Publications by authors named "Martine J Jager"

175 Publications

Targeting the YAP/TAZ Pathway in Uveal and Conjunctival Melanoma With Verteporfin.

Invest Ophthalmol Vis Sci 2021 Apr;62(4)

Department of Ophthalmology, Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, United States.

Purpose: The purpose of this study was to determine whether YAP/TAZ activation in uveal melanoma (UM) and the susceptibility of melanoma cell lines to YAP/TAZ inhibition by verteporfin (VP) is related to the tumor's genetic background.

Methods: Characteristics of 144 patients with enucleated UM were analyzed together with mRNA expression levels of YAP/TAZ-related genes (80 patients from the The Cancer Genome Atlas [TCGA] project and 64 patients from Leiden, The Netherlands). VP was administered to cell lines 92.1, OMM1, Mel270, XMP46, and MM28 (UM), CRMM1 and CRMM2 (conjunctival melanoma), and OCM3 (cutaneous melanoma). Viability, growth speed, and expression of YAP1-related proteins were assessed.

Results: In TCGA data, high expression of YAP1 and WWTR1 correlated with the presence of monosomy 3 (P = 0.009 and P < 0.001, respectively) and BAP1-loss (P = 0.003 and P = 0.001, respectively) in the primary UM; metastasis development correlated with higher expression of YAP1 (P = 0.05) and WWTR1 (P = 0.003). In Leiden data, downstream transcription factor TEAD4 was increased in cases with M3/BAP1-loss (P = 0.002 and P = 0.006) and related to metastasis (P = 0.004). UM cell lines 92.1, OMM1, and Mel270 (GNAQ/11-mutation, BAP1-positive) and the fast-growing cell line OCM3 (BRAF-mutation) showed decreased proliferation after exposure to VP. Two slow-growing UM cell lines XMP46 and MM28 (GNAQ/11-mutation, BAP1-negative) were not sensitive to VP, and neither were the two conjunctival melanoma cell lines (BRAF/NRAS-mutation).

Conclusions: High risk UM showed an increased expression of YAP/TAZ-related genes. Although most UM cell lines responded in vitro to VP, BAP1-negative and conjunctival melanoma cell lines did not. Not only the mutational background, but also cell growth rate is an important predictor of response to YAP/TAZ inhibition by VP.
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http://dx.doi.org/10.1167/iovs.62.4.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024781PMC
April 2021

The role of melanocytes in the human choroidal microenvironment and inflammation: Insights from the transcriptome.

Pigment Cell Melanoma Res 2021 Mar 22. Epub 2021 Mar 22.

School of Optometry and Vision Science, University of NSW, Sydney, NSW, Australia.

The choroid within the human eye contains a rich milieu of cells including melanocytes. Human choroidal melanocytes (HCMs) absorb light, regulate free radical production, and were recently shown to modulate inflammation. This study aimed to identify key genes and pathways involved in the inflammatory response of HCMs through the use of RNA-seq. Primary HCMs were cultured from donor choroids, RNA was extracted from control and lipopolysaccharide (LPS)-treated HCMs, and mRNA was sequenced. Functional annotation and pathway analysis were performed using gene ontology and gene set enrichment analyses. Representative RNA-seq results were verified with RT-qPCR and protein measurements. We detected 100 differentially expressed genes including an array of CCL and CXCL cytokines and mediators of cell-cell and cell-matrix adhesion, such as ICAM1, CLDN1, CCN3, ITGA1 and ITGA11. Functional annotation showed that these gene sets control inflammatory pathways, immune cell trafficking, cell-cell adhesion, interactions with the extracellular matrix and blood vessels, angiogenesis and epithelial-to-mesenchymal transitions. Our study provides insights into the transcriptional regulation of primary HCMs in response to inflammatory stimuli and identifies novel melanocyte-driven mechanisms potentially involved in choroidal homeostasis and inflammation.
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http://dx.doi.org/10.1111/pcmr.12972DOI Listing
March 2021

Involvement of mutant and wild-type CYSLTR2 in the development and progression of uveal nevi and melanoma.

BMC Cancer 2021 Feb 15;21(1):164. Epub 2021 Feb 15.

Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.

Background: Activating Gα signalling mutations are considered an early event in the development of uveal melanoma. Whereas most tumours harbour a mutation in GNAQ or GNA11, CYSLTR2 (encoding G-protein coupled receptor CysLTR) forms a rare alternative. The role of wild-type CysLTR in uveal melanoma remains unknown.

Methods: We performed a digital PCR-based molecular analysis of benign choroidal nevi and primary uveal melanomas. Publicly available bulk and single cell sequencing data were mined to further study mutant and wild-type CYSLTR2 in primary and metastatic uveal melanoma.

Results: 1/16 nevi and 2/120 melanomas carried the CYSLTR2 mutation. The mutation was found in a subpopulation of the nevus, while being clonal in both melanomas. In the melanomas, secondary, subclonal CYSLTR2 alterations shifted the allelic balance towards the mutant. The resulting genetic heterogeneity was confirmed in distinct areas of both tumours. At the RNA level, further silencing of wild-type and preferential expression of mutant CYSLTR2 was identified, which was also observed in two CYSLTR2 mutant primary melanomas and one metastatic lesion from other cohorts. In CYSLTR2 wild-type melanomas, high expression of CYSLTR2 correlated to tumour inflammation, but expression originated from melanoma cells specifically.

