal UM metastases. Full article

(This article belongs to the Special Issue Genetic Basis and Molecular Mechanisms of Uveal Melanomas)

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Review

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18 pages, 3289 KiB

Open AccessReview

Genetics of Ocular Melanoma: Insights into Genetics, Inheritance and Testing

by Natasha M. van Poppelen, Daniël P. de Bruyn, Tolga Bicer, Rob Verdijk, Nicole Naus, Hanneke Mensink, Dion Paridaens, Annelies de Klein, Erwin Brosens and Emine Kiliҫ

Int. J. Mol. Sci. 2021, 22(1), 336; https://doi.org/10.3390/ijms22010336 - 30 Dec 2020

Cited by 24 | Viewed by 9278

Abstract

Ocular melanoma consists of posterior uveal melanoma, iris melanoma and conjunctival melanoma. These malignancies derive from melanocytes in the uveal tract or conjunctiva. The genetic profiles of these different entities differ from each other. In uveal melanoma, GNAQ and GNA11 gene mutations are frequently found and prognosis is based on mutation status of BAP1, SF3B1 and EIF1AX genes. Iris melanoma, also originating from the uvea, has similarities to the genetic makeups of both posterior uveal melanoma (UM) and conjunctival melanoma since mutations in GNAQ and GNA11 are less common and genes involved in conjunctival melanoma such as BRAF have been described. The genetic spectrum of conjunctival melanoma, however, includes frequent mutations in the BRAF, NRAS and TERT promoter genes, which are found in cutaneous melanoma as well. The BRAF status of the tumor is not correlated to prognosis, whereas the TERT promoter gene mutations are. Clinical presentation, histopathological characteristics and copy number alterations are associated with survival in ocular melanoma. Tissue material is needed to classify ocular melanoma in the different subgroups, which creates a need for the use of noninvasive techniques to prognosticate patients who underwent eye preserving treatment. Full article

(This article belongs to the Special Issue Genetic Basis and Molecular Mechanisms of Uveal Melanomas)

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15 pages, 1982 KiB

Open AccessReview

Spliceosome Mutations in Uveal Melanoma

by Josephine Q.N. Nguyen, Wojtek Drabarek, Serdar Yavuzyigitoglu, Eva Medico Salsench, Robert M. Verdijk, Nicole C. Naus, Annelies de Klein, Emine Kiliç and Erwin Brosens

Int. J. Mol. Sci. 2020, 21(24), 9546; https://doi.org/10.3390/ijms21249546 - 15 Dec 2020

Cited by 12 | Viewed by 4100

Abstract

Uveal melanoma (UM) is the most common primary intraocular malignancy of the eye. It has a high metastatic potential and mainly spreads to the liver. Genetics play a vital role in tumor classification and prognostication of UM metastatic disease. One of the driver genes mutated in metastasized UM is subunit 1 of splicing factor 3b (SF3B1), a component of the spliceosome complex. Recurrent mutations in components of the spliceosome complex are observed in UM and other malignancies, suggesting an important role in tumorigenesis. SF3B1 is the most common mutated spliceosome gene and in UM it is associated with late-onset metastasis. This review summarizes the genetic and epigenetic insights of spliceosome mutations in UM. They form a distinct subgroup of UM and have similarities with other spliceosome mutated malignancies. Full article

(This article belongs to the Special Issue Genetic Basis and Molecular Mechanisms of Uveal Melanomas)

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17 pages, 402 KiB

Open AccessReview

Iris Colour and the Risk of Developing Uveal Melanoma

by Laurien E. Houtzagers, Annemijn P. A. Wierenga, Aleid A. M. Ruys, Gregorius P. M. Luyten and Martine J. Jager

Int. J. Mol. Sci. 2020, 21(19), 7172; https://doi.org/10.3390/ijms21197172 - 28 Sep 2020

Cited by 35 | Viewed by 5916

Abstract

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. Full article

(This article belongs to the Special Issue Genetic Basis and Molecular Mechanisms of Uveal Melanomas)

16 pages, 1937 KiB

Open AccessReview

MicroRNAs and Uveal Melanoma: Understanding the Diverse Role of These Small Molecular Regulators

by Karen Aughton, Helen Kalirai and Sarah E. Coupland

Int. J. Mol. Sci. 2020, 21(16), 5648; https://doi.org/10.3390/ijms21165648 - 6 Aug 2020

