Germline BAP1 mutations predispose to malignant mesothelioma

Testa, Joseph R.; Cheung, Mitchell; Pei, Jianming; Below, Jennifer E.; Tan, Yinfei; Sementino, Eleonora; Cox, Nancy J.; Doğan, A. Umran; Pass, Harvey I.; Trusa, Sandra; Hesdorffer, Mary; Nasu, Masaki; Powers, Amy; Rivera, Zeyana; Cömertpay, Sabahattin; Tanji, Mika; Gaudino, Giovanni; Yang, Haining; Carbone, Michele

doi:10.1038/ng.912

Cited by 928 publications

(915 citation statements)

References 29 publications

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“…Similarly, somatic mutations in BAP1 have been reported in approximