Spectrum of clinical phenotype of the BAP1-tumor predisposition syndrome (BAP1-TPDS)

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ABSTRACT Germline mutation in the tumor suppressor gene BAP1 is associated with the hereditary tumor predisposition syndrome, BAP1-TPDS (OMIM 614327), that we and others identified in 2011. The syndrome is associated with predisposition to mainly four cancers: uveal melanoma, mesothelioma, cutaneous melanoma, and renal cell carcinoma in addition to a preneoplastic melanocytic skin lesions (BAP1-Inactivated Melanocytic Tumors). Other cancers have been also reported in patients with germline BAP1 mutation but it is not clear whether they are part of the BAP1-TPDS. Since its characterization, more than 200 distinct families have been reported with an increasing number of pathogenic/likely pathogenic variants being deposited in ClinVar. Our our analysis of variants in the Exome Aggregation Consortium (ExAC) database suggests that BAP1-TPDS is underreported in cancer patients. BAP1 is a deubiquitinating hydrolase that has four known functions: (i) cell cycle regulation and cell growth, (ii) DNA damage repair, (iii) chromatin remodelling and regulation of gene expression, and (iv) regulation of apoptosis. Which of these complex functional roles are responsible for its tumor suppressor function is unknown, and needs to be determined to enable identification of the best experimental model system(s) to predict the clinical significance of the variants of uncertain significance. Our goal is to characterize the clinical phenotypes associated with different germline variants of BAP1 in order to dissect its complex functions. We will address the following critical barriers: 1) the limited number of reported germline variants in BAP1 with known clinical phenotype; 2) the need for experimental model system(s) to assess the clinical impact of different coding variants in BAP1; and 3) the need to assess the contribution of non-coding variants in germline inactivation of BAP1. Specific Aim1: To expand the understanding of the clinical phenotypes of BAP1-TPDS and correlate with variants in the gene. Specific Aim2: Establish experimental model systems for evaluation of BAP1 germline missense variants of uncertain significance. Specific Aim3: To assess the contribution of non-coding variants in germline inactivation of BAP1. Scientific and Translational Impact: The outcomes of these studies have the potential to provide clinicians with crucial resources needed to address a major barrier for proper counseling and management of patients and families with germline mutations in BAP1. The results will also provide basic scientists with important resources for further studies of various tumor suppressor functions of BAP1, as well as crucial resources for the NCI ClinGen and ClinVar projects.