Conclusions: Our findings suggest that CYSLTR2 is involved in both early and late development of uveal melanoma. Whereas the CYSLTR2 p.L129Q mutation is likely to be the initiating oncogenic event, various mechanisms further increase the mutant allele abundance during tumour progression. This makes mutant CysLTR an attractive therapeutic target in uveal melanoma.
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http://dx.doi.org/10.1186/s12885-021-07865-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885466PMC
February 2021

The Effect of Mutation on the DNA Damage Response and Nonsense-Mediated mRNA Decay in Cancer.

Front Oncol 2020 29;10:609409. Epub 2021 Jan 29.

Department of Experimental Immunology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, Netherlands.

Recurrent mutations in splicing factor 3B subunit 1 () have been identified in several malignancies and are associated with an increased expression of 3' cryptic transcripts as a result of alternative branchpoint recognition. A large fraction of cryptic transcripts associated with mutations is expected to be sensitive for RNA degradation nonsense-mediated mRNA decay (NMD). Several studies indicated alterations in various signaling pathways in SF3B1-mutated cells, including an impaired DNA damage response (DDR) in chronic lymphocytic leukemia (CLL). In this study, we investigated isogenic cell lines and treatment naïve primary CLL samples without any and/or defect, and found no significant effects of mutations on the ATM/p53 response, phosphorylation of H2AX and sensitivity to fludarabine. Cryptic transcripts associated with mutation status were observed at relatively low levels compared to the canonical transcripts and were validated as target for mRNA degradation NMD. Expression of cryptic transcripts increased after NMD inhibition. In conclusion, our results confirm involvement of NMD in the biological effects of mutations. Further studies may elucidate whether -mutant patients could benefit from NMD modulatory agents.
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http://dx.doi.org/10.3389/fonc.2020.609409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880055PMC
January 2021

In-vivo imaging for assessing tumor growth in mouse models of ocular melanoma.

Exp Eye Res 2021 Mar 3;204:108431. Epub 2021 Jan 3.

Ophthalmology Research Laboratory, Kaplan Medical Center, Rehovot, Israel. Electronic address:

Uveal melanoma (UM) and conjunctival melanoma (CM) are ocular malignancies that give rise to life-threatening metastases. Although local disease can often be treated successfully, it is often associated with significant vision impairment and treatments are often not effective against metastatic disease. Novel treatment modalities that preserve vision may enable elimination of small tumors and may prevent subsequent metastatic spread. Very few mouse models of metastatic CM and UM are available for research and for development of novel therapies. One of the challenges is to follow tumor growth in-vivo and to determine the right size for treatment, mainly of the posterior, choroidal melanoma. Hence, the purpose of this study was to establish a simple, noninvasive imaging tool that will simplify visualization and tumor follow-up in mouse models of CM and UM. Tumors were induced by inoculation of murine B16LS9 cells into the sub-conjunctival or the choroidal space of a C57BL/6 mouse eye under a surgical microscope. Five to ten days following injection, tumor size was assessed by Phoenix MicronIV™ image-guided Optical Coherence Tomography (OCT) imaging, which included a real-time camera view and OCT scan of the conjunctiva and the retina. In addition, tumor size was evaluated by ultrasound and histopathological examination of eye sections. Tumor growth was observed 5-9 days following sub-conjunctival or sub-retinal injection of seven-thousand or seventy-thousand cells, respectively. A clear tumor mass was detected at these regions using the MicronIV™ imaging system camera and OCT scans. Histology of eye sections confirmed the presence of tumor tissue. OCT allowed an accurate measurement of tumor size in the UM model and a qualitative assessment of tumor size in the CM model. Moreover, OCT enabled assessing the success rate of the choroidal tumor induction and importantly, predicted final tumor size already on the day of cell inoculation. In conclusion, by using a simple, non-invasive imaging tool, we were able to follow intraocular tumor growth of both CM and UM, and to define, already at the time of cell inoculation, a grading scale to evaluate tumor size. This tool may be utilized for evaluation of new mouse models for CM and UM, as well as for testing new therapies for these diseases.
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http://dx.doi.org/10.1016/j.exer.2020.108431DOI Listing
March 2021

New developments in corneal endothelial cell replacement.

Acta Ophthalmol 2020 Dec 24. Epub 2020 Dec 24.

Netherlands Institute for Innovative Ocular Surgery, Rotterdam, The Netherlands.

Corneal transplantation is currently the most effective treatment to restore corneal clarity in patients with endothelial disorders. Endothelial transplantation, either by Descemet membrane endothelial keratoplasty (DMEK) or by Descemet stripping (automated) endothelial keratoplasty (DS(A)EK), is a surgical approach that replaces diseased Descemet membrane and endothelium with tissue from a healthy donor eye. Its application, however, is limited by the availability of healthy donor tissue. To increase the pool of endothelial grafts, research has focused on developing new treatment options as alternatives to conventional corneal transplantation. These treatment options can be considered as either 'surgery-based', that is tissue-efficient modifications of the current techniques (e.g. Descemet stripping only (DSO)/Descemetorhexis without endothelial keratoplasty (DWEK) and Quarter-DMEK), or 'cell-based' approaches, which rely on in vitro expansion of human corneal endothelial cells (hCEC) (i.e. cultured corneal endothelial cell sheet transplantation and cell injection). In this review, we will focus on the most recent developments in the field of the 'cell-based' approaches. Starting with the description of aspects involved in the isolation of hCEC from donor tissue, we then describe the different natural and bioengineered carriers currently used in endothelial cell sheet transplantation, and finally, we discuss the current 'state of the art' in novel therapeutic approaches such as endothelial cell injection.
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http://dx.doi.org/10.1111/aos.14722DOI Listing
December 2020

HDAC Inhibition Increases HLA Class I Expression in Uveal Melanoma.

