Prognosis Of Uveal Melanoma Research Articles

VEGF-R1/Flt-1 Receptor as a Characteristic of the Angiogenic Phenotype of Uveal Melanoma

Thanks to new fundamental data, our understanding of the angiogenesis’ role and its molecular participants has changed. Molecular genetic mechanisms of activation of signaling pathways of proliferation, malignancy, suppression of the tumor cells’ apoptosis, carried out through the interaction of the VEGF molecule with its receptors, have been deciphered. Molecular genetic mechanisms of activation of signaling pathways of proliferation, malignancy, suppression of apoptosis of tumor cells, carried out through the interaction of the VEGF molecule with its receptors, have been deciphered. The doctrine of angiogenesis has changed. Angiogenesis began to be considered in the aspect of the increasing anaplasia mechanism, accelerating proliferation, the formation of a clone of stem tumor cells, highly resistant to chemotherapy and radiation therapy with a high potential for metastasis. It is time to reconsider the role of individual biological markers of angiogenesis in their suitability in predicting disease outcome and evaluating them as a potential target for targeted therapy. In this aspect, uveal melanoma (UM) as a model of an extremely aggressive malignant tumor using its angiogenic phenotype to accelerate hematogenous metastasis is of particular interest. One of the characteristics of the angiogenic phenotype is VEGF-R1/Flt-1. The purpose: to study the expression of the VEGF-R1/Flt-1 receptor as a characteristic of the angiogenic phenotype of UM in correlation with its clinical and morphological indicators and the outcome of the disease. The authors conducted a retrospective study on 98 archival paraffin blocks of the eyes of patients with UM. The following general patterns of Flt expression in UM cells are revealed: Basic expression takes place in the smallest tumor proliferates UM (T1). Moreover, overexpression (IGH-gradation III) of Flt in the nucleus (39.7 %) and cytoplasm (36.3 %) occurred in every third patient with UM in stage T1. The peak of reception for the maximum average percentage of positive cells and the average cellular IGH gradation of expression was recorded at the T2 stage, after which there was a slow decline to the T4 stage. The number of overexpressive Flt in the nucleus and cytoplasm of UM cells increased x 2 times (75.3 %) to the T2 stage. The peak of Flt nuclear expression in terms of the number of immunopositive cells was also recorded at the T2 stage. The authors concluded that VEGF-R1/Flt-1 expression is a very important characteristic of the UM angiogenic phenotype. In the vast majority of UM, there is an expression of the VEGF-R1/Flt-1 receptor in the nucleus and cytoplasm of tumor cells. The revealed correlations of VEGF-R1/Flt-1 expression with the volume and histological type of tumor, disease stage and metastasis allow them to consider Flt-1 an important indicator associated with the pathogenesis and prognosis of uveal melanoma and a potential target for targeted therapy. A prognostic adverse factor in the aspect of the prognosis of the risk of metastases should be considered the index of the ratio Flt C/Flt N ≥ 3.

Prognostic Biomarkers in Uveal Melanoma: The Status Quo, Recent Advances and Future Directions.

Simple SummaryAlthough rare, uveal melanoma (UM) is the most common cancer that develops inside adult eyes. The prognosis is poor, since 50% of patients will develop lethal metastases in the first decade, especially to the liver. Once metastases are detected, life expectancy is limited, given that the available treatments are mostly unsuccessful. Thus, there is a need to find methods that can accurately predict UM prognosis and also effective therapeutic strategies to treat this cancer. In this manuscript, we initially compile the current knowledge on epidemiological, clinical, pathological and molecular features of UM. Then, we cover the most relevant prognostic factors currently used for the evaluation and follow-up of UM patients. Afterwards, we highlight emerging molecular markers in UM published over the last three years. Finally, we discuss the problems preventing meaningful advances in the treatment and prognostication of UM patients, as well as forecast new roadblocks and paths of UM-related research.Uveal melanoma (UM) is the most common malignant intraocular tumour in the adult population. It is a rare cancer with an incidence of nearly five cases per million inhabitants per year, which develops from the uncontrolled proliferation of melanocytes in the choroid (≈90%), ciliary body (≈6%) or iris (≈4%). Patients initially present either with symptoms like blurred vision or photopsia, or without symptoms, with the tumour being detected in routine eye exams. Over the course of the disease, metastases, which are initially dormant, develop in nearly 50% of patients, preferentially in the liver. Despite decades of intensive research, the only approach proven to mildly control disease spread are early treatments directed to ablate liver metastases, such as surgical excision or chemoembolization. However, most patients have a limited life expectancy once metastases are detected, since there are limited therapeutic approaches for the metastatic disease, including immunotherapy, which unlike in cutaneous melanoma, has been mostly ineffective for UM patients. Therefore, in order to offer the best care possible to these patients, there is an urgent need to find robust models that can accurately predict the prognosis of UM, as well as therapeutic strategies that effectively block and/or limit the spread of the metastatic disease. Here, we initially summarized the current knowledge about UM by compiling the most relevant epidemiological, clinical, pathological and molecular data. Then, we revisited the most important prognostic factors currently used for the evaluation and follow-up of primary UM cases. Afterwards, we addressed emerging prognostic biomarkers in UM, by comprehensively reviewing gene signatures, immunohistochemistry-based markers and proteomic markers resulting from research studies conducted over the past three years. Finally, we discussed the current hurdles in the field and anticipated the future challenges and novel avenues of research in UM.

