Early genetic evolution of driver mutations in uveal melanoma

Uveal melanoma (UM) is an aggressive eye cancer that frequently results in metastatic death despite successful primary tumor treatment. Subclinical micrometastasis is thought to occur early, when tumors are small and difficult to distinguish from benign nevi. However, the early genetic evolution of UM is poorly understood, and biomarkers for malignant transformation are lacking. Here, we perform integrated genetic profiling of 1140 primary UMs, including 131 small tumors. A clinically available 15-gene expression profile (15-GEP) prospectively validated by our group is more accurate than driver mutations for predicting patient survival. Small tumors are significantly more likely to be in earlier stages of genetic evolution than larger tumors. Further, the 15-GEP support vector machine discriminant score predicts small tumors undergoing transformation from low-risk Class 1 to high-risk Class 2 profile. These results shed light on the early genetic evolution of UM and move us closer to a molecular definition of malignant transformation in this cancer type.

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Publication Details

Journal
Nature Communications
Published
2025-12-12
DOI
https://doi.org/10.1038/s41467-025-66428-x
Primary Topic
Ocular Oncology and Treatments
Type
article
Field-Weighted Citation Impact
0.00

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article

Early genetic evolution of driver mutations in uveal melanoma

Devron H. Char, Cameron G. Javid, Kisha Piggott, Michael M. Altaweel et al.
Nature Communications
Ocular Oncology and Treatments
article

Early genetic evolution of driver mutations in uveal melanoma

Devron H. Char, Cameron G. Javid, Kisha Piggott, Michael M. Altaweel, Scott C. N. Oliver, Timothy S. Fuller, Basil K. Williams, Miguel Angel Materin, Jay S. Duker, Ivana K. Kim, James J. Dollar, Scott D. Walter, Amy C Schefler, Christina L. Decatur, Alison H. Skalet, Prithvi Mruthyunjaya, Thomas Aaberg, Zélia M. Corrêa, Tony Tsai, David Alan Reichstein, Kyle R. Covington, Ezekiel Weis, Hakan Demirci, Dan S. Gombos, Michael Durante, J. William Harbour, Peter G. Hovland, Song Zhang, Antonio Capone, John O. Mason, Jill Razor Wells, Eugene Shildkrot
article en

Abstract

Uveal melanoma (UM) is an aggressive eye cancer that frequently results in metastatic death despite successful primary tumor treatment. Subclinical micrometastasis is thought to occur early, when tumors are small and difficult to distinguish from benign nevi. However, the early genetic evolution of UM is poorly understood, and biomarkers for malignant transformation are lacking. Here, we perform integrated genetic profiling of 1140 primary UMs, including 131 small tumors. A clinically available 15-gene expression profile (15-GEP) prospectively validated by our group is more accurate than driver mutations for predicting patient survival. Small tumors are significantly more likely to be in earlier stages of genetic evolution than larger tumors. Further, the 15-GEP support vector machine discriminant score predicts small tumors undergoing transformation from low-risk Class 1 to high-risk Class 2 profile. These results shed light on the early genetic evolution of UM and move us closer to a molecular definition of malignant transformation in this cancer type.

Nature CommunicationsVol. 16(1)
Grand Rapids Community College (US), Tufts University (US), Massachusetts Eye and Ear Infirmary (US), Tufts Medical Center (US), The University of Texas MD Anderson Cancer Center (US), University of Wisconsin–Madison (US), University of Miami (US), Emory University (US), University of Alberta (CA), University of Hartford (US), Oregon Health & Science University (US), University of Calgary (CA), Duke University (US), University of Michigan (US), University of Alabama at Birmingham (US), California Retina Consultants (US), Retina Consultants of Texas (US), Southwestern Medical Center (US), Associated Retinal Consultants (US), Colorado Retina Center (US), Retina Associates (US), Gerald R. Ford Presidential Foundation (US), Tumori Foundation (US), Sylvester Comprehensive Cancer Center (US), Tennessee Retina (US), Retina Specialists of Michigan (US), Texas Retina Associates (United States) (US), Hartford Financial Services (United States), University of Virginia (US), University of Colorado Anschutz Medical Campus (US), University of Cincinnati (US), The University of Texas Southwestern Medical Center (US), Michigan State University (US), Stanford University (US)
Research to Prevent Blindness, University of Miami, Sylvester Comprehensive Cancer Center, University of Miami Health Systems, Castle Biosciences, National Cancer Institute, National Institute of General Medical Sciences
Openalex Percentile: Top 45%
Ocular Oncology and Treatments
DOIOpen Access PDFOpenAlex
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