Cancers (Basel) 2020 Dec 9;12(12). Epub 2020 Dec 9.

Department of Ophthalmology, LUMC, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.

The treatment of uveal melanoma (UM) metastases or adjuvant treatment may imply immunological approaches or chemotherapy. It is to date unknown how epigenetic modifiers affect the expression of immunologically relevant targets, such as the HLA Class I antigens, in UM. We investigated the expression of HDACs and the histone methyl transferase EZH2 in a set of 64 UMs, using an Illumina HT12V4 array, and determined whether a histone deacetylase (HDAC) inhibitor and EZH2 inhibitor modified the expression of HLA Class I on three UM cell lines. Several HDACs (HDAC1, HDAC3, HDAC4, and HDAC8) showed an increased expression in high-risk UM, and were correlated with an increased HLA expression. HDAC11 had the opposite expression pattern. While in vitro tests showed that Tazemetostat did not influence cell growth, Quisinostat decreased cell survival. In the three tested cell lines, Quisinostat increased HLA Class I expression at the protein and mRNA level, while Tazemetostat did not have an effect on the cell surface HLA Class I levels. Combination therapy mostly followed the Quisinostat results. Our findings indicate that epigenetic drugs (in this case an HDAC inhibitor) may influence the expression of immunologically relevant cell surface molecules in UM, demonstrating that these drugs potentially influence immunotherapy.
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http://dx.doi.org/10.3390/cancers12123690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763827PMC
December 2020

Eye Diseases Direct Interest to Complement Pathway and Macrophages as Regulators of Inflammation in COVID-19.

Asia Pac J Ophthalmol (Phila) 2020 Dec 7;10(1):114-120. Epub 2020 Dec 7.

University of Massachusetts Medical School, Department of Ophthalmology and Visual Sciences, Worcester, MA, USA.

Abstract: Many of the risk factors for developing severe coronavirus disease 2019 (COVID-19) are also risk factors for eye diseases such as age-related macular degeneration (AMD). During the past decades, macrophages and the complement pathway (as a part of the innate immune system) have been identified as important contributors to the development of AMD, and we suggest that these mechanisms are of similar importance for the clinical course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Based on the experience with AMD, we discuss how behavioral factors such as diet, smoking and higher body mass index, as well as genetic determinants such as the complement and immune pathway genes may lead to the overactive inflammatory phenotypes seen in some patients with COVID-19, and may in part explain the heterogeneity of disease manifestations and outcomes. Based on this experience, we discuss potential genetic research projects and elaborate on preventive and treatment approaches related to COVID-19.
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http://dx.doi.org/10.1097/APO.0000000000000346DOI Listing
December 2020

Prognostic significance of PD-1/PD-L1 expression in uveal melanoma: correlation with tumor-infiltrating lymphocytes and clinicopathological parameters.

Cancer Immunol Immunother 2021 May 2;70(5):1291-1303. Epub 2020 Nov 2.

Department of Ocular Pathology, Dr. R P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India.

Background: To understand how to improve the effect of immune checkpoint inhibitors in uveal melanoma (UM), we need a better understanding of the expression of PD-1 and PD-L1, their relation with the presence of tumor-infiltrating lymphocytes (TILs), and their prognostic relevance in UM patients.

Materials And Methods: Expression of PD-1 and PD-L1 was assessed in 71 UM tissue samples by immunohistochemistry and quantitative real-time PCR (qRT-PCR), and further validated by western blotting. The effect of interferon gamma (IFN-γ) on PD-1/PD-L1 expression was determined on four UM cell lines.

Results: Immunoreactivity of PD-1 was found in 30/71 cases and of PD-L1 in 44/71 UM samples. Tumor-infiltrating lymphocytes were found in 46% of UM tissues. PD-1 was expressed on TILs while tumor cells expressed PD-L1. UM with and without TILs showed expression of PD-1 in 69% and 18% cases, respectively (p = 0.001). Similarly, PD-L1 was found in 75% of UM with TILs and in 50% of cases without TILs, respectively (p = 0.03). DFS rate were lower in patients with TILs with expression of PD-1 and PD-L1, but the rate of DFS was higher with expression of PD-L1 in patients without TILs. After treatment of UM cell lines with IFN-γ, PD-1 expression was induced in all UM cell lines whereas PD-L1 expression was found at a lower level in untreated cells, while expression also increased following treatment with IFN-γ.

Conclusion: Our study suggests that increased infiltration with TILs promotes the aggressive behavior and suppresses the immune response of UM cells, thereby inhibiting immunotherapy.
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http://dx.doi.org/10.1007/s00262-020-02773-8DOI Listing
May 2021

Iris Colour and the Risk of Developing Uveal Melanoma.

Int J Mol Sci 2020 Sep 28;21(19). Epub 2020 Sep 28.

Department of Ophthalmology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.

Uveal melanoma (UM) is a global disease which especially occurs in elderly people. Its incidence varies widely between populations, with the highest incidence among Caucasians, and a South-to-North increase in Europe. As northern Europeans often have blond hair and light eyes, we wondered whether iris colour may be a predisposing factor for UM and if so, why. We compared the distribution of iris colour between Dutch UM patients and healthy Dutch controls, using data from the Rotterdam Study (RS), and reviewed the literature regarding iris colour. We describe molecular mechanisms that might explain the observed associations. When comparing a group of Dutch UM patients with controls, we observed that individuals from Caucasian ancestry with a green/hazel iris colour (Odds Ratio (OR) = 3.64, 95% Confidence Interval (CI) 2.57-5.14) and individuals with a blue/grey iris colour (OR = 1.38, 95% CI 1.04-1.82) had a significantly higher crude risk of UM than those with brown eyes. According to the literature, this may be due to a difference in the function of pheomelanin (associated with a light iris colour) and eumelanin (associated with a brown iris colour). The combination of light-induced stress and aging may affect pheomelanin-carrying melanocytes in a different way than eumelanin-carrying melanocytes, increasing the risk of developing a malignancy.
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http://dx.doi.org/10.3390/ijms21197172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583924PMC
September 2020

Anterior Segment OCTA of Melanocytic Lesions of the Conjunctiva and Iris.

