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Melanoma: HELP
Articles by Sarah Ellen Coupland
Based on 83 articles published since 2010
(Why 83 articles?)
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Between 2010 and 2020, S. Coupland wrote the following 83 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Guideline Uveal Melanoma UK National Guidelines. 2015

Nathan, P / Cohen, V / Coupland, S / Curtis, K / Damato, B / Evans, J / Fenwick, S / Kirkpatrick, L / Li, O / Marshall, E / McGuirk, K / Ottensmeier, C / Pearce, N / Salvi, S / Stedman, B / Szlosarek, P / Turnbull, N / Anonymous4080839. ·Mount Vernon Cancer Centre, Northwood, Middlesex, UK. Electronic address: nathan.pd@gmail.com. · Ocular Oncology Service, St Bartholomew's and Moorfields Eye Hospital, London, UK. · Department Molecular and Clinical Cancer Medicine, University of Liverpool, UK. · OcuMel UK, UK. · Royal Liverpool University Hospital, Liverpool, UK. · University Hospital Aintree, Liverpool, UK. · Patient Representative, UK. · Moorfields Eye Hospital, London, UK. · The Clatterbridge Cancer Centre, NHS Foundation Trust, Liverpool, UK. · Southampton University Hospitals and University of Southampton, UK. · University Hospital Southampton, Southampton, UK. · Royal Hallamshire Hospital, Sheffield, UK. · Southampton University Hospitals, NHS Trust, Southampton, UK. · St Bartholomew's Hospital, UK; Barts Cancer Institute, Queen Mary University of London, London, UK. · Project Manager, London, UK. ·Eur J Cancer · Pubmed #26278648.

ABSTRACT: The United Kingdom (UK) uveal melanoma guideline development group used an evidence based systematic approach (Scottish Intercollegiate Guidelines Network (SIGN)) to make recommendations in key areas of uncertainty in the field including: the use and effectiveness of new technologies for prognostication, the appropriate pathway for the surveillance of patients following treatment for primary uveal melanoma, the use and effectiveness of new technologies in the treatment of hepatic recurrence and the use of systemic treatments. The guidelines were sent for international peer review and have been accredited by NICE. A summary of key recommendations is presented. The full documents are available on the Melanoma Focus website.

2 Editorial Recent breakthroughs in metastatic uveal melanoma: a cause for optimism? 2018

Sacco, Joseph J / Kalirai, Helen / Kenyani, Jenna / Figueiredo, Carlos R / Coulson, Judy M / Coupland, Sarah E. ·Liverpool Ocular Oncology Research Group, Department of Molecular & Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, UK. · Department of Medical Oncology, Clatterbridge Cancer Centre, Bebington, UK. · Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, UK. · Department of Cellular Pathology, Royal Liverpool University Hospital, Liverpool, UK. ·Future Oncol · Pubmed #29741103.

ABSTRACT: -- No abstract --

3 Review Kinome-wide transcriptional profiling of uveal melanoma reveals new vulnerabilities to targeted therapeutics. 2018

Bailey, Fiona P / Clarke, Kim / Kalirai, Helen / Kenyani, Jenna / Shahidipour, Haleh / Falciani, Francesco / Coulson, Judy M / Sacco, Joseph J / Coupland, Sarah E / Eyers, Patrick A. ·Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, UK. · Computational Biology Facility, Functional and Comparative Genomics, Institute of Integrative Biology, University of Liverpool, Liverpool, UK. · Department of Molecular and Clinical Cancer Medicine, Institute of Translational Research, University of Liverpool, Liverpool, UK. · Cellular and Molecular Physiology, Institute of Translational Research, University of Liverpool, Liverpool, UK. ·Pigment Cell Melanoma Res · Pubmed #28972303.

ABSTRACT: Metastatic uveal melanoma (UM) is invariably fatal, usually within a year of diagnosis. There are currently no effective therapies, and clinical studies employing kinase inhibitors have so far demonstrated limited success. This is despite common activating mutations in GNAQ/11 genes, which trigger signalling pathways that might predispose tumours to a variety of targeted drugs. In this study, we have profiled kinome expression network dynamics in various human ocular melanomas. We uncovered a shared transcriptional profile in human primary UM samples and across a variety of experimental cell-based models. The poor overall response of UM cells to FDA-approved kinase inhibitors contrasted with much higher sensitivity to the bromodomain inhibitor JQ1, a broad transcriptional repressor. Mechanistically, we identified a repressed FOXM1-dependent kinase subnetwork in JQ1-exposed cells that contained multiple cell cycle-regulated protein kinases. Consistently, we demonstrated vulnerability of UM cells to inhibitors of mitotic protein kinases within this network, including the investigational PLK1 inhibitor BI6727. We conclude that analysis of kinome-wide signalling network dynamics has the potential to reveal actionable drug targets and inhibitors of potential therapeutic benefit for UM patients.

4 Review [Ocular melanomas : An update]. 2017

Kalirai, H / Müller, P L / Jaehne, D / Coupland, S E. ·Liverpool Ocular Oncology Research Group, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, Großbritannien. · Universitäts-Augenklinik Bonn, Bonn, Deutschland. · Institut für Gewebediagnostik Pathologie MVZ HELIOS Klinik Emil von Behring, Berlin, Deutschland. · Liverpool Ocular Oncology Research Group, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, Großbritannien. s.e.coupland@liv.ac.uk. · Institute of Translational Medicine, 6th Floor Duncan Building, University of Liverpool, Daulby Street, L69 3GA, Liverpool, Großbritannien. s.e.coupland@liv.ac.uk. ·Pathologe · Pubmed #29038913.

ABSTRACT: Melanoma is the most common type of primary cancer to affect the adult eye. Approximately 95% of ocular melanomas are intraocular and arise from the uvea (i. e. iris, ciliary body, and choroid), while the remaining 5% are located in the conjunctiva. Although both uveal and conjunctival melanomas are thought to derive from malignantly transformed melanocytes, uveal melanoma is clinically and biologically distinct from conjunctival melanoma, and indeed from its more common cutaneous counterpart. Intense efforts have been recently made to understand the molecular biology involved in the development of ocular melanomas, and in their progression. Molecular advances, particularly for uveal melanoma, have enhanced prognostication and the identification of rational therapeutic targets for disseminated disease. In this review, recent advances in the molecular characterisation of both uveal and conjunctival melanomas are discussed, and how these may be used to develop personalised therapeutic strategies.

