BAP1

Gene Summary

Gene:BAP1; BRCA1 associated protein 1
Aliases: UCHL2, hucep-6, HUCEP-13
Location:3p21.1
Summary:This gene belongs to the ubiquitin C-terminal hydrolase subfamily of deubiquitinating enzymes that are involved in the removal of ubiquitin from proteins. The encoded enzyme binds to the breast cancer type 1 susceptibility protein (BRCA1) via the RING finger domain of the latter and acts as a tumor suppressor. In addition, the enzyme may be involved in regulation of transcription, regulation of cell cycle and growth, response to DNA damage and chromatin dynamics. Germline mutations in this gene may be associated with tumor predisposition syndrome (TPDS), which involves increased risk of cancers including malignant mesothelioma, uveal melanoma and cutaneous melanoma. [provided by RefSeq, May 2013]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:ubiquitin carboxyl-terminal hydrolase BAP1
Source:NCBIAccessed: 01 September, 2019

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: BAP1 (cancer-related)

He M, Chaurushiya MS, Webster JD, et al.
Intrinsic apoptosis shapes the tumor spectrum linked to inactivation of the deubiquitinase BAP1.
Science. 2019; 364(6437):283-285 [PubMed] Related Publications
Malignancies arising from mutation of tumor suppressors have unexplained tissue proclivity. For example,

Huang Y, Wang J, Jia P, et al.
Clonal architectures predict clinical outcome in clear cell renal cell carcinoma.
Nat Commun. 2019; 10(1):1245 [PubMed] Free Access to Full Article Related Publications
The genetic landscape of clear cell renal cell carcinoma (ccRCC) had been investigated extensively but its evolution patterns remained unclear. Here we analyze the clonal architectures of 473 patients from three different populations. We find that the mutational signatures vary substantially across different populations and evolution stages. The evolution patterns of ccRCC have great inter-patient heterogeneities, with del(3p) being regarded as the common earliest event followed by three early departure points: VHL and PBRM1 mutations, del(14q) and other somatic copy number alterations (SCNAs) including amp(7), del(1p) and del(6q). We identify three prognostic subtypes of ccRCC with distinct clonal architectures and immune infiltrates: long-lived patients, enriched with VHL but depleted of BAP1 mutations, have high levels of Th17 and CD8

Shrestha R, Nabavi N, Lin YY, et al.
BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma.
Genome Med. 2019; 11(1):8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Malignant peritoneal mesothelioma (PeM) is a rare and fatal cancer that originates from the peritoneal lining of the abdomen. Standard treatment of PeM is limited to cytoreductive surgery and/or chemotherapy, and no effective targeted therapies for PeM exist. Some immune checkpoint inhibitor studies of mesothelioma have found positivity to be associated with a worse prognosis.
METHODS: To search for novel therapeutic targets for PeM, we performed a comprehensive integrative multi-omics analysis of the genome, transcriptome, and proteome of 19 treatment-naïve PeM, and in particular, we examined BAP1 mutation and copy number status and its relationship to immune checkpoint inhibitor activation.
RESULTS: We found that PeM could be divided into tumors with an inflammatory tumor microenvironment and those without and that this distinction correlated with haploinsufficiency of BAP1. To further investigate the role of BAP1, we used our recently developed cancer driver gene prioritization algorithm, HIT'nDRIVE, and observed that PeM with BAP1 haploinsufficiency form a distinct molecular subtype characterized by distinct gene expression patterns of chromatin remodeling, DNA repair pathways, and immune checkpoint receptor activation. We demonstrate that this subtype is correlated with an inflammatory tumor microenvironment and thus is a candidate for immune checkpoint blockade therapies.
CONCLUSIONS: Our findings reveal BAP1 to be a potential, easily trackable prognostic and predictive biomarker for PeM immunotherapy that refines PeM disease classification. BAP1 stratification may improve drug response rates in ongoing phases I and II clinical trials exploring the use of immune checkpoint blockade therapies in PeM in which BAP1 status is not considered. This integrated molecular characterization provides a comprehensive foundation for improved management of a subset of PeM patients.

Borchert S, Wessolly M, Schmeller J, et al.
Gene expression profiling of homologous recombination repair pathway indicates susceptibility for olaparib treatment in malignant pleural mesothelioma in vitro.
BMC Cancer. 2019; 19(1):108 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Malignant pleural mesothelioma (MPM) is a tumour arising from pleural cavities with poor prognosis. Multimodality treatment with pemetrexed combined with cisplatin shows unsatisfying response-rates of 40%. The reasons for the rather poor efficacy of chemotherapeutic treatment are largely unknown. However, it is conceivable that DNA repair mechanisms lead to an impaired therapy response. We hypothesize a major role of homologous recombination (HR) for genome stability and survival of this tumour. Therefore, we analysed genes compiled under the term "BRCAness". An inhibition of this pathway with olaparib might abrogate this effect and induce apoptosis.
METHODS: We investigated the response of three MPM cell lines and lung fibroblasts serving as a control to treatment with pemetrexed, cisplatin and olaparib. Furthermore, we aimed to find possible correlations between response and gene expression patterns associated with BRCAness phenotype. Therefore, 91 clinical MPM samples were digitally screened for gene expression patterns of HR members.
RESULTS: A BRCAness-dependent increase of apoptosis and senescence during olaparib-based treatment of BRCA-associated-protein 1 (BAP1)-mutated cell lines was observed. The gene expression pattern identified could be found in approx. 10% of patient samples. Against this background, patients could be grouped according to their defects in the HR system. Gene expression levels of Aurora Kinase A (AURKA), RAD50 as well as DNA damage-binding protein 2 (DDB2) could be identified as prognostic markers in MPM.
CONCLUSIONS: Defects in HR compiled under the term BRCAness are a common event in MPM. The present data can lead to a better understanding of the underlaying cellular mechanisms and leave the door wide open for new therapeutic approaches for this severe disease with infaust prognosis. Response to Poly (ADP-ribose)-Polymerase (PARP)-Inhibition could be demonstrated in the BAP1-mutated NCI-H2452 cells, especially when combined with cisplatin. Thus, this combination therapy might be effective for up to 2/3 of patients, promising to enhance patients' clinical management and outcome.