Identification of heterogeneity and prognostic key genes associated with uveal melanoma using single-cell RNA-sequencing technology.

Uveal melanoma (UM) is the most common intraocular malignancy in adults. The prognosis is poor once metastasis has developed. The treatment of metastatic UM remains challenging nowadays due to lacking a deep understanding of the biological characteristics of this disease. Here, we revealed the cell subpopulations with distinct functional status and the existence of cells with high invasive potential within heterogeneous primary and metastatic UM. The single-cell sequencing data were retrieved from GSE139829 and GSE138433, through which we identified a new cell cluster related to metastatic UM as a unique type of immune cell. The cell-cell communication was conducted by 'Cellchat' to understand the cell crosstalk between these immune cells and their surrounding cells. The crucial signals contributing most to outgoing or incoming signaling of this cell group were identified to reveal the crucial pathway genes. Furthermore, we judged the prognostic value of these candidates on the basis of the data downloaded from The Cancer Genome Atlas. The results demonstrated that the increased IL10, SELPLG, EPHB and ITGB2 signaling pathways could be promising predicting factors for the patient prognosis in UM. Conclusively, we discover the potential key signals of UM for occurrence and metastasis, and also provide a theoretical basis for judging whether there is a high risk of metastasis or recurrence.

Immune classification and identification of prognostic genes for uveal melanoma based on six immune cell signatures

Cutaneous melanoma could be treated by immunotherapy, which only has limited efficacy on uveal melanoma (UM). UM immunotyping for predicting immunotherapeutic responses and guiding immunotherapy should be better understood. This study identified molecular subtypes and key genetic markers associated with immunotherapy through immunosignature analysis. We screened a 6-immune cell signature simultaneously correlated with UM prognosis. Three immune subtypes (IS) were determined based on the 6-immune cell signature. Overall survival (OS) of IS3 was the longest. Significant differences of linear discriminant analysis (LDA) score were detected among the three IS types. IS3 with the highest LDA score showed a low immunosuppression. IS1 with the lowest LDA score was more immunosuppressive. LDA score was significantly negatively correlated with most immune checkpoint-related genes, and could reflect UM patients’ response to anti-PD1 immunotherapy. Weighted correlation network analysis (WGCNA) identified that salmon, purple, yellow modules were related to IS and screened 6 prognostic genes. Patients with high-expressed NME1 and TMEM255A developed poor prognosis, while those with high-expressed BEX5 and ROPN1 had better prognosis. There was no notable difference in OS between patients with high-expressed LRRN1 and ST13 and those with low-expressed LRRN1 and ST13. NME1, TMEM255A, Bex5 and ROPN1 showed potential prognostic significance in UM.

