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Uveal Melanoma
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Uveal Melanoma

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 June 2019) | Viewed by 202766

Special Issue Editor

Dr. Ulrich Pfeffer

E-Mail Website
Guest Editor
Molecular Pathology, Ospedale Policlinico San Martino, Genova, Italy
Interests: cancer genomics; melanoma; uveal melanoma; gene editing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Uveal melanoma is among the best characterized solid tumors. It has become clear that there are mainly two subtypes that can eventually be subdivided into three or four, which are clearly distinct by their histopathological, cytogenetic, and molecular characteristics. The analysis of the subtypes allows to prognosticate the metastatic risk of each patient with an unmatched accuracy. While we essentially understand the molecular steps in uveal melanoma carcinogenesis, the mechanisms of metastasization and pronounced liver tropism are still poorly understood.

Unfortunately, the diagnostic and prognostic power is not matched by efficacy of therapy. The primary tumor is controlled by radiological and surgical interventions and local relapses are extremely rare. Nevertheless, approximately half of the patients develop metastases that rapidly progress to the fatal stage. Despite research, survival of patients with metastatic uveal melanoma has not changed over decades. The identification of the most frequent putative driver mutations, which occur in a mutually exclusive manner in two genes encoding alpha-subunits of G-proteins GNAQ and GNA11, has indicated G-protein signaling and the activation of MAP-kinases as potential targets, but MEK-inhibitors have failed to show major effects in clinical trials. More recently, the HIPPO independent activation of the YAP/TAZ signaling pathway by mutated GNAQ and GNA11 has been described, but, at present, no specific inhibitors have been tested in clinics. Recent reports on a specific inhibitor of the mutated form of GNAQ must be confirmed and translated into clinical applications. Immune checkpoint blockers that have met considerable success in the treatment of several cancers, including cutaneous melanoma, show very low response rates in uveal melanoma, likely due to the low number of neo-antigens, a consequence of a very low mutational burden.

Just like for other cancers, the identification of its Achilles’ heel will rely on a deep understanding of the molecular and cellular features of the cancer cell in its permissive microenvironment. This will likely be possible by the thorough molecular characterization of ever more tumors, the development of better cellular and animal models, such as three dimensional cultures, organoids, and patient derived xenografts, and the testing of new drugs, whether targeted at the molecular lesions typical of metastatic uveal melanoma or at the immune system.

In the present thematic issue, we try to summarize the current state of our understanding of uveal melanoma biology and recent advancements in uveal melanoma therapy and we discuss opportunities for therapeutic interventions that will hopefully soon improve the survival rates of metastatic uveal melanoma patients.

Dr. Ulrich Pfeffer
Guest Editor

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Editorial

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7 pages, 454 KiB  
Editorial
Uveal Melanoma
by Ulrich Pfeffer
Cancers 2019, 11(12), 1986; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11121986 - 10 Dec 2019
Cited by 2 | Viewed by 2621
Abstract
Uveal melanoma (UM) is among the best characterized solid tumors [...] Full article
(This article belongs to the Special Issue Uveal Melanoma)
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Research

Jump to: Editorial, Review, Other

18 pages, 3266 KiB  
Article
Secondary Somatic Mutations in G-Protein-Related Pathways and Mutation Signatures in Uveal Melanoma
by Francesca Piaggio, Veronica Tozzo, Cinzia Bernardi, Michela Croce, Roberto Puzone, Silvia Viaggi, Serena Patrone, Annalisa Barla, Domenico Coviello, Martine J. Jager, Pieter A. van der Velden, Michael Zeschnigk, Davide Cangelosi, Alessandra Eva, Ulrich Pfeffer and Adriana Amaro
Cancers 2019, 11(11), 1688; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11111688 - 30 Oct 2019
Cited by 18 | Viewed by 4566
Abstract
Background: Uveal melanoma (UM), a rare cancer of the eye, is characterized by initiating mutations in the genes G-protein subunit alpha Q (GNAQ), G-protein subunit alpha 11 (GNA11), cysteinyl leukotriene receptor 2 (CYSLTR2), and phospholipase C beta [...] Read more.
Background: Uveal melanoma (UM), a rare cancer of the eye, is characterized by initiating mutations in the genes G-protein subunit alpha Q (GNAQ), G-protein subunit alpha 11 (GNA11), cysteinyl leukotriene receptor 2 (CYSLTR2), and phospholipase C beta 4 (PLCB4) and by metastasis-promoting mutations in the genes splicing factor 3B1 (SF3B1), serine and arginine rich splicing factor 2 (SRSF2), and BRCA1-associated protein 1 (BAP1). Here, we tested the hypothesis that additional mutations, though occurring in only a few cases (“secondary drivers”), might influence tumor development. Methods: We analyzed all the 4125 mutations detected in exome sequencing datasets, comprising a total of 139 Ums, and tested the enrichment of secondary drivers in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that also contained the initiating mutations. We searched for additional mutations in the putative secondary driver gene protein tyrosine kinase 2 beta (PTK2B) and we developed new mutational signatures that explain the mutational pattern observed in UM. Results: Secondary drivers were significantly enriched in KEGG pathways that also contained GNAQ and GNA11, such as the calcium-signaling pathway. Many of the secondary drivers were known cancer driver genes and were strongly associated with metastasis and survival. We identified additional mutations in PTK2B. Sparse dictionary learning allowed for the identification of mutational signatures specific for UM. Conclusions: A considerable part of rare mutations that occur in addition to known driver mutations are likely to affect tumor development and progression. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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16 pages, 4810 KiB  
Article
Prediction of BAP1 Expression in Uveal Melanoma Using Densely-Connected Deep Classification Networks
by Muyi Sun, Wei Zhou, Xingqun Qi, Guanhong Zhang, Leonard Girnita, Stefan Seregard, Hans E. Grossniklaus, Zeyi Yao, Xiaoguang Zhou and Gustav Stålhammar
Cancers 2019, 11(10), 1579; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11101579 - 16 Oct 2019
Cited by 27 | Viewed by 4243
Abstract
Uveal melanoma is the most common primary intraocular malignancy in adults, with nearly half of all patients eventually developing metastases, which are invariably fatal. Manual assessment of the level of expression of the tumor suppressor BRCA1-associated protein 1 (BAP1) in tumor cell nuclei [...] Read more.
Uveal melanoma is the most common primary intraocular malignancy in adults, with nearly half of all patients eventually developing metastases, which are invariably fatal. Manual assessment of the level of expression of the tumor suppressor BRCA1-associated protein 1 (BAP1) in tumor cell nuclei can identify patients with a high risk of developing metastases, but may suffer from poor reproducibility. In this study, we verified whether artificial intelligence could predict manual assessments of BAP1 expression in 47 enucleated eyes with uveal melanoma, collected from one European and one American referral center. Digitally scanned pathology slides were divided into 8176 patches, each with a size of 256 × 256 pixels. These were in turn divided into a training cohort of 6800 patches and a validation cohort of 1376 patches. A densely-connected classification network based on deep learning was then applied to each patch. This achieved a sensitivity of 97.1%, a specificity of 98.1%, an overall diagnostic accuracy of 97.1%, and an F1-score of 97.8% for the prediction of BAP1 expression in individual high resolution patches, and slightly less with lower resolution. The area under the receiver operating characteristic (ROC) curves of the deep learning model achieved an average of 0.99. On a full tumor level, our network classified all 47 tumors identically with an ophthalmic pathologist. We conclude that this deep learning model provides an accurate and reproducible method for the prediction of BAP1 expression in uveal melanoma. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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11 pages, 1083 KiB  
Article
Real-World Impact of Immune Checkpoint Inhibitors in Metastatic Uveal Melanoma
by Kalijn Fredrike Bol, Eva Ellebaek, Lise Hoejberg, Mette Marie Bagger, Mathilde Skaarup Larsen, Tobias Wirenfeldt Klausen, Ulrich Heide Køhler, Henrik Schmidt, Lars Bastholt, Jens Folke Kiilgaard, Marco Donia and Inge Marie Svane
Cancers 2019, 11(10), 1489; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11101489 - 03 Oct 2019
Cited by 40 | Viewed by 3381
Abstract
Uveal melanoma (UM) is the most common intraocular malignancy in adults and shows a high rate of metastatic spread. As randomized clinical trials with immune checkpoint inhibitors (ICI) have not been performed in patients with metastatic UM, we analyzed the real-world outcomes in [...] Read more.
Uveal melanoma (UM) is the most common intraocular malignancy in adults and shows a high rate of metastatic spread. As randomized clinical trials with immune checkpoint inhibitors (ICI) have not been performed in patients with metastatic UM, we analyzed the real-world outcomes in a nationwide population-based study. Clinical data of patients with UM were extracted from the Danish Metastatic Melanoma database, a nationwide database containing unselected records of patients diagnosed with metastatic melanoma in Denmark. Survival before (pre-ICI, n = 32) and after (post-ICI, n = 94) the approval of first-line treatment with ICI was analyzed. A partial response to first-line treatment was observed in 7% of patients treated with anti-programmed cell death protein (PD)-1 monotherapy and in 21% with combined anti-cytotoxic T lymphocyte antigen (CTLA)-4 plus anti-PD-1 therapy. Median progression-free survival was 2.5 months for patients treated in the pre-ICI era compared to 3.5 months in the post-ICI era (hazard ratio (HR) 0.43; 95% confidence interval (CI) 0.28–0.67; p < 0.001). The estimated one-year overall survival rate increased from 25.0% to 41.9% and the median overall survival improved from 7.8 months to 10.0 months, respectively (HR 0.52; 95% CI 0.34–0.79; p = 0.003). Thus, the introduction of ICI as first-line treatment appears to have significantly improved the real-world survival of patients with metastatic UM, despite relatively low response rates compared to cutaneous melanoma. With the lack of therapies proven effective in randomized trials, these data support the current treatment with ICI in patients with metastatic UM. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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13 pages, 4128 KiB  
Article
Data Fusion Techniques for the Integration of Multi-Domain Genomic Data from Uveal Melanoma
by Max Pfeffer, André Uschmajew, Adriana Amaro and Ulrich Pfeffer
Cancers 2019, 11(10), 1434; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11101434 - 26 Sep 2019
Cited by 8 | Viewed by 3045
Abstract
Uveal melanoma (UM) is a rare cancer that is well characterized at the molecular level. Two to four classes have been identified by the analyses of gene expression (mRNA, ncRNA), DNA copy number, DNA-methylation and somatic mutations yet no factual integration of these [...] Read more.
