BAP1 deficiency causes loss of melanocytic cell identity in uveal melanoma

Matatall, Katie A.; Agapova, Olga A.; Onken, Michael D.; Worley, Lori A.; Bowcock, Anne M.; Harbour, J. William

doi:10.1186/1471-2407-13-371

Cited by 134 publications

(135 citation statements)

References 34 publications

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“…Recent work of Matatall and associates 31 demonstrated that BAP1 depletion induces a primitive, stem-like phenotype and these findings implicate BAP1 in the maintenance of melanocyte identity in uveal melanoma cells. Therapeutic strategies that target these specific pathways in uveal melanoma are urgently needed.…”

Section: Discussionmentioning

confidence: 88%

Clinical significance of immunohistochemistry for detection of BAP1 mutations in uveal melanoma

et al. 2014

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Uveal melanoma is a lethal cancer with a strong propensity to metastasize. Limited therapeutic options are available once the disease has disseminated. A strong predictor for metastasis is the loss of chromosome 3. Inactivating mutations in BAP1 encoding the BRCA1-associated protein 1 and located on chromosome 3p21.1, have been described in uveal melanoma and other types of cancer. In this study, we determined the prevalence of somatic BAP1 mutations and examined whether these mutations correlate with the functional expression of BAP1 in uveal melanoma tissue and with other clinical, histopathological and chromosomal parameters. We screened a cohort of 74 uveal melanomas for BAP1 mutations, using different deep sequencing methods. The frequency of BAP1 mutations in our study group was 47%. The expression of BAP1 protein was studied using immunohistochemistry. BAP1 staining was absent in 43% of the cases. BAP1 mutation status was strongly associated with BAP1 protein expression (Po0.001), loss of chromosome 3 (Po0.001), and other aggressive prognostic factors. Patients with a BAP1 mutation and absent BAP1 expression had an almost eightfold higher chance of developing metastases compared with those without these changes (P ¼ 0.002). We found a strong correlation between the immunohistochemical and sequencing data and therefore propose that, immunohistochemical screening for BAP1 should become routine in the histopathological work-up of uveal melanoma. Furthermore, our analysis indicates that loss of BAP1 may be particularly involved in the progression of uveal melanoma to an aggressive, metastatic phenotype.

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Section: Discussionmentioning

confidence: 88%

Clinical significance of immunohistochemistry for detection of BAP1 mutations in uveal melanoma

et al. 2014

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“…In fact, a study in human cells has shown that BAP1 activates YY1-regulated genes in a DUB-dependent manner (22). In addition, genome-wide gene expression analyses showed that many genes are up-or down-regulated by BAP1 knockdown or knockout, indicating that BAP1 can be a corepressor or coactivator (13,22,23 are needed to understand which genes are regulated by BAP1, how BAP1 is recruited to the target genes, and how BAP1 controls gene expression. In particular, assessing the role of DUB activity and the requirement of the interactions with coregulators such as HCF-1 are necessary to figure out the complex mechanism of gene regulation by BAP1.…”

mentioning

confidence: 99%

BRCA1-associated Protein 1 (BAP1) Deubiquitinase Antagonizes the Ubiquitin-mediated Activation of FoxK2 Target Genes

Okino¹,

Machida²,

Frankland-Searby

et al. 2015

Journal of Biological Chemistry

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Background:The mechanism of gene regulation by the H2A deubiquitinase BAP1 is unclear. Results: BAP1 loss increases FoxK2 target gene expression but not in the absence of the H2A ubiquitin ligase complex Ring1B-Bmi1. Conclusion: BAP1 counteracts Ring1B-Bmi1-dependent activation of FoxK2 target genes. Significance: BAP1 deficiency in cancer cells might cause up-regulation of target genes in a Ring1B-Bmi1-dependent manner.

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“…In uveal melanoma, depletion of BAP1 seems to result in a loss of differentiation and gain of stem-like properties, without altering proliferation [15]. More recently, BAP1 mutations were also described in spitzoid-looking cutaneous melanocytic tumors, which are also called melanocytic BAP1-associated intradermal tumors (MBAIT).…”

Section: Discussionmentioning

confidence: 99%

NRAS-mutated melanocytic BAP1-associated intradermal tumor (MBAIT): a case report

et al. 2014

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Melanocytic BAP1-associated intradermal tumors (MBAITs) are epithelioid spitzoid looking, mostly intradermally located melanocytic tumors that often have tumor-infiltrating lymphocytes and a common nevus component. They occur sporadically but also in the context of an underlying BAP1 germline mutation. Recognition of these lesions is important because they can be a marker for an underlying BAP1-associated cancer syndrome. Most cases reported in the literature thus far were found to have both a BRAF and BAP1 mutation. Here, we report an unusual case of an MBAIT lesion with a combined NRAS and BAP1 mutation. A BAP1 germline mutation was excluded. Our case is the second case reported until now with this combination of mutations in this subset of lesions. In the other reported NRAS-/BAP1-mutated MBAIT case, presence of a BAP1 germline mutation was not tested. Our case confirms that the mutational spectrum in MBAITs is broader than previously thought. Just as in the BRAF-mutated cases, it is likely that a subset might be associated with a BAP1 germline mutation. In case of suspicion of an MBAIT lesion based on histological examination, diagnostic work-up should include assessment of protein expression and/or mutation analysis of at least BRAF, NRAS, and BAP1. Work-up should not be limited to analyzing only BRAF protein expression or mutation, since NRAS-mutated MBAITs might be missed.

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BAP1 deficiency causes loss of melanocytic cell identity in uveal melanoma

Cited by 134 publications

References 34 publications

Clinical significance of immunohistochemistry for detection of BAP1 mutations in uveal melanoma

Clinical significance of immunohistochemistry for detection of BAP1 mutations in uveal melanoma

BRCA1-associated Protein 1 (BAP1) Deubiquitinase Antagonizes the Ubiquitin-mediated Activation of FoxK2 Target Genes

NRAS-mutated melanocytic BAP1-associated intradermal tumor (MBAIT): a case report

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