5 Review Use of the Chick Embryo Model in Uveal Melanoma. 2015

Kalirai, Helen / Shahidipour, Haleh / Coupland, Sarah E / Luyten, Gregorius. ·Department of Molecular and Clinical Cancer Medicine, Institute of Translational Research, University of Liverpool, Liverpool, UK. · Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands. ·Ocul Oncol Pathol · Pubmed #27171889.

ABSTRACT: Animal models play a crucial role in basic and translational oncology research. Conventional rodent experiments, however, face ethical, practical and technical issues that limit their use. The chick embryo represents an accessible and economical in vivo model, which has long been used in developmental biology and for the study of angiogenesis. It is also a recognised xenograft model, and because of its lack of immune system in early development, the chick embryo has established itself as a key model system for cancer research, with which to study various steps in the metastatic process. In this chapter, we review the chick embryo model and the technical approaches adopted by cancer biologists, including advances in real-time imaging, and discuss how this has been or can be applied to improve our understanding of the biological events during uveal melanoma development and metastasis.

6 Review Intraocular collision tumour: case report and literature review. 2013

Coupland, Sarah E / Dodson, Andrew / Liu, Hongxiang / Du, Ming-Qing / Angi, Martina / Damato, Bertil E. ·Department of Molecular and Clinical Cancer Medicine, University of Liverpool, 5th Floor Duncan Building, Daulby Street, Liverpool, L69 3GA, UK. s.e.coupland@liverpool.ac.uk ·Graefes Arch Clin Exp Ophthalmol · Pubmed #23232651.

ABSTRACT: BACKGROUND: "Collision" tumours consist of different neoplasms coexisting within a single lesion. Whilst quite common in the skin, the gastrointestional tract, and the ovaries, intraocular collision tumours are exceedingly rare. We describe an exceptional case of a combined uveal melanoma and intraocular plasmacytoma. METHODS: Observational case report. A 61-year-old woman underwent enucleation for rubeotic glaucoma and cells in the anterior chamber after proton-beam radiotherapy of a cilio-choroidal melanoma of the right eye. Examination of the enucleated eye was performed with immunohistochemistry, multiplex ligation dependent probe amplification (MLPA), and polymerase chain reaction (PCR) for immunoglobulin heavy- and light-chain gene rearrangements. A review of the literature on ocular collision tumours and uveal involvement by plasma cell neoplasms was also performed. RESULTS: Morphological, immunophenotypical, and genotypical examination of the tumour revealed the co-existence of both a melanoma and a plasmacytoma within the choroid and ciliary body. The glaucoma was caused by extensive infiltration of the iris and trabecular meshwork by the plasmacytoma cells. Review of the literature revealed only four collision tumours involving the eyelid and three involving the choroid. All three intraocular collision tumours consisted of uveal melanoma and choroidal non-Hodgkin lymphoma. Uveal involvement by plasma cell neoplasms is also extremely rare, with only six reported cases. CONCLUSIONS: This is the first documented intraocular collision tumour consisting of a uveal melanoma and isolated plasmacytoma. If a patient presents with 'uveitis' after proton-beam radiotherapy of a cilio-choroidal melanoma, there may be scope for performing biopsies to determine whether the lymphoid infiltrate is reactive or neoplastic.

7 Review Conjunctival melanoma and melanocytic intra-epithelial neoplasia. 2013

Kenawy, N / Lake, S L / Coupland, S E / Damato, B E. ·St Paul's Eye Unit, Liverpool Ocular Oncology Service, Royal Liverpool University Hospital, Liverpool, UK. nkenawy@liv.ac.uk ·Eye (Lond) · Pubmed #23222568.

ABSTRACT: The rarity of conjunctival melanoma has impeded progress in the management of patients with this cancer; however, much progress has occurred in recent years. Primary acquired melanosis is now differentiated histologically into hypermelanosis and conjunctival melanocytic intra-epithelial neoplasia, for which an objective reproducible scoring system has been developed. Mapping and clinical staging of conjunctival disease has improved. Adjunctive radiotherapy and topical chemotherapy have made tumour control more successful, with reduced morbidity. Genetic analyses have identified BRAF and other mutations, which may predict responsiveness to new chemotherapeutic agents, for example Vemurafenib, should metastatic disease develop. Multicentre studies are under way to enhance survival prediction by integrating clinical stage of disease with histological grade of malignancy and genetic abnormalities. Such improved prognostication would not only be more relevant to individual patients, but would also provide greater opportunities for basic science research.

8 Review Molecular pathology of uveal melanoma. 2013

Coupland, S E / Lake, S L / Zeschnigk, M / Damato, B E. ·Pathology, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK. s.e.coupland@liverpool.ac.uk ·Eye (Lond) · Pubmed #23222563.

ABSTRACT: Like other cancers, uveal melanomas (UM) are characterised by an uncontrolled, clonal, cellular proliferation, occurring as a result of numerous genetic, and epigenetic aberrations. Signalling pathways known to be disrupted in UM include: (1) the retinoblastoma pathway, probably as a result of cyclin D1 overexpression; p53 signalling, possibly as a consequence of MDM2 overexpression; and the P13K/AKT and mitogen-activated protein kinase/extracellular signal-related kinase pathway pathways that are disturbed as a result of PTEN and GNAQ/11 mutations, respectively. Characteristic chromosomal abnormalities are common and include 6p gain, associated with a good prognosis, as well as 1p loss, 3 loss, and 8q gain, which correlate with high mortality. These are identified by techniques such as fluorescence in situ hybridisation, comparative genomic hybridisation, microsatellite analysis, multiplex ligation-dependent probe amplification, and single-nucleotide polymorphisms. UM can also be categorised by their gene expression profiles as class 1 or class 2, the latter correlating with poor survival, as do BRCA1-associated protein-1 (BAP1) inactivating mutations. Genetic testing of UM has enhanced prognostication, especially when results are integrated with histological and clinical data. The identification of abnormal signalling pathways, genes and proteins in UM opens the way for target-based therapies, improving prospects for conserving vision and prolonging life.