Neviere Z, Berthet P, Polycarpe F, et al.
[Malignant mesothelioma and constitutional BAP1 gene mutations].
Rev Mal Respir. 2019; 36(2):241-248 [PubMed] Related Publications
Malignant mesothelioma is a rare tumour, usually the result of asbestos exposure. Several cases of familial aggregation have been reported and recently shown to be associated with constitutional mutations of the BAP1 gene. BAP1 is a deubiquitinating enzyme implicated in several different cellular mechanisms such as the repair or differentiation of DNA. About a half of malignant mesotheliomas present a somatic, bi-allelic inactivation of BAP1, demonstrated by nuclear extinction on histochemistry. Constitutional alterations of BAP1 are extremely rare. Present in the heterozygous state they are transmitted as an autosomal dominant. They are associated with a risk of developing other tumours such as uveal and cutaneous melanomas, benign melanocytic tumours (melanocytic BAP1-mutated atypical intradermal tumour or MBAITS) and clear cell renal carcinomas. The causal link between mesothelioma and germinal mutations of BAP1 has still not been clearly identified. At present there is, in France, no consensus on recommendations for the management of patients with these mutations. This article is a synthesis of the literature on the functions of the BAP1 gene, the tumour risks related to its alteration and the follow up of patients bearing a constitutional mutation.

Sargen MR, Cloutier JM, Sarin KY, et al.
Biomarker discovery analysis: Alterations in p14, p16, p53, and BAP1 expression in nevi, cutaneous melanoma, and metastatic melanoma.
Pigment Cell Melanoma Res. 2019; 32(3):474-478 [PubMed] Related Publications

Guazzelli A, Meysami P, Bakker E, et al.
Int J Mol Sci. 2019; 20(2) [PubMed] Free Access to Full Article Related Publications
Malignant mesothelioma (MMe) is a cancer with poor prognosis and resistance to standard treatments. Recent reports have highlighted the role of the

Bihr S, Ohashi R, Moore AL, et al.
Expression and Mutation Patterns of PBRM1, BAP1 and SETD2 Mirror Specific Evolutionary Subtypes in Clear Cell Renal Cell Carcinoma.
Neoplasia. 2019; 21(2):247-256 [PubMed] Free Access to Full Article Related Publications
Bi-allelic inactivation of the VHL gene on chromosome 3p is the characteristic feature in most clear cell renal cell carcinomas (ccRCC). Frequent gene alterations were also identified in SETD2, BAP1 and PBRM1, all of which are situated on chromosome 3p and encode histone/chromatin regulators. The relationship between gene mutation, loss of protein expression and the correlations with clinicopathological parameters is important for the understanding of renal cancer progression. We analyzed PBRM1 and BAP1 protein expression as well as the tri-methylation state of H3K36 as a surrogate marker for SETD2 activity in more than 700 RCC samples. In ccRCC loss of nuclear PBRM1 (68%), BAP1 (40%) and H3K36me3 (47%) expression was significantly correlated with each other, advanced tumor stage, poor tumor differentiation (P < .0001 each), and necrosis (P < .005) Targeted next generation sequencing of 83 ccRCC samples demonstrated a significant association of genetic mutations in PBRM1, BAP1, and SETD2 with absence of PBRM1, BAP1, and HEK36me3 protein expression (P < .05, each). By assigning the protein expression patterns to evolutionary subtypes, we revealed similar clinical phenotypes as suggested by TRACERx Renal. Given their important contribution to tumor suppression, we conclude that combined functional inactivation of PBRM1, BAP1, SETD2 and pVHL is critical for ccRCC progression.

Melzer C, Sharma A, Peters S, et al.
Basal cell carcinomas developing independently from BAP1-tumor predisposition syndrome in a patient with bilateral uveal melanoma: Diagnostic challenges to identify patients with BAP1-TPDS.
Genes Chromosomes Cancer. 2019; 58(6):357-364 [PubMed] Related Publications
Basal cell carcinomas (BCC) have been recently included into the spectrum of BAP1-tumor predisposition syndrome (TPDS). Uveal melanoma (UM) is also a tumor often observed in patients with this hereditary tumor syndrome, in particular bilateral UM is highly suspicious for BAP1-TPDS although no patient has been reported yet. Based on our index patient with BAP1-TPDS with bilateral UM (choroid OD, oculus dexter; iris OS, oculus sinister), several BCCs and thyroid cancer as well as a family history for cancer, this paper analyzes hints and pitfalls to diagnose this syndrome clinically and histologically. A previously undescribed germline variant, namely a heterozygous deletion of a single nucleotide on position 2001 (c.2001delG;p.[Thr668Profs*24] in exon 16 of the BAP1 gene), was identified. Structural changes in the C-terminal of the BAP1 protein were observed by in silico analysis. While the excised iris melanoma showed loss of BAP1 nuclear staining by immunohistochemical staining, the BCCs of our patient (and in the control group, n = 13) were BAP1 positive. Genetic analysis of the BCC of the ocular adnexae confirmed a remaining intact BAP1 copy. The constellation of (bilateral) UM in combination with BCC should raise suspicion for a BAP1-TPDS. As our BCCs probably developed independently from the BAP1-TPDS and UMs frequently show loss of nuclear BAP1 staining, genetic analysis is mandatory to diagnose this syndrome.

