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

Authors

Emilie Lalonde
Dong Li
Kathryn Ewens
Carol L. Shields, Thomas Jefferson UniversityFollow
Arupa Ganguly

Document Type

Article

Publication Date

7-25-2024

Comments

This article is the author's final published version in Cancers, Volume 16, Issue 15, August 2024, Article number 2650.

The published version is available at https://doi.org/10.3390/cancers16152650.

Copyright © 2024 by the authors

Abstract

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 patients with pUM with stage T2-T4 and 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 comprised the final signature, named MethylSig-UM. MethylSig-UM could distinguish individuals with pUM at diagnosis who develop future metastasis with an area under the curve of ~81% in the independent validation cohort, and remained 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 in larger cohort sizes including T1 tumors.

Recommended Citation

Lalonde, Emilie; Li, Dong; Ewens, Kathryn; Shields, Carol L.; and Ganguly, Arupa, "Genome-Wide Methylation Patterns in Primary Uveal Melanoma: Development of MethylSig-UM, an Epigenomic Prognostic Signature to Improve Patient Stratification" (2024). Wills Eye Hospital Papers. Paper 226.
https://jdc.jefferson.edu/willsfp/226

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

39123378

Language

English