Am J Ophthalmol 2021 02 12;222:137-147. Epub 2020 Sep 12.

Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.

Purpose: To study the feasibility and diagnostic value of vascular imaging using optical coherence tomography (OCT)-angiography (OCTA) of melanocytic lesions of the conjunctiva and iris.

Design: Cross-sectional study.

Methods: Twenty-five patients with an untreated conjunctival lesion (5 melanoma, 13 nevus, 7 primary acquired melanosis [PAM]) and 52 patients with an untreated iris lesion (10 melanoma, 42 nevus) were included. Patients were imaged using a commercially available OCTA device, with the addition of an anterior segment lens and manual focussing. Tumor vessel presence, vascular patterns and vascular density were assessed.

Results: Good OCTA images were obtained in 18 of 25 conjunctival lesions and 42 of 52 iris lesions. Failure was caused by lack of patient cooperation, an unfavorable location, or mydriasis. In all imaged conjunctival lesions and 77% of iris lesions, vascular structures were detected. Conjunctival melanoma and nevi demonstrated the same intralesional tortuous patterns, whereas vasculature in eyes with PAM was similar to normal conjunctiva. Both iris melanoma and nevi demonstrated tortuous patterns, distinct from the radially oriented normal iris vasculature.

Conclusions: Optical coherence tomography angiography (OCTA) allows for noninvasive imaging of the vasculature in melanocytic lesions of the conjunctiva and iris. Good image quality depends highly on patient cooperation and lesion characteristics. Differentiation of benign and malignant lesions was not possible. New software is called for to improve image acquisition and analysis.
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http://dx.doi.org/10.1016/j.ajo.2020.09.009DOI Listing
February 2021

Potential Onco-Suppressive Role of miR122 and miR144 in Uveal Melanoma through ADAM10 and C-Met Inhibition.

Cancers (Basel) 2020 Jun 4;12(6). Epub 2020 Jun 4.

IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy.

Uveal melanoma (UM) is a rare tumor of the eye that leads to deadly metastases in about half of the patients. ADAM10 correlates with c-Met expression in UM and high levels of both molecules are related to the development of metastases. MiR122 and miR144 modulate and expression in different settings. We hypothesized a potential onco-suppressive role for miR122 and miR144 through modulation of ADAM10 and c-Met in UM. We analyzed the UM Cancer Genome Atlas data portal (TCGA) dataset, two other cohorts of primary tumors and five human UM cell lines for miR122 and miR144 expression by miR microarray, RT-qPCR, Western blotting, miR transfection and luciferase reporter assay. Our results indicate that miR122 and miR144 are expressed at low levels in the UM cell lines and in the TCGA UM dataset and were down-modulated in a cohort of seven UM samples, compared to normal choroid. Both miR122 and miR144 directly targeted and . Overexpression of miR122 and miR144 led to reduced expression of ADAM10 and c-Met in the UM cell lines and impaired cell proliferation, migration, cell cycle and shedding of c-Met ecto-domain. Our results show that miR122 and miR144 display an onco-suppressive role in UM through ADAM10 and c-Met modulation.
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http://dx.doi.org/10.3390/cancers12061468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352235PMC
June 2020

CD4 T-Cell Responses Mediate Progressive Neurodegeneration in Experimental Ischemic Retinopathy.

Am J Pathol 2020 08 8;190(8):1723-1734. Epub 2020 May 8.

Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts. Electronic address:

Retinal ischemic events, which result from occlusion of the ocular vasculature share similar causes as those for central nervous system stroke and are among the most common cause of acute and irreversible vision loss in elderly patients. Currently, there is no established treatment, and the condition often leaves patients with seriously impaired vision or blindness. The immune system, particularly T-cell-mediated responses, is thought to be intricately involved, but the exact roles remain elusive. We found that acute ischemia-reperfusion injury to the retina induced a prolonged phase of retinal ganglion cell loss that continued to progress during 8 weeks after the procedure. This phase was accompanied by microglial activation and CD4 T-cell infiltration into the retina. Adoptive transfer of CD4 T cells isolated from diseased mice exacerbated retinal ganglion cell loss in mice with retinal reperfusion damage. On the other hand, T-cell deficiency or administration of T-cell or interferon-γ-neutralizing antibody attenuated retinal ganglion cell degeneration and retinal function loss after injury. These findings demonstrate a crucial role for T-cell-mediated responses in the pathogenesis of neural ischemia. These findings point to novel therapeutic targets of limiting or preventing neuron and function loss for currently untreatable conditions of optic neuropathy and/or central nervous system ischemic stroke.
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http://dx.doi.org/10.1016/j.ajpath.2020.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397460PMC
August 2020

Management of conjunctival melanoma with local excision and adjuvant brachytherapy.

Eye (Lond) 2021 Feb 24;35(2):490-498. Epub 2020 Apr 24.

Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands.

Background/objectives: To evaluate the management of conjunctival melanoma with local excision and adjuvant brachytherapy.

