Abstract
Uveal melanoma (UM) is an aggressive intra-ocular cancer with a strong tendency to metastasize. Metastatic UM is associated with mutations in BAP1 and SF3B1, however only little is known about the epigenetic modifications that arise in metastatic UM. In this study we aim to unravel epigenetic changes contributing to UM metastasis using a new genome-wide methylation analysis technique that covers over 50% of all CpG’s. We identified aberrant methylation contributing to BAP1 and SF3B1-mediated UM metastasis. The methylation data was integrated with expression data and surveyed in matched UM metastases from the liver, skin and bone. UM metastases showed no commonly shared novel epigenetic modifications, implying that epigenetic changes contributing to metastatic spreading and colonization in distant tissues occur early in the development of UM and epigenetic changes that occur after metastasis are mainly patient-specific. Our findings reveal a plethora of epigenetic modifications in metastatic UM and its metastases, which could subsequently result in aberrant repression or activation of many tumor-related genes. This observation points towards additional layers of complexity at the level of gene expression regulation, which may explain the low mutational burden of UM.
Highlights
Uveal melanoma (UM) is an aggressive malignancy that arises from melanocytes located in the uveal tract of the eye
To identify differentially methylated regions (DMRs) in metastatic UM, we performed genome sequencing on LpnP1-digested DNA from 29 primary UM samples
Unique DMRs were identified by comparing the total amount of reads generated per group (i.e. BRCA-associated protein 1 (BAP1) vs EIF1AX/SF3B1, SF3B1 vs EIF1AX/BAP1 EIF1AX vs BAP1/SF3B1 ) at every LpnP1-site
Summary
Uveal melanoma (UM) is an aggressive malignancy that arises from melanocytes located in the uveal tract of the eye. Several studies have focused on identifying aberrant methylation in high metastatic risk, BAP1-mutated UM These studies were performed by using bisulphite conversion of the DNA and subsequently analysed methylation by Sanger sequencing of one specific gene or using an Illumina methylation array c hip[8,9,10,11,12]. More than 50% of the CpG’s in the human genome are covered, whereas most commonly used techniques such as the Illumina methylation array will detect less than 2% of the CpG’s This is the first study to use genome-wide methylation sequencing in metastatic primary UM and its corresponding metastases. We compared the methylation status in primary UM and its metastases in liver, bone or skin, thereby allowing us to identify metastases-specific DMRs
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