Rose AM, Luo R, Radia UK, et al.
Detection of mutations in SF3B1, EIF1AX and GNAQ in primary orbital melanoma by candidate gene analysis.
BMC Cancer. 2018; 18(1):1262 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Ocular melanoma is a rare but often deadly malignancy that arises in the uvea (commonest primary site), conjunctiva or the orbit. Primary orbital melanoma (POM) is exceedingly rare, with approximately 60 cases reported to date. Despite recent advances in our understanding of the genetics of primary uveal and conjunctival melanomas, this information is lacking for POM.
METHODS: DNA was extracted from 12 POM tissues, with matched germline DNA (where available). MLPA was conducted to detect chromosomal alterations and Sanger sequencing used to identify point mutations in candidate melanoma driver genes (BRAF, NRAS, KRAS, GNA11, GNAQ), and other genes implicated in melanoma prognosis (EIF1AX, SF3B1). Immunohistochemistry was performed to analyse BAP1 nuclear expression.
RESULTS: MLPA detected copy number alterations in chromosomes 1p, 3, 6 and 8. Sequencing of melanoma driver genes revealed GNAQ (p.Q209L) mutations in two samples; although it is possible that these samples represent extraocular spread of an occult uveal melanoma. A recurrent mutation in SF3B1 (p.R625H) was observed in indolent, but not aggressive, tumours; a mutation in EIF1AX (p.N4S) was detected in one patient with non-aggressive disease.
CONCLUSIONS: EIF1AX and SF3B1 mutations appear have a role in determining the clinical course of POM and detection of these changes could have clinical significance. Further in depth analysis of this rare group using differing 'omic technologies will provide novel insights into tumour pathogenesis.

Bahnasy AA, El-Din RS, Sabri NA, et al.
BAP1 gene mutations in Egyptian patients with advanced sporadic malignant pleural mesothelioma (MPM): relation with clinical outcomes and survival.
Cancer Genet. 2018; 228-229:83-92 [PubMed] Related Publications
BACKGROUND: Malignant Pleural Mesothelioma (MPM) is a lethal cancer with few therapeutic options. Patients with MPM have a poor prognosis, with estimated 1 year median survival and currently no treatment is curative. The BRCA associated protein 1 (BAP1) has the highest prevalence of protein-altering mutations identified in MPM.
AIMS: Assessment of the frequency and pattern of BAP1 gene mutations in Egyptian patients with advanced sporadic MPM in relation to disease progression and survival rates in order to identify a novel therapeutic target for MPM.
METHODS: This prospective, cohort study included 122 patients who were diagnosed and treated as advanced MPM. BAP1 gene mutations were assessed from circulating tumor cells (CTCs) by polymerase chain reaction (PCR) and sequencing and these mutations have been confirmed using the tumor tissue. BAP1 immunohistochemistry was performed using the Dako Envision visualization system. The relationship between BAP1 gene mutations, PFS and OS rates was assessed using the log rank test. The relationship between BAP1 gene mutations, clinical response and patient's clinicopathological characteristics was assessed using chi-square test.
RESULTS: Forty seven (38.5%) MPM cases showed one or more mutations in BAP1 gene. The presence of BAP1 mutations associated significantly with BAP1 protein expression (p < 0.001), the incidence of organ metastasis (p = 0.04), PFS after second line treatment (p = 0.04) and clinical response after second line treatment (p = 0.01) only.
CONCLUSION: BAP1 gene mutations are relatively common in Egyptian patients with advanced sporadic MPM. BAP1 mutations are associated with disease progression especially after second line therapy and the incidence of organ metastasis.

Ewens KG, Lalonde E, Richards-Yutz J, et al.
Comparison of Germline versus Somatic BAP1 Mutations for Risk of Metastasis in Uveal Melanoma.
BMC Cancer. 2018; 18(1):1172 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Germline mutations in BAP1 have been associated with BAP1-Tumor Predisposition Syndrome (BAP1-TPDS), a predisposition to multiple tumors within a family that includes uveal melanoma (UM), cutaneous melanoma, malignant mesothelioma and renal cell carcinoma. Alternatively, somatic mutations in BAP1 in UM have been associated with high risk for metastasis. In this study, we compare the risk of metastasis in UM that carry germline versus somatic BAP1 mutations and mutation-negative tumors.
METHODS: DNA extracted from 142 UM and matched blood samples was sequenced using Sanger or next generation sequencing to identify BAP1 gene mutations.
RESULTS: Eleven of 142 UM (8%) carried germline BAP1 mutations, 43 (30%) had somatic mutations, and 88 (62%) were mutation-negative. All BAP1 mutations identified in blood samples were also present in the matched UM. There were 52 unique mutations in 54 tumors. All were pathogenic or likely pathogenic. A comparison of tumors carrying somatic vs. germline mutations, or no mutations, showed a higher frequency of metastasis in tumors carrying somatic mutations: 74% vs. 36%, P=0.03 and 74% vs. 26% P<0.001, respectively. Tumors with a somatic mutation compared to mutation-negative had an older age of diagnosis of (61.8 vs. 52.2 years, P=0.002), and shorter time to metastasis (16 vs. 26 months, P=0.04). Kaplan-Meier analysis further showed that tumors with somatic (vs. germline) mutations demonstrated a greater metastatic risk (P=0.03). Cox multivariate analysis showed in addition to chromosome-3 monosomy and larger tumor diameter, the presence of BAP1 somatic, but not germline mutations, was significantly associated with risk of metastasis(P=0.02). Personal or family history of BAP1-TPDS was available for 79 of the cases. All eight cases with germline mutations reported a history of BAP1-TPDS, which was significantly greater than what was observed in cases with somatic mutations (10 of 23, P=0.009) or mutation-negative cases (11 of 48, P<0.001).
CONCLUSIONS: Defining germline vs. somatic nature of BAP1 mutations in UM can inform the individual about both the risk of metastasis, and the time to metastasis, which are critically important outcomes for the individual. This information can also change the cascade screening and surveillance of family members.

