June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
A Computational Model of BAP-1 Expression in Uveal Melanoma Reveals Early-Onset Mutagenesis
Author Affiliations & Notes
  • Ogul Ersin Uner
    Emory University School of Medicine, Atlanta, Georgia, United States
  • Thonnie Rose O See
    Ophthalmology and Pathology, Emory University School of Medicine, Atlanta, Georgia, United States
  • Eszter Szalai
    Department of Ophthalmology, University of Pécs Medical School, Pécs, Hungary
    Ophthalmology and Pathology, Emory University School of Medicine, Atlanta, Georgia, United States
  • Hans E Grossniklaus
    Ophthalmology and Pathology, Emory University School of Medicine, Atlanta, Georgia, United States
  • Gustav Stålhammar
    St. Erik Eye Hospital, Stockholm, Sweden
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Stockholm, Sweden
  • Footnotes
    Commercial Relationships   Ogul Uner, None; Thonnie See, None; Eszter Szalai, None; Hans Grossniklaus, None; Gustav Stålhammar, None
  • Footnotes
    Support  Alpha Omega Alpha Carolyn L. Kuckein Student Research Fellowship (Boulder, CO)
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 36. doi:
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      Ogul Ersin Uner, Thonnie Rose O See, Eszter Szalai, Hans E Grossniklaus, Gustav Stålhammar; A Computational Model of BAP-1 Expression in Uveal Melanoma Reveals Early-Onset Mutagenesis. Invest. Ophthalmol. Vis. Sci. 2021;62(8):36.

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      © ARVO (1962-2015); The Authors (2016-present)

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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.

 

Proposed model of UM BAP-1 mutagenesis. A) In a tumor’s infancy, G-protein subunit mutations occur. B) BAP-1 mutations follow, coinciding with micrometastases. C) As the primary tumor grows, the BAP-1 mutant has a survival advantage over BAP-1 wild type cells. D) The tumor is eventually composed of BAP-1 mutants only, with few exceptions.

Proposed model of UM BAP-1 mutagenesis. A) In a tumor’s infancy, G-protein subunit mutations occur. B) BAP-1 mutations follow, coinciding with micrometastases. C) As the primary tumor grows, the BAP-1 mutant has a survival advantage over BAP-1 wild type cells. D) The tumor is eventually composed of BAP-1 mutants only, with few exceptions.

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