Abstract
Purpose :
Uveal melanoma (UM) is the most common primary intraocular malignancy. Mutations in BRCA1 associated protein-1 (BAP-1) is correlated with increased metastatic risk and has been assumed to occur late in tumor progression, though the latter has not been well-studied (Fig. 1). We investigated the spatial and temporal characteristics of UM BAP-1 mutagenesis using mathematical modeling.
Methods :
Enucleated eyes with UM were obtained from Emory Eye Center (USA) and St. Erik Eye Hospital (Sweden). After BAP-1 immunohistochemistry, digital image analysis was used to measure each tumor cell size and grade BAP-1 immunoreactivity. Tumor size and DNA sequencing data from The Cancer Genome Atlas were added. A computational model of the proportion of BAP-1 mutant cells as a function of total tumor size was created in SPSS-26, with the ANOVA F-test used for curve fitting.
Results :
A total of 156 tumors were included and 8.3 million tumor cells were measured. Tumors with a BAP-1 mutation had significantly larger mean volume than those without (2109 vs. 1552 mm3, p=0.03). Similarly, tumor cells with loss of BAP-1 expression had significantly larger mean volume than those with retained expression (801 vs. 524 μm3, p=0.04). The growth of the BAP-1 mutated clone was best fitted to a logarithmic curve (F-score 7, p=0.01), with the proportion of mutants to total number of cells described as −73.6+18.2×ln(tumor volume in mm3). The mutation occurred within a UM’s second mitosis at a tumor age of 0.8 to 2.8 years and volume of <1 to 37 mm3, depending on the UM doubling time used in the calculation. The largest volume corresponds to a lesion with 2 mm in thickness and 6 mm in diameter.
Conclusions :
The BAP-1 mutation occurs within 2 tumor doublings, explaining early seeding of liver micrometastases. BAP-1 mutant cells are larger in size and the mutagenesis follows a logarithmic function, a variant of the Gompertzian tumor growth model. Our findings challenge the notion that the critical mutation occurs late in UM and underscores the importance of conducting BAP-1 testing at UM diagnosis.
This is a 2021 ARVO Annual Meeting abstract.