Kinoshita Y, Hamasaki M, Yoshimura M, et al.
A combination of MTAP and BAP1 immunohistochemistry is effective for distinguishing sarcomatoid mesothelioma from fibrous pleuritis.
Lung Cancer. 2018; 125:198-204 [PubMed] Related Publications
OBJECTIVES: Histologic diagnosis of malignant pleural mesothelioma (MPM) is not always straightforward. Loss of BRCA1-associated protein 1 (BAP1) expression as detected by immunohistochemistry (IHC) (BAP1 IHC) and homozygous deletion (HD) of 9p21 as detected by fluorescencein situ hybridization (FISH) (9p21 FISH) are effective for distinguishing malignant mesothelial proliferation from benign proliferation. We have previously reported that immunohistochemical expression of the protein product of the methylthioadenosine phosphorylase (MTAP) gene, which is localized in the 9p21 chromosomal region, is correlated with the deletion status of 9p21 FISH in MPM tissues. In this study, we investigated whether a combination of MTAP and BAP1 IHC could distinguish sarcomatoid MPM from fibrous pleuritis.
MATERIALS AND METHODS: We examined IHC expressions of MTAP and BAP1 and 9p21 FISH in sarcomatoid/desmoplastic (n = 18) and biphasic MPM (n = 12) and in fibrous pleuritis (n = 17). In biphasic MPM, only sarcomatoid components were evaluated for IHC and FISH. The sensitivity and specificity of each detection assay for discriminating MPM cases from fibrous pleuritis was determined. In addition, we compared the IHC expression of MTAP with the deletion status of 9p21 FISH.
RESULTS: MTAP IHC and BAP1 IHC showed 80% and 36.7% sensitivity, respectively, and both showed 100% specificity in differentiating MPM from fibrous pleuritis. A combination of MTAP and BAP1 IHC yielded greater sensitivity (90%) than that detected for MTAP IHC alone or BAP1 IHC alone. Moreover, a high degree of concordance was observed between the results of MTAP IHC and HD of 9p21 FISH (κ = 0.63).
CONCLUSIONS: With an accurate interpretation of results, combined MTAP and BAP1 IHC is a reliable and effective method for distinguishing sarcomatoid MPM from fibrous pleuritis.

Voss MH, Reising A, Cheng Y, et al.
Genomically annotated risk model for advanced renal-cell carcinoma: a retrospective cohort study.
Lancet Oncol. 2018; 19(12):1688-1698 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: The Memorial Sloan Kettering Cancer Center (MSKCC) risk model is an established prognostic tool for metastatic renal-cell carcinoma that integrates clinical and laboratory data, but is agnostic to tumour genomics. Several mutations, including BAP1 and PBRM1, have prognostic value in renal-cell carcinoma. Using two independent clinical trial datasets of patients with metastatic renal-cell carcinoma, we aimed to study whether the addition of the mutation status for several candidate prognostic genes to the MSKCC model could improve the model's prognostic performance.
METHODS: In this retrospective cohort study, we used available formalin-fixed paraffin-embedded tumour tissue and clinical outcome data from patients with metastatic renal-cell carcinoma assigned to treatment with tyrosine kinase inhibitors in the COMPARZ trial (training cohort; n=357) and RECORD-3 trial (validation cohort; n=258). Eligible patients in both trials were treatment-naive; had histologically confirmed, advanced, or metastatic renal-cell carcinoma; and a Karnofsky performance status score of at least 70. For each cohort, data from patients in all treatment groups (sunitinib and pazopanib in the training cohort, and everolimus and sunitinib in the validation cohort) were pooled for this analysis. In the training cohort, tumour tissue was used to evaluate somatic mutations by next-generation sequencing, and the association between cancer-specific outcomes (overall survival, progression-free survival, and overall response) and the mutation status of six genes of interest (BAP1, PBRM1, TP53, TERT, KDM5C, and SETD2) was tested. Only those genes with prognostic value in this setting were added to the MSKCC risk model to create a genomically annotated version. The validation cohort was used to independently test the prognostic value of the annotated model compared with the original MSKCC risk model.
FINDINGS: 357 (32%) of 1110 patients assigned to protocol treatment in the COMPARZ study between August, 2008, and September, 2011, were evaluable for mutation status and clinical outcomes in the training cohort. The independent validation cohort included 258 (55%) of 471 evaluable patients, enrolled between October, 2009, and June, 2011, on the RECORD-3 study. In the training cohort, the presence of any mutation in BAP1 or TP53, or both, and absence of any mutation in PBRM1 were prognostic in terms of overall survival (TP53
INTERPRETATION: The mutation status of BAP1, PBRM1, and TP53 has independent prognostic value in patients with advanced or metastatic renal-cell carcinoma treated with first-line tyrosine kinase inhibitors. Improved stratification of patients across risk groups by use of a genomically annotated model including the mutational status of these three genes warrants further investigation in prospective trials and could be of use as a model to stratify patients with metastatic renal-cell carcinoma in clinical trials.
FUNDING: Novartis Pharmaceuticals Corporation, MSKCC Support Grant/Core Grant, and the J Randall & Kathleen L MacDonald Research Fund.

