Estimation of the timing of BAP1 mutation in uveal melanoma progression

Uveal melanoma is the most common primary intraocular malignancy. A vast majority of metastasizing tumors have mutations in the BAP1 gene. Here, we investigate the spatiotemporal timing of these mutations. The size of 177 uveal melanomas and 8.3 million individual tumor cells was measured. BAP1 sequencing results and BAP1 IHC were available and for 76 (43%) and 101 (57%) of these, respectively. Tumors with a BAP1 mutation had significantly larger volume (2109 vs. 1552 mm 3 , p = 0.025). Similarly, tumor cells with loss of BAP1 protein expression had significantly larger volume (2657 vs. 1593 μm 3 , p = 0.027). Using observations of the time elapsed between mitoses, the BAP1 mutation was calculated to occur when the primary tumor had a size of a few malignant cells to 6 mm 3 , 0.5 to 4.6 years after tumor initiation and at least 9 years before diagnosis. We conclude that BAP1 mutations occur early in the growth of uveal melanoma, well before the average tumor is diagnosed. Its timing coincides with the seeding of micrometastases.