Subjects/methods: Data of all patients who received local excision and adjuvant brachytherapy for conjunctival melanoma between 1999 and 2016 in a Dutch national referral centre were reviewed. A protocol with Sr-90 was used until 2012, a protocol with Ru-106 was used hereafter. Local recurrence, metastasis, survival, visual acuity and treatment complications were assessed.

Results: A total of 58 patients was identified: 32 patients were treated with Sr-90 and 26 with Ru-106. Mean follow-up time was 97.3 months (143.1 months after Sr-90, and 40.2 months after Ru-106). All lesions were epibulbar, the median tumour thickness was 0.9 mm. Local recurrence occurred in 13/58 cases (22%), with a 5-year recurrence rate of 21%. Local recurrence occurred equally often in both protocols, with 5-year recurrence rates of 19% (Sr-90) versus 23% (Ru-106) (p = 0.68). Metastasis developed in 3/58 cases (5%), with 2 cases after Sr-90, and 1 after Ru-106 (p = 1.00). The most reported complications were pain (29%), dry eyes (21%), symblepharon (9%), ptosis (12%) and cataract (9%). No severe corneal or scleral complications were observed. Median visual acuity was 1.00 pre-surgery, at the end of follow-up this was 1.00 (Sr-90) and 0.95 (Ru-106).

Conclusion: Local excision with adjuvant brachytherapy provides good tumour control with excellent visual outcome and mild side effects in patients with limited conjunctival melanoma. Results after Sr-90 or Ru-106 were comparable; a choice for either treatment may be based on experience of the clinician and availability of materials.
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http://dx.doi.org/10.1038/s41433-020-0879-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027634PMC
February 2021

Uveal melanoma.

Nat Rev Dis Primers 2020 04 9;6(1):24. Epub 2020 Apr 9.

Nuffield Department of Clinical Neurosciences, University of Oxford, West Wing, John Radcliffe Hospital, Oxford, UK.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. UMs are usually initiated by a mutation in GNAQ or GNA11, unlike cutaneous melanomas, which usually harbour a BRAF or NRAS mutation. The annual incidence in Europe and the USA is ~6 per million population per year. Risk factors include fair skin, light-coloured eyes, congenital ocular melanocytosis, ocular melanocytoma and the BAP1-tumour predisposition syndrome. Ocular treatment aims at preserving the eye and useful vision and, if possible, preventing metastases. Enucleation has largely been superseded by various forms of radiotherapy, phototherapy and local tumour resection, often administered in combination. Ocular outcomes are best with small tumours not extending close to the optic disc and/or fovea. Almost 50% of patients develop metastatic disease, which usually involves the liver, and is usually fatal within 1 year. Although UM metastases are less responsive than cutaneous melanoma to chemotherapy or immune checkpoint inhibitors, encouraging results have been reported with partial hepatectomy for solitary metastases, with percutaneous hepatic perfusion with melphalan or with tebentafusp. Better insight into tumour immunology and metabolism may lead to new treatments.
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http://dx.doi.org/10.1038/s41572-020-0158-0DOI Listing
April 2020

Prognostic Factors Five Years After Enucleation for Uveal Melanoma.

Invest Ophthalmol Vis Sci 2020 03;61(3):31

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Purpose: A subgroup of uveal melanoma (UM) gives rise to metastases at a late stage. Our objective was to identify patient and tumor characteristics that are associated with UM-related death in patients who survived 5 years following enucleation.

Methods: A retrospective analysis was performed in 583 primary UM cases, enucleated at the Leiden University Medical Center between 1983 and 2013. Univariable and multivariable Cox regression analyses were performed in the total cohort and separately in those surviving more than 5 years (n = 297).

Results: In the total cohort, the median age was 62.6 years, and the median tumor diameter was 12.0 mm. Monosomy 3 was detected in 53% of cases and gain of 8q in 47%. In the cohort surviving 5 years, the median age was 59.5 years, and the median tumor diameter was 11.0 mm. Monosomy 3 and gain of 8q were detected in 33% and 31% of cases, respectively. In the total cohort, male gender (P = 0.03), tumor diameter (P < 0.001), mitotic count (P < 0.001), extravascular matrix loops (P = 0.03), extraocular growth (P < 0.001), and gain of 8q (P < 0.001) were independently associated with UM-related death. In patients surviving 5 years after enucleation, univariable analysis revealed that age (P = 0.03), tumor diameter (P < 0.001), monosomy 3 (P = 0.04), and 8q gain (P = 0.003) were associated with subsequent UM-related death. Using a multivariable analysis, only male gender (P = 0.03) and gain of 8q (P = 0.01) remained significant.

Conclusions: Predictors of UM-related death change over time. Among UM patients who survived the initial 5 years following enucleation, male gender and chromosome 8q status were the remaining factors related to UM-related death later on.
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http://dx.doi.org/10.1167/iovs.61.3.31DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401572PMC
March 2020

TLD1433 Photosensitizer Inhibits Conjunctival Melanoma Cells in Zebrafish Ectopic and Orthotopic Tumour Models.

Cancers (Basel) 2020 Mar 4;12(3). Epub 2020 Mar 4.

Institute of Biology, Leiden University, 2333 CC Leiden, The Netherlands.