Vasculogenic mimicry correlates to presenting symptoms and mortality in uveal melanoma

PurposeFluid-conducting extracellular matrix patterns known as vasculogenic mimicry (VM) have been associated with poor prognosis in uveal melanoma and other cancers. We investigate the correlations between VM, presenting symptoms, mortality, and the area density of periodic acid-Schiff positive histological patterns (PAS density).MethodsSixty-nine patients that underwent enucleation for uveal melanoma between 2000 and 2007 were included. Clinicopathological parameters presenting symptoms and outcomes were collected. Histological tumor sections were evaluated for VM and PAS density was quantified with digital image analysis.ResultsThirty-four patients (49%) presented with blurred vision. 18 (26%) with a shadow in the visual field, 7 (10%) with photopsia and/or floaters, and 2 (3%) with metamorphopsia. Nine patients (13%) had no symptoms at all. Median follow-up was 16.7 years (SD 2.6). A shadow in the visual field, but no other symptom, was positively correlated with the presence of VM (φ 0.70, p < 0.001) and greater PAS density (p < 0.001). In multivariate regression, retinal detachment (RD), presence of VM, and PAS density ≥ median were independent predictors of a shadow, but not tumor distance to the macula, tumor apical thickness, tumor diameter, or ciliary body engagement. The presence of VM was associated with significantly shorter cumulative disease-specific survival (Wilcoxon p = 0.04), but not PAS density ≥ median, presenting symptoms or RD (p > 0.28).ConclusionTumors from uveal melanoma patients that report a visual field shadow are likely to display VM and greater PAS density, likely explaining the previously reported association between this symptom and poor prognosis.

Identification of molecular subtyping system and four-gene prognostic signature with immune-related genes for uveal melanoma.

Immunotherapy is the most promising treatment for uveal melanoma patients with metastasis. Tumor microenvironment plays an essential role in tumor progression and greatly affects the efficacy of immunotherapy. This research constructed an immune-related subtyping system and discovered immune prognostic genes to further understand the immune mechanism in uveal melanoma. Immune-related genes were determined from literature. Gene expression profiles of uveal melanoma were clustered using consensus clustering based on immune-related genes. Subtypes were further divided by applying immune landscape, and weighted correlation network analysis was performed to construct immune gene modules. Univariate Cox regression analysis was conducted to generate a prognostic model. Enriched immune cells were determined after gene set enrichment analysis. Three major immune subtypes (IS1, IS2, and IS3) were identified, and IS2 could be further divided into IS2A and IS2B. The subtypes were closely associated with uveal melanoma prognosis. IS3 group had the most favorable prognosis and was sensitive to PD-1 inhibitor. Immune genes in IS1 group showed an overall higher expression than IS3 group. Six immune gene modules were identified, and the enrichment score of immune genes varied within immune subtypes. Four immune prognostic genes (IL32, IRF1, SNX20, and VAV1) were found to be closely related to survival. This novel immune subtyping system and immune landscape provide a new understanding of immunotherapy in uveal melanoma. The four prognostic genes can predict prognosis of uveal melanoma patients and contribute to new development of targeted drugs.

Improved Prognostic Precision in Uveal Melanoma through a Combined Score of Clinical Stage and Molecular Prognostication

Introduction: Prognosis of uveal melanoma (UM) is assessed using clinical staging or molecular testing. Two modalities often used for prognostication are the American Joint Committee on Cancer (AJCC) staging and a tumor gene expression profile (GEP), the outcomes of which are often discordant. This article discusses a total risk score created to combine the discordant information from both sources. Methods: A retrospective case series was conducted of all patients presenting with UM over 6 years to 2 referral centers. Each tumor was classified using the AJCC and the GEP. A total risk score was calculated for each patient using results from both AJCC and GEP. Kaplan-Meier analysis of metastasis-free survival was used to compare groups. Results: A total of 294 patients were included in the study. Kaplan-Meier estimates showed significant curve separation between individual AJCC and GEP risk groups. The combined total risk score provided an accurate estimate of prognosis that incorporated results from both AJCC and GEP. Conclusions: Clinical staging and molecular prognostication of UM can be discordant. There is important information provided by each system that is not provided by the other. The total risk score provides a simple method to combine information from both AJCC stage and the GEP class in order to provide patients and care teams with a more complete understanding of metastatic risk.

Prognostic Factor Utility of BAP1 Immunohistochemistry in Uveal Melanoma: A Single Center Study in Spain.

