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UBC Theses and Dissertations

Molecular mechanisms of BAP1 mutations in uveal melanoma Farag, Roula


Uveal melanoma (UM), a cancer that arises in the eye, is distinguished by activating mutations in either GNAQ or GNA11. These mutations are early events in tumor progression and are often followed by loss of function mutations in BAP1. BAP1 is a deubiquitinase protein that regulates the cell cycle, DNA damage response and cellular differentiation. BAP1 mutations are associated with liver metastasis and worse prognosis in UM. To investigate the effect of BAP1 mutations on a transcriptomic level, we analyzed RNA-sequencing data from primary tumors of UM mouse models and patient data from The Cancer Genome Atlas (TCGA). We performed in-depth differential gene expression analysis, Gene Ontology, Gene Set Enrichment Analysis and KEGG pathway analysis to identify significant pathways and biological processes that are affected as a result of BAP1 loss. In addition, we compared findings from mouse and patient data to validate the enriched pathways and determine their biological significance with relation to the BAP1 function. Using a |Log Fold Change| > 1, our differential expression analysis showed a total of 838 differentially expressed genes in the mouse data and 3118 in the TCGA data in primary tumors with or without BAP1 loss. There were more down-regulated than up-regulated genes in the BAP1 mutant samples from both mouse and patient data. However, the majority of significantly enriched pathways involved up-regulated genes. The enriched pathways and biological processes in both mouse and patient data included neuroactive ligand receptor interaction, leukocyte migration, immune response activation and cytokine production. Comparison of orthologous differentially expressed genes showed significant overlap between the mouse and human datasets. This validates that our mouse model recapitulates the effect of BAP1 loss in primary tumors of UM patients. In addition, the G protein coupled receptor, HTR2B, was consistently up-regulated in human and mouse UM. Up-regulation of HTR2B was previously correlated with a worse prognosis in human UM. To study this candidate gene, we performed HTR2B immunohistochemistry staining of mouse UM with or without Bap1 loss. Further investigation of these pathways is required to shed light on the mechanism in which BAP1 mutations leads to worse prognosis in UM.

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