ROLES OF BAP1 IN CANCER AND LIVER DAMAGE RESPONSE

BAP1 is a tumor suppressor gene and deubiquitinase which has been demonstrated to be of particular importance as a genetic risk factor and prognostic biomarker in a subset of cancer types in which it is frequently mutated, such as uveal melanoma. BAP1 is known to play many prominent roles in biological pathways regarded as “hallmarks of cancer,” such as cell cycle and proliferation, DNA damage repair, and apoptosis. BAP1 displays tissue-specific patterns of expression, and thus loss of function may play context-dependent roles. However, due to historical technical and computational limitations, we and others have shown that BAP1 alterations have been underestimated by as much as 40%, leaving substantial room for new analyses and insights into the consequences of BAP1 loss. This motivated our work described in Chapter 2, where we explore BAP1 loss in cancer by using an updated computational approach to enhance alteration detection in multi-omic data from The Cancer Genome Atlas, a repository for 33 cancer types from over 10,000 patient samples. In this work, we developed an expression-based BAP1 activity signature that reflected biological changes driven by BAP1 loss and that can be used to compare samples across cancer types, sequencing platforms, and species. In a focused analysis, we demonstrated that lower BAP1 activity scores were correlated with less-differentiated cell states in liver hepatocellular carcinoma and found evidence that supported a role for BAP1 in regulating transdifferentiation in the liver, which is a process that occurs as a regenerative response to tissue damage.Chapter 3 describes our work with an experimental liver hepatocyte-specific Bap1 knockout mouse model. Our goal was to assess overall changes in cell states, liver cell populations, and gene expression in response to acute liver damage. While Bap1 loss alone did not seem to be sufficient to promote transdifferentiation in the liver during early the damage response, there was evidence to support Bap1 loss instead promoted increased inflammation, development of an immunosuppressive microenvironment, and dysregulation of genes associated with normal liver function. Taken together, our work emphasizes the multifaceted roles of BAP1 both in cancer and tissue damage responses in the liver.