Simple SummaryAs uveal melanoma metastasis rates are still very high, the mechanisms by which it spreads need to be evaluated. Our research sought to determine which pathological and clinical features were correlated with the prognosis of uveal melanoma in a Spanish community. BAP1 (BRCA1-Associated Protein 1) gene mutation is one of the strongest predictors for metastasis in uveal melanoma. The BAP1 protein has a tumor suppressor function and the presence of the BAP1 protein can be shown using immunohistochemical staining. Our study showed that nuclear BAP1 immunostaining had a significant correlation with survival rate in our sample, and patients with a lack of nuclear BAP1 immunostaining should be considered high-risk and receive a close follow-up. This stain can be used as routine technique in the pathological examination of uveal melanoma.Even today, the mortality rate for uveal melanoma (UM) remains very high. In our research, we sought to determine which pathological and clinical features were correlated with the prognosis of UM. BAP1 (BRCA1-Associated Protein 1) gene mutation has been analyzed as one of the strongest predictors for metastasis in UM. The BAP1 gene codifies the BAP1 protein which has a tumor suppressor function. The presence of this protein can be determined by BAP1 immunohistochemical staining. Eighty-four uveal melanoma patients and forty enucleated eyeballs were examined. Metastasis was present in 24 patients. Nuclear BAP1 staining was low in 23 patients. The presence of a higher large basal diameter tumor (p < 0.001), tumor infiltrating lymphocytes (p = 0.020), and a lack of nuclear BAP1 immunostaining (p = 0.001) ocurred significantly more often in the metastatic group. Metastasis-free survival was lower in patients with low nuclear BAP1 staining (p = 0.003). In conclusion, to the best of our knowledge, this is the first time that BAP1 staining has been studied in uveal melanoma in a Spanish community. We believe that this technique should become routine in the pathological examination of uveal melanoma in order to allow adequate classification of patients and to establish an individual follow-up plan.

Primary Sites of Uveal Melanoma Associated with Distinct Survival Outcomes and Clinicopathological Features: A SEER Population-Based Study of 4359 Cases.

ObjectiveWe sought to investigate clinicopathological characteristics correlated with the prognosis of uveal melanoma (UM) patients and find the driving factors of prognosis for ciliary/iris melanoma relative to choroid melanoma.Materials and MethodsWe collected patients with uveal melanoma between 1983 and 2012 from the Surveillance, Epidemiology, and End Results (SEER) database. Primary outcomes were evaluated as cancer-specific survival (CSS) and overall survival (OS). The Kaplan-Meier analysis was applied for the univariate analysis of CSS and OS and corresponding survival curves. Cox proportional hazards regression was used for multivariate analysis to value hazard ratio (HR) of ciliary body/iris melanoma subgroup versus choroid melanoma subgroup.ResultsA total of 4359 eligible patients were collected in our study. Novel potential prognostic factors for CSS and OS of UM were identified. Age at diagnosis, sex, primary tumor site, histologic subtype, tumor size, the extent of disease, and treatment were the independent prognostic factors for UM patients (P < 0.05). Interestingly, when concerned with the primary site of UM, we found that the ciliary body/iris melanoma subgroup showed significant differences in prognosis (both CSS and OS), sex, histologic type, the extent of disease, and treatment options relative to choroid melanoma subgroup (P < 0.05). Subsequently, stratification analyses suggested that the distinct survival outcomes between the ciliary body/iris melanoma and choroid melanoma subgroups mainly attributed to patient sex, age, tumor size, the extent of disease, and treatment options (P < 0.05).ConclusionAge, sex, primary tumor site, histologic subtype, tumor size, the extent of disease, and treatment options are independent prognostic indicators for UM patients. Besides, the ciliary body/iris melanoma subgroup shows worse survival outcomes than choroid melanoma. Our findings offer inspiration to the individual treatment for UM patients with different primary sites.

Analysis of Ferroptosis-Mediated Modification Patterns and Tumor Immune Microenvironment Characterization in Uveal Melanoma.

Uveal melanoma (UVM) is an intraocular malignancy in adults in which approximately 50% of patients develop metastatic disease and have a poor prognosis. The need for immunotherapies has rapidly emerged, and recent research has yielded impressive results. Emerging evidence has implicated ferroptosis as a novel type of cell death that may mediate tumor-infiltrating immune cells to influence anticancer immunity. In this study, we first selected 11 ferroptosis regulators in UVM samples from the training set (TCGA and GSE84976 databases) by Cox analysis. We then divided these molecules into modules A and B based on the STRING database and used consensus clustering analysis to classify genes in both modules. According to the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA), the results revealed that the clusters in module A were remarkably related to immune-related pathways. Next, we applied the ESTIMATE and CIBERSORT algorithms and found that these ferroptosis-related patterns may affect a proportion of TME infiltrating cells, thereby mediating the tumor immune environment. Additionally, to further develop the prognostic signatures based on the immune landscape, we established a six-gene-regulator prognostic model in the training set and successfully verified it in the validation set (GSE44295 and GSE27831). Subsequently, we identified the key molecules, including ABCC1, CHAC1, and GSS, which were associated with poor overall survival, progression-free survival, disease-specific survival, and progression-free interval. We constructed a competing endogenous RNA network to further elucidate the mechanisms, which consisted of 29 lncRNAs, 12 miRNAs, and 25 ferroptosis-related mRNAs. Our findings indicate that the ferroptosis-related genes may be suitable potential biomarkers to provide novel insights into UVM prognosis and decipher the underlying mechanisms in tumor microenvironment characterization.