Uveal melanoma (UM) is a rare cancer that is well characterized at the molecular level. Two to four classes have been identified by the analyses of gene expression (mRNA, ncRNA), DNA copy number, DNA-methylation and somatic mutations yet no factual integration of these data has been reported. We therefore applied novel algorithms for data fusion, joint Singular Value Decomposition (jSVD) and joint Constrained Matrix Factorization (jCMF), as well as similarity network fusion (SNF), for the integration of gene expression, methylation and copy number data that we applied to the Cancer Genome Atlas (TCGA) UM dataset. Variant features that most strongly impact on definition of classes were extracted for biological interpretation of the classes. Data fusion allows for the identification of the two to four classes previously described. Not all of these classes are evident at all levels indicating that integrative analyses add to genomic discrimination power. The classes are also characterized by different frequencies of somatic mutations in putative driver genes (GNAQ, GNA11, SF3B1, BAP1). Innovative data fusion techniques confirm, as expected, the existence of two main types of uveal melanoma mainly characterized by copy number alterations. Subtypes were also confirmed but are somewhat less defined. Data fusion allows for real integration of multi-domain genomic data. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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14 pages, 11105 KiB  
Article
The Potential Use of Electrochemotherapy in the Treatment of Uveal Melanoma: In Vitro Results in 3D Tumor Cultures and In Vivo Results in a Chick Embryo Model
by Miltiadis Fiorentzis, Arne Viestenz, Udo Siebolts, Berthold Seitz, Sarah E. Coupland and Joana Heinzelmann
Cancers 2019, 11(9), 1344; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11091344 - 11 Sep 2019
Cited by 25 | Viewed by 3843
Abstract
Uveal melanoma (UM) is the most common primary intraocular tumor that arises from neoplastic melanocytes in the choroid, iris, and ciliary body. Electrochemotherapy (ECT) has been successfully established for the treatment of skin and soft tissue metastatic lesions, deep-seated tumors of the liver, [...] Read more.
Uveal melanoma (UM) is the most common primary intraocular tumor that arises from neoplastic melanocytes in the choroid, iris, and ciliary body. Electrochemotherapy (ECT) has been successfully established for the treatment of skin and soft tissue metastatic lesions, deep-seated tumors of the liver, bone metastases, and unresectable pancreas lesions. The aim of this study was to evaluate the effect of ECT in vitro in 3D spheroid culture systems in primary and metastatic UM cell lines. We also investigated the chick embryo chorioallantoic membrane (CAM) as an in vivo model system for the growth and treatment of UM tumors using ECT. The cytotoxic effect of ECT in 3D spheroids was analyzed seven days following treatment by assessment of the size and MTT [(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium reduction] assay. The cytotoxicity of ECT after intratumoral or intraarterial administration was evaluated histologically. In vitro and in vivo ECT caused a significant reduction in tumor size and viability compared to electroporation or chemotherapy in both sections of our study. The current results underline the effectiveness of ECT in the treatment of UM and prepare the way for further investigation of its potential application in UM. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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16 pages, 3460 KiB  
Article
The Autocrine FGF/FGFR System in both Skin and Uveal Melanoma: FGF Trapping as a Possible Therapeutic Approach
by Sara Rezzola, Roberto Ronca, Alessandra Loda, Mohd Imtiaz Nawaz, Chiara Tobia, Giuseppe Paganini, Federica Maccarinelli, Arianna Giacomini, Francesco Semeraro, Marco Mor and Marco Presta
Cancers 2019, 11(9), 1305; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11091305 - 04 Sep 2019
Cited by 19 | Viewed by 3819
Abstract
Fibroblast growth factors (FGFs) play non-redundant autocrine/paracrine functions in various human cancers. The Cancer Genome Atlas (TCGA) data mining indicates that high levels of FGF and/or FGF receptor (FGFR) expression are associated with reduced overall survival, chromosome 3 monosomy and BAP1 mutation in [...] Read more.
Fibroblast growth factors (FGFs) play non-redundant autocrine/paracrine functions in various human cancers. The Cancer Genome Atlas (TCGA) data mining indicates that high levels of FGF and/or FGF receptor (FGFR) expression are associated with reduced overall survival, chromosome 3 monosomy and BAP1 mutation in human uveal melanoma (UM), pointing to the FGF/FGFR system as a target for UM treatment. Here, we investigated the impact of different FGF trapping approaches on the tumorigenic and liver metastatic activity of liver metastasis-derived murine melanoma B16-LS9 cells that, similar to human UM, are characterized by a distinctive hepatic tropism. In vitro and in vivo experiments demonstrated that the overexpression of the natural FGF trap inhibitor long-pentraxin 3 (PTX3) inhibits the oncogenic activity of B16-LS9 cells. In addition, B16-LS9 cells showed a reduced tumor growth and liver metastatic activity when grafted in PTX3-overexpressing transgenic mice. The efficacy of the FGF trapping approach was confirmed by the capacity of the PTX3-derived pan-FGF trap small molecule NSC12 to inhibit B16-LS9 cell growth in vitro, in a zebrafish embryo orthotopic tumor model and in an experimental model of liver metastasis. Possible translational implications for these observations were provided by the capacity of NSC12 to inhibit FGF signaling and cell proliferation in human UM Mel285, Mel270, 92.1, and OMM2.3 cells. In addition, NSC12 caused caspase-3 activation and PARP cleavage followed by apoptotic cell death as well as β-catenin degradation and inhibition of UM cell migration. Together, our findings indicate that FGF trapping may represent a novel therapeutic strategy in UM. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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13 pages, 1330 KiB  
Article
Increased Non-Homologous End Joining Makes DNA-PK a Promising Target for Therapeutic Intervention in Uveal Melanoma
by Rachel E. Doherty, Helen E. Bryant, Manoj K. Valluru, Ian G. Rennie and Karen Sisley
Cancers 2019, 11(9), 1278; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11091278 - 30 Aug 2019
Cited by 14 | Viewed by 3511
Abstract
Uveal melanoma (UM) is the most common primary intraocular tumour in adults, with a mean survival of six months following metastasis. The survival rates have not improved in over 30 years. This study has shown that sister chromatid exchange (SCE) is low in [...] Read more.
Uveal melanoma (UM) is the most common primary intraocular tumour in adults, with a mean survival of six months following metastasis. The survival rates have not improved in over 30 years. This study has shown that sister chromatid exchange (SCE) is low in UM which is likely due to a reduced expression of FANCD2. As FANCD2 can function to suppress non-homologous end joining (NHEJ), this study therefore investigated NHEJ in UM. The activation of the catalytic subunit of the NHEJ pathway protein DNA-dependent protein kinase (DNA-PK) was measured by analysing the foci formation and the ligation efficiency by NHEJ determined using a plasmid-based end-joining assay. Using small-interfering RNA (siRNA) knock-down, and chemical inhibitors of DNA-PK, the survival of primary UM cultures and two cell lines were determined. To assess the homologous recombination capacity in response to the inhibition of DNA-PK, a SCE analysis was performed. In addition, to support the findings, the messenger RNA (mRNA) expression of genes associated with NHEJ was analysed using the Cancer Genome Atlas (TCGA)-UM RNAseq data (n = 79). The NHEJ activity and DNA-PKcs activation was upregulated in UM and the inhibition of DNA-PK selectively induced apoptosis and sensitized to ionising radiation and inter-strand cross-linking agents. The inhibition of the NHEJ protein DNA-PK is lethal to UM, indicating a potentially effective therapeutic option, either alone or as a sensitizer for other treatments. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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11 pages, 455 KiB  
Article
Soluble HLA in the Aqueous Humour of Uveal Melanoma Is Associated with Unfavourable Tumour Characteristics
by Annemijn P. A. Wierenga, Gülçin Gezgin, Els van Beelen, Michael Eikmans, Marijke Spruyt-Gerritse, Niels J. Brouwer, Mieke Versluis, Robert M. Verdijk, Sjoerd G. van Duinen, Marina Marinkovic, Gregorius P. M. Luyten and Martine J. Jager
Cancers 2019, 11(8), 1202; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11081202 - 18 Aug 2019
Cited by 18 | Viewed by 3220
Abstract
A high HLA expression in uveal melanoma (UM) is part of the prognostically unfavorable inflammatory phenotype. We wondered whether the presence of soluble HLA (sHLA) in the aqueous humour is associated with clinical, histopathological or genetic tumour characteristics, and represents tumour HLA expression [...] Read more.
A high HLA expression in uveal melanoma (UM) is part of the prognostically unfavorable inflammatory phenotype. We wondered whether the presence of soluble HLA (sHLA) in the aqueous humour is associated with clinical, histopathological or genetic tumour characteristics, and represents tumour HLA expression and intratumoural inflammation. Aqueous humour from 108 UM patients was analysed for the presence of sHLA, using a Luminex assay specific for HLA Class I. Clinical and genetic parameters were compared between sHLA-positive and negative eyes. A qPCR analysis was performed on tumour tissue using a Fluidigm assay. In 19/108 UM-containing eyes, the sHLA level in the aqueous was above the detection limit. Tumours in sHLA-positive eyes were significantly larger, more frequently involved the ciliary body, and more often showed monosomy 3, gain of chromosome 8q and loss of BAP1 staining. Melanoma-related survival was worse in patients with sHLA-positive aqueous humour. sHLA in the aqueous did not represent the tumour’s HLA expression and did not relate to immune cell infiltration in the tumour. We conclude that UM-containing eyes may contain sHLA in the aqueous humour, where it is a prognostically-unfavourable sign and may influence local immune responses. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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8 pages, 785 KiB  
Communication
SRSF2 Mutations in Uveal Melanoma: A Preference for In-Frame Deletions?
by Natasha M. van Poppelen, Wojtek Drabarek, Kyra N. Smit, Jolanda Vaarwater, Tom Brands, Dion Paridaens, Emine Kiliç and Annelies de Klein
Cancers 2019, 11(8), 1200; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11081200 - 17 Aug 2019
Cited by 15 | Viewed by 3665
Abstract
Background: Uveal melanoma (UM) is the most common primary ocular malignancy in adults in the Western world. UM with a mutation in SF3B1, a spliceosome gene, is characterized by three or more structural changes of chromosome 1, 6, 8, 9, or 11. [...] Read more.
Background: Uveal melanoma (UM) is the most common primary ocular malignancy in adults in the Western world. UM with a mutation in SF3B1, a spliceosome gene, is characterized by three or more structural changes of chromosome 1, 6, 8, 9, or 11. Also UM without a mutation in SF3B1 harbors similar chromosomal aberrations. Since, in addition to SF3B1, mutations in U2AF1 and SRSF2 have also been observed in hematological malignancies, UM without a SF3B1 mutation—but with the characteristic chromosomal pattern—might harbor mutations in one of these genes. Methods: 42 UMs were selected based on their chromosomal profile and wildtype SF3B1 status. Sanger sequencing covering the U2AF1 (exon 2 and 7) hotspots and SRSF2 (exon 1 and 2) was performed on DNA extracted from tumor tissue. Data of three UM with an SRSF2 mutation was extracted from the The Cancer Genome Atlas (TCGA). Results: Heterozygous in-frame SRSF2 deletions affecting amino acids 92–100 were detected in two UMs (5%) of 42 selected tumors and in three TGCA UM specimens. Both the UM with an SRSF2 mutation from our cohort and the UM samples from the TCGA showed more than four structural chromosomal aberrations including (partial) gain of chromosome 6 and 8, although in two TCGA UMs monosomy 3 was observed. Conclusions: Whereas in myelodysplastic syndrome predominantly missense SRSF2 mutations are described, the observed SRSF2 mutations in UM are all in-frame deletions of 8–9 amino acids. This suggests that the R625 missense SF3B1 mutations and SRSF2 mutations in UM are different compared to the spliceosome gene mutations in hematological cancers, and probably target a different, as yet unknown, set of genes involved in uveal melanoma etiology. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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13 pages, 3560 KiB  
Article
Comparative Cytogenetic Abnormalities in Paired Choroidal Melanoma Samples Obtained Before and After Proton Beam Irradiation by Transscleral Fine-Needle Aspiration Biopsy and Endoresection
by Alexandre Matet, Khadija Aït Raïs, Denis Malaise, Martina Angi, Rémi Dendale, Sarah Tick, Livia Lumbroso-Le Rouic, Christine Lévy-Gabriel, Manuel Rodrigues, Gaëlle Pierron and Nathalie Cassoux
Cancers 2019, 11(8), 1173; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11081173 - 14 Aug 2019
Cited by 5 | Viewed by 2530
Abstract
This study compared the cytogenetic profiles of choroidal melanoma samples retrieved before and after proton beam irradiation. Twenty-four consecutive patients who underwent both fine-needle aspiration biopsy (FNAB) during tantalum clip positioning, and endoresection within three months of irradiation, were retrospectively included. Chromosome alterations [...] Read more.