9 Review Estimating prognosis for survival after treatment of choroidal melanoma. 2011

Damato, Bertil / Eleuteri, Antonio / Taktak, Azzam F G / Coupland, Sarah E. ·Ocular Oncology Service, Royal Liverpool University Hospital, Prescot St, Liverpool L7 8XP, UK. Bertil@damato.co.uk ·Prog Retin Eye Res · Pubmed #21658465.

ABSTRACT: Choroidal melanoma is fatal in about 50% of patients. This is because of metastatic disease, which usually involves the liver. Kaplan-Meier survival curves based only on tumor size and extent do not give a true indication of prognosis. This is because the survival prognosis of choroidal melanoma correlates not only with clinical stage but also with histologic grade, genetic type, and competing causes of death. We have developed an online tool that predicts survival using all these data also taking normal life-expectancy into account. The estimated prognosis is accurate enough to be relevant to individual patients. Such personalized prognostication improves the well-being of patients having an excellent survival probability, not least because it spares them from unnecessary screening tests. Such screening can be targeted at high-risk patients, so that metastases are detected sooner, thereby enhancing any opportunities for treatment. Concerns about psychological harm have proved exaggerated. At least in Britain, patients want to know their prognosis, even if this is poor. The ability to select patients with a high risk of metastasis improves prospects for randomised studies evaluating systemic adjuvant therapy aimed at preventing or delaying metastatic disease. Furthermore, categorization of tissue samples according to survival prognosis enables laboratory studies to be undertaken without waiting many years for survival to be measured. As a result of advances in histologic and genetic studies, biopsy techniques and statistics, prognostication has become established as a routine procedure in our clinical practice, thereby enhancing the care of patients with uveal melanoma.

10 Clinical Trial Concordant chromosome 3 results in paired choroidal melanoma biopsies and subsequent tumour resection specimens. 2015

Coupland, Sarah E / Kalirai, Helen / Ho, Vivian / Thornton, Sophie / Damato, Bertil E / Heimann, Heinrich. ·Department of Pathology, Royal Liverpool and Broadgreen University Hospital Trust (RLBUHT), University of Liverpool, Liverpool, UK. · Department of Ophthalmology, Royal Liverpool and Broadgreen University Hospital Trust (RLBUHT), Liverpool, UK. · Department of Ophthalmology, Royal Liverpool and Broadgreen University Hospital Trust (RLBUHT), Liverpool, UK Ocular Oncology Service, University of California, San Francisco, California, USA. ·Br J Ophthalmol · Pubmed #26206786.

ABSTRACT: BACKGROUND/AIM: The study's aim was to compare chromosome 3 aberrations of choroidal melanoma (CM) as determined by multiplex ligation dependent probe amplification (MLPA) or microsatellite analysis (MSA) in intraocular tumour biopsies with those results obtained from subsequent endoresection/enucleation of the same CM. METHODS: A retrospective cohort of 28 patients with CM seen between 2007 and 2014 at the Liverpool Ocular Oncology Centre was analysed. Prognostic genetic testing, for chromosome 3 status, was performed on all tumour specimens, either by MLPA or MSA, depending on DNA yield. In nine cases genetic testing was performed on a sample taken after radiotherapy; four of these had genetic information pre- and post-radiotherapy. RESULTS: Fourteen biopsy specimens were analysed by MLPA and 14 by MSA. Twenty-seven endoresection or enucleation specimens were analysed by MLPA, and a single enucleation specimen by MSA. Chromosome 3 data showed prognostic concordance for the patient-matched samples in all 28 cases including 4 cases where samples were taken pre pre- and post radiotherapy. Thirteen cases were classified as monosomy 3 and 12 as disomy 3. Two cases had a loss of chromosome arm 3q in both samples and a single case showed loss of 3p in the biopsy sample with complete monosomy 3 in the subsequent enucleation sample taken 5 months later. CONCLUSIONS: Intraocular biopsy of CM yields similar prognostic information to larger surgical specimens. Initial evidence, that genetic testing can be successfully conducted post radiotherapy, is also provided. TRIAL REGISTRATION NUMBER: NITRO trial, ISRCTN35236442.

11 Article Loss of BAP1 expression is associated with an immunosuppressive microenvironment in uveal melanoma, with implications for immunotherapy development. 2020

Figueiredo, Carlos R / Kalirai, Helen / Sacco, Joseph J / Azevedo, Ricardo A / Duckworth, Andrew / Slupsky, Joseph R / Coulson, Judy M / Coupland, Sarah E. ·Department of Molecular and Clinical Cancer Medicine, ITM, University of Liverpool, Liverpool, UK. · MediCity Research Laboratory and Institute of Biomedicine, University of Turku, Turku, Finland. · The Clatterbridge Cancer Centre, Wirral, UK. · Department of Cancer Biology, The University of Texas -MD Anderson Cancer Center, Houston, TX, USA. · Dept. of Cellular and Molecular Physiology, University of Liverpool, UK. · Liverpool Clinical Laboratories, Royal Liverpool University Hospital, Liverpool, UK. ·J Pathol · Pubmed #31960425.

ABSTRACT: Immunotherapy using immune checkpoint inhibitors (ICIs) induces durable responses in many metastatic cancers. Metastatic uveal melanoma (mUM), typically occurring in the liver, is one of the most refractory tumours to ICIs and has dismal outcomes. Monosomy 3 (M3), polysomy 8q and BAP1 loss in primary uveal melanoma (pUM) are associated with poor prognoses. The presence of tumour infiltrating lymphocytes (TILs) within pUM and surrounding mUM - and some evidence of clinical responses to adoptive TIL transfer - strongly suggest that UM are indeed immunogenic despite their low mutational burden. The mechanisms that suppress TILs in pUM and mUM are unknown. We show that BAP1 loss is correlated with upregulation of several genes associated with suppressive immune responses, some of which build an immune suppressive axis, including HLA-DR, CD38, and CD74. Further, single-cell analysis of pUM by mass cytometry confirmed the expression of these and other markers revealing important functions of infiltrating immune cells in UM, most being a regulatory CD8

12 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. 2019

Fiorentzis, Miltiadis / Viestenz, Arne / Siebolts, Udo / Seitz, Berthold / Coupland, Sarah E / Heinzelmann, Joana. ·Department of Ophthalmology, University Hospital Halle (Saale), Martin-Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany. miltiadis.fiorentzis@gmail.com. · Department of Ophthalmology, University Hospital Halle (Saale), Martin-Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany. arne.viestenz@uk-halle.de. · Department of Pathology, University Hospital Halle (Saale), Martin-Luther University Halle-Wittenberg, Magdeburger Str. 14, 06112 Halle (Saale), Germany. udo.siebolts@uk-halle.de. · Department of Ophthalmology, Saarland University Medical Center, Kirrberger Str. 100, 66421 Homburg/Saar, Germany. berthold.seitz@uks.eu. · Liverpool Ocular Oncology Research Group, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, West Derby Street, Liverpool L7 8TX, UK. S.E.Coupland@liverpool.ac.uk. · Liverpool Clinical Laboratories, Royal Liverpool University Hospital, Liverpool L69 3GA, UK. S.E.Coupland@liverpool.ac.uk. · Department of Ophthalmology, University Hospital Halle (Saale), Martin-Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany. joana.heinzelmann@uk-halle.de. ·Cancers (Basel) · Pubmed #31514412.

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, 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.

13 Article So Close, yet so Far: Discrepancies between Uveal and Other Melanomas. A Position Paper from UM Cure 2020. 2019

Rodrigues, Manuel / Koning, Leanne de / Coupland, Sarah E / Jochemsen, Aart G / Marais, Richard / Stern, Marc-Henri / Valente, André / Barnhill, Raymond / Cassoux, Nathalie / Evans, Andrew / Galloway, Iain / Jager, Martine J / Kapiteijn, Ellen / Romanowska-Dixon, Bozena / Ryll, Bettina / Roman-Roman, Sergio / Piperno-Neumann, Sophie / Anonymous4280998. ·Department of Medical Oncology and INSERM U830, Institut Curie, PSL Research University, 75005 Paris, France. manuel.rodrigues@curie.fr. · Translational Research Department, Institut Curie, PSL Research University, 75005 Paris, France. · Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L69 3BX, UK. · Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. · Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M13 9PL, UK. · Department of Genetics, Institut Curie, PSL Research University, 75005 Paris, France. · Champalimaud Foundation, 1400-038 Lisbon, Portugal. · Department of Biopathology, Institut Curie, PSL Research University, 75005 Paris, France. · Department of Ocular Oncology, Institut Curie, PSL Research University, 75005 Paris, France. · Melanoma Patient Network Europe, 75597 Uppsala, Sweden. · Department of Ophthalmology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. · Department of Medical Oncology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. · Department of Ophthalmology and Ocular Oncology, Jagiellonian University Medical 31007 Krakow, Poland. · Department of Medical Oncology, Institut Curie, PSL Research University, 75005 Paris, France. · Department of Medical Oncology and INSERM U830, Institut Curie, PSL Research University, 75005 Paris, France. ·Cancers (Basel) · Pubmed #31336679.

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 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

14 Article CD166high Uveal Melanoma Cells Represent a Subpopulation With Enhanced Migratory Capacity. 2019

Djirackor, Luna / Kalirai, Helen / Coupland, Sarah E / Petrovski, Goran. ·Liverpool Ocular Oncology Research Group, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom. · Department of Ophthalmology, Faculty of Medicine, Albert Szent-Gyorgyi Clinical Center, University of Szeged, Szeged, Hungary. · Centre for Eye Research, Department of Ophthalmology, Oslo University Hospital and University of Oslo, Oslo, Norway. ·Invest Ophthalmol Vis Sci · Pubmed #31242292.

ABSTRACT: Purpose: Cancer stem cells (CSCs) are a subpopulation of cells with the capacity to drive tumor growth. While there is evidence of the existence of CSCs in uveal melanoma (UM), there is no consensus on their defining markers. In this study, we examined putative CSC markers in UM cell lines, primary UM (PUM), and normal choroidal melanocytes (NCM). Methods: Nonadherent sphere assays were used to assess the tumorigenic potential of 15 PUMs, 8 high (M3) and 7 low (D3) metastatic risk. Flow cytometry was used to compare the expression of CSC markers between 10 PUMs and 4 NCMs, as well as in 8 UM cell lines grown under adherent and nonadherent conditions. Based on the data generated and from TCGA analyses, CD166 was investigated in detail, including its effect on cell migration using a tumor transendothelial migration assay. Results: M3 PUM had a greater melanosphere-forming efficiency than D3 PUM. CD166 and Nestin expression was upregulated in PUM compared to NCM by flow cytometry. UM cell lines resistant to anoikis had increased levels of CD271, Nestin, and CD166 compared with adherent cells. TCGA analysis showed that patients with higher CD166 expression had a poorer prognosis: this was supported by a Mel270 CD166high subpopulation that had enhanced migratory capabilities compared with CD166low cells. IHC showed that CD166 is expressed in the cytoplasm and cell membrane of PUM cells. Conclusions: UM contain a population of cells with characteristics of CSCs. In particular, CD166high UM cells appear to represent a subpopulation with enhanced migratory capacity.

15 Article Conjunctival melanoma copy number alterations and correlation with mutation status, tumor features, and clinical outcome. 2019

Kenawy, Nihal / Kalirai, Helen / Sacco, Joseph J / Lake, Sarah L / Heegaard, Steffen / Larsen, Ann-Cathrine / Finger, Paul T / Milman, Tatyana / Chin, Kimberly / Mosci, Carlo / Lanza, Francesco / Moulin, Alexandre / Schmitt, Caroline A / Caujolle, Jean Pierre / Maschi, Célia / Marinkovic, Marina / Taktak, Azzam F / Heimann, Heinrich / Damato, Bertil E / Coupland, Sarah E. ·Liverpool Ocular Oncology Research Group, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Aintree University Hospital, Liverpool, UK. · Clatterbridge Cancer Centre, Wirral, UK. · Eye Pathology Section, Department of Pathology and Department of Ophthalmology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. · The New York Eye Cancer Centre, New York. · Ocular Oncology Service, Galliera Hospital, Genoa, Italy. · Ophthalmic Pathology Laboratory and Department of Ophthalmology, Jules Gonin Eye Hospital, Lausanne, Switzerland. · Ophthalmology Department, Oslo University Hospital, Oslo, Norway. · Ophthalmology Department, University Hospital of Nice, Nice, France. · Ophthalmology Department, Leiden University Medical Centre, Leiden, The Netherlands. · Department of Medical Physics and Clinical Engineering, Royal Liverpool University Hospital, Liverpool, UK. · Liverpool Ocular Oncology Centre, Royal Liverpool University Hospital, Liverpool, UK. · Oxford Eye Hospital and Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. · Cellular Pathology, Liverpool Clinical Laboratories, Royal Liverpool University Hospital, Liverpool, UK. ·Pigment Cell Melanoma Res · Pubmed #30672666.

