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Novel Methylation Patterns Predict Outcome in Uveal Melanoma.

ABSTRACT: 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.

SUBMITTER: Ferrier ST

PROVIDER: S-EPMC7589184 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Novel Methylation Patterns Predict Outcome in Uveal Melanoma.

Ferrier Sarah Tadhg ST Burnier Julia Valdemarin JV

Life (Basel, Switzerland) 20201020 10

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 fr ...[more]

PMID: 33092094

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Project description:BackgroundUveal 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.MethodsUM 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.ResultsA 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.ConclusionsIn 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.

Project description:BackgroundTumor regression of uveal melanomas (UMs) after radiotherapy has been reported as a valuable prognostic factor for metastasis and metastatic death. But its effect on prognosis is questionable. The purpose of this study was to summarize the regression features of uveal melanoma after iodine-125 plaque brachytherapy and the relationship with prognosis.MethodsAdult uveal melanoma patients who only received iodine-125 plaque brachytherapy between December 2009 and March 2018 at the Beijing Tongren Hospital, Capital Medical University were enrolled in this study. The regression rate was calculated as the percent change in tumor height, and each eye was classified for four main regression patterns: Decrease (D), Stable (S), Others (O), and Increase (I), according to the trend of height change. Statistical analysis was performed using one-way ANOVA and chi-square test, univariate and multivariate logistic regression, and Kaplan-Meier analysis.ResultsA total of 139 patients was included in the study. The median follow-up was 35 months. Regression patterns status was pattern D in 65 tumors (46.8%), pattern S in 50 tumors (36.0%), pattern O in 6 tumors (4.3%), and pattern I in 18 tumors (12.9%). Reductions of tumor mean height for each follow-up visit were 5.26% (3 months), 10.66% (6 months), 9.37% (12 months), and 14.68% (18 months). A comparison (D vs. S vs. O vs. I) revealed the preoperative height of pattern I was significantly lower than the pattern D, S and O (mean: 7.24 vs. 7.30 vs. 6.77 vs. 5.09 mm, respectively; P = 0.037). LBD (largest basal diameter) was strongly associated with the metastasis (P = 0.03). However, an association between the tumor regression and subsequent melanoma-related metastasis and mortality could not be confirmed (P = 0.66 and P = 0.27, respectively). The tumor regression rate increased with increasing tumor height (P = 0.04) and decreased with increasing of LBD (P = 0.01).ConclusionOur study showed a lack of association between the prognosis and the regression of uveal melanomas following I-125 plaque radiotherapy. The LBD and original height of the tumor have predictive value in tumor regression rate, and LBD was positively associated with metastasis.

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Novel Methylation Patterns Predict Outcome in Uveal Melanoma.

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Novel Methylation Patterns Predict Outcome in Uveal Melanoma.

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