Potjer TP, Bollen S, Grimbergen AJEM, et al.
Multigene panel sequencing of established and candidate melanoma susceptibility genes in a large cohort of Dutch non-CDKN2A/CDK4 melanoma families.
Int J Cancer. 2019; 144(10):2453-2464 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Germline mutations in the major melanoma susceptibility gene CDKN2A explain genetic predisposition in only 10-40% of melanoma-prone families. In our study we comprehensively characterized 488 melanoma cases from 451 non-CDKN2A/CDK4 families for mutations in 30 established and candidate melanoma susceptibility genes using a custom-designed targeted gene panel approach. We identified (likely) pathogenic variants in established melanoma susceptibility genes in 18 families (n = 3 BAP1, n = 15 MITF p.E318K; diagnostic yield 4.0%). Among the three identified BAP1-families, there were no reported diagnoses of uveal melanoma or malignant mesothelioma. We additionally identified two potentially deleterious missense variants in the telomere maintenance genes ACD and TERF2IP, but none in the POT1 gene. MC1R risk variants were strongly enriched in our familial melanoma cohort compared to healthy controls (R variants: OR 3.67, 95% CI 2.88-4.68, p <0.001). Several variants of interest were also identified in candidate melanoma susceptibility genes, in particular rare (pathogenic) variants in the albinism gene OCA2 were repeatedly found. We conclude that multigene panel testing for familial melanoma is appropriate considering the additional 4% diagnostic yield in non-CDKN2A/CDK4 families. Our study shows that BAP1 and MITF are important genes to be included in such a diagnostic test.

Yen M, Qi Z, Chen X, et al.
Transposase mapping identifies the genomic targets of BAP1 in uveal melanoma.
BMC Med Genomics. 2018; 11(1):97 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: BAP1 is a histone deubiquitinase that acts as a tumor and metastasis suppressor associated with disease progression in human cancer. We have used the "Calling Card System" of transposase-directed transposon insertion mapping to identify the genomic targets of BAP1 in uveal melanoma (UM). This system was developed to identify the genomic loci visited by transcription factors that bind directly to DNA; our study is the first use of the system with a chromatin-remodeling factor that binds to histones but does not interact directly with DNA.
METHODS: The transposase piggyBac (PBase) was fused to BAP1 and expressed in OCM-1A UM cells. The insertion of transposons near BAP1 binding sites in UM cells were identified by genomic sequencing. We also examined RNA expression in the same OCM-1A UM cells after BAP1 depletion to identify BAP1 binding sites associated with BAP1-responsive genes. Sets of significant genes were analyzed for common pathways, transcription factor binding sites, and ability to identify molecular tumor classes.
RESULTS: We found a strong correlation between multiple calling-card transposon insertions targeted by BAP1-PBase and BAP1-responsive expression of adjacent genes. BAP1-bound genomic loci showed narrow distributions of insertions and were near transcription start sites, consistent with recruitment of BAP1 to these sites by specific DNA-binding proteins. Sequence consensus analysis of BAP1-bound sites showed enrichment of motifs specific for YY1, NRF1 and Ets transcription factors, which have been shown to interact with BAP1 in other cell types. Further, a subset of the BAP1 genomic target genes was able to discriminate aggressive tumors in published gene expression data from primary UM tumors.
CONCLUSIONS: The calling card methodology works equally well for chromatin regulatory factors that do not interact directly with DNA as for transcription factors. This technique has generated a new and expanded list of BAP1 targets in UM that provides important insight into metastasis pathways and identifies novel potential therapeutic targets.

Hirosawa T, Ishida M, Ishii K, et al.
Loss of BAP1 expression is associated with genetic mutation and can predict outcomes in gallbladder cancer.
PLoS One. 2018; 13(11):e0206643 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: BRCA-1 associated protein (BAP1) is a de-ubiquitinating enzyme that regulates gene expression. Recently, the BAP1 mutation and its involvement in cancer survival have been reported in a range of tumor types, including uveal melanoma, mesothelioma, renal cancers, and biliary tract cancers. However, the frequency of BAP1 mutation and down-regulation varies among tumor types, and little is known about the function of BAP1 silencing in cancer cells. Gallbladder carcinoma (GBC) is a type of biliary tract cancer with a poor prognosis. Few mutational studies have investigated the role of BAP1 in GBC, and no functional study in vitro-, or clinical studies about cancer survival have been done.
METHODS: GBC cells were studied by following the small interfering RNA mediated silencing of BAP1 with regard to proliferation, migration, invasion, and drug sensitivity. We carried out genomic, epigenomic and immunohistochemical analyses to detect somatic BAP1 alterations in 47 GBC patients undergoing surgical resection.
RESULTS: BAP1 depletion resulted in increased migration and invasion, but not proliferation, and also resulted in decreased sensitivity to bortezomib, a proteasome inhibitor. Suppressed expression of BAP1 occurred in 22 GBC cases (46.8%) and showed a strong trend toward a worse median survival time of 13.3 months (95% CI, 17.6-62.6) (p = 0.0034). Sanger sequencing revealed a loss-of-function mutation of BAP1 in 11 out of these 22 GBC cases (50%) with low BAP1 expression, whereas 2 out of 25 GBC cases (8%) were detected in cases with high BAP1 expression. Partial changes in methylation were observed in 6 out of 47 cases, but methylation did not show a strong relationship to BAP1 expression or to the prognosis.
CONCLUSION: Our findings showed that genetic mutations are involved in BAP1 down-regulation, leading to promotion of the invasive character of cancer cells and poor prognosis in GBC.