ABSTRACT: Relatively little is known about the genetic aberrations of conjunctival melanomas (CoM) and their correlation with clinical and histomorphological features as well as prognosis. The aim of this large collaborative multicenter study was to determine potential key biomarkers for metastatic risk and any druggable targets for high metastatic risk CoM. Using Affymetrix single nucleotide polymorphism genotyping arrays on 59 CoM, we detected frequent amplifications on chromosome (chr) 6p and deletions on 7q, and characterized mutation-specific copy number alterations. Deletions on chr 10q11.21-26.2, a region harboring the tumor suppressor genes, PDCD4, SUFU, NEURL1, PTEN, RASSF4, DMBT1, and C10orf90 and C10orf99, significantly correlated with metastasis (Fisher's exact, p ≤ 0.04), lymphatic invasion (Fisher's exact, p ≤ 0.02), increasing tumor thickness (Mann-Whitney, p ≤ 0.02), and BRAF mutation (Fisher's exact, p ≤ 0.05). This enhanced insight into CoM biology is a step toward identifying patients at risk of metastasis and potential therapeutic targets for systemic disease.

16 Article Conjunctival melanoma and electrochemotherapy: preliminary results using 2D and 3D cell culture models in vitro. 2019

Fiorentzis, Miltiadis / Katopodis, Periklis / Kalirai, Helen / Seitz, Berthold / Viestenz, Arne / Coupland, Sarah E. ·Department of Ophthalmology, University Hospital Halle (Saale), Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany. · Liverpool Ocular Oncology Research Group, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Department of Ophthalmology, Saarland University Medical Center, Homburg/Saar, Germany. ·Acta Ophthalmol · Pubmed #30548215.

ABSTRACT: PURPOSE: To investigate the cytotoxic effect of bleomycin, mitomycin C (MMC) and Fluorouracil (5-FU) in combination with electroporation (EP) on human conjunctival melanoma (CM) and normal conjunctival cell lines using 2D and 3D cell culture systems in vitro. METHODS: Two CM (CRMM1, CRMM2) and one normal conjunctival epithelial cell line (HCjE-Gi) were treated with various EP conditions and increasing concentrations of 5-FU, MMC and bleomycin. Cell survival was assessed by MTT viability assay. All cell lines were seeded to create spheroids and were treated with bleomycin on day 3 and day 8 combined with EP. Spheroids were collected, fixed in buffered formalin and subsequently paraffin embedded for histological assessment of the effects of the treatment on cell viability. RESULTS: CM cell lines were resistant to electroporation alone and showed a reduction in cell number only when treated with 1000 Volts/cm and 8 pulses. HCjE-Gi cells showed higher sensitivity to electric pulses over 750 Volts/cm. MMC and 5-FU demonstrated a higher cytotoxicity for the HCjE-Gi cell line. The CM cell lines were resistant to MMC and 5-FU. Bleomycin (1 μg/ml) alone had no significant effect on the HCjE-Gi even when combined with EP conditions ≥750 Volts/cm. In contrast, it significantly (p -, paired t-test) reduced cell viability in the CM cell lines. Spheroids treated with bleomycin and EP showed a reduction in tumour mass and proliferation rates after treatment. CONCLUSION: Our in vitro study using 2D and 3D models indicates that the application of EP may effectively enhance chemotherapy with bleomycin in CM. This may offer new viable perspectives for CM treatment.

17 Article [Uveal Melanoma Cell Under Oxidative Stress - Influence of VEGF and VEGF-Inhibitors]. 2019

Dithmer, M / Kirsch, A M / Gräfenstein, L / Wang, F / Schmidt, H / Coupland, S E / Fuchs, S / Roider, J / Klettner, A K. ·Augenklinik, Universitätsklinikum Schleswig-Holstein, Campus Kiel. · Klinik für Unfallchirurgie, Universitätsklinikum Schleswig-Holstein, Campus Kiel. · MetaPhysiol, Essenheim. · Molecular and Clinical Cancer Medicine, Liverpool Ocular Oncology Research Group, University of Liverpool, United Kingdom of Great Britain and Northern Ireland. ·Klin Monbl Augenheilkd · Pubmed #28376556.

ABSTRACT: BACKGROUND: The role of oxidative stress in cancer is complex. While the pathological alterations induced by oxidative stress may be involved in the induction of tumours, in the late stages of tumour development, it can facilitate the loss of tumour cells and might even prevent metastasis. Tumour cells show metabolic alterations, often inducing an increased production of reactive oxygen species, which makes these cells particularly vulnerable to additional oxidative stress. This is an important mode of action in the use of many chemotherapeutics and in the application of ionizing radiation. Uveal melanoma is the most frequent primary tumour in the adult eye. For metastasis of this tumour, which affects about 50 % of the patients, no appropriate treatment is currently available. However, the primary tumour can efficiently be treated with ionizing radiation. A frequent side effect of this treatment is radiation retinopathy, which is treated with vascular endothelial growth factor (VEGF) antagonists. A therapy of the primary tumour with VEGF antagonists is under discussion. So far, little data is available on this subject, however, a paradoxical worsening of the situation has been found in a mouse model of uveal melanoma treated with bevacizumab. METHODS: We have investigated the effect of VEGF and of the VEGF-antagonist bevacizumab on the survival of five different melanoma cell lines under oxidative stress treatment with hydrogen peroxide. In addition, we investigated the expression of relevant proteins and the effect of bevacizumab on the proliferation of the cells as well as its effect on the angiogenic behaviour of endothelial cells, co-cultured with uveal melanoma cells. RESULTS: Our study showed that not only VEGF but also, paradoxically, the VEGF-antagonist bevacizumab is able to protect uveal melanoma cells from oxidative stress-induced cell death. Bevacizumab did not influence the proliferation of the cells and showed only limited effectiveness to reduce angiogenic structures. CONCLUSION: Considering that oxidative stress is the mode of action for ionizing radiation to induce cell death, a protective effect of bevacizumab on uveal melanoma cells against oxidative stress is worrisome and argues against the use of VEGF in uveal melanoma.

