Author:
Uner Ogul E.,See Thonnie Rose O.,Szalai Eszter,Grossniklaus Hans E.,Stålhammar Gustav
Abstract
AbstractUveal 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 mm3, p = 0.025). Similarly, tumor cells with loss of BAP1 protein expression had significantly larger volume (2657 vs. 1593 μm3, 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 mm3, 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.
Funder
The Alpha Omega Alpha Carolyn L. Kuckein Student Research Fellowship
Emory Eye Center Trainee Pilot Grant
Unrestricted departmental grant to the Emory Eye Center from Research to Prevent Blindness
National Institutes of Health, National Eye Institute
The Royal Swedish Academy of Sciences
The Swedish Cancer Society
The Swedish Society of Medicine
The Swedish Eye Foundation
Karolinska Institutet
Region Stockholm
Stiftelsen Kronprinsessan Margaretas Arbetsnämnd för Synskadade
Carmen and Bertil Regnér Foundation
Karolinska Institute
Publisher
Springer Science and Business Media LLC