Venur VA, Santagata S, Galanis E, Brastianos PK
New molecular targets in meningiomas: the present and the future.
Curr Opin Neurol. 2018; 31(6):740-746 [PubMed] Related Publications
PURPOSE OF REVIEW: Meningiomas, the most common primary brain tumor, have historically been managed with surgery and radiation. Traditional chemotherapy has not been effective. Fortunately, recent advances in genetic sequencing have led to an improved understanding of the molecular drivers in meningioma. This article aims to discuss the diagnostic and therapeutic implications of recently discovered genetic alterations in meningiomas.
RECENT FINDINGS: Many of the recently discovered genetic alterations correlate with distinct clinical phenotypes. SMO, AKT and PIK3CA mutations are enriched in the anterior skull base. KLF4 mutations are specific for secretory histology, and BAP1 alterations are common in progressive rhabdoid meningiomas. Alterations in TERT, DMD and BAP1 correlate with poor clinical outcomes. Importantly, the discovery of clinically actionable alterations in a number of genes, including SMO, AKT1 and PIK3CA, has opened up novel potential avenues for therapeutic management of meningiomas. Overexpression of PD-L1 in higher grade meningiomas also provides preclinical support for the investigation of checkpoint blockade.
SUMMARY: The discovery of genetic alterations has improved our understanding of the natural history and classification of meningiomas. Clinical trials with several novel agents targeting driver mutations are currently accruing patients and they can lead to better treatment strategies.

Sarcognato S, Gringeri E, Fassan M, et al.
Prognostic role of BAP-1 and PBRM-1 expression in intrahepatic cholangiocarcinoma.
Virchows Arch. 2019; 474(1):29-37 [PubMed] Related Publications
Intrahepatic cholangiocarcinoma (ICC) has universally poor outcome, mainly due to its late clinical presentation. Identification of specific biomarkers and development of effective treatment are still urgently required. Mutations in PBRM-1 and BAP-1 genes, and the expression of S100P have been related to survival in ICC. miR-31 seems also to play important regulatory functions in ICC and it directly regulates BAP-1 expression in lung cancer. In this study, tissue expression of BAP-1, PBRM-1, S100P, and miR-31 was investigated in ICC and correlated with clinical-pathological features. Sixty-one consecutive patients who underwent curative hepatic resection for ICC were enrolled. None received any therapy prior to surgery. Immunostaining for BAP-1, PBRM-1, and S100P, and in situ hybridization for miR-31 were performed, using tissue microarray slides. A strong retained expression of BAP-1 and PBRM-1 was associated with a reduced overall (p = 0.04 and p = 0.002, respectively) and disease-free survival (p = 0.05 and p = 0.02, respectively). An overexpression of S100P was related to a reduced overall survival (p = 0.005). The multivariate analyses identified the presence of perineural invasion and the retained PBRM-1 expression as independent predictors of worse overall [p = 0.02, hazard ratio (HR) = 2.25 (1.16-4.39) and p = 0.001, HR = 3.13 (1.56-6.28), respectively] and disease-free survivals [p = 0.03, HR = 2.43 (1.09-5.4) and p = 0.03, HR = 2.51 (1.11-5.67), respectively]. An overexpression of S100P was predictive of a worse overall survival [p = 0.02, HR = 1.66 (1.08-2.55)]. High levels of miR-31 were significantly associated to a low expression of BAP-1 protein (p = 0.03). In ICC, a retained expression of BAP-1 and PBRM-1, and an overexpression of S100P are related to a poor prognosis.

Konstantinov NK, Berry TM, Elwood HR, Zlotoff BJ
Nevus of Ota associated with a primary uveal melanoma and intracranial melanoma metastasis.
Cutis. 2018; 102(3):E2-E4 [PubMed] Related Publications
Nevus of Ota is a blue, hyperpigmented, benign dermatosis of the skin and mucosae that most often occurs unilaterally in the distribution of the ophthalmic (V1) and maxillary (V2) branches of the trigeminal nerve. Although uncommon, association with malignant melanoma is a complication that must be considered in the evaluation of patients with nevus of Ota. Mutations in the

Liao L, Liu ZZ, Langbein L, et al.
Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer.
Elife. 2018; 7 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Whereas

Betti M, Aspesi A, Ferrante D, et al.
Sensitivity to asbestos is increased in patients with mesothelioma and pathogenic germline variants in BAP1 or other DNA repair genes.
Genes Chromosomes Cancer. 2018; 57(11):573-583 [PubMed] Related Publications
Pathogenic germline variants in the BAP1 tumor suppressor gene can cause a cancer syndrome called BAP1 tumor predisposition syndrome (BAP1-TPDS), which is characterized by predisposition to mesothelioma, melanoma, renal cell carcinoma, basal cell carcinoma, and other tumors. Other genes that may predispose to mesothelioma are CDKN2A and DNA repair genes. Asbestos exposure has often been reported in patients with malignant pleural mesothelioma (MPM) and germline variants in BAP1, but this exposure has never been quantified. We aimed to search for germline variants in BAP1 among 25 new Italian probands with suspected BAP1-TPDS, summarize the prevalence of these variants in 39 Italian patients with familial MPM and other tumors recruited over a 5-year period, and compare cumulative asbestos exposure in 14 patients with MPM and pathogenic germline variants in BAP1, CDKN2A, or DNA repair genes with that of 67 patients without germline variants in 94 cancer-predisposing genes. We report here a new pathogenic germline variant in BAP1: c.783 + 2 T > C. The prevalence of pathogenic germline variants in BAP1 was 7.7% among patients with familial MPM (3/39). Patients with pathogenic germline variants in BAP1, CDKN2A, or DNA repair genes showed lower cumulative asbestos exposure than patients without germline variants in 94 cancer-predisposing genes (P = .00002). This suggests an interaction between genetic risk factors and asbestos in the development of mesothelioma.