18 Article Detection of mutations in SF3B1, EIF1AX and GNAQ in primary orbital melanoma by candidate gene analysis. 2018

Rose, Anna M / Luo, Rong / Radia, Utsav K / Kalirai, Helen / Thornton, Sophie / Luthert, Philip J / Jayasena, Channa N / Verity, David H / Coupland, Sarah E / Rose, Geoffrey E. ·Orbital Service, Moorfields Eye Hospital, City Road, London, EC1V 2PD, UK. · UCL Institute of Ophthalmology, London, UK. · Department of Medicine, Imperial College, London, UK. · Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK. · Department of Cellular Pathology, Royal Liverpool University Hospital, Liverpool, UK. · Orbital Service, Moorfields Eye Hospital, City Road, London, EC1V 2PD, UK. geoff.rose@moorfields.nhs.uk. · UCL Institute of Ophthalmology, London, UK. geoff.rose@moorfields.nhs.uk. ·BMC Cancer · Pubmed #30558566.

ABSTRACT: BACKGROUND: Ocular melanoma is a rare but often deadly malignancy that arises in the uvea (commonest primary site), conjunctiva or the orbit. Primary orbital melanoma (POM) is exceedingly rare, with approximately 60 cases reported to date. Despite recent advances in our understanding of the genetics of primary uveal and conjunctival melanomas, this information is lacking for POM. METHODS: DNA was extracted from 12 POM tissues, with matched germline DNA (where available). MLPA was conducted to detect chromosomal alterations and Sanger sequencing used to identify point mutations in candidate melanoma driver genes (BRAF, NRAS, KRAS, GNA11, GNAQ), and other genes implicated in melanoma prognosis (EIF1AX, SF3B1). Immunohistochemistry was performed to analyse BAP1 nuclear expression. RESULTS: MLPA detected copy number alterations in chromosomes 1p, 3, 6 and 8. Sequencing of melanoma driver genes revealed GNAQ (p.Q209L) mutations in two samples; although it is possible that these samples represent extraocular spread of an occult uveal melanoma. A recurrent mutation in SF3B1 (p.R625H) was observed in indolent, but not aggressive, tumours; a mutation in EIF1AX (p.N4S) was detected in one patient with non-aggressive disease. CONCLUSIONS: EIF1AX and SF3B1 mutations appear have a role in determining the clinical course of POM and detection of these changes could have clinical significance. Further in depth analysis of this rare group using differing 'omic technologies will provide novel insights into tumour pathogenesis.

19 Article Prognostication of metastatic death in uveal melanoma patients: A Markov multi-state model. 2018

Eleuteri, Antonio / Taktak, Azzam F G / Coupland, Sarah E / Heimann, Heinrich / Kalirai, Helen / Damato, Bertil. ·Department of Medical Physics and Clinical Engineering, Royal Liverpool and Broadgreen University Hospitals NHS Trust, 1st Floor Duncan Building, L7 8XP, Liverpool, UK; Department of Physics, The Oliver Lodge, University of Liverpool, Oxford St, L69 7ZE, Liverpool, UK. Electronic address: antonio.eleuteri@liverpool.ac.uk. · Department of Medical Physics and Clinical Engineering, Royal Liverpool and Broadgreen University Hospitals NHS Trust, 1st Floor Duncan Building, L7 8XP, Liverpool, UK; Department of Physics, The Oliver Lodge, University of Liverpool, Oxford St, L69 7ZE, Liverpool, UK. Electronic address: afgt@liverpool.ac.uk. · Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Crown Street, L69 3BX, Liverpool, UK. Electronic address: S.E.Coupland@liverpool.ac.uk. · Liverpool Ocular Oncology Centre, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Prescot St, L7 8XP, Liverpool, UK. Electronic address: Heinrich.Heimann@rlbuht.nhs.uk. · Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Crown Street, L69 3BX, Liverpool, UK. Electronic address: H.Kalirai@liverpool.ac.uk. · Liverpool Ocular Oncology Centre, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Prescot St, L7 8XP, Liverpool, UK; Ocular Oncology Service, University of California, 8 Koret Way, San Francisco, USA. Electronic address: Bertil.Damato@ucsf.edu. ·Comput Biol Med · Pubmed #30278339.

ABSTRACT: BACKGROUND/AIMS: Uveal melanoma is fatal in almost 50% of patients. We previously developed a prognostic model to predict all-cause mortality. The aim of this study was to improve our model by predicting metastatic death as a cause-specific event distinct from other causes of death. METHODS: Patients treated in Liverpool were included if they resided in England, Scotland or Wales and if their uveal melanoma involved the choroid. They were flagged at the National Health Service Cancer Registry, which automatically informed us of the date and cause of death of any deceased patients. A semiparametric Markov multi-state model was fitted. Two different baseline hazard rates were assumed, with state transition-specific covariates. For both failure types, age at treatment and sex were used. For the metastatic death case, these factors were added: anterior margin position, largest basal tumour diameter, tumour thickness, extra-ocular extension, presence of epithelioid melanoma cells, presence of closed connective tissue loops, increased mitotic count, chromosome 3 loss, and chromosome 8q gain. Missing data required a multiple-imputation procedure. RESULTS: The cohort comprised 4161 patients, 893 of whom died of metastastic disease with another 772 dying of other causes. The optimism-corrected, bootstrapped C-index for metastatic death prediction was 0.86, denoting very good discriminative performance. Bootstrapped calibration curves at two and five years also showed very good performance. CONCLUSIONS: Our improved model provides reliable, personalised metastatic death prognostication using clinical, histological and genetic information, and it can be used as a decision support tool to individualize patient care in a clinical environment.

20 Article Altered Nuclear Expression of the Deubiquitylase BAP1 Cannot be Used as a Prognostic Marker for Canine Melanoma. 2018

Jama, N / Farquhar, N / Butt, Z / Coupland, S E / Sacco, J J / Scase, T / Fielding, A B / Coulson, J M / Kalirai, H / Killick, D R. ·Department of Small Animal Clinical Sciences, Institute of Veterinary Science, University of Liverpool, Liverpool, UK; Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK; Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Bridge Pathology Ltd., 637 Gloucester Road, Bristol, UK. · Department of Small Animal Clinical Sciences, Institute of Veterinary Science, University of Liverpool, Liverpool, UK. Electronic address: drk@liverpool.ac.uk. ·J Comp Pathol · Pubmed #30060843.