This study compared the cytogenetic profiles of choroidal melanoma samples retrieved before and after proton beam irradiation. Twenty-four consecutive patients who underwent both fine-needle aspiration biopsy (FNAB) during tantalum clip positioning, and endoresection within three months of irradiation, were retrospectively included. Chromosome alterations were explored by array comparative genomic hybridization. Age at diagnosis was 50 ± 14 years, tumor thickness was 8.6 ± 1.7 mm and tumor diameter was 12.4 ± 2.3 mm. Six FNAB samples were non-contributive (25%), versus one endoresection sample (4%) (p = 0.049). Among 17 cases with paired contributive samples, the profiles of chromosomes 3 and 8 were identical in all cases, except one with partial chromosome 3 loss on the FNAB sample only. Three cases presented additional discordant aberrations on chromosomes other than 3 or 8q. Overall, we identified monosomy 3 in two cases, 8q gain in six cases, and both alterations in three cases. All cases presented GNAQ or GNA11 mutations assessed by a custom next-generation sequencing panel. Among the six cases with non-contributive initial FNAB, three cases presented abnormal 3 or 8q chromosomes detected on the endoresection material. These results demonstrate the higher rentability of endoresection material for cytogenetic analysis compared to FNAB, and provide clinical evidence of tumor heterogeneity in choroidal melanoma. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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15 pages, 2367 KiB  
Article
Do GNAQ and GNA11 Differentially Affect Inflammation and HLA Expression in Uveal Melanoma?
by Christiaan van Weeghel, Annemijn P. A. Wierenga, Mieke Versluis, Thorbald van Hall, Pieter A. van der Velden, Wilma G. M. Kroes, Ulrich Pfeffer, Gregorius P. M. Luyten and Martine J. Jager
Cancers 2019, 11(8), 1127; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11081127 - 07 Aug 2019
Cited by 11 | Viewed by 3222
Abstract
Inflammation, characterized by high numbers of infiltrating leukocytes and a high HLA Class I expression, is associated with a bad prognosis in uveal melanoma (UM). We wondered whether mutations in GNA11 or GNAQ differentially affect inflammation and HLA expression, and thereby progression of [...] Read more.
Inflammation, characterized by high numbers of infiltrating leukocytes and a high HLA Class I expression, is associated with a bad prognosis in uveal melanoma (UM). We wondered whether mutations in GNA11 or GNAQ differentially affect inflammation and HLA expression, and thereby progression of the disease. We analyzed data of 59 primarily enucleated UM eyes. The type of GNAQ/11 mutation was analyzed using dPCR; chromosome aberrations were determined by Fluorescence in Situ Hybridization (FISH), karyotyping, and single nucleotide polymorphism (SNP) analysis, and mRNA expression by Illumina PCR. Comparing tumors with a GNAQ mutation with those with a GNA11 mutation yielded no significant differences in histopathological characteristics, infiltrate, or HLA expression. When comparing the Q209L mutations with Q209P mutations in tumors with monosomy of chromosome 3, a higher mitotic count was found in the Q209P/M3 tumors (p = 0.007). The Kaplan-Meier (KM) curves between the patients of the different groups were not significantly different. We conclude that the type (Q209P/Q209L) or location of the mutation (GNA11/GNAQ) do not have a significant effect on the immunological characteristics of the tumors, such as infiltrate and HLA Class I expression. Chromosome 3 status was the main determinant in explaining the difference in infiltrate and HLA expression. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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12 pages, 1094 KiB  
Article
Predicting Visual Acuity Deterioration and Radiation-Induced Toxicities after Brachytherapy for Choroidal Melanomas
by Charlotte A. Espensen, Ane L. Appelt, Lotte S. Fog, Anita B. Gothelf, Juliette Thariat and Jens F. Kiilgaard
Cancers 2019, 11(8), 1124; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11081124 - 06 Aug 2019
Cited by 19 | Viewed by 2810
Abstract
Ruthenium-106 (Ru-106) brachytherapy is an established modality for eye-preserving treatment of choroidal melanoma. To achieve optimal treatment outcomes, there should be a balance between tumour control and the risk of healthy tissue toxicity. In this retrospective study, we examined normal tissue complication probability [...] Read more.
Ruthenium-106 (Ru-106) brachytherapy is an established modality for eye-preserving treatment of choroidal melanoma. To achieve optimal treatment outcomes, there should be a balance between tumour control and the risk of healthy tissue toxicity. In this retrospective study, we examined normal tissue complication probability (NTCP) for visual acuity deterioration and late complications to aid the understanding of dose-dependence after Ru-106 treatments. We considered consecutive patients diagnosed with choroidal melanoma and primarily treated at a single institution from 2005–2014. Treatment plans were retrospectively recreated using dedicated software and image guidance to contour the tumour and determine the actual plaque position. Dose distributions were extracted from each plan for all relevant anatomical structures. We considered visual acuity deterioration and late complications (maculopathy, optic neuropathy, ocular hypertension, vascular obliteration, cataract and retinal detachment). Lasso statistics were used to select the most important variables for each analysis. Outcomes were related to dose and clinical characteristics using multivariate Cox regressions analysis. In total, 227 patients were considered and 226 of those were eligible for analysis. Median potential follow-up time was 5.0 years (95% CI: 4.5–6.0). Visual acuity deterioration was related to optic disc-tumour distance and dose metrics from the retina and the macula, with retina V10Gy showing the strongest correlation. Macula V10Gy was the only dose metric impacting risk of maculopathy, while optic disc-tumour distance also proved important. Optic disc V50Gy had the largest impact on optic neuropathy along with optic disc-tumour distance. Optic disc V20Gy was the only variable associated with vascular obliteration. Lens D2% had the largest impact on the risk of cataract along with older age and the largest base dimension. We found no variables associated with the risk of ocular hypertension and retinal detachment. Visual acuity deterioration and most late complications demonstrated dependence on dose delivered to healthy structures in the eye after Ru-106 brachytherapy for choroidal melanomas. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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21 pages, 652 KiB  
Article
Families with BAP1-Tumor Predisposition Syndrome in The Netherlands: Path to Identification and a Proposal for Genetic Screening Guidelines
by Cindy Chau, Remco van Doorn, Natasha M. van Poppelen, Nienke van der Stoep, Arjen R. Mensenkamp, Rolf H. Sijmons, Barbara W. van Paassen, Ans M. W. van den Ouweland, Nicole C. Naus, Annemieke H. van der Hout, Thomas P. Potjer, Fonnet E. Bleeker, Marijke R. Wevers, Liselotte P. van Hest, Marjolijn C. J. Jongmans, Marina Marinkovic, Jaco C. Bleeker, Martine J. Jager, Gregorius P. M. Luyten and Maartje Nielsen
Cancers 2019, 11(8), 1114; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11081114 - 04 Aug 2019
Cited by 45 | Viewed by 5740
Abstract
Germline pathogenic variants in the BRCA1-associated protein-1 (BAP1) gene cause the BAP1-tumor predisposition syndrome (BAP1-TPDS, OMIM 614327). BAP1-TPDS is associated with an increased risk of developing uveal melanoma (UM), cutaneous melanoma (CM), malignant mesothelioma (MMe), renal cell carcinoma (RCC), meningioma, cholangiocarcinoma, [...] Read more.
Germline pathogenic variants in the BRCA1-associated protein-1 (BAP1) gene cause the BAP1-tumor predisposition syndrome (BAP1-TPDS, OMIM 614327). BAP1-TPDS is associated with an increased risk of developing uveal melanoma (UM), cutaneous melanoma (CM), malignant mesothelioma (MMe), renal cell carcinoma (RCC), meningioma, cholangiocarcinoma, multiple non-melanoma skin cancers, and BAP1-inactivated nevi. Because of this increased risk, it is important to identify patients with BAP1-TPDS. The associated tumors are treated by different medical disciplines, emphasizing the need for generally applicable guidelines for initiating genetic analysis. In this study, we describe the path to identification of BAP1-TPDS in 21 probands found in the Netherlands and the family history at the time of presentation. We report two cases of de novo BAP1 germline mutations (2/21, 9.5%). Findings of this study combined with previously published literature, led to a proposal of guidelines for genetic referral. We recommend genetic analysis in patients with ≥2 BAP1-TPDS-associated tumors in their medical history and/or family history. We also propose to test germline BAP1 in patients diagnosed with UM <40 years, CM <18 years, MMe <50 years, or RCC <46 years. Furthermore, other candidate susceptibility genes for tumor types associated with BAP1-TPDS are discussed, which can be included in gene panels when testing patients. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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28 pages, 3075 KiB  
Article
Differential Expression of DNA Repair Genes in Prognostically-Favorable versus Unfavorable Uveal Melanoma
by Mehmet Dogrusöz, Andrea Ruschel Trasel, Jinfeng Cao, Selҫuk Ҫolak, Sake I. van Pelt, Wilma G. M. Kroes, Amina F. A. S. Teunisse, Samar Alsafadi, Sjoerd G. van Duinen, Gregorius P. M. Luyten, Pieter A. van der Velden, Adriana Amaro, Ulrich Pfeffer, Aart G. Jochemsen and Martine J. Jager
Cancers 2019, 11(8), 1104; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11081104 - 02 Aug 2019
Cited by 12 | Viewed by 4006
Abstract
Expression of DNA repair genes was studied in uveal melanoma (UM) in order to identify genes that may play a role in metastases formation. We searched for genes that are differentially expressed between tumors with a favorable and unfavorable prognosis. Gene-expression profiling was [...] Read more.
Expression of DNA repair genes was studied in uveal melanoma (UM) in order to identify genes that may play a role in metastases formation. We searched for genes that are differentially expressed between tumors with a favorable and unfavorable prognosis. Gene-expression profiling was performed on 64 primary UM from the Leiden University Medical Center (LUMC), Leiden, The Netherlands. The expression of 121 genes encoding proteins involved in DNA repair pathways was analyzed: a total of 44 genes differed between disomy 3 and monosomy 3 tumors. Results were validated in a cohort from Genoa and Paris and the The Cancer Genome Atlas (TCGA) cohort. Expression of the PRKDC, WDR48, XPC, and BAP1 genes was significantly associated with clinical outcome after validation. PRKDC was highly expressed in metastasizing UM (p < 0.001), whereas WDR48, XPC, and BAP1 were lowly expressed (p < 0.001, p = 0.006, p = 0.003, respectively). Low expression of WDR48 and XPC was related to a large tumor diameter (p = 0.01 and p = 0.004, respectively), and a mixed/epithelioid cell type (p = 0.007 and p = 0.03, respectively). We conclude that the expression of WDR48, XPC, and BAP1 is significantly lower in UM with an unfavorable prognosis, while these tumors have a significantly higher expression of PRKDC. Pharmacological inhibition of DNA-PKcs resulted in decreased survival of UM cells. PRKDC may be involved in proliferation, invasion and metastasis of UM cells. Unraveling the role of DNA repair genes may enhance our understanding of UM biology and result in the identification of new therapeutic targets. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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16 pages, 3424 KiB  
Article
Loss of BAP1 Is Associated with Upregulation of the NFkB Pathway and Increased HLA Class I Expression in Uveal Melanoma
by Zahra Souri, Annemijn P. A. Wierenga, Christiaan van Weeghel, Pieter A. van der Velden, Wilma G. M. Kroes, Gregorius P. M. Luyten, Sjoerd H. van der Burg, Aart G. Jochemsen and Martine J. Jager
Cancers 2019, 11(8), 1102; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11081102 - 02 Aug 2019
Cited by 34 | Viewed by 4973
Abstract
One of the characteristics of prognostically infaust uveal melanoma (UM) is an inflammatory phenotype, which is characterized by high numbers of infiltrating T cells and macrophages, and a high HLA Class I expression. We wondered how this inflammation is regulated, and considered that [...] Read more.