A Novel Ferroptosis-Associated Gene Signature to Predict Prognosis in Patients with Uveal Melanoma.

Background: Uveal melanoma (UM) is the most common intraocular tumor in adults. Ferroptosis is a newly recognized process of cell death, which is different from other forms of cell death in terms of morphology, biochemistry and genetics, and has played a vital role in cancer biology. The present research aimed to construct a gene signature from ferroptosis-related genes that have the prognostic capacity of UM. Methods: UM patients from The Cancer Genome Atlas (TCGA) were taken as the training cohort, and GSE22138 from Gene Expression Omnibus (GEO) was treated as the validation cohort. A total of 103 ferroptosis-related genes were retrieved from the GeneCards. We performed Kaplan–Meier and univariate Cox analysis for preliminary screening of ferroptosis-related genes with potential prognostic capacity in the training cohort. These genes were then applied into an overall survival-based LASSO Cox regression model, constructing a gene signature. The discovered gene signature was then evaluated via Kaplan–Meier (KM), Cox, and ROC analyses in both cohorts. The Pearson correlation coefficient examined the correlations between risk score and UM common mutations and autophagy. The analyses of GSEA and immune infiltrating were performed to better study the functional annotation of the gene signature and the character of each kind of immune cell in the tumor microenvironment. Results: A seven-gene signature was found from the training cohort and validated in all cohorts by Kaplan–Meier and Cox regression analyses, revealing its independent prognosis value in UM. Moreover, ROC analysis was conducted, confirming the strong predictive ability that this signature had for UM prognosis. A total of 52.24% (256/490) autophagy-related genes were significantly correlated with risk scores. Analyses of GSEA and immune infiltrating detailed exhibited specific pathways associated with the seven-gene signature, also confirming the crucial role that Mast cells resting played in the prognosis of the seven-gene signature. Conclusions: In this study, a novel ferroptosis-related seven-gene signature (ALOX12, CD44, MAP1LC3C, STEAP3, HMOX1, ITGA6, and AIFM2/FSP1) was built. It could accurately predict UM prognosis and was related to Mast cells resting, which provides the potential for personalized outcome prediction and the development of new therapies in the UM population.

Role of somatic mutations and chromosomal aberrations in the prognosis of uveal melanoma in a Spanish patient cohort.

Uveal melanoma (UM) has a high tendency to cause liver metastases. Metastatic disease is fatal, with a low survival rate. There are two large groups of UMs that, according to their risk of metastatic disease, can be divided into risk subgroups based on histopathological, cytogenetic and molecular characteristics. The presence of somatic mutations in certain genes may explain the origin and prognosis of these tumours. Forty-six UM samples previously classified as high or low metastatic risk according to chromosome 3 copy number status were tested for somatic mutations. A multi-gene targeting strategy was adopted, and sequencing was performed using AmpliSeq technology. Mutations were found in all major UM-related genes. BAP1 mutations confer an increased risk of metastases in high-risk tumours; thus, this gene acts as a strong prognostic predictor in UM. The presence of somatic mutations in LZTS1 did not show significant differences in the risk of metastases. This result supports the idea that exploring mutations and copy number variations in UM provides insights into patient outcomes. Genetic tests allow the determination of accurate personalized molecular profiles with a fundamental prognostic purpose.

Construction and validation of a novel prognostic signature for uveal melanoma based on five metabolism-related genes.

