Early genetic evolution of driver mutations in uveal melanoma

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

doi:10.1038/s41467-025-66428-x

Early genetic evolution of driver mutations in uveal melanoma

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	11322
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-66428-x
State	Published - Dec 2025

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General
General Physics and Astronomy

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Dollar, J. J., Decatur, C. L., Weis, E., Schefler, A. C., Materin, M. A., Fuller, T. S., Skalet, A. H., Reichstein, D. A., Kim, I. K., Piggott, K. D., Demirci, H., Aaberg, T. A., Mruthyunjaya, P., Williams, B. K., Shildkrot, E., Oliver, S. C. N., Char, D. H., Capone, A., Mason, J. O., ... Harbour, J. W. (2025). Early genetic evolution of driver mutations in uveal melanoma. Nature Communications, 16(1), Article 11322. https://doi.org/10.1038/s41467-025-66428-x

Dollar, JJ, Decatur, CL, Weis, E, Schefler, AC, Materin, MA, Fuller, TS, Skalet, AH, Reichstein, DA, Kim, IK, Piggott, KD, Demirci, H, Aaberg, TA, Mruthyunjaya, P, Williams, BK, Shildkrot, E, Oliver, SCN, Char, DH, Capone, A, Mason, JO, Walter, SD, Altaweel, MM, Wells, JR, Gombos, DS, Duker, JS, Hovland, PG, Tsai, T, Javid, C, Durante, MA, Covington, KR, Zhang, S, Correa, ZM & Harbour, JW 2025, 'Early genetic evolution of driver mutations in uveal melanoma', Nature Communications, vol. 16, no. 1, 11322. https://doi.org/10.1038/s41467-025-66428-x

@article{284282cc0cd2426da6d35cdab47c21fe,

title = "Early genetic evolution of driver mutations in uveal melanoma",

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.",

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

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doi = "10.1038/s41467-025-66428-x",

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AU - Dollar, James J.

AU - Decatur, Christina L.

AU - Weis, Ezekiel

AU - Schefler, Amy C.

AU - Materin, Miguel A.

AU - Fuller, Timothy S.

AU - Skalet, Alison H.

AU - Reichstein, David A.

AU - Kim, Ivana K.

AU - Piggott, Kisha D.

AU - Demirci, Hakan

AU - Aaberg, Thomas A.

AU - Mruthyunjaya, Prithvi

AU - Williams, Basil K.

AU - Shildkrot, Eugene

AU - Oliver, Scott C.N.

AU - Char, Devron H.

AU - Capone, Antonio

AU - Mason, John O.

AU - Walter, Scott D.

AU - Altaweel, Michael M.

AU - Wells, Jill R.

AU - Gombos, Dan S.

AU - Duker, Jay S.

AU - Hovland, Peter G.

AU - Tsai, Tony

AU - Javid, Cameron

AU - Durante, Michael A.

AU - Covington, Kyle R.

AU - Zhang, Song

AU - Correa, Zelia M.

AU - Harbour, J. William

PY - 2025/12

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N2 - 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.

AB - 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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Early genetic evolution of driver mutations in uveal melanoma

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