One of the characteristics of prognostically infaust uveal melanoma (UM) is an inflammatory phenotype, which is characterized by high numbers of infiltrating T cells and macrophages, and a high HLA Class I expression. We wondered how this inflammation is regulated, and considered that one of the most important regulators of inflammation, the NFkB pathway, might play a role. We analyzed 64 UM samples for expression of HLA Class I, its regulators, and of members of the NFkB transcription family, using an Illumina HT12V4 array. HLA Class I expression and infiltrating immune cells were also determined by immunohistochemical staining. Information was obtained regarding chromosome status by Affymetrix Nsp array. Our analysis shows that expression of NFkB1, NFkB2 and RELB positively correlates with the level of HLA Class I expression and the number of infiltrating T cells and macrophages, while SPP1 and PPARγ are negatively correlated. Increased levels of NFkB1 and NFkB2 and decreased levels of SPP1 and PPARγ are seen in Monosomy 3/BAP1-negative tumors. This is also the case in non-inflammatory UM, indicating that our observation not only involves infiltrating leukocytes but the tumor cells themselves. We report that the NFkB pathway is associated with inflammation and HLA Class I expression in UM, and is upregulated when BAP1 expression is lost. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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12 pages, 3044 KiB  
Article
Infectious Knockdown of CREB and HIF-1 for the Treatment of Metastatic Uveal Melanoma
by Hanna Voropaev, Maria Gimmelshein Vatkin, Dudi Shneor, Shahar Luski, Alik Honigman and Shahar Frenkel
Cancers 2019, 11(8), 1056; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11081056 - 26 Jul 2019
Cited by 13 | Viewed by 2914
Abstract
Uveal melanoma (UM) is the most prevalent primary intraocular cancer in adults. Up to half the patients develop metastases that are currently incurable, and most patients die within two years following the diagnosis of metastases. Therefore, novel therapeutic approaches are required. It has [...] Read more.
Uveal melanoma (UM) is the most prevalent primary intraocular cancer in adults. Up to half the patients develop metastases that are currently incurable, and most patients die within two years following the diagnosis of metastases. Therefore, novel therapeutic approaches are required. It has been established that tumor cells are more resistant to the hypoxia cue than non-malignant cells and can remain viable in hypoxia. Oxygen absence in hypoxic tumor areas means the absence of chemotherapeutics and the absence of the effector for radiotherapy (free oxygen radicals). To overcome this treatment resistance, we constructed MuLV-based replication-competent retroviral (RCR) vectors expressing shRNA targeting the hypoxia-response regulating genes CREB and HIF-1. These RCRs express shRNAs either against a single exon or against an exon and the poly-A signal to minimize the point-mutation resistance. These RCRs that only infect replicating cells will preferentially infect tumor cells. Pre-infected Mel270 UM subcutaneous xenografts in SCID mice were monitored weekly in vivo via bioluminescence. Here, we demonstrate that the knockdown of CREB or HIF-1 in UM cells dramatically decreases UM tumor progression. The reduction of the expression of Glut-1, which is a major glucose transporter in cancer cells, within tumors that are infected with the armed viruses may indicate UM’s dependence on glycolysis for tumor progression. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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11 pages, 1242 KiB  
Article
Long-Term Visual Outcomes for Small Uveal Melanoma Staged T1 Treated by Proton Beam Radiotherapy
by Adélaïde Toutée, Martina Angi, Sylvain Dureau, Christine Lévy-Gabriel, Livia Lumbroso-Le Rouic, Rémi Dendale, Laurence Desjardins and Nathalie Cassoux
Cancers 2019, 11(8), 1047; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11081047 - 24 Jul 2019
Cited by 12 | Viewed by 2731
Abstract
There is increasing evidence of the survival benefit of treating uveal melanoma in an early stage, however it is important to discuss with the patient the associated risk of visual loss. We investigated visual outcomes for uveal melanomas staged T1 (T1UM) treated by [...] Read more.
There is increasing evidence of the survival benefit of treating uveal melanoma in an early stage, however it is important to discuss with the patient the associated risk of visual loss. We investigated visual outcomes for uveal melanomas staged T1 (T1UM) treated by proton beam radiotherapy (PBR) as a function of their distance to fovea-optic disc. This retrospective study included a cohort of 424 patients with T1UM treated with PBR between 1991 and 2010 with at least a 5-year follow-up. Visual acuity (VA) was analyzed for patients with posterior edge of tumor located at ≥3 mm (GSup3) or <3 mm (GInf3) from fovea-optic disc. The mean follow-up duration was 122 months, no tumor recurrence was observed. The mean baseline and final VA were 20/25 and 20/32 for GSup3 (n = 75), and 20/40 and 20/80 for GInf3 (n = 317) respectively. The frequency of a 20/200 or greater visual conservation was 93.2%(CI95%:87.7–99.1) and 60.1%(CI95%:54.9–65.9) for GSup3 and GInf3 respectively. This difference between groups was statistically significant (p < 0.001). The risk factors for significant VA loss (less than 20/200) were GInf3 location (p < 0.001), tumor touching optic disc (p = 0.04), initial VA inferior to 20/40 (p < 0.001), documented growth (p = 0.002), and age greater than 60 years (p < 0.001). In summary, PBR for T1UM yields excellent tumor control and good long-term visual outcomes for tumors located ≥3 mm from fovea-optic disc. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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12 pages, 10985 KiB  
Article
Synergic Interactions Between Hepatic Stellate Cells and Uveal Melanoma in Metastatic Growth
by Léo Piquet, Louise Dewit, Nathan Schoonjans, Martial Millet, Julie Bérubé, Peter R. A. Gerges, François Bordeleau and Solange Landreville
Cancers 2019, 11(8), 1043; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11081043 - 24 Jul 2019
Cited by 15 | Viewed by 3435
Abstract
Uveal melanoma (UM) is a malignant intraocular tumor that spreads to the liver in half of the cases. Since hepatic cells could play a role in the therapeutic resistance of metastatic UM, the purpose of our study was to investigate the pro-invasive role [...] Read more.
Uveal melanoma (UM) is a malignant intraocular tumor that spreads to the liver in half of the cases. Since hepatic cells could play a role in the therapeutic resistance of metastatic UM, the purpose of our study was to investigate the pro-invasive role of hepatic stellate cells (HSteCs) in metastatic UM at the micro- and macro-metastatic stages. We first performed an immunostaining with the alpha-smooth muscle actin (αSMA) to localize activated HSteCs in UM liver macro-metastases from four patients. Their accumulation of collagen was assessed with Masson’s Trichrome stain. Next, we inoculated metastatic UM cells alone or with human HSteCs in triple-immunodeficient mice, in order to determine if HSteCs are recruited as early as the micro-metastatic stage. The growth of metastatic foci was imaged in the liver by ex vivo fluorescence imaging. Histological analyses were performed with Masson’s Trichrome and Picrosirius Red stains, and antibodies against Melan-A and αSMA. The collagen content was measured in xenografts by quantitative polarization microscopy. In patient hepatectomy samples, activated HSteCs and their pathological matrix were localized surrounding the malignant lesions. In the mouse xenograft model, the number of hepatic metastases was increased when human HSteCs were co-inoculated. Histological analyses revealed a significant recruitment of HSteCs near the micro/macrolesions, and an increase in fibrillar collagen production. Our results show that HSteCs can provide a permissive microenvironment and might increase the therapeutic resistance of metastatic UM. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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11 pages, 1026 KiB  
Article
GNAQ Q209R Mutations Are Highly Specific for Circumscribed Choroidal Hemangioma
by Claudia Helga Dorothee Le Guin, Klaus Alfred Metz, Stefan Horst Kreis, Nikolaos Emmanouel Bechrakis, Norbert Bornfeld, Michael Zeschnigk and Dietmar Rudolf Lohmann
Cancers 2019, 11(7), 1031; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11071031 - 22 Jul 2019
Cited by 14 | Viewed by 3380
Abstract
Several tumors, including uveal melanoma, show somatic mutations of GNAQ/GNA11. Circumscribed choroidal hemangioma is a benign tumor that becomes symptomatic in adulthood. In some patients, morphologic examination of biopsies is required for differential diagnosis between amelanotic choroidal melanoma and circumscribed choroidal hemangioma. [...] Read more.
Several tumors, including uveal melanoma, show somatic mutations of GNAQ/GNA11. Circumscribed choroidal hemangioma is a benign tumor that becomes symptomatic in adulthood. In some patients, morphologic examination of biopsies is required for differential diagnosis between amelanotic choroidal melanoma and circumscribed choroidal hemangioma. Here, we report the results of GNAQ/GNA11 mutation analysis in samples from circumscribed choroidal hemangioma. Deep amplicon sequencing (Illumina MiSeq, San Diego, CA, USA) of positions R183 and Q209 of GNAQ and GNA11 in tissue samples from 33 patients with histologically diagnosed circumscribed choroidal hemangioma. All patients underwent biopsy or enucleation at our clinic between 2008 and 2018. To enable detection of variant alleles at low fractions, read depth exceeded 15,000-fold. DNA for genetic analysis was prepared from either snap-frozen (n = 22) or FFPE (n = 11) tissue samples. Samples from 28/33 patients (85%) showed a somatic missense mutation of GNAQ (c.626 A > G) predicted to result in p.Q209R. Variant allele fraction was variable (range 2.3% to 28%). Variants of GNAQ resulting in p.Q209 are characteristic for circumscribed choroidal hemangiomas. It appears that the GNAQ mutation spectrum in this tumor is narrow, possibly restricted to p.Q209R. Moreover, the spectrum is distinct from that of uveal melanoma, in which alterations resulting in p.Q209R are very rare. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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13 pages, 2142 KiB  
Article
Metastatic Uveal Melanoma: Treatment Strategies and Survival—Results from the Dutch Melanoma Treatment Registry
by Anouk Jochems, Monique K. van der Kooij, Marta Fiocco, Maartje G. Schouwenburg, Maureen J. Aarts, Alexander C. van Akkooi, Franchette W.P.J. van den Berkmortel, Christian U. Blank, Alfonsus J.M. van den Eertwegh, Margreet G. Franken, JanWillem B. de Groot, John B.A.G. Haanen, Geke A.P. Hospers, Rutger H. Koornstra, Wim H.J. Kruit, Marieke Louwman, Djura Piersma, Rozemarijn S. van Rijn, Karijn P.M. Suijkerbuijk, Albert J. ten Tije, Gerard Vreugdenhil, Michel W.J.M. Wouters, Michiel C.T. van Zeijl, Koos J.M. van der Hoeven and Ellen Kapiteijnadd Show full author list remove Hide full author list
Cancers 2019, 11(7), 1007; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11071007 - 18 Jul 2019
Cited by 24 | Viewed by 6798
Abstract
Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Up to 50% of UM patients will develop metastases. We present data of 175 metastatic UM patients diagnosed in the Netherlands between July 2012 and March 2018. In our cohort, elevated [...] Read more.
Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Up to 50% of UM patients will develop metastases. We present data of 175 metastatic UM patients diagnosed in the Netherlands between July 2012 and March 2018. In our cohort, elevated lactate dehydrogenase level (LDH) is an important factor associated with poorer survival (Hazard Ratio (HR) 9.0, 95% Confidence Interval (CI) 5.63–14.35), and the presence of liver metastases is negatively associated with survival (HR 2.09, 95%CI 1.07–4.08). We used data from the nation-wide Dutch Melanoma Treatment Registry (DMTR) providing a complete overview of the location of metastases at time of stage IV disease. In 154 (88%) patients, the liver was affected, and only 3 patients were reported to have brain metastases. In 63 (36%) patients, mutation analysis was performed, showing a GNA11 mutation in 28.6% and a GNAQ mutation in 49.2% of the analyzed patients. In the absence of standard care of treatment options, metastatic UM patients are often directed to clinical trials. Patients participating in clinical trials are often subject to selection and usually do not represent the entire metastatic UM population. By using our nation-wide cohort, we are able to describe real-life treatment choices made in metastatic UM patients and 1-year survival rates in selected groups of patients. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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12 pages, 1166 KiB  
Article
Ischemia Is Related to Tumour Genetics in Uveal Melanoma
by Niels J. Brouwer, Annemijn P. A. Wierenga, Gülçin Gezgin, Marina Marinkovic, Gregorius P. M. Luyten, Wilma G. M. Kroes, Mieke Versluis, Pieter A. van der Velden, Robert M. Verdijk and Martine J. Jager
Cancers 2019, 11(7), 1004; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11071004 - 18 Jul 2019
Cited by 21 | Viewed by 3600
Abstract
Hypoxia-inducible factor 1-alpha (HIF1a) and its regulator von Hippel–Lindau protein (VHL) play an important role in tumour ischemia. Currently, drugs that target HIF1a are being developed to treat malignancies. Although HIF1a is known to be expressed in uveal melanoma (UM), it is as [...] Read more.
Hypoxia-inducible factor 1-alpha (HIF1a) and its regulator von Hippel–Lindau protein (VHL) play an important role in tumour ischemia. Currently, drugs that target HIF1a are being developed to treat malignancies. Although HIF1a is known to be expressed in uveal melanoma (UM), it is as yet unknown which factors, such as tumour size or genetics, determine its expression. Therefore, we aimed to determine which tumour characteristics relate to HIF1a expression in UM. Data from 64 patients who were enucleated for UM were analysed. Messenger RNA (mRNA) expression was determined with the Illumina HT-12 v4 chip. In 54 cases, the status of chromosomes 3 and 8q, and BRCA1-associated protein 1 (BAP1) protein expression (immunohistochemistry) were determined. Findings were corroborated using data of 80 patients from the Cancer Genome Atlas (TCGA) study. A significantly increased expression of HIF1a, and a decreased expression of VHL were associated with monosomy 3/loss of BAP1 expression. The relationship between BAP1 loss and HIF1a expression was independent of chromosome 3. The largest basal diameter and tumour thickness showed no relationship with HIF1a. HIF1a expression related to an increased presence of infiltrating T cells and macrophages. From this study, we conclude that HIF1a is strongly related to tumour genetics in UM, especially to loss of BAP1 expression, and less to tumour size. Tumour ischemia is furthermore related to the presence of an inflammatory phenotype. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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12 pages, 1128 KiB  
Article
Tumour Angiogenesis in Uveal Melanoma Is Related to Genetic Evolution
by Niels J. Brouwer, Gülçin Gezgin, Annemijn P.A. Wierenga, Inge H.G. Bronkhorst, Marina Marinkovic, Gregorius P.M. Luyten, Mieke Versluis, Wilma G.M. Kroes, Pieter A. van der Velden, Robert M. Verdijk and Martine J. Jager
Cancers 2019, 11(7), 979; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11070979 - 13 Jul 2019
Cited by 29 | Viewed by 2973
Abstract
Increased angiogenesis is associated with a higher metastasis- and mortality rate in uveal melanoma (UM). Recently, it was demonstrated that genetic events, such as 8q-gain and BAP1-loss, influence the level of immune infiltrate. We aimed to determine whether genetic events, and specific cytokines, [...] Read more.
Increased angiogenesis is associated with a higher metastasis- and mortality rate in uveal melanoma (UM). Recently, it was demonstrated that genetic events, such as 8q-gain and BAP1-loss, influence the level of immune infiltrate. We aimed to determine whether genetic events, and specific cytokines, relate to angiogenesis in UM. Data from UM patients who underwent enucleation between 1999 and 2008 were analysed. Microvascular density (MVD) and the presence of infiltrating immune cells were determined with immunohistochemistry (IHC) and immunofluorescence in 43 cases. Chromosome status, BAP1 IHC and mRNA expression of angiogenesis-related genes were known in 54 cases. Tumours with monosomy 3/BAP1-loss showed a higher MVD compared to tumours with disomy 3/normal BAP1 expression (p = 0.008 and p = 0.004, respectively). Within BAP1-positive lesions (n = 20), 8q-gain did not relate to MVD (p = 0.51). A high MVD was associated with an increased expression of angiopoietin 2 (ANGPT2) (p = 0.041), Von Willebrand Factor (VWF) (p = 0.010), a decreased expression of vascular endothelial growth factor B (VEGF-B) (p = 0.024), and increased numbers of tumour-infiltrating macrophages (CD68+, p = 0.017; CD68+CD163+, p = 0.031) and lymphocytes (CD4+, p = 0.027). Concluding, vascular density of UM relates to its genetic profile: Monosomy 3 and BAP1-loss are associated with an increased MVD, while an early event (gain of 8q) is not independently related to MVD, but may initiate a preparation phase towards development of vessels. Interestingly, VEGF-B expression is decreased in UM with a high MVD. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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17 pages, 4038 KiB  
Article
Uptake of Ranibizumab but Not Bevacizumab into Uveal Melanoma Cells Correlates with a Sustained Decline in VEGF-A Levels and Metastatic Activities
by Aysegül Tura, Vera E. Pawlik, Martin Rudolf, Justus S. Ernesti, Jan-Niklas Stutzer, Salvatore Grisanti and Mahdy Ranjbar
Cancers 2019, 11(6), 868; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11060868 - 21 Jun 2019
Cited by 11 | Viewed by 3608
Abstract
Despite the implication of vascular endothelial growth factor-A (VEGF-A) in the pathophysiology of uveal melanoma (UM), the anti-VEGF-A antibody bevacizumab yielded conflicting results on UM growth. Here, we evaluated whether bevacizumab and ranibizumab, a humanized Fab-fragment against VEGF-A, can enter UM cells and [...] Read more.
Despite the implication of vascular endothelial growth factor-A (VEGF-A) in the pathophysiology of uveal melanoma (UM), the anti-VEGF-A antibody bevacizumab yielded conflicting results on UM growth. Here, we evaluated whether bevacizumab and ranibizumab, a humanized Fab-fragment against VEGF-A, can enter UM cells and induce a sustained physiological response. The primary and metastatic UM cell lines Mel-270 and OMM-2.5 were exposed to bevacizumab or ranibizumab for one day and were maintained further in untreated medium for a total of three days. Both antibodies significantly reduced the levels of extracellular VEGF-A and the angiogenic potential of the conditioned medium after one day. These inhibitory effects of bevacizumab diminished by day three. Ranibizumab suppressed the metabolic activity, proliferation, and intracellular VEGF-A levels in a cell-type and concentration-dependent manner, whereas bevacizumab exerted no effect. Both drugs were detected inside early endosomes within the UM cells, with the stronger and sustained colocalization of ranibizumab. Our results therefore demonstrated the more potent and persistent suppressive activity of ranibizumab on the UM cells, possibly due to its higher level of uptake and prolonged intracellular retention. Further research on the endosome dynamics in UM cells might provide valuable insight into the response of these heterogenous tumors to therapeutic antibodies. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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12 pages, 958 KiB  
Article
Development of a Prognostic Nomogram for Liver Metastasis of Uveal Melanoma Patients Selected by Liver MRI
by Pascale Mariani, Sylvain Dureau, Alexia Savignoni, Livia Lumbroso-Le Rouic, Christine Levy-Gabriel, Sophie Piperno-Neumann, Manuel J. Rodrigues, Laurence Desjardins, Nathalie Cassoux and Vincent Servois
Cancers 2019, 11(6), 863; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11060863 - 21 Jun 2019
Cited by 20 | Viewed by 2988
Abstract
Patients with liver metastases of uveal melanoma (LMUM) die from their metastatic evolution within 2 years. We established a nomogram to choose a treatment adapted to life expectancy. From 2002 to 2013, we reviewed 224 patients with LMUM selected by liver MRI. A [...] Read more.
Patients with liver metastases of uveal melanoma (LMUM) die from their metastatic evolution within 2 years. We established a nomogram to choose a treatment adapted to life expectancy. From 2002 to 2013, we reviewed 224 patients with LMUM selected by liver MRI. A nomogram was developed based on a Cox model. The predictive performance of the model was assessed according to the C-statistic, Kaplan–Meier curve, and calibration plots. The median follow-up was 49.2 months (range, 0.6–70.9). The survival rates at 6, 12, and 24 months were 0.88 (0.95 CI [0.84–0.93]), 0.68 (0.95 CI [0.62–0.75]), and 0.26 (0.95 CI [0.21–0.33]), respectively. The four factors selected for the nomogram with a worse prognosis were: A disease-free interval between the UM and LMUM groups of less than 6 months (HR = 3.39; 0.95 CI [1.90–6.05]), more than 10 LMUM (HR = 3.95; 0.95 CI [1.97–4.43]), a maximum LMUM of more than 1200 mm2 (HR = 2.47; 0.95 CI [1.53–3.98]), and a lactate dehydrogenase (LDH) value greater than 1.5 (HR = 3.72; 0.95 CI [2.30–6.00]). The model achieved relatively good discrimination and calibration (C-statistic 0.71). This nomogram could be useful for decision-making and risk stratification for therapeutic options. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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8 pages, 1079 KiB  
Article
Pilot Study of Circulating Tumor Cells in Early-Stage and Metastatic Uveal Melanoma
by Kartik Anand, Jason Roszik, Dan Gombos, Joshua Upshaw, Vanessa Sarli, Salyna Meas, Anthony Lucci, Carolyn Hall and Sapna Patel
Cancers 2019, 11(6), 856; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11060856 - 20 Jun 2019
Cited by 29 | Viewed by 4599
Abstract
Nearly 50% of uveal melanoma (UM) patients develop metastatic disease, and there remains no current standard assay for detection of minimal residual disease. We conducted a pilot study to check the feasibility of circulating tumor cell (CTC) detection in UM. We enrolled 40 [...] Read more.
