Abstract
The BAP1 (BRCA1-associated protein 1) gene is associated with a variety of human cancers. With its gene product being a nuclear ubiquitin carboxy-terminal hydrolase with deubiquitinase activity, BAP1 acts as a tumor suppressor gene with potential pleiotropic effects in multiple tumor types. Herein, we focused specifically on uveal melanoma (UM) in which BAP1 mutations are associated with a metastasizing phenotype and decreased survival rates. We identified the ubiquitin carboxyl hydrolase (UCH) domain as a major hotspot region for the pathogenic mutations with a high evolutionary action (EA) score. This also includes the mutations at conserved catalytic sites and the ones overlapping with the phosphorylation residues. Computational protein interaction studies revealed that distant BAP1-associated protein complexes (FOXK2, ASXL1, BARD1, BRCA1) could be directly impacted by this mutation paradigm. We also described the conformational transition related to BAP1-BRCA-BARD1 complex, which may pose critical implications for mutations, especially at the docking interfaces of these three proteins. The mutations affect - independent of being somatic or germline - the binding affinity of miRNAs embedded within the BAP1 locus, thereby altering the unique regulatory network. Apart from UM, BAP1 gene expression and survival associations were found to be predictive for the prognosis in several (n = 29) other cancer types. Herein, we suggest that although BAP1 is conceptually a driver gene in UM, it might contribute through its interaction partners and its regulatory miRNA network to various aspects of cancer. Taken together, these findings will pave the way to evaluate BAP1 in a variety of other human cancers with a shared mutational spectrum.
Highlights
BAP1 (BRCA1-associated protein 1) with its gene product acting as a deubiquitinating enzyme, is a critical tumor suppressor gene that is mutated in various human cancers, including metastatic uveal melanoma, pleural mesothelioma, and renal cell carcinoma [1,2,3,4]
We focused on 34 BAP1 specific missense mutations which were previously shown to be associated with uveal melanoma (UM) (Figure 1B)
The analysis showed that the regulatory network associated with BAP1-miRNAs is distinct from the global miRNAs regulatory network associated with UM
Summary
BAP1 (BRCA1-associated protein 1) with its gene product acting as a deubiquitinating enzyme, is a critical tumor suppressor gene that is mutated in various human cancers, including metastatic uveal melanoma, pleural mesothelioma, and renal cell carcinoma [1,2,3,4]. Germline BAP1 mutations define the recently identified BAP1 cancer syndrome with affected patients developing different tumor entities, such as uveal and cutaneous melanoma, malignant mesothelioma, atypical Spitz tumors and others. The D3/M3 status or gene expression panels can be used to determine the risk for metastasis in UM patients. Other genetic alterations, such as deletion/duplication of driver genes (GNAQ, GNA11, EIFAX, SF3B1, and BPA1) act as additional contributors towards the UM specific clinical evaluations [9,10]. We determined the distinctive gene expression spectra of the BAP1 gene in different types of cancer
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