ABSTRACT: BRCA1-associated protein-1 (BAP1) is a nuclear localized deubiquitylating enzyme that belongs to the ubiquitin c-terminal hydrolase subfamily. The encoded protein is highly homologous between man and dogs, suggesting a functional significance preserved by evolution. BAP1 has multiple properties, including tumour suppressor activity. Loss of BAP1 function is implicated in the oncogenesis of several types of cancers including uveal, mucosal and some cutaneous melanomas in humans, as well as in mesothelioma. In this study we investigate the significance of BAP1 in canine melanoma. Nuclear BAP1 protein was detected in five canine oral melanoma cell lines using an antibody commonly used for analysis of human tissues. BAP1 loss of function mutations often lead to loss of nuclear BAP1 (nBAP1) expression in humans; this is associated with a poorer prognosis in uveal and mucosal melanoma. Therefore, as a prelude to a study evaluating the prognostic significance of nBAP1 expression in dogs, immunohistochemistry (IHC) was used to assess cases of canine melanoma for nBAP1 expression. In 89 cases where tumour cells were identified by melan-A labelling, 100% of tumour cells were positive for nBAP1 expression, including eight uveal tract and 29 oral mucosal melanomas. This finding indicates that BAP1 IHC cannot be used as a prognostic marker in canine uveal and mucosal melanoma. Moreover, this observation suggests that either BAP1 has a different functional significance in canine melanoma or that loss of BAP1 function is achieved by a different route. This is a novel finding that warrants further investigation to determine the comparative biological relevance.

21 Article Electrochemotherapy with bleomycin and cisplatin enhances cytotoxicity in primary and metastatic uveal melanoma cell lines in vitro. 2018

Fiorentzis, M / Kalirai, H / Katopodis, P / Seitz, B / Viestenz, A / Coupland, S E. · ·Neoplasma · Pubmed #29534581.

ABSTRACT: Electrochemotherapy (ECT) enhances responsiveness to cytotoxic drugs in numerous cell lines in vitro. Clinically ECT is widely applied for skin tumor ablation and has shown efficacy in treating non-resectable colorectal liver metastases. There is limited experience of ECT for ocular tumor therapy. We investigated the cytotoxic effect of bleomycin and cisplatin in combination with electroporation on chemoresistant human uveal melanoma (UM) cell lines in vitro. Four UM cell lines (Mel 270, 92-1, OMM-1, OMM-2.5) were treated with electroporation (pulse amplitude 300-1000 V/cm, 8-80 pulses, 100 μs, 5 Hz) and increasing concentrations of bleomycin and cisplatin (0-7.5 μg/ml). Cell survival was analyzed by MTT viability assay after 36 hours. UM cell lines were resistant to both bleomycin and cisplatin. In combination with electro- poration, the effects of bleomycin and cisplatin were increased 8-70 fold and 3-15 fold, respectively, in all UM cell lines. At the lowest concentration of bleomycin tested (1 μg/ml), viability was maximally reduced in all UM cell lines by ≥69% with electroporation conditions of 750 V/cm and 20 pulses. All UM cell lines were more resistant to cisplatin; however, electro- poration of 1000 V/cm and 8 pulses resulted in similar reductions in cell viability of 92-1, Mel270 with 2.5 μg/ml cisplatin, OMM2-5 cells with 5 μg/ml cisplatin and OMM1 cells with 1 μg/ml cisplatin. In vitro ECT with bleomycin or cisplatin is more effective than the highest concentration of the antineoplastic drug or electroporation alone, opening new perspectives in primary and metastatic UM treatment.

22 Article Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma. 2018

Farquhar, Neil / Thornton, Sophie / Coupland, Sarah E / Coulson, Judy M / Sacco, Joseph J / Krishna, Yamini / Heimann, Heinrich / Taktak, Azzam / Cebulla, Colleen M / Abdel-Rahman, Mohamed H / Kalirai, Helen. ·Liverpool Ocular Oncology Research Group, Department of Molecular and Clinical Cancer MedicineInstitute of Translational Medicine, University of LiverpoolLiverpoolUK. · Department of Cellular PathologyRoyal Liverpool University HospitalLiverpoolUK. · Department of Cellular and Molecular PhysiologyInstitute of Translational Medicine, University of LiverpoolLiverpoolUK. · Department of Medical OncologyClatterbridge Cancer CentreClatterbridgeUK. · Liverpool Ocular Oncology CentreRoyal Liverpool University HospitalLiverpoolUK. · Department of Medical Physics & Clinical EngineeringRoyal Liverpool University HospitalLiverpoolUK. · Department of Ophthalmology and Visual ScienceHavener Eye Institute, The Ohio State UniversityColumbusOHUSA. · Division of Human Genetics, Department of Internal MedicineThe Ohio State UniversityColumbusOHUSA. ·J Pathol Clin Res · Pubmed #29416875.

ABSTRACT: Uveal melanoma (UM) is a rare aggressive intraocular tumour with a propensity for liver metastases, occurring in ∼50% of patients. The tumour suppressor

23 Article Nestin expression in primary and metastatic uveal melanoma - possible biomarker for high-risk uveal melanoma. 2018

Djirackor, Luna / Shakir, Dilem / Kalirai, Helen / Petrovski, Goran / Coupland, Sarah E. ·Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Stem Cells and Eye Research Laboratory, Department of Ophthalmology, Faculty of Medicine, Albert Szent-Gyorgyi Clinical Center, University of Szeged, Szeged, Hungary. · Centre for Eye Research, Department of Ophthalmology, Oslo University Hospital and University of Oslo, Oslo, Norway. ·Acta Ophthalmol · Pubmed #29338117.