The ruthenium-based photosensitizer (PS) TLD1433 has completed a phase I clinical trial for photodynamic therapy (PDT) treatment of bladder cancer. Here, we investigated a possible repurposing of this drug for treatment of conjunctival melanoma (CM). CM is a rare but often deadly ocular cancer. The efficacy of TLD1433 was tested on several cell lines from CM (CRMM1, CRMM2 and CM2005), uveal melanoma (OMM1, OMM2.5, MEL270), epidermoid carcinoma (A431) and cutaneous melanoma (A375). Using 15 min green light irradiation (21 mW/cm, 19 J.cm, 520 nm), the highest phototherapeutic index (PI) was reached in CM cells, with cell death occurring via apoptosis and necrosis. The therapeutic potential of TLD1433 was hence further validated in zebrafish ectopic and newly-developed orthotopic CM models. Fluorescent CRMM1 and CRMM2 cells were injected into the circulation of zebrafish (ectopic model) or behind the eye (orthotopic model) and 24 h later, the engrafted embryos were treated with the maximally-tolerated dose of TLD1433. The drug was administrated in three ways, either by (i) incubating the fish in drug-containing water (WA), or (ii) injecting the drug intravenously into the fish (IV), or (iii) injecting the drug retro-orbitally (RO) into the fish. Optimally, four consecutive PDT treatments were performed on engrafted embryos using 60 min drug-to-light intervals and 90 min green light irradiation (21 mW/cm, 114 J.cm, 520 nm). This PDT protocol was not toxic to the fish. In the ectopic tumour model, both systemic administration by IV injection and RO injection of TLD1433 significantly inhibited growth of engrafted CRMM1 and CRMM2 cells. However, in the orthotopic model, tumour growth was only attenuated by localized RO injection of TLD1433. These data unequivocally prove that the zebrafish provides a fast vertebrate cancer model that can be used to test the administration regimen, host toxicity and anti-cancer efficacy of PDT drugs against CM. Based on our results, we suggest repurposing of TLD1433 for treatment of incurable CM and further testing in alternative pre-clinical models.
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http://dx.doi.org/10.3390/cancers12030587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139549PMC
March 2020

Multicenter External Validation of the Liverpool Uveal Melanoma Prognosticator Online: An OOG Collaborative Study.

Cancers (Basel) 2020 Feb 18;12(2). Epub 2020 Feb 18.

Department of Ophthalmology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany.

Uveal melanoma (UM) is fatal in ~50% of patients as a result of disseminated disease. This study aims to externally validate the Liverpool Uveal Melanoma Prognosticator Online V3 (LUMPO3) to determine its reliability in predicting survival after treatment for choroidal melanoma when utilizing external data from other ocular oncology centers. Anonymized data of 1836 UM patients from seven international ocular oncology centers were analyzed with LUMPO3 to predict the 10-year survival for each patient in each external dataset. The analysts were masked to the patient outcomes. Model predictions were sent to an independent statistician to evaluate LUMPO3's performance using discrimination and calibration methods. LUMPO3's ability to discriminate between UM patients who died of metastatic UM and those who were still alive was fair-to-good, with C-statistics ranging from 0.64 to 0.85 at year 1. The pooled estimate for all external centers was 0.72 (95% confidence interval: 0.68 to 0.75). Agreement between observed and predicted survival probabilities was generally good given differences in case mix and survival rates between different centers. Despite the differences between the international cohorts of patients with primary UM, LUMPO3 is a valuable tool for predicting all-cause mortality in this disease when using data from external centers.
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http://dx.doi.org/10.3390/cancers12020477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072188PMC
February 2020

Effect of Surgical Indication and Preoperative Lens Status on Descemet Membrane Endothelial Keratoplasty Outcomes.

Am J Ophthalmol 2020 04 18;212:79-87. Epub 2019 Dec 18.

Netherlands Institute for Innovative Ocular Surgery (NIIOS), Rotterdam, Netherlands; Melles Cornea Clinic Rotterdam, Rotterdam, Netherlands; Amnitrans Eye Bank Rotterdam, Rotterdam, Netherlands; NIIOS-USA, San Diego, California, USA. Electronic address:

Purpose: To analyze 6-month results of 1000 consecutive Descemet membrane endothelial keratoplasty (DMEK) cases, and to evaluate if outcomes are influenced by surgical indication and preoperative lens status.

Design: Retrospective, interventional case series.

Methods: A series of 1000 eyes (738 patients) underwent DMEK mainly for Fuchs endothelial corneal dystrophy (FECD; 85.3%) or bullous keratopathy (BK; 10.5%). Main outcome measures were best-corrected visual acuity (BCVA), endothelial cell density, postoperative complications, and retransplantations.

Results: At 6 months after DMEK, there was no difference in BCVA outcome between FECD and BK eyes (P = .170), or between phakic and pseudophakic FECD eyes (P = .066) after correcting for patient age and preoperative BCVA. Endothelial cell loss at 6 months postoperatively was similar for phakic and pseudophakic FECD eyes (39%; P = .852), but higher for BK eyes than for FECD eyes (46% vs 39%, P = .001). Primary and secondary graft failure occurred in 3 (0.3%) and 2 eyes (0.2%), respectively, and 7 eyes developed allograft rejection (0.7%). Eighty-two eyes (8.2%) received rebubbling for graft detachment and retransplantation was performed in 20 eyes (2.0%). Rebubbling was more often required in eyes treated for BK vs FECD eyes (12.4% vs 7.4%, P = .022).

Conclusion: DMEK consistently provides excellent short-term results, with similar high visual acuity levels for both FECD and BK eyes. As preoperative lens status did not influence DMEK outcomes, for phakic FECD eyes with a still relatively clear crystalline lens, lens preservation may be preferable in a selected group of younger patients, who may still benefit from their residual accommodative capacity.
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http://dx.doi.org/10.1016/j.ajo.2019.12.011DOI Listing
April 2020

RETINAL OXIMETRY IS ALTERED IN EYES WITH CHOROIDAL MELANOMA BUT NOT IN EYES WITH CHOROIDAL NEVI.

