Mutational Landscape of the BAP1 Locus Reveals an Intrinsic Control to Regulate the miRNA Network and the Binding of Protein Complexes in Uveal Melanoma

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.

The Potential Role of Selected miRNA in Uveal Melanoma Primary Tumors as Early Biomarkers of Disease Progression

“…Sharma et al analyzed the mutational landscape of the BAP1 locus in the context of binding sites for miRNA. They showed that either germline or somatic mutations can affect the mRNA binding region located within the locus, which leads to disruption of the whole regulatory network, not only in uveal melanoma, but also in several other cancers [47]. Several different miRNAs were shown to influence BAP1 function in cervical cancer, renal carcinoma, lung cancer, breast cancer, and others [48][49][50][51].…”

DNA Methylation and Bladder Cancer: Where Genotype does not Predict Phenotype

“…Despite a large number of studies that have addressed the local/global DNA methylation changes in multiple human cancers and other diseases [11,15,16], the key link showing the switch towards the dynamics of DNA hypo-/hypermethylation is still missing. Perhaps, defining the distinct roles of hypo-and hypermethylation within the same individual might help to undermine their potential consequences.…”

Genome organization in proximity to the BAP1 locus appears to play a pivotal role in a variety of cancers

“…Interestingly, inversions in the vicinity of the hotspot region in lower hominoids were also found. Apart from this, some genes were also found to be duplicated during evolution, as previously described . Due to widespread genomic rearrangements within the genome of gibbons, it was cautiously not incorporated into this study.…”

“…This is also evident from the clinical spectrum as BAP1 is the only gene of the hotspot region that is known to be mutated in UM, whereas genes such as BAP1 , PBRM1 , and SETD2 are frequently involved in renal cell carcinoma. Recently, we showed the altered expression of the BAP1 gene in 29 cancer types . In addition, we showed that C‐terminal BAP1 mutations have a stronger intrinsic control to regulate the miRNA network and the binding of subsequent protein complexes.…”