Nearly 50% of uveal melanoma (UM) patients develop metastatic disease, and there remains no current standard assay for detection of minimal residual disease. We conducted a pilot study to check the feasibility of circulating tumor cell (CTC) detection in UM. We enrolled 40 patients with early or metastatic UM of which 20 patients had early-stage disease, 19 had metastatic disease, and one was not evaluable. At initial blood draw, 36% of patients had detectable CTCs (30% in early-stage vs. 42% in metastatic), which increased to 54% at data cutoff (40% in early-stage vs. 68% in metastatic). Five early-stage patients developed distant metastases, 60% (3/5) had detectable CTCs before radiographic detection of the metastasis. Landmark overall survival (from study enrollment) at 24 months was statistically lower in CTC-positive vs. negative early-stage UM (p < 0.05). Within this small dataset, the presence of CTCs in early-stage UM predicted an increased risk of metastatic disease and was associated with worse outcomes. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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14 pages, 6232 KiB  
Article
Aberrant MicroRNA Expression and Its Implications for Uveal Melanoma Metastasis
by Kyra N. Smit, Jiang Chang, Kasper Derks, Jolanda Vaarwater, Tom Brands, Rob M. Verdijk, Erik A.C. Wiemer, Hanneke W. Mensink, Joris Pothof, Annelies de Klein and Emine Kilic
Cancers 2019, 11(6), 815; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11060815 - 12 Jun 2019
Cited by 31 | Viewed by 3675
Abstract
Uveal melanoma (UM) is the most frequently found primary intra-ocular tumor in adults. It is a highly aggressive cancer that causes metastasis-related mortality in up to half of the patients. Many independent studies have reported somatic genetic changes associated with high metastatic risk, [...] Read more.
Uveal melanoma (UM) is the most frequently found primary intra-ocular tumor in adults. It is a highly aggressive cancer that causes metastasis-related mortality in up to half of the patients. Many independent studies have reported somatic genetic changes associated with high metastatic risk, such as monosomy of chromosome 3 and mutations in BAP1. Still, the mechanisms that drive metastatic spread are largely unknown. This study aimed to elucidate the potential role of microRNAs in the metastasis of UM. Using a next-generation sequencing approach in 26 UM samples we identified thirteen differentially expressed microRNAs between high-risk UM and low/intermediate-risk UM, including the known oncomirs microRNA-17-5p, microRNA-21-5p, and miR-151a-3p. Integration of the differentially expressed microRNAs with expression data of predicted target genes revealed 106 genes likely to be affected by aberrant microRNA expression. These genes were involved in pathways such as cell cycle regulation, EGF signaling and EIF2 signaling. Our findings demonstrate that aberrant microRNA expression in UM may affect the expression of genes in a variety of cancer-related pathways. This implies that some microRNAs can be responsible for UM metastasis and are promising potential targets for future treatment. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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16 pages, 5033 KiB  
Article
PARP Inhibition Increases the Response to Chemotherapy in Uveal Melanoma
by Leanne de Koning, Didier Decaudin, Rania El Botty, André Nicolas, Guillaume Carita, Mathieu Schuller, Bérengère Ouine, Aurélie Cartier, Adnan Naguez, Justine Fleury, Vesselina Cooke, Andrew Wylie, Paul Smith, Elisabetta Marangoni, David Gentien, Didier Meseure, Pascale Mariani, Nathalie Cassoux, Sophie Piperno-Neumann, Sergio Roman-Roman and Fariba Nématiadd Show full author list remove Hide full author list
Cancers 2019, 11(6), 751; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11060751 - 29 May 2019
Cited by 32 | Viewed by 4100
Abstract
Uveal melanoma (UM) remains without effective therapy at the metastatic stage, which is associated with BAP-1 (BRCA1 associated protein) mutations. However, no data on DNA repair capacities in UM are available. Here, we use UM patient-derived xenografts (PDXs) to study the therapeutic activity [...] Read more.
Uveal melanoma (UM) remains without effective therapy at the metastatic stage, which is associated with BAP-1 (BRCA1 associated protein) mutations. However, no data on DNA repair capacities in UM are available. Here, we use UM patient-derived xenografts (PDXs) to study the therapeutic activity of the PARP inhibitor olaparib, alone or in combination. First, we show that the expression and the activity of PARP proteins is similar between the PDXs and the corresponding patient’s tumors. In vivo experiments in the PDX models showed that olaparib was not efficient alone, but significantly increased the efficacy of dacarbazine. Finally, using reverse phase protein arrays and immunohistochemistry, we identified proteins involved in DNA repair and apoptosis as potential biomarkers predicting response to the combination of olaparib and dacarbazine. We also observed a high increase of phosphorylated YAP and TAZ proteins after dacarbazine + olaparib treatment. Our results suggest that PARP inhibition in combination with the alkylating agent dacarbazine could be of clinical interest for UM treatment. We also observe an interesting effect of dacarbazine on the Hippo pathway, confirming the importance of this pathway in UM. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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12 pages, 2784 KiB  
Article
Changes in Ultraviolet Radiation Exposure to the Ocular Region: A Population-Based Study
by Ezekiel Weis, Sebastian Q. Vrouwe, David B. LeBaron, Matthew B. Parliament, Jerry Shields and Carol L. Shields
Cancers 2019, 11(5), 719; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11050719 - 24 May 2019
Cited by 6 | Viewed by 3153
Abstract
In contrast to the well-established association between ultraviolet radiation (UVR) exposure and skin cancers, the relationship between UVR and uveal malignant melanoma (UM) remains controversial. To address this controversy, we evaluated the incidence rates of cutaneous malignancies in the eyelids as a proxy [...] Read more.
In contrast to the well-established association between ultraviolet radiation (UVR) exposure and skin cancers, the relationship between UVR and uveal malignant melanoma (UM) remains controversial. To address this controversy, we evaluated the incidence rates of cutaneous malignancies in the eyelids as a proxy for UVR exposure in the ocular region using a population-based cancer registry. Overall, 74,053 cases of eyelid basal cell carcinoma (BCC) and 7890 cases of melanoma over a 26-year period (1982–2007) were analyzed. The incidence of eyelid basal cell carcinoma and uveal melanoma remained stable, whereas other cutaneous areas demonstrated an increase in the rates. A comparability test demonstrated that BCC incidence trends were significantly different between the eyelid versus both chronically exposed (males p = 0.001; females p = 0.01) and intermittently exposed skin (males and females, p = 0.0002), as well as the skin of the face (males p = 0.002; females p = 0.02). Similarly, melanoma trends were significantly different between the UM group versus both chronically exposed cutaneous melanoma (CM) (males p = 0.001; females p = 0.04) and intermittently exposed CM (males p = 0.005), as well as facial skin CM (males and females p = 0.0002). The discrepancy of cancer incidence between tumors in the peri-ocular region versus the rest of the body suggests that the peri-ocular region might have a different or unique exposure pattern to ultraviolet radiation. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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20 pages, 5790 KiB  
Article
MRI of Uveal Melanoma
by Teresa A. Ferreira, Lorna Grech Fonk, Myriam G. Jaarsma-Coes, Guido G. R. van Haren, Marina Marinkovic and Jan-Willem M. Beenakker
Cancers 2019, 11(3), 377; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11030377 - 17 Mar 2019
Cited by 49 | Viewed by 6988
Abstract
Uveal Melanoma (UM) is the most common primary malignant ocular tumor. The high soft tissue contrast and spatial resolution, and the possibility of generating 3D volumetric and functional images, make Magnetic Resonance Imaging (MRI) a valuable diagnostic imaging technique in UM. Current clinical [...] Read more.
Uveal Melanoma (UM) is the most common primary malignant ocular tumor. The high soft tissue contrast and spatial resolution, and the possibility of generating 3D volumetric and functional images, make Magnetic Resonance Imaging (MRI) a valuable diagnostic imaging technique in UM. Current clinical MRI protocols, however, are not optimized for UM and therefore lack the quality for accurate assessments. We therefore developed a dedicated protocol at a 3 Tesla MRI, using an eye coil, consisting of multi-slice 2D sequences, different isotropic sequences and diffusion and perfusion-weighted images. This protocol was prospectively evaluated in 9 uveal melanoma patients. The multi-slice 2D sequences had the highest in-plane resolution, being the most suited for lesion characterization and local extension evaluation. The isotropic 3D Turbo-Spin Echo (TSE) sequences were the most suitable for accurate geometric measurements of the tumor and are therefore important for therapy planning. Diffusion and perfusion-weighted images aid in differentiating benign from malignant lesions and provide quantitative measures on tumor hemodynamics and cellularity, which have been reported to be effective in predicting and assessing treatment outcome. Overall, this dedicated MRI protocol provides high-quality imaging of UM, which can be used to improve its diagnosis, treatment planning, and follow-up. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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14 pages, 8463 KiB  
Article
Absence of Intraocular Lymphatic Vessels in Uveal Melanomas with Extrascleral Growth
by Jackelien G. M. van Beek, Quincy C. C. van den Bosch, Nicole Naus, Dion Paridaens, Annelies de Klein, Emine Kiliç and Robert M. Verdijk
Cancers 2019, 11(2), 228; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11020228 - 15 Feb 2019
Cited by 14 | Viewed by 3159
Abstract
The aim of this study was to investigate the presence of intraocular lymphatic vessels in patients with uveal melanomas and extrascleral extension using a panel of lymphatic markers. The following immunohistochemical markers were analyzed: lymphatic vessel endothelial hyaluronic acid receptor-1 (LYVE-1), podoplanin (D2-40), [...] Read more.
The aim of this study was to investigate the presence of intraocular lymphatic vessels in patients with uveal melanomas and extrascleral extension using a panel of lymphatic markers. The following immunohistochemical markers were analyzed: lymphatic vessel endothelial hyaluronic acid receptor-1 (LYVE-1), podoplanin (D2-40), prospero-related homeobox gene-1 (Prox-1), pan-endothelial marker cluster of differentiation 31 (CD31), and blood vessel endothelium-specific CD34. Lymphatic vessels were defined as a combination of staining of the following positive markers: LYVE-1, D2-40, Prox-1, and CD31; and no staining of the negative marker CD34. In total, 456 patients were enucleated; 16 of the 46 uveal melanomas with extrascleral extension were contained in stored paraffin tissue. Two samples of the 16 uveal melanomas showed focal positive intraocular vascular staining for LYVE-1 and co-expression of CD31 and CD34. Due to the lack of Prox-1 and D2-40, and positive expression of CD34, these cannot be classified as lymphatic vessels. In one case recruitment of an extraocular, intratumoral lymphatic vascular structure was observed in the periphery of the subconjunctival extrascleral extension. Intraocular lymphatic vessels are absent in uveal melanomas with extrascleral extension; however, we provide proof for recruitment of intratumoral lymphatics by uveal melanomas with extraocular extension from subconjunctival lymphatics that may explain the rare cases of regional lymphatic spread. A panel of antibodies is necessary to detect lymphatic vessels with high specificity. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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10 pages, 476 KiB  
Article
Adjuvant Ipilimumab in High-Risk Uveal Melanoma
by Eric Fountain, Roland L. Bassett, Suzanne Cain, Liberty Posada, Dan S. Gombos, Patrick Hwu, Agop Bedikian and Sapna P. Patel
Cancers 2019, 11(2), 152; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11020152 - 29 Jan 2019
Cited by 28 | Viewed by 4605
Abstract
Uveal melanoma is a common intraocular malignant tumor that is uniformly fatal once metastatic. No effective adjuvant therapy currently exists to reduce the risk of distant metastasis after definitive treatment of the primary lesion. Immunotherapy has been used effectively in the adjuvant setting [...] Read more.