Retina 2020 Nov;40(11):2207-2215

Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands.

Purpose: To compare retinal vessel oxygenation in eyes with an untreated choroidal nevus or choroidal melanoma.

Methods: The affected and fellow eye of patients with an untreated choroidal nevus (n = 42) or choroidal melanoma (n = 45) were investigated using noninvasive retinal oximetry (Oxymap T1). Oxygen saturation of arterioles (ArtSat) and venules (VenSat) was determined, together with the arteriovenous difference (AV-difference).

Results: In choroidal nevus patients, retinal oximetry did not differ between the affected and fellow eye: the mean ArtSat was 94.5% and 94.2% (P = 0.56), the VenSat was 60.5% and 61.3% (P = 0.35), and the AV-difference was 34.0% and 32.9% (P = 0.18), respectively. In choroidal melanoma patients, alterations were detected: the mean ArtSat was 94.8% and 93.2% (P = 0.006), the VenSat was 58.0% and 60.0% (P = 0.014), and the AV-difference was 36.8% and 33.2% (P < 0.001), respectively. The largest increase in AV-difference was observed between the retinal halves without the lesion in melanoma eyes compared with the corresponding half in the fellow eye (37.5% vs. 32.1%, P < 0.001).

Conclusion: Although retinal oximetry was not significantly altered in eyes with a choroidal nevus, eyes with choroidal melanoma showed an increased ArtSat and decreased VenSat, leading to an increased AV-difference. These changes may be caused by inflammation and a higher metabolism, with larger oxygen consumption, leading to altered blood flow and intraocular oxygen relocation.
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http://dx.doi.org/10.1097/IAE.0000000000002719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575014PMC
November 2020

Aqueous Humor Biomarkers Identify Three Prognostic Groups in Uveal Melanoma.

Invest Ophthalmol Vis Sci 2019 11;60(14):4740-4747

Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands.

Purpose: To investigate whether we can identify different patterns of inflammation in the aqueous humor of a uveal melanoma (UM)-containing eye, and whether these are related to prognosis.

Methods: Ninety samples of aqueous humor from UM-containing eyes were analyzed using a high-throughput multiplex immunoassay that enables simultaneous analysis of 92 predefined protein biomarkers. Cytokine expression was compared to clinical and histopathological characteristics. Cluster analysis was performed, after which the clusters were compared with clinical and histopathological tumor characteristics.

Results: Cluster analysis revealed three distinct clusters, with one cluster showing hardly any inflammatory cytokines, one showing intermediate levels, and one showing a high expression of inflammation-related biomarkers. Significant differences between the clusters were seen with regard to patient age (P = 0.008), tumor prominence (P = 0.001), ciliary body involvement (P < 0.001), American Joint Committee on Cancer (AJCC) stage (P < 0.001), monosomy of chromosome 3 (P = 0.03), and gain of chromosome 8q (P = 0.04), with the cluster with a highest cytokine expression having the worst prognostic markers. Especially apoptosis-related cytokines were differentially expressed.

Conclusions: Analysis of cytokines in the aqueous humor shows distinct differences between aqueous humor samples and allocates these samples into three different prognostic tumor clusters. Especially large tumors with ciliary body involvement and monosomy 3 were associated with many cytokines, especially apoptosis-related cytokines. The presence of these cytokines in the aqueous humor may play a role in the lack of effective antitumor immune responses.
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http://dx.doi.org/10.1167/iovs.19-28309DOI Listing
November 2019

Secondary Somatic Mutations in G-Protein-Related Pathways and Mutation Signatures in Uveal Melanoma.

Cancers (Basel) 2019 10 30;11(11). Epub 2019 Oct 30.

Tumor Epigenetics; IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy.

Background: Uveal melanoma (UM), a rare cancer of the eye, is characterized by initiating mutations in the genes G-protein subunit alpha Q (), G-protein subunit alpha 11 (), cysteinyl leukotriene receptor 2 (), and phospholipase C beta 4 () and by metastasis-promoting mutations in the genes splicing factor 3B1 (), serine and arginine rich splicing factor 2 (SRSF2), and BRCA1-associated protein 1 (). 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 () 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 and , 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 . 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.
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http://dx.doi.org/10.3390/cancers11111688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896012PMC
October 2019

Uveal melanoma: Towards a molecular understanding.

Prog Retin Eye Res 2020 03 26;75:100800. Epub 2019 Sep 26.

Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands. Electronic address:

Uveal melanoma is an aggressive malignancy that originates from melanocytes in the eye. Even if the primary tumor has been successfully treated with radiation or surgery, up to half of all UM patients will eventually develop metastatic disease. Despite the common origin from neural crest-derived cells, uveal and cutaneous melanoma have few overlapping genetic signatures and uveal melanoma has been shown to have a lower mutational burden. As a consequence, many therapies that have proven effective in cutaneous melanoma -such as immunotherapy- have little or no success in uveal melanoma. Several independent studies have recently identified the underlying genetic aberrancies in uveal melanoma, which allow improved tumor classification and prognostication of metastatic disease. In most cases, activating mutations in the Gα11/Q pathway drive uveal melanoma oncogenesis, whereas mutations in the BAP1, SF3B1 or EIF1AX genes predict progression towards metastasis. Intriguingly, the composition of chromosomal anomalies of chromosome 3, 6 and 8, shown to correlate with an adverse outcome, are distinctive in the BAP1, SF3B1 and EIF1AX uveal melanoma subtypes. Expression profiling and epigenetic studies underline this subdivision in high-, intermediate-, or low-metastatic risk subgroups and suggest a different approach in the future towards prevention and/or treatment based on the specific mutation present in the tumor of the patients. In this review we discuss the current knowledge of the underlying genetic events that lead to uveal melanoma, their implication for the disease course and prognosis, as well as the therapeutic possibilities that arise from targeting these different aberrant pathways.
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http://dx.doi.org/10.1016/j.preteyeres.2019.100800DOI Listing
March 2020

Five-Year Graft Survival and Clinical Outcomes of 500 Consecutive Cases After Descemet Membrane Endothelial Keratoplasty.

