Abstract
Purpose :
Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Despite successful local treatment, approximately 50% of these patients develop lethal metastatic disease. BAP1 encodes BRCA1-associated protein 1 which functions as a tumor suppressor. Inactivation by a somatic mutation in BAP1 results in a loss of protein expression, which is associated with increased risk of metastasis. The aim of this study is to analyze the presence of BAP protein expression in primary uveal tumours and their corresponding metastasis in an animal model of UM and to determine whether BAP-1 is lost during the metastatic process.
Methods :
Post-mortem eyes and lungs with metastasis from 9 rabbits previously inoculated with human UM cells expressing BAP1 (92.1 strain) were analyzed. Immunohistochemistry using the Ventana Benchmark Automated Platform was performed on paraffin-embedded samples using a monoclonal BAP1 (C-4) antibody. Slides were digitalized using the Zeiss AxioScan.Z1 Scanner. Expression was evaluated by extent and intensity of staining. Extent was scored as either focal or diffuse and intensity was scored as mild or moderate.
Results :
All primary tumors and metastasis were positive for BAP1. Three rabbits were excluded from our dataset, due to quality control. As per the BAP1 WT status of the 92.1 cells inoculated in the animals, all primary uveal tumours were BAP-1 positive. The staining was diffuse and intense in four rabbits (67%), focal-intense in one rabbit and focal-mild in one rabbit. Conversely, all lung metastasis showed a focal staining, independently of the primary tumour. Five metastasis showed mild staining and only one showed to be more intense than the primary tumour or the normal lung parenchyma. All animals with intense BAP1 staining in the primary tumour showed mild BAP1 in the metastasis.
Conclusions :
To the best of our knowledge, this is the first study to investigate the potential loss of BAP1 in a primary UM tumor and its metastasis using a rabbit animal model. A predominant pattern observed between primary and metastatic lesion shows a transition from moderate into mild intensity and diffuse into focal extent, suggesting a decrease in BAP1 expression. This indicates that a BAP1 mutation occurs after primary tumor formation. Future studies including human tissue of primary UM and their corresponding metastasis should be performed to corroborate these findings.
This is a 2020 ARVO Annual Meeting abstract.