Uveal melanoma is a common intraocular malignant tumor that is uniformly fatal once metastatic. No effective adjuvant therapy currently exists to reduce the risk of distant metastasis after definitive treatment of the primary lesion. Immunotherapy has been used effectively in the adjuvant setting in locally advanced cutaneous melanoma. We performed a Phase I/II clinical trial of adjuvant ipilimumab in high-risk primary uveal melanoma with distant metastasis-free survival (DMFS) as the primary objective. A total of 10 patients with genomically high-risk disease were treated: three at a dose of 3 mg/kg and seven at 10 mg/kg. Two of the seven patients at the higher dose had to discontinue therapy secondary to grade 3 toxicity. At 36 months follow-up, 80% of patients had no evidence of distant disease (95% CI, 58.7–100). With recent advancements in CTLA-4 inhibition, PD-1 inhibition, and combined checkpoint blockade, immunotherapy is a promising avenue of treatment in uveal melanoma. Further clinical trials are needed to elucidate the role of immunotherapy in the adjuvant setting. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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Review

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18 pages, 1888 KiB  
Review
HLA Expression in Uveal Melanoma: An Indicator of Malignancy and a Modifiable Immunological Target
by Zahra Souri, Annemijn P.A. Wierenga, Arend Mulder, Aart G. Jochemsen and Martine J. Jager
Cancers 2019, 11(8), 1132; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11081132 - 07 Aug 2019
Cited by 27 | Viewed by 4124
Abstract
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, and gives rise to metastases in 50% of cases. The presence of an inflammatory phenotype is a well-known risk factor for the development of metastases. This inflammatory phenotype is characterized by [...] Read more.
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, and gives rise to metastases in 50% of cases. The presence of an inflammatory phenotype is a well-known risk factor for the development of metastases. This inflammatory phenotype is characterized by the presence of high numbers of lymphocytes and macrophages, and a high expression of the HLA Class I and II antigens. An abnormal expression of HLA Class I may influence cytotoxic T lymphocyte (CTL) as well as Natural Killer (NK) cell responses. We provide a comprehensive review regarding the inflammatory phenotype in UM and the expression of locus- and allele-specific HLA Class I and of Class II antigens in primary UM and its metastases. Furthermore, we describe the known regulators and the role of genetics (especially chromosome 3 and BRCA-Associated Protein 1 (BAP1 status)), and, last but not least, the effect of putative therapeutic treatments on HLA expression. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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26 pages, 19390 KiB  
Review
Uveal Melanoma Biopsy: A Review
by Luisa Frizziero, Edoardo Midena, Sara Trainiti, Davide Londei, Laura Bonaldi, Silvia Bini and Raffaele Parrozzani
Cancers 2019, 11(8), 1075; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11081075 - 30 Jul 2019
Cited by 33 | Viewed by 4193
Abstract
Intraocular tumor diagnosis is based on clinical findings supported by additional imaging tools, such as ultrasound, optical coherence tomography and angiographic techniques, usually without the need for invasive procedures or tissue sampling. Despite improvements in the local treatment of uveal melanoma (UM), the [...] Read more.
Intraocular tumor diagnosis is based on clinical findings supported by additional imaging tools, such as ultrasound, optical coherence tomography and angiographic techniques, usually without the need for invasive procedures or tissue sampling. Despite improvements in the local treatment of uveal melanoma (UM), the prevention and treatment of the metastatic disease remain unsolved, and nearly 50% of patients develop liver metastasis. The current model suggests that tumor cells have already spread by the time of diagnosis, remaining dormant until there are favorable conditions. Tumor sampling procedures at the time of primary tumor diagnosis/treatment are therefore now commonly performed, usually not to confirm the diagnosis of UM, but to obtain a tissue sample for prognostication, to assess patient’s specific metastatic risk. Moreover, several studies are ongoing to identify genes specific to UM tumorigenesis, leading to several potential targeted therapeutic strategies. Genetic information can also influence the surveillance timing and metastatic screening type of patients affected by UM. In spite of the widespread use of biopsies in general surgical practice, in ophthalmic oncology the indications and contraindications for tumor biopsy continue to be under debate. The purpose of this review paper is to critically evaluate the role of uveal melanoma biopsy in ophthalmic oncology. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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11 pages, 696 KiB  
Review
Molecular Characteristics of Uveal Melanoma: Insights from the Cancer Genome Atlas (TCGA) Project
by Mathieu F. Bakhoum and Bita Esmaeli
Cancers 2019, 11(8), 1061; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11081061 - 27 Jul 2019
Cited by 52 | Viewed by 6476
Abstract
The Cancer Genome Atlas (TCGA) uveal melanoma project was a comprehensive multi-platform deep molecular investigation of 80 uveal melanoma primary tissue samples supported by the National Cancer Institute. In addition to identification of important mutations for the first time, it identified four different [...] Read more.
The Cancer Genome Atlas (TCGA) uveal melanoma project was a comprehensive multi-platform deep molecular investigation of 80 uveal melanoma primary tissue samples supported by the National Cancer Institute. In addition to identification of important mutations for the first time, it identified four different clusters (subgroups) of patients paralleling prognosis. The findings of the TCGA marker paper are summarized in this review manuscript and other investigations that have stemmed from the findings of the TCGA project are reviewed. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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12 pages, 1498 KiB  
Review
Immunological Backbone of Uveal Melanoma: Is There a Rationale for Immunotherapy?
by Ernesto Rossi, Giovanni Schinzari, Ilaria Grazia Zizzari, Brigida Anna Maiorano, Monica Maria Pagliara, Maria Grazia Sammarco, Vincenzo Fiorentino, Gianluigi Petrone, Alessandra Cassano, Guido Rindi, Emilio Bria, Maria Antonietta Blasi, Marianna Nuti and Giampaolo Tortora
Cancers 2019, 11(8), 1055; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11081055 - 26 Jul 2019
Cited by 35 | Viewed by 5321
Abstract
No standard treatment has been established for metastatic uveal melanoma (mUM). Immunotherapy is commonly used for this disease even though UM has not been included in phase III clinical trials with checkpoint inhibitors. Unfortunately, only a minority of patients obtain a clinical benefit [...] Read more.
No standard treatment has been established for metastatic uveal melanoma (mUM). Immunotherapy is commonly used for this disease even though UM has not been included in phase III clinical trials with checkpoint inhibitors. Unfortunately, only a minority of patients obtain a clinical benefit with immunotherapy. The immunological features of mUM were reviewed in order to understand if immunotherapy could still play a role for this disease. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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14 pages, 877 KiB  
Review
Immunotherapies for the Treatment of Uveal Melanoma—History and Future
by Timo E. Schank and Jessica C. Hassel
Cancers 2019, 11(8), 1048; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11081048 - 24 Jul 2019
Cited by 55 | Viewed by 5532
Abstract
Background: Uveal melanoma is the most common primary intraocular malignancy among adults. It is, nevertheless, a rare disease, with an incidence of approximately one case per 100,000 individuals per year in Europe. Approximately half of tumors will eventually metastasize, and the liver is [...] Read more.
Background: Uveal melanoma is the most common primary intraocular malignancy among adults. It is, nevertheless, a rare disease, with an incidence of approximately one case per 100,000 individuals per year in Europe. Approximately half of tumors will eventually metastasize, and the liver is the organ usually affected. No standard-of-care treatment exists for metastasized uveal melanoma. Chemotherapies or liver-directed treatments do not usually result in long-term tumor control. Immunotherapies are currently the most promising therapy option available. Methods: We reviewed both relevant recent literature on PubMed concerning the treatment of uveal melanoma with immunotherapies, and currently investigated drugs on ClinicalTrials.gov. Our own experiences with immune checkpoint blockers are included in a case series of 20 patients. Results: Because few clinical trials have been conducted for metastasized uveal melanoma, no definitive treatment strategy exists for this rare disease. The outcomes of most immunotherapies are poor, especially compared with cutaneous melanoma. However, encouraging results have been found for some very recently investigated agents such as the bispecific tebentafusp, for which a remarkably increased one-year overall survival rate, and similarly increased disease control rate, were observed in early phase studies. Conclusions: The treatment of metastatic uveal melanoma remains challenging, and almost all patients still die from the disease. Long-term responses might be achievable by means of new immunological strategies. Patients should therefore be referred to large medical centers where they can take part in controlled clinical studies. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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17 pages, 1891 KiB  
Review
Emerging Therapeutic Opportunities Based on Current Knowledge of Uveal Melanoma Biology
by Raquel Vivet-Noguer, Malcy Tarin, Sergio Roman-Roman and Samar Alsafadi
Cancers 2019, 11(7), 1019; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11071019 - 20 Jul 2019
Cited by 30 | Viewed by 4902
Abstract
Uveal Melanoma (UM) is a rare and malignant intraocular tumor with dismal prognosis. Despite the efficient control of the primary tumor by radiation or surgery, up to 50% of patients subsequently develop metastasis, mainly in the liver. Once the tumor has spread from [...] Read more.
Uveal Melanoma (UM) is a rare and malignant intraocular tumor with dismal prognosis. Despite the efficient control of the primary tumor by radiation or surgery, up to 50% of patients subsequently develop metastasis, mainly in the liver. Once the tumor has spread from the eye, the treatment is challenging and the median survival is only nine months. UM represents an intriguing model of oncogenesis that is characterized by a relatively homogeneous histopathological architecture and a low burden of genetic alterations, in contrast to other melanomas. UM is driven by recurrent activating mutations in Gαq pathway, which are associated with a second mutation in BRCA1 associated protein 1 (BAP1), splicing factor 3b subunit 1 (SF3B1), or eukaryotic translation initiation factor 1A X-linked (EIF1AX), occurring in an almost mutually exclusive manner. The monosomy of chromosome 3 is also a recurrent feature that is associated with high metastatic risk. These events driving UM oncogenesis have been thoroughly investigated over the last decade. However, no efficient related therapeutic strategies are yet available and the metastatic disease remains mostly incurable. Here, we review current knowledge regarding the molecular biology and the genetics of uveal melanoma and highlight the related therapeutic applications and perspectives. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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16 pages, 2056 KiB  
Review
Tebentafusp: T Cell Redirection for the Treatment of Metastatic Uveal Melanoma
by Bertil E. Damato, Joseph Dukes, Howard Goodall and Richard D. Carvajal
Cancers 2019, 11(7), 971; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11070971 - 11 Jul 2019
Cited by 91 | Viewed by 16198
Abstract
Metastatic disease from uveal melanoma occurs in almost 50% of patients suffering from this ocular tumour, with median survival from development of symptoms being around 1 year. In contrast to cutaneous melanoma, kinase inhibitors and immune checkpoint inhibitors are usually ineffective in patients [...] Read more.
Metastatic disease from uveal melanoma occurs in almost 50% of patients suffering from this ocular tumour, with median survival from development of symptoms being around 1 year. In contrast to cutaneous melanoma, kinase inhibitors and immune checkpoint inhibitors are usually ineffective in patients with metastatic uveal melanoma. Tebentafusp is a novel form of immunotherapy based on the immune-mobilising monoclonal T cell receptor against cancer (ImmTAC) platform, which comprises a soluble T cell receptor that is fused to an anti-CD3 single-chain variable fragment. The T cell receptor domain of tebentafusp targets cells present a human leukocyte antigen-A*02:01 complexed with a peptide derived from the melanoma-associated antigen gp100, which is expressed strongly by melanoma cells, weakly by normal melanocytes and minimally by other tissues. The anti-CD3 domain recruits CD3+ T cells (and, indirectly, other immune cells), redirecting these to the melanoma cells. The most common adverse events with tebentafusp are manageable and usually transient. Early survival data in patients with metastatic uveal melanoma are promising when considered alongside historical data. Based on these encouraging results, a randomised study comparing tebentafusp to investigator’s choice of therapy in metastatic uveal melanoma is ongoing. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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16 pages, 487 KiB  
Review
Uveal Versus Cutaneous Melanoma; Same Origin, Very Distinct Tumor Types
by Monique K. van der Kooij, Frank M. Speetjens, Sjoerd H. van der Burg and Ellen Kapiteijn
Cancers 2019, 11(6), 845; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11060845 - 19 Jun 2019
Cited by 56 | Viewed by 4962
Abstract
Here, we critically evaluated the knowledge on cutaneous melanoma (CM) and uveal melanoma (UM). Both cancer types derive from melanocytes that share the same embryonic origin and display the same cellular function. Despite their common origin, both CM and UM display extreme differences [...] Read more.
Here, we critically evaluated the knowledge on cutaneous melanoma (CM) and uveal melanoma (UM). Both cancer types derive from melanocytes that share the same embryonic origin and display the same cellular function. Despite their common origin, both CM and UM display extreme differences in their genetic alterations and biological behavior. We discuss the differences in genetic alterations, metastatic routes, tumor biology, and tumor-host interactions in the context of their clinical responses to targeted- and immunotherapy. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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21 pages, 1103 KiB  
Review
Targeted Therapy of Uveal Melanoma: Recent Failures and New Perspectives
by Michela Croce, Silvano Ferrini, Ulrich Pfeffer and Rosaria Gangemi
Cancers 2019, 11(6), 846; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11060846 - 18 Jun 2019
Cited by 63 | Viewed by 6380
Abstract
Among Uveal Melanoma (UM) driver mutations, those involving GNAQ or GNA11 genes are the most frequent, while a minor fraction of tumors bears mutations in the PLCB4 or CYSLTR2 genes. Direct inhibition of constitutively active oncoproteins deriving from these mutations is still in [...] Read more.
Among Uveal Melanoma (UM) driver mutations, those involving GNAQ or GNA11 genes are the most frequent, while a minor fraction of tumors bears mutations in the PLCB4 or CYSLTR2 genes. Direct inhibition of constitutively active oncoproteins deriving from these mutations is still in its infancy in UM, whereas BRAFV600E-targeted therapy has obtained relevant results in cutaneous melanoma. However, UM driver mutations converge on common downstream signaling pathways such as PKC/MAPK, PI3K/AKT, and YAP/TAZ, which are presently considered as actionable targets. In addition, BAP1 loss, which characterizes UM metastatic progression, affects chromatin structure via histone H2A deubiquitylation that may be counteracted by histone deacetylase inhibitors. Encouraging results of preclinical studies targeting signaling molecules such as MAPK and PKC were unfortunately not confirmed in early clinical studies. Indeed, a general survey of all clinical trials applying new targeted and immune therapy to UM displayed disappointing results. This paper summarizes the most recent studies of UM-targeted therapies, analyzing the possible origins of failures. We also focus on hyperexpressed molecules involved in UM aggressiveness as potential new targets for therapy. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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22 pages, 1932 KiB  
Review
Uveal Melanoma, Angiogenesis and Immunotherapy, Is There Any Hope?
by Florian Castet, Sandra Garcia-Mulero, Rebeca Sanz-Pamplona, Andres Cuellar, Oriol Casanovas, Josep Maria Caminal and Josep Maria Piulats
Cancers 2019, 11(6), 834; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11060834 - 17 Jun 2019
Cited by 38 | Viewed by 4666
Abstract
Uveal melanoma is considered a rare disease but it is the most common intraocular malignancy in adults. Local treatments are effective, but the systemic recurrence rate is unacceptably high. Moreover, once metastasis have developed the prognosis is poor, with a 5-year survival rate [...] Read more.
Uveal melanoma is considered a rare disease but it is the most common intraocular malignancy in adults. Local treatments are effective, but the systemic recurrence rate is unacceptably high. Moreover, once metastasis have developed the prognosis is poor, with a 5-year survival rate of less than 5%, and systemic therapies, including immunotherapy, have rendered poor results. The tumour biology is complex, but angiogenesis is a highly important pathway in these tumours. Vasculogenic mimicry, the ability of melanomas to generate vascular channels independently of endothelial cells, could play an important role, but no effective therapy targeting this process has been developed so far. Angiogenesis modulates the tumour microenvironment of melanomas, and a close interplay is established between them. Therefore, combining immune strategies with drugs targeting angiogenesis offers a new therapeutic paradigm. In preclinical studies, these approaches effectively target these tumours, and a phase I clinical study has shown encouraging results in cutaneous melanomas. In this review, we will discuss the importance of angiogenesis in uveal melanoma, with a special focus on vasculogenic mimicry, and describe the interplay between angiogenesis and the tumour microenvironment. In addition, we will suggest future therapeutic approaches based on these observations and mention ways in which to potentially enhance current treatments. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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25 pages, 599 KiB  
Review
New Insights into Molecular Oncogenesis and Therapy of Uveal Melanoma
by Sara Silvia Violanti, Ilaria Bononi, Carla Enrica Gallenga, Fernanda Martini, Mauro Tognon and Paolo Perri
Cancers 2019, 11(5), 694; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11050694 - 19 May 2019
Cited by 21 | Viewed by 4978
Abstract
Uveal melanoma (UM), which is the most common cancer of the eye, was investigated in recent years by many teams in the field of biomedical sciences and eye clinicians. New knowledge was acquired on molecular pathways found to be dysregulated during the multistep [...] Read more.
Uveal melanoma (UM), which is the most common cancer of the eye, was investigated in recent years by many teams in the field of biomedical sciences and eye clinicians. New knowledge was acquired on molecular pathways found to be dysregulated during the multistep process of oncogenesis, whereas novel therapeutic approaches gave significant results in the clinical applications. Uveal melanoma-affected patients greatly benefited from recent advances of the research in this eye cancer. Tumour biology, genetics, epigenetics and immunology contributed significantly in elucidating the role of different genes and related pathways during uveal melanoma onset/progression and UM treatments. Indeed, these investigations allowed identification of new target genes and to develop new therapeutic strategies/compounds to cure this aggressive melanoma of the eye. Unfortunately, the advances reported in the treatment of cutaneous melanoma have not produced analogous benefits in metastatic uveal melanoma. Nowadays, no systemic adjuvant therapy has been shown to improve overall survival or reduce the risk of metastasis. However, the increasing knowledge of this disease, and the encouraging results seen in clinical trials, offer promise for future effective therapies. Herein, different pathways/genes involved in uveal melanoma onset/progression were taken into consideration, together with novel therapeutic approaches. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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8 pages, 835 KiB  
Opinion
So Close, yet so Far: Discrepancies between Uveal and Other Melanomas. A Position Paper from UM Cure 2020
by Manuel Rodrigues, Leanne de Koning, Sarah E. Coupland, Aart G. Jochemsen, Richard Marais, Marc-Henri Stern, André Valente, Raymond Barnhill, Nathalie Cassoux, Andrew Evans, Iain Galloway, Martine J. Jager, Ellen Kapiteijn, Bozena Romanowska-Dixon, Bettina Ryll, Sergio Roman-Roman, Sophie Piperno-Neumann and the UM Cure 2020 Consortium
Cancers 2019, 11(7), 1032; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11071032 - 22 Jul 2019
Cited by 49 | Viewed by 5470
Abstract
Despite much progress in our understanding of uveal melanoma (UM) over the past decades, this rare tumour is still often misclassified. Although UM, like other melanomas, is very probably derived from melanocytes, it is drastically different from cutaneous melanoma and most other melanoma [...] Read more.
Despite much progress in our understanding of uveal melanoma (UM) over the past decades, this rare tumour is still often misclassified. Although UM, like other melanomas, is very probably derived from melanocytes, it is drastically different from cutaneous melanoma and most other melanoma subtypes in terms of epidemiology, aetiology, biology and clinical features, including an intriguing metastatic hepatotropism. UM carries distinctive prognostic chromosome alterations, somatic mutations and gene expression profiles, allowing an active tailored surveillance strategy and dedicated adjuvant clinical trials. There is no standard systemic treatment for disseminated UM at present. In contrast to cutaneous melanoma, UMs are not BRAF-mutated, thus curtailing the use of B-Raf inhibitors. Although these tumours are characterised by some immune infiltrates, immune checkpoint inhibitors are rarely effective, possibly due to a low mutation burden. UM patients across the world not only face rare cancer-related issues (e.g., specific management strategies, access to information and to expert centres), but also specific UM problems, which can be exacerbated by the common misconception that it is a subtype of cutaneous melanoma. As a European Consortium dedicated to research on UM and awareness on the disease, “UM Cure 2020” participants urge medical oncologists, pharmaceutical companies, and regulatory agencies to acknowledge UM as a melanoma with specific issues, in order to accelerate the development of new therapies for patients. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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10 pages, 582 KiB  
Perspective
Uveal Melanoma: A European Network to Face the Many Challenges of a Rare Cancer
by Sophie Piperno-Neumann, Jose Maria Piulats, Matthias Goebeler, Iain Galloway, Iwona Lugowska, Jürgen C. Becker, Pia Vihinen, Joachim Van Calster, Theodora Hadjistilianou, Rui Proença, Jose Maria Caminal, Muriel Rogasik, Jean-Yves Blay and Ellen Kapiteijn
Cancers 2019, 11(6), 817; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11060817 - 13 Jun 2019
Cited by 12 | Viewed by 5525
Abstract
Uveal melanoma (UM) is the most frequent primary ocular cancer in adults, accounting for 5% of all melanomas. Despite effective treatments for the primary tumour, up to 50% of UM patients will develop metastasis, leading to a very poor prognosis and a median [...] Read more.
Uveal melanoma (UM) is the most frequent primary ocular cancer in adults, accounting for 5% of all melanomas. Despite effective treatments for the primary tumour, up to 50% of UM patients will develop metastasis, leading to a very poor prognosis and a median overall survival of 6 to 12 months, with no major improvements in the last 30 years. There is no standard oncological treatment available for metastatic UM patients, and BRAF/MEK and immune checkpoint inhibitors show disappointing results when compared to cutaneous melanoma (CM). Recent advances in biology, however, identified specific gene and chromosome alterations, potentially permitting an actively tailored surveillance strategy, and dedicated clinical studies. Being a rare cancer, UM patients have to overcome issues such as identifying referral centres, having access to information, and partnering with oncologists for specific management strategies and research priorities. Here, we describe how the European Rare Adult solid Cancer Network (EURACAN) will help in addressing these challenges and accelerating international collaborations to enhance the development of innovative treatments in UM. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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