Cornea 2020 Mar;39(3):290-297

Netherlands Institute for Innovative Ocular Surgery (NIIOS), Rotterdam, The Netherlands.

Purpose: To report the 5-year graft survival and clinical outcomes after Descemet membrane endothelial keratoplasty (DMEK).

Methods: A retrospective, interventional case series was performed at a tertiary referral center. Five hundred eyes of 393 patients that underwent DMEK for Fuchs endothelial corneal dystrophy, bullous keratopathy, failed previous corneal transplants other than DMEK, or other indications were evaluated for graft survival, best-corrected visual acuity (BCVA), endothelial cell density, postoperative complications, and retransplantation rate.

Results: Kaplan-Meier analysis demonstrated an estimated survival probability of 0.90 [95% confidence interval, 0.87-0.94] for the entire cohort at 5 years after DMEK. At this time point, 82% of the eyes achieved a BCVA of ≥20/25 (0.8), 54% achieved ≥20/20 (1.0), and 16% achieved ≥20/17 (1.2). BCVA continued to improve from 6 to 36 months after DMEK surgery (P ≤ 0.005) and then remained stable up to 60 months postoperatively (P > 0.08). Preoperative donor endothelial cell density averaged 2530 (±210) cells/mm and decreased by 37% at 6 months, 40% at 1 year, and 55% at 5 years after DMEK surgery (P < 0.001 between all follow-up time points). During the study period, allograft rejection episodes developed in 2.8% of the eyes, primary graft failure occurred in 0.2%, and secondary graft failure in 2.8% of the eyes. Re-keratoplasty was required in 8.8% of the eyes.

Conclusions: Five-year graft survival after DMEK is high, and visual acuity outcomes remain excellent and are accompanied by a low longer-term complication rate.
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http://dx.doi.org/10.1097/ICO.0000000000002120DOI Listing
March 2020

Soluble HLA in the Aqueous Humour of Uveal Melanoma Is Associated with Unfavourable Tumour Characteristics.

Cancers (Basel) 2019 Aug 18;11(8). Epub 2019 Aug 18.

Department of Ophthalmology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.

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.
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http://dx.doi.org/10.3390/cancers11081202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721510PMC
August 2019

HLA Expression in Uveal Melanoma: An Indicator of Malignancy and a Modifiable Immunological Target.

Cancers (Basel) 2019 Aug 7;11(8). Epub 2019 Aug 7.

Department of Ophthalmology, Leiden University Medical Center (LUMC), Albinusdreef 2, 2333 ZA Leiden, The Netherlands.

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.
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http://dx.doi.org/10.3390/cancers11081132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721545PMC
August 2019

Do GNAQ and GNA11 Differentially Affect Inflammation and HLA Expression in Uveal Melanoma?

Cancers (Basel) 2019 Aug 7;11(8). Epub 2019 Aug 7.

Department of Ophthalmology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.

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 or differentially affect inflammation and HLA expression, and thereby progression of the disease. We analyzed data of 59 primarily enucleated UM eyes. The type of / 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 mutation with those with a 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 ( = 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 (/) 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.
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http://dx.doi.org/10.3390/cancers11081127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721447PMC
August 2019

Families with BAP1-Tumor Predisposition Syndrome in The Netherlands: Path to Identification and a Proposal for Genetic Screening Guidelines.

Cancers (Basel) 2019 Aug 4;11(8). Epub 2019 Aug 4.

Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.

Germline pathogenic variants in the BRCA1-associated protein-1 () 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 -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 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 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.
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http://dx.doi.org/10.3390/cancers11081114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721807PMC
August 2019

Differential Expression of DNA Repair Genes in Prognostically-Favorable versus Unfavorable Uveal Melanoma.

Cancers (Basel) 2019 Aug 2;11(8). Epub 2019 Aug 2.

Department of Ophthalmology, Leiden University Medical Center, 2333 AZ Leiden, The Netherlands.

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 , , , and genes was significantly associated with clinical outcome after validation. was highly expressed in metastasizing UM ( < 0.001), whereas , , and were lowly expressed ( < 0.001, = 0.006, = 0.003, respectively). Low expression of and was related to a large tumor diameter ( = 0.01 and = 0.004, respectively), and a mixed/epithelioid cell type ( = 0.007 and = 0.03, respectively). We conclude that the expression of , , and is significantly lower in UM with an unfavorable prognosis, while these tumors have a significantly higher expression of . Pharmacological inhibition of DNA-PKcs resulted in decreased survival of UM cells. 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.
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http://dx.doi.org/10.3390/cancers11081104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721581PMC
August 2019

Loss of BAP1 Is Associated with Upregulation of the NFkB Pathway and Increased HLA Class I Expression in Uveal Melanoma.

Cancers (Basel) 2019 Aug 2;11(8). Epub 2019 Aug 2.

Department of Ophthalmology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.

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.
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http://dx.doi.org/10.3390/cancers11081102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721427PMC
August 2019