ABSTRACT: PURPOSE: Nestin, a member of the intermediate filament protein family, has been described as a putative cancer stem cell marker (CSC) in uveal melanoma and poor prognostic factor in a variety of tumours, including cutaneous melanoma. In this study, we examined the expression of nestin in primary (PUM) and metastatic uveal melanoma (MUM) samples, and correlated the findings with histological, clinical and survival data. METHODS: Nestin expression was assessed by immunohistochemistry in 141 PUM and 26 MUM samples; 11 PUM cases were matched with their corresponding metastases. The percentage of tumour cells expressing nestin was scored by three independent observers. Statistical analysis of all data was performed with SPSS. RESULTS: Nestin expression was identified in both the cytoplasm and membrane of UM cells. Increased expression of nestin in PUM samples was associated with known poor prognostic parameters, including epithelioid cell morphology (p < 0.001), closed loops (p = 0.001), higher mitotic count (p < 0.001), monosomy 3 (p = 0.007) and chromosome 8q gain (p < 0.001). Primary uveal melanoma (PUM) with nestin expression levels above a cut-off value of 10% [as determined by receiver operating characteristic (ROC) analysis] was associated with a significantly reduced survival time (Log-rank, p = 0.002). In MUM, a higher percentage of nestin-positive tumour cells combined with poor prognostic markers in the PUM led to a shorter survival time following the development of metastases. CONCLUSION: In conclusion, increased nestin expression in PUM is a predictor of a tumour phenotype associated with metastatic progression and reduced survival time at onset of metastasis.

24 Article Combined mutation and copy-number variation detection by targeted next-generation sequencing in uveal melanoma. 2018

Smit, Kyra N / van Poppelen, Natasha M / Vaarwater, Jolanda / Verdijk, Robert / van Marion, Ronald / Kalirai, Helen / Coupland, Sarah E / Thornton, Sophie / Farquhar, Neil / Dubbink, Hendrikus-Jan / Paridaens, Dion / de Klein, Annelies / Kiliç, Emine. ·Department of Ophthalmology, Erasmus University Medical Center, Rotterdam, The Netherlands. · Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands. · Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands. · Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK. · The Rotterdam Eye Hospital, Rotterdam, The Netherlands. ·Mod Pathol · Pubmed #29327717.

ABSTRACT: Uveal melanoma is a highly aggressive cancer of the eye, in which nearly 50% of the patients die from metastasis. It is the most common type of primary eye cancer in adults. Chromosome and mutation status have been shown to correlate with the disease-free survival. Loss of chromosome 3 and inactivating mutations in BAP1, which is located on chromosome 3, are strongly associated with 'high-risk' tumors that metastasize early. Other genes often involved in uveal melanoma are SF3B1 and EIF1AX, which are found to be mutated in intermediate- and low-risk tumors, respectively. To obtain genetic information of all genes in one test, we developed a targeted sequencing method that can detect mutations in uveal melanoma genes and chromosomal anomalies in chromosome 1, 3, and 8. With as little as 10 ng DNA, we obtained enough coverage on all genes to detect mutations, such as substitutions, deletions, and insertions. These results were validated with Sanger sequencing in 28 samples. In >90% of the cases, the BAP1 mutation status corresponded to the BAP1 immunohistochemistry. The results obtained in the Ion Torrent single-nucleotide polymorphism assay were confirmed with several other techniques, such as fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and Illumina SNP array. By validating our assay in 27 formalin-fixed paraffin-embedded and 43 fresh uveal melanomas, we show that mutations and chromosome status can reliably be obtained using targeted next-generation sequencing. Implementing this technique as a diagnostic pathology application for uveal melanoma will allow prediction of the patients' metastatic risk and potentially assess eligibility for new therapies.

25 Article Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma. 2017

Robertson, A Gordon / Shih, Juliann / Yau, Christina / Gibb, Ewan A / Oba, Junna / Mungall, Karen L / Hess, Julian M / Uzunangelov, Vladislav / Walter, Vonn / Danilova, Ludmila / Lichtenberg, Tara M / Kucherlapati, Melanie / Kimes, Patrick K / Tang, Ming / Penson, Alexander / Babur, Ozgun / Akbani, Rehan / Bristow, Christopher A / Hoadley, Katherine A / Iype, Lisa / Chang, Matthew T / Anonymous1140916 / Cherniack, Andrew D / Benz, Christopher / Mills, Gordon B / Verhaak, Roel G W / Griewank, Klaus G / Felau, Ina / Zenklusen, Jean C / Gershenwald, Jeffrey E / Schoenfield, Lynn / Lazar, Alexander J / Abdel-Rahman, Mohamed H / Roman-Roman, Sergio / Stern, Marc-Henri / Cebulla, Colleen M / Williams, Michelle D / Jager, Martine J / Coupland, Sarah E / Esmaeli, Bita / Kandoth, Cyriac / Woodman, Scott E. ·Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada. · The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. · Buck Institute for Research on Aging, Novato, CA 94945, USA. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA. · Department of Biomolecular Engineering, Center for Biomolecular Sciences and Engineering, University of California, Santa Cruz, CA 95064, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Public Health Sciences, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA. · The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 21287, USA. · The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA. · Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Human Oncology and Pathogenesis Program, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA. · Molecular and Medical Genetics, Computational Biology, Oregon Health and Science University, Portland, OR 97239, USA. · Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Institute for Applied Cancer Science, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. · Institute for Systems Biology, Seattle, WA 98109, USA. · Human Oncology and Pathogenesis Program, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Departments of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94122, USA. · Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Dermatology, University Hospital Essen, 45157 Essen, Germany. · Center for Cancer Genomics, National Cancer Institute, Bethesda, MD 20892, USA. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Pathology, The Ohio State University, Wexner Medical Center, Columbus, OH 43210, USA. · Department of Pathology, Dermatology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Departments of Ophthalmology and Internal Medicine, Division of Human Genetics, The Ohio State University, Columbus, OH 43210, USA. · Department of Translational Research, Institut Curie, PSL Research University, Paris 75248, France. · Havener Eye Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43212, USA. · Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands. · Department of Molecular & Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool L7 8TX, UK; Department of Cellular Pathology, Royal Liverpool University Hospital, Liverpool, L69 3GA, UK. · Orbital Oncology & Ophthalmic Plastic Surgery, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: besmaeli@mdanderson.org. · Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA. Electronic address: kandothc@mskcc.org. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: swoodman@mdanderson.org. ·Cancer Cell · Pubmed #28810145.

ABSTRACT: Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1-mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low- versus intermediate-risk clinical mutation subtypes.

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