Uveal melanoma (UM) is the most aggressive intraocular tumor worldwide. Accurate prognostic models are urgently needed. The present research aimed to construct and validate a prognostic signature is associated with overall survival (OS) for UM patients based on metabolism-related genes (MRGs). MRGs were obtained from molecular signature database (MSigDB). The gene expression profiles and patient clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. In the training datasets, MRGs were analyzed through univariate Cox regression analyses and least absolute shrinkage and selection operator (LASSO) Cox analyses to build a prognostic model. The GSE84976 was treated as the validation cohort. In addition, time-dependent receiver operating characteristic (ROC) and Kaplan-Meier survival curve analyses the reliability of the developed model. Then, gene set enrichment analysis (GSEA) was used for gene enrichment analysis. Nomogram that combined the five-gene signature was used to evaluate the predictive OS value of UM patients. Five MRGs were identified and used to establish the prognostic model for UM patients. The model was successfully validated using the testing cohort. Moreover, ROC analysis demonstrated a strong predictive ability that our prognostic signature had for UM prognosis. Multivariable Cox regression analysis revealed that the risk model was an independent predictor of prognosis. UM patients with a high-risk score showed a higher level of immune checkpoint molecules. We established a novel metabolism-related signature that could predict survival and might be therapeutic targets for the treatment of UM patients.

The Macro-Autophagy-Related Protein Beclin-1 Immunohistochemical Expression Correlates With Tumor Cell Type and Clinical Behavior of Uveal Melanoma.

Uveal melanoma, in spite of its rarity, represents the most common primitive intraocular malignant neoplasm of the adults; it affects choroid, ciliary bodied and iris and remains clinically silent for a long time, being accidentally discovered by routine ophthalmic exams. Prognosis of uveal melanoma is poor and frequently characterized by liver metastases, within 10–15 years from diagnosis. Autophagy is a multi-step catabolic process by which cells remove damaged organelles and proteins and recycle nutrients. It has been hypothesized that in early stages of tumorigenesis autophagy has a tumor suppressor role while, in more advanced stages, it may represent a survival mechanism of neoplastic cells in response to stress. Several proteins related to autophagy cascade have been investigated in numerous subtypes of human cancer, with overall controversal results. In this paper we studied the immunohistochemical expression of 3 autophagy related proteins (Beclin-1, p62 and ATG7) in a cohort of 85 primary uveal melanoma treated by primary enucleation (39 with metastasis and 46 non metastatic) and correlated their expression with clinico-pathological parameters and blood vascular microvessel density, in order to investigate the potential prognostic role of autophagy in this rare neoplasm. We found that high immunohistochemical levels of Beclin-1 correlated with a lower risk of metastasis and higher disease-free survival times, indicating a positive prognostic role for Beclin-1 in uveal melanoma. No statistically significative differences regarding the expression of ATG7 and p62 between metastatic and non metastatic patients was detected.

Prognostic Implications of Novel Ten-Gene Signature in Uveal Melanoma.

Background: Uveal melanoma (UM) is the most common primary intraocular cancer in adults. Genomic studies have provided insights into molecular subgroups and oncogenic drivers of UM that may lead to novel therapeutic strategies.Methods: Dataset TCGA-UVM, download from TCGA portal, were taken as the training cohort, and dataset GSE22138, obtained from GEO database, was set as the validation cohort. In training cohort, Kaplan–Meier analysis and univariate Cox regression model were applied to preliminary screen prognostic genes. Besides, the Cox regression model with LASSO was implemented to build a multi-gene signature, which was then validated in the validation cohorts through Kaplan–Meier, Cox, and ROC analyses. In addition, the correlation between copy number aberrations and risk score was evaluated by Spearman test. GSEA and immune infiltrating analyses were conducted for understanding function annotation and the role of the signature in the tumor microenvironment.Results: A ten-gene signature was built, and it was examined by Kaplan–Meier analysis revealing that significantly overall survival, progression-free survival, and metastasis-free survival difference was seen. The ten-gene signature was further proven to be an independent risk factor compared to other clinic-pathological parameters via the Cox regression analysis. Moreover, the receiver operating characteristic curve (ROC) analysis results demonstrated a better predictive power of the UM prognosis that our signature owned. The ten-gene signature was significantly correlated with copy numbers of chromosome 3, 8q, 6q, and 6p. Furthermore, GSEA and immune infiltrating analyses showed that the signature had close interactions with immune-related pathways and the tumor environment.Conclusions: Identifying the ten-gene signature (SIRT3, HMCES, SLC44A3, TCTN1, STPG1, POMGNT2, RNF208, ANXA2P2, ULBP1, and CA12) could accurately identify patients' prognosis and had close interactions with the immunodominant tumor environment, which may provide UM patients with personalized prognosis prediction and new treatment insights.

