Abstract
Uveal melanoma (UM) is an aggressive cancer of the eye that frequently
results in metastatic death. UMs are most likely to metastasize when they
are small, at a time when they are difficult to distinguish from benign
nevi and often observed without treatment. Unfortunately, little is known
about the early genetic evolution of UM or potential biomarkers to
indicate small tumors undergoing malignant transformation. Here, we
performed targeted next generation sequencing for the 7 canonical UM
driver mutations in 1140 primary UMs, including 131 small early-stage
tumors. We found that the evolutionary burst of genetic aberrations that
determines the archetypal UM subtypes and metastatic propensity has
already occurred by the time most small tumors are biopsied, although a
significantly larger proportion of small tumors are still evolving
compared to larger tumors. We found that the 15-gene expression profile
(15-GEP) support vector machine discriminant score was the best indicator
of tumors in transition from low-risk Class 1 to high-risk Class 2
signature. While BAP1, SF3B1, and EIF1AX mutations were associated with
poor, intermediate, and good prognosis, respectively, mutation analysis
was inferior to the prospectively validated 15-GEP + PRAME expression
classifier for predicting metastasis-free and overall survival. These
results provide a more complete picture of genetic evolution in UM, and
they move us closer to a molecular definition of malignant transformation
in this cancer type.