Novel Methylation Patterns Predict Outcome in Uveal Melanoma.

Sarah Tadhg Ferrier,Julia Valdemarin Burnier

doi:10.3390/life10100248

Sarah Tadhg Ferrier, Julia Valdemarin Burnier

Open Access

https://doi.org/10.3390/life10100248

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Journal: Life	Publication Date: Oct 20, 2020
Citations: 7	License type: CC BY 4.0

Affiliation: McGill University Health Centre, McGill University

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.

Highlights

Uveal melanoma (UM) is the most common primary intraocular tumor in adults and the most common non-skin form of melanoma, with a reported incidence of 5.1 cases per million in the US [1]
Our analysis revealed that the most significant Differentially Methylated Probes (DMPs) were especially enriched for genes involved in signal transduction, including genes associated with pathways in cancer (KEGG pathways) (Figure 5A, Table S1) and in tumor suppressor genes (Figure 5A, Table S2)
Unsupervised clustering analysis of 80 UM cases showed separation of patients into two groups based on methylation changes

Summary

Introduction

Uveal melanoma (UM) is the most common primary intraocular tumor in adults and the most common non-skin form of melanoma, with a reported incidence of 5.1 cases per million in the US [1]. Unlike cutaneous melanoma (CM), UM arises from melanocytes located in the uveal tract, most commonly in the choroid, and displays different genomic mutations and molecular profile than the more common CM [2]. Despite effective methods for treating the primary tumor–either through local radiotherapy or less commonly enucleation [3]—there is currently no effective treatment for metastatic disease, which occurs in approximately 50% of patients regardless of primary ocular treatment [4]. Prognostic factors of UM include features such as cell type, with a poorer prognosis in patients with epithelioid cell tumors and better prognosis for spindle cell tumors as well as tumor size. UM is characterized by a set of chromosomal aberrations and somatic mutations.

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