Novel Methylation Patterns Predict Outcome in Uveal Melanoma.

Uveal melanoma (UM) is the most common intraocular tumor in adults. Despite effective local treatments, 50% of patients develop metastasis. Better ways to determine prognosis are needed as well as new therapeutic targets. Epigenetic changes are important events driving cancer progression; however, few studies exist on methylation changes in UM. Our aim was to identify methylation events associated with UM prognosis. Matched clinical, genetic, and methylation data for 80 UM cases were obtained from The Cancer Genome Atlas (TCGA). Top differentially methylated loci were sorted through hierarchical clustering based on methylation patterns, and these patterns were compared to tumor characteristics, genomic aberrations, and patient outcome. Hierarchical clustering revealed two distinct groups. These classifications effectively separated high and low-risk cases, with significant differences between groups in patient survival (p < 0.0001) and correlation with known prognostic factors. Major differences in methylation of specific genes, notably NFIA, HDAC4, and IL12RB2, were also seen. The methylation patterns identified in this study indicate potential novel prognostic indicators of UM and highlight the power of methylation changes in predicting outcome. The methylation events enriched in the high-risk group suggest that epigenetic modulating drugs may be useful in reducing metastatic potential, and that specific differentially methylated loci could act as biomarkers of therapeutic response.

Molecular Insights and Emerging Strategies for Treatment of Metastatic Uveal Melanoma.

Simple SummaryAround 50% of patients with uveal melanoma (UM) still develop metastatic disease. Despite recent advances in the diagnosis and prognosis of UM, improvements in overall survival have not been achieved. At present, there is no available standard of care for adjuvant and metastatic settings. The aim of our review article was to discuss the latest advances in understanding the molecular mechanisms underlying uveal melanoma and novel treatment options for metastatic disease. We provided a detailed analysis of the most recently published works in the Literature along with a number of ongoing clinical trials for adjuvant and metastatic treatment of uveal melanoma. New insights into the pathogenesis of UM and promising results from the study of innovative tailored therapies could offer viable opportunities for translating in clinical practice.Uveal melanoma (UM) is the most common intraocular cancer. In recent decades, major advances have been achieved in the diagnosis and prognosis of UM allowing for tailored treatments. However, nearly 50% of patients still develop metastatic disease with survival rates of less than 1 year. There is currently no standard of adjuvant and metastatic treatment in UM, and available therapies are ineffective resulting from cutaneous melanoma protocols. Advances and novel treatment options including liver-directed therapies, immunotherapy, and targeted-therapy have been investigated in UM-dedicated clinical trials on single compounds or combinational therapies, with promising results. Therapies aimed at prolonging or targeting metastatic tumor dormancy provided encouraging results in other cancers, and need to be explored in UM. In this review, the latest progress in the diagnosis, prognosis, and treatment of UM in adjuvant and metastatic settings are discussed. In addition, novel insights into tumor genetics, biology and immunology, and the mechanisms underlying metastatic dormancy are discussed. As evident from the numerous studies discussed in this review, the increasing knowledge of this disease and the promising results from testing of novel individualized therapies could offer future perspectives for translating in clinical use.

LncRNA SNHG15 predicts poor prognosis in uveal melanoma and its potential pathways.

To evaluate the role of long noncoding RNA (lncRNA) SNHG15 and its potential pathways in uveal melanoma (UM). The SNHG15 mRNA expression level and corresponding clinicopathological characteristics of 80 patients with UM were obtained from the Cancer Genome Atlas (TCGA) database and further analyzed. The SPSS 24.0 statistical software package was used for statistical analyses. To investigate the potential function of SNHG15 in UM, we conducted in-depth research on Gene Set Enrichment Analysis (GSEA). The univariate analysis revealed that the age, tumor diameter, pathological type, extrascleral extension, cancer status, and high expression of SNHG15 were statistical risk factors for death from all causes. The multivariate analysis suggested that the mRNA expression level of SNHG15 was an independent risk factor for death from all causes, as was age and pathological type. Kaplan-Meier survival analysis confirmed that UM patients with high SNHG15 expression might have a poor prognosis. In addition, SNHG15 was significantly differentially expressed in the different groups of tumor pathologic stage, metastasis and living status. Besides, the logistic regression analysis indicated that high SNHG15 expression group in UM was significantly associated with cancer status, pathologic stage, metastasis, and living status. Moreover, the GSEA indicated the potential pathways regulated by SNHG15 in UM. Our research suggests that SNHG15 may play a vital role as a potential marker in UM that predicts poor prognosis. Besides, GSEA indicates the underlying signaling pathways enriched differentially in SNHG15 high expression phenotype.