Sarun KH, Lee K, Williams M, et al.
Genomic Deletion of
Int J Mol Sci. 2018; 19(10) [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Malignant pleural mesothelioma (MPM) is a deadly cancer that is caused by asbestos exposure and that has limited treatment options. The current standard of MPM diagnosis requires the testing of multiple immunohistochemical (IHC) markers on formalin-fixed paraffin-embedded tissue to differentiate MPM from other lung malignancies. To date, no single biomarker exists for definitive diagnosis of MPM due to the lack of specificity and sensitivity; therefore, there is ongoing research and development in order to identify alternative biomarkers for this purpose. In this study, we utilized primary MPM cell lines and tested the expression of clinically used biomarker panels, including CK8/18, Calretinin, CK 5/6, CD141, HBME-1, WT-1, D2-40, EMA, CEA, TAG72, BG8, CD15, TTF-1, BAP1, and Ber-Ep4. The genomic alteration of

Chen X, Zhou Z, Hannan R, et al.
Reliable gene mutation prediction in clear cell renal cell carcinoma through multi-classifier multi-objective radiogenomics model.
Phys Med Biol. 2018; 63(21):215008 [PubMed] Article available free on PMC after 24/10/2019 Related Publications
Genetic studies have identified associations between gene mutations and clear cell renal cell carcinoma (ccRCC). Since the complete gene mutational landscape cannot be characterized through biopsy and sequencing assays for each patient, non-invasive tools are needed to determine the mutation status for tumors. Radiogenomics may be an attractive alternative tool to identify disease genomics by analyzing amounts of features extracted from medical images. Most current radiogenomics predictive models are built based on a single classifier and trained through a single objective. However, since many classifiers are available, selecting an optimal model is challenging. On the other hand, a single objective may not be a good measure to guide model training. We proposed a new multi-classifier multi-objective (MCMO) radiogenomics predictive model. To obtain more reliable prediction results, similarity-based sensitivity and specificity were defined and considered as the two objective functions simultaneously during training. To take advantage of different classifiers, the evidential reasoning (ER) approach was used for fusing the output of each classifier. Additionally, a new similarity-based multi-objective optimization algorithm (SMO) was developed for training the MCMO to predict ccRCC related gene mutations (VHL, PBRM1 and BAP1) using quantitative CT features. Using the proposed MCMO model, we achieved a predictive area under the receiver operating characteristic curve (AUC) over 0.85 for VHL, PBRM1 and BAP1 genes with balanced sensitivity and specificity. Furthermore, MCMO outperformed all the individual classifiers, and yielded more reliable results than other optimization algorithms and commonly used fusion strategies.

Zhang Y, Shi J, Liu X, et al.
BAP1 links metabolic regulation of ferroptosis to tumour suppression.
Nat Cell Biol. 2018; 20(10):1181-1192 [PubMed] Article available free on PMC after 24/10/2019 Related Publications
The roles and regulatory mechanisms of ferroptosis (a non-apoptotic form of cell death) in cancer remain unclear. The tumour suppressor BRCA1-associated protein 1 (BAP1) encodes a nuclear deubiquitinating enzyme to reduce histone 2A ubiquitination (H2Aub) on chromatin. Here, integrated transcriptomic, epigenomic and cancer genomic analyses link BAP1 to metabolism-related biological processes, and identify cystine transporter SLC7A11 as a key BAP1 target gene in human cancers. Functional studies reveal that BAP1 decreases H2Aub occupancy on the SLC7A11 promoter and represses SLC7A11 expression in a deubiquitinating-dependent manner, and that BAP1 inhibits cystine uptake by repressing SLC7A11 expression, leading to elevated lipid peroxidation and ferroptosis. Furthermore, we show that BAP1 inhibits tumour development partly through SLC7A11 and ferroptosis, and that cancer-associated BAP1 mutants lose their abilities to repress SLC7A11 and to promote ferroptosis. Together, our results uncover a previously unappreciated epigenetic mechanism coupling ferroptosis to tumour suppression.

Webster JD, Pham TH, Wu X, et al.
The tumor suppressor BAP1 cooperates with BRAFV600E to promote tumor formation in cutaneous melanoma.
Pigment Cell Melanoma Res. 2019; 32(2):269-279 [PubMed] Related Publications
The deubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with a high risk of mesothelioma and melanocytic tumors. Here, we show that Bap1 deletion in melanocytes cooperates with the constitutively active, oncogenic form of BRAF (BRAF

Mitchell TJ, Rossi SH, Klatte T, Stewart GD
Genomics and clinical correlates of renal cell carcinoma.
World J Urol. 2018; 36(12):1899-1911 [PubMed] Article available free on PMC after 24/10/2019 Related Publications
PURPOSE: Clear cell, papillary cell, and chromophobe renal cell carcinomas (RCCs) have now been well characterised thanks to large collaborative projects such as The Cancer Genome Atlas (TCGA). Not only has knowledge of the genomic landscape helped inform the development of new drugs, it also promises to fine tune prognostication.
METHODS: A literature review was performed summarising the current knowledge on the genetic basis of RCC.
RESULTS: The Von Hippel-Lindau (VHL) tumour suppressor gene undergoes bi-allelic knockout in the vast majority of clear cell RCCs. The next most prevalent aberrations include a cohort of chromatin-modifying genes with diverse roles including PBRM1, SETD2, BAP1, and KMD5C. The most common non-clear cell renal cancers have also undergone genomic profiling and are characterised by distinct genomic landscapes. Many recurrent mutations have prognostic value and show promise in aiding decisions regarding treatment stratification. Intra-tumour heterogeneity appears to hamper the clinical applicability of sparsely sampled tumours. Ways to abrogate heterogeneity will be required to optimise the genomic classification of tumours.
CONCLUSION: The somatic mutational landscape of the more common renal cancers is well known. Correlation with outcome needs to be more comprehensively furnished, particularly for small renal masses, rarer non-clear cell renal cancers, and for all tumours undergoing targeted therapy.

