Early genetic evolution of driver mutations in uveal melanoma.

PubMed ID: 41387680

Author(s): Dollar JJ, Decatur CL, Weis E, Schefler AC, Materin MA, Fuller TS, Skalet AH, Reichstein DA, Kim IK, Piggott KD, Demirci H, Aaberg TA Jr, Mruthyunjaya P, Williams BK Jr, Shildkrot E, Oliver SCN, Char DH, Capone A Jr, Mason JO 3rd, 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. Early genetic evolution of driver mutations in uveal melanoma. Nat Commun. 2025 Dec 12. doi: 10.1038/s41467-025-66428-x. Online ahead of print. PMID 41387680

Journal: Nature Communications, Dec 2025

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.