Bioinformatic Analysis of Differentially Expressed Genes and Screening of Hub Genes in Uveal Melanoma Cells with BRCA1-Associated Protein 1 Related Protein 1 Depletion.

Recent studies have found that chromosome 3 is frequently mutated in metastatic uveal melanoma (UVM), which leads to the loss of BAP1 expression or the weakening of BRCA1-associated protein 1 (BAP1) function and promotes metastasis of uveal melanoma cells. However, the specific signaling pathways that are affected by BAP1 depletion in uveal melanoma remain unclear. Our aim in this study was to verify the effect and regulatory mechanism of BAP1 on uveal melanoma. RT-qPCR and western blotting results showed that BAP1 was significantly down-regulated in OCM-1A cells treated with a BAP1 shRNA vector. MTT, cell scratch and transwell migration assays showed that low expression of BAP1 significantly promoted the proliferation and migration of UVM cells. A total of 269 up-regulated and 807 down-regulated genes were identified from the combined GSE110193 and GSE48863 data sets. These differentially expressed genes are mainly involved in the composition of extracellular matrix and the regulation of the Wnt signaling pathway and are closely related to the cell adhesion pathway. CXCL8, COL5A3, COL11A1, and COL12A1 were among the differentially expressed genes and are closely related to the prognosis of UVM. Therefore, the deletion of BAP1 is closely related to poor prognosis of UVM and is a risk factor for UVM metastasis. The potential targets of BAP1 include CXCL8, COL5A3, COL11A1, and COL12A1. It is believed that BAP1 regulates UVM cell adhesion through these four genes and ultimately regulates tumor development and migration.

Identification of differentially expressed metastatic genes and their signatures to predict the overall survival of uveal melanoma patients by bioinformatics analysis.

To identify metastatic genes and miRNAs and to investigate the metastatic mechanism of uveal melanoma (UVM). GSE27831, GSE39717, and GSE73652 gene expression profiles were downloaded from the Gene Expression Omnibus (GEO) database, and the limma R package was used to identify differentially expressed genes (DEGs). Gene Ontology (GO) term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed using the DAVID online tool. A comprehensive list of interacting DEGs was constructed using the Search Tool for the Retrieval of Interacting Genes (STRING) database and Cytoscape software. The Cytoscape MCODE plug-in was used to identify clustered sub-networks and modules of hub genes from the protein-protein interaction network. GEPIA online software was used for survival analysis of UVM patients (n=80) from the The Cancer Genome Atlas (TCGA) cohort. OncomiR online software was used to find that the miRNAs were associated with UVM prognosis from the TCGA cohort. TargetScan Human 7.2 software was then used to identify the miRNAs targeting the genes. There were 1600 up-regulated genes and 1399 down-regulated genes. The up-regulated genes were mainly involved in protein translation in the cytosol, whereas the down-regulated genes were correlated with extracellular matrix organization and cell adhesion in the extracellular space. Among the 2999 DEGs, five genes, Znf391, Mrps11, Htra3, Sulf2, and Smarcd3 were potential predictors of UVM prognosis. Otherwise, three miRNAs, hsa-miR-509-3-5p, hsa-miR-513a-5p, and hsa-miR-1269a were associated with UVM prognosis. After analyzing the metastasis-related enriched terms and signaling pathways, the up-regulated DEGs are mainly involved in protein synthesis and cell proliferation by ribosome and mitogen-activated protein kinase (MAPK) pathways. However, the down-regulated DEGs are mainly involved in processes that reduced cell-cell adhesion and promoted cell migration in the extracellular matrix through PI3K-Akt signaling pathway, focal adhesion, and extracellular matrix-receptor interactions. Bioinformatics and interaction analysis may provide new insights on the events leading up to the development and progression of UVM.