Asada S, Goyama S, Inoue D, et al.
Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis.
Nat Commun. 2018; 9(1):2733 [PubMed] Article available free on PMC after 24/10/2019 Related Publications
ASXL1 mutations occur frequently in myeloid neoplasms and are associated with poor prognosis. However, the mechanisms by which mutant ASXL1 induces leukaemogenesis remain unclear. In this study, we report mutually reinforcing effects between a C-terminally truncated form of mutant ASXL1 (ASXL1-MT) and BAP1 in promoting myeloid leukaemogenesis. BAP1 expression results in increased monoubiquitination of ASXL1-MT, which in turn increases the catalytic function of BAP1. This hyperactive ASXL1-MT/BAP1 complex promotes aberrant myeloid differentiation of haematopoietic progenitor cells and accelerates RUNX1-ETO-driven leukaemogenesis. Mechanistically, this complex induces upregulation of posterior HOXA genes and IRF8 through removal of H2AK119 ubiquitination. Importantly, BAP1 depletion inhibits posterior HOXA gene expression and leukaemogenicity of ASXL1-MT-expressing myeloid leukemia cells. Furthermore, BAP1 is also required for the growth of MLL-fusion leukemia cells with posterior HOXA gene dysregulation. These data indicate that BAP1, which has long been considered a tumor suppressor, in fact plays tumor-promoting roles in myeloid neoplasms.

Ravanpay AC, Barkley A, White-Dzuro GA, et al.
Giant Pediatric Rhabdoid Meningioma Associated with a Germline BAP1 Pathogenic Variation: A Rare Clinical Case.
World Neurosurg. 2018; 119:402-415 [PubMed] Related Publications
BACKGROUND: Rhabdoid meningiomas are rare World Health Organization grade 3 tumors that tend to follow an aggressive course, with an increased likelihood for local recurrence, remote metastasis, and cerebrospinal fluid dissemination. Genetic testing has found certain genes associated with reduced time to tumor recurrence. BAP1 (BRCA1-associated protein 1) is a tumor suppressor gene that is associated with multiple tumors, including rhabdoid meningiomas.
CASE DESCRIPTION: We present a case of a pediatric patient who presented with a rhabdoid meningioma occurring in the right tentorium and invading multiple venous structures, including the right jugular vein. The patient underwent 5 separate operations for management of this tumor. The first surgery was an intracranial tumor debulking with reconstruction of venous structures. Postoperatively, the patient was unable to have the ventricular catheter removed and underwent placement of a ventriculoperitoneal shunt. Significant recurrence of the intracranial portion of tumor was found during preoperative imaging for her second stage procedure. She underwent a second craniotomy for resection of the tumor. Her postoperative magnetic resonance imaging showed significant residual tumor and the patient therefore underwent a third craniotomy for total tumor resection, which involved reconstruction of the superior sagittal sinus. She did well after this surgery, with no new neurologic deficits. Her final operation involved resection of the residual tumor in the neck and chest by both otolaryngology and cardiothoracic surgery. This surgery involved opening the jugular vein and resecting residual tumor from the intima. Pathologic results from all surgeries were consistent with rhabdoid meningioma; however, the tissue from the biopsy and first craniotomy lacked the high-grade features that were found on subsequent resections. Genetic analysis found loss of both BAP1 tumor suppressor genes. Peripheral blood testing showed that this patient was a germline carrier of a pathogenic BAP1 variant.
DISCUSSION: Pediatric rhabdoid meningiomas represent a rare disease and are found on recurrent tumors in conjunction with lower-grade meningioma disease. Our patient presented with what was initially believed to be a low-grade meningioma with rhabdoid features, which then transformed into a World Health Organization grade III rhabdoid meningioma on recurrence. This tumor was discovered to have a biallelic loss of BAP-1 mutation and the patient was found to have a germline mutation in 1 of her BAP-1 alleles. Germline mutations in BAP-1 are associated with a cancer syndrome that involves uveal and cutaneous melanoma, malignant mesothelioma, atypical Spitz tumors, and clear-cell renal cell carcinoma. Patients with this mutation are encouraged to undergo annual eye examinations starting at the age of 11 years. The BAP-1 tumor predisposition syndrome is most commonly an inherited mutation associated with incomplete penetrance and variation with nonoverlapping tumor types.
CONCLUSIONS: Rhabdoid meningiomas are unlikely to be found in children and have a high rate of local recurrence. Gross total resection has to be balanced with risk of postoperative deficit. Genetic testing of this rare entity should be performed to identify any hereditary germline mutations.

Hylebos M, Op de Beeck K, van den Ende J, et al.
Molecular analysis of an asbestos-exposed Belgian family with a high prevalence of mesothelioma.
Fam Cancer. 2018; 17(4):569-576 [PubMed] Related Publications
Familial clustering of malignant mesothelioma (MM) has been linked to the presence of germline mutations in BAP1. However, families with multiple MM patients, without segregating BAP1 mutation were described, suggesting the existence of other predisposing genetic factors. In this study, we report a previously undescribed Belgian family, in which BAP1 was found to be absent in the epithelial malignant mesothelial cells of the index patient. Whole exome analysis did not reveal a germline or somatic BAP1 variant. Also, no germline or somatic copy number changes in the BAP1 region could be identified. However, germline variants, predicted to be damaging, were detected in 11 other 'Cancer census genes' (i.e. MPL, RBM15, TET2, FAT1, HLA-A, EGFR, KMT2C, BRD3, NOTCH1, RB1 and MYO5A). Of these, the one in RBM15 seems to be the most interesting given its low minor allele frequency and absence in the germline DNA of the index patient's mother. The importance of this 'Cancer census gene' in familial MM clustering needs to be evaluated further. Nevertheless, this study strengthens the suspicion that, next to germline BAP1 alterations, other genetic factors might predispose families to the development of MM.

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