Cited by 20 | Viewed by 3413

Abstract

Uveal melanoma (UM) is a rare tumour of the eye, characterised by a high propensity to metastasise in half of all patients, most frequently to the liver. Although there are effective treatment options for the primary tumour, once metastasis has occurred prognosis is poor, with overall survival limited to months. Currently, there are no effective treatments for metastatic UM, despite the tumour having a well-defined signalling pathway to which many therapies have been directed. In an effort to develop novel treatment approaches, understanding the role of other signalling molecules, such as microRNAs, is fundamental. MicroRNAs (miRNAs) are small non-coding RNA molecules involved in posttranscriptional gene regulation, resulting in reduced target gene expression and subsequent protein translation. In UM, several dysregulated miRNAs have been proposed to play a functional role in disease progression, whereas others have been put forward as clinical biomarkers of high-risk disease following isolation from blood, plasma and exosomes. Most recently, analyses of large datasets have identified promising prognostic miRNA signatures and panels. This review navigates the plethora of aberrant miRNAs disclosed so far in UM, and maps these to signalling pathways, which could be targeted in future therapies for the disseminated disease. Full article

(This article belongs to the Special Issue Genetic Basis and Molecular Mechanisms of Uveal Melanomas)

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21 pages, 1128 KiB

Open AccessReview

Targeting Epigenetic Modifications in Uveal Melanoma

by Pooneh Chokhachi Baradaran, Zuzana Kozovska, Alena Furdova and Bozena Smolkova

Int. J. Mol. Sci. 2020, 21(15), 5314; https://doi.org/10.3390/ijms21155314 - 27 Jul 2020

Cited by 17 | Viewed by 5130

Abstract

Uveal melanoma (UM), the most common intraocular malignancy in adults, is a rare subset of melanoma. Despite effective primary therapy, around 50% of patients will develop the metastatic disease. Several clinical trials have been evaluated for patients with advanced UM, though outcomes remain dismal due to the lack of efficient therapies. Epigenetic dysregulation consisting of aberrant DNA methylation, histone modifications, and small non-coding RNA expression, silencing tumor suppressor genes, or activating oncogenes, have been shown to play a significant role in UM initiation and progression. Given that there is no evidence any approach improves results so far, adopting combination therapies, incorporating a new generation of epigenetic drugs targeting these alterations, may pave the way for novel promising therapeutic options. Furthermore, the fusion of effector enzymes with nuclease-deficient Cas9 (dCas9) in clustered regularly interspaced short palindromic repeats (CRISPR) associated protein 9 (Cas9) system equips a potent tool for locus-specific erasure or establishment of DNA methylation as well as histone modifications and, therefore, transcriptional regulation of specific genes. Both, CRISPR-dCas9 potential for driver epigenetic alterations discovery, and possibilities for their targeting in UM are highlighted in this review. Full article

(This article belongs to the Special Issue Genetic Basis and Molecular Mechanisms of Uveal Melanomas)

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14 pages, 1171 KiB

Open AccessReview

Genetic Biomarkers in Melanoma of the Ocular Region: What the Medical Oncologist Should Know

by Kalijn Fredrike Bol, Marco Donia, Steffen Heegaard, Jens Folke Kiilgaard and Inge Marie Svane

Int. J. Mol. Sci. 2020, 21(15), 5231; https://doi.org/10.3390/ijms21155231 - 23 Jul 2020

Cited by 18 | Viewed by 4008

Abstract

Melanoma of the ocular region (ocular melanoma) comprises about 5% of all patients with melanoma and covers posterior uveal melanoma, iris melanoma, and conjunctival melanoma. The risk of metastasis is much higher in patients with ocular melanoma compared to a primary melanoma of the skin. The subtypes of ocular melanoma have distinct genetic features, which should be taken into consideration when making clinical decisions. Most relevant for current practice is the absence of BRAF mutations in posterior uveal melanoma, although present in some iris melanomas and conjunctival melanomas. In this review, we discuss the genetic biomarkers of the subtypes of ocular melanoma and their impacts on the clinical care of these patients. Full article

(This article belongs to the Special Issue Genetic Basis and Molecular Mechanisms of Uveal Melanomas)

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