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Special Issue "Genetic Basis and Molecular Mechanisms of Uveal Melanomas"

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: 31 October 2020.

Special Issue Editors

Dr. Karen Sisley
Website
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
Dr. Emma Chilton
Website
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

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

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

Published Papers (4 papers)

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Review

Open AccessReview
Iris Colour and the Risk of Developing Uveal Melanoma
Int. J. Mol. Sci. 2020, 21(19), 7172; https://doi.org/10.3390/ijms21197172 - 28 Sep 2020
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 [...] Read more.
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)
Open AccessReview
MicroRNAs and Uveal Melanoma: Understanding the Diverse Role of These Small Molecular Regulators
Int. J. Mol. Sci. 2020, 21(16), 5648; https://doi.org/10.3390/ijms21165648 - 06 Aug 2020
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 [...] Read more.
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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Open AccessReview
Targeting Epigenetic Modifications in Uveal Melanoma
Int. J. Mol. Sci. 2020, 21(15), 5314; https://doi.org/10.3390/ijms21155314 - 27 Jul 2020
Cited by 1
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 [...] Read more.
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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Open AccessReview
Genetic Biomarkers in Melanoma of the Ocular Region: What the Medical Oncologist Should Know
Int. J. Mol. Sci. 2020, 21(15), 5231; https://doi.org/10.3390/ijms21155231 - 23 Jul 2020
Cited by 1
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 [...] Read more.
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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