2001P - Synergistic role of BAP1 and DNA damage response pathway in uveal melanoma and its prognostic significance

Abstract

BackgroundUveal melanoma is the most common primary cancer of the eye mainly arising from choroid which metastasizes to the liver and frequently leads to death. Till date, there is no current study on the correlation between ATM and BAP1 expression in uveal melanoma. Both proteins trigger DNA damage response (DDR) which leads to DNA repair. Literature reveals that ATM modifies the BAP1for the activation of DNA repair which signifies that there is a connecting link between ATM and BAP1. Therefore, the aim of the study is to detect the co-expression of ATM and BAP1 protein in uveal melanoma patients. MethodsSixty-nine formalin fixed paraffin embedded choroidal melanoma samples were taken to evaluate the expression of ATM and BAP1 by immunohistochemistry and validated by western blotting. To check BAP1 mutation, Sanger sequencing was done on control and UM samples. Results were then correlated with clinical and histopathological parameters. To determine the prognostic significance, Kaplan–Meier analysis and multivariate analysis by Cox’s Proportional Hazards Model was performed. ResultsThere was a male preponderance in our study. Histopathological high-risk factors were identified in 48% cases. Both ATM and BAP1 show loss of nuclear expression in 55% of the cases and this was statistically significant with high pigmentation, LTD >10mm, TIL and cell type (p<0.05). On multivariate analysis, advanced tumour staging and epithelioid cell type are found to be independent prognostic factors. ConclusionsOur data suggest that loss of nATM and nBAP1might serve as a potential prognostic marker in the pathogenesis of uveal melanoma leading to increased risk of metastasis. These findings demonstrate the synergistic role of ATM and BAP1 proteins and may have a therapeutic potential in uveal melanoma. However, further studies are required in a larger cohort of patients with longer follow up and translational validation needs to be performed. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.