Abstract
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults and leads to deadly metastases for which there is no approved treatment. Genetic events driving early tumor development are well-described, but those occurring later during metastatic progression remain poorly understood. We performed multiregional genomic sequencing on 22 tumors collected from two patients with widely metastatic UM who underwent rapid autopsy. We observed multiple seeding events from the primary tumors, metastasis-to-metastasis seeding, polyclonal seeding, and late driver variants in ATM, KRAS, and other genes previously unreported in UM. These findings reveal previously unrecognized temporal and anatomic complexity in the genetic evolution of metastatic uveal melanoma, and they highlight the distinction between early and late phases of UM genetic evolution with implications for novel therapeutic approaches.
Highlights
Uveal melanoma (UM) is the most common primary cancer of the eye and leads to metastatic death in up to 50% of patients
The primary tumor arises through an initiating mutation in one of several genes in the Gaq/11 signaling pathway (GNAQ, GNA11, PLCB4, or CYSLTR2), followed by a “BSE” progression mutation in BAP1, SF3B1, or EIF1AX, associated with high, intermediate, and low metastatic risk, respectively[1,2,3,4,5,6,7]
A 51-year-old Caucasian man was diagnosed with UM involving the choroid of the left eye and underwent plaque brachytherapy
Summary
UM is the most common primary cancer of the eye and leads to metastatic death in up to 50% of patients. The primary tumor arises through an initiating mutation in one of several genes in the Gaq/11 signaling pathway (GNAQ, GNA11, PLCB4, or CYSLTR2), followed by a “BSE” progression mutation in BAP1, SF3B1 (and rarely other splicing factors), or EIF1AX, associated with high, intermediate, and low metastatic risk, respectively[1,2,3,4,5,6,7]. These canonical mutations arise early in a punctuated burst or selective sweep within the primary tumor and are often accompanied or followed by copy number variations (CNVs) involving chromosomes 1, 3, 6, and 84,7. We performed multiregional genomic sequencing of 22 tumors from two patients with widely metastatic UM involving 10 different organs and tissues using whole-exome sequencing (WES) or whole-genome sequencing (WGS)
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