Genome-wide Methylation Patterns in Primary Uveal Melanoma: MethylSig-UM, an Epigenomic Prognostic Signature to Improve Patient Stratification

Despite studies highlighting the prognostic utility of DNA methylation in primary uveal melanoma (pUM), it has not been translated into a clinically-useful tool. We sought to define a methylation signature to identify newly diagnosed individuals at high risk for developing metastasis. Methylation profiling was performed on 41 pUM with at least three years of follow-up using the Illumina Infinium HumanMethylation450K BeadChip (n=24) and the EPIC BeadChip (n= 17). Findings were validated in the TCGA cohort with known metastatic outcome (n=69). Differentially methylated probes were identified in patients who developed metastasis. Unsupervised consensus clustering revealed three epigenomic subtypes associated with metastasis. To identify a prognostic signature, recursive feature elimination and random forest models were utilized within repeated cross-validation iterations. The 250 most commonly selected probes compose the final signature, named MethylSig-UM. MethylSig-UM can distinguish individuals with pUM at diagnosis who developed future metastasis with an area under the curve of ~81% in the independent validation cohort, and remains significant in Cox proportional hazard models when combined with clinical features and established genomic biomarkers. Altered expression of immune modulating genes were detected in MethylSig-UM positive tumors, providing clues for pUM resistance to immunotherapy. The MethylSig-UM model is available to enable additional validation. Methylation profiling was performed on 41 pUM with at least three years of follow-up using the Illumina Infinium HumanMethylation450K BeadChip (n=24) and the EPIC BeadChip (n= 17).