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<p>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.</p>

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Early genetic evolution of driver mutations in uveal melanoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月12日

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  • 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 Jr.,
  • Prithvi Mruthyunjaya,
  • Basil K. Williams Jr.,
  • Eugene Shildkrot,
  • Scott C. N. Oliver,
  • Devron H. Char,
  • Antonio Capone Jr.,
  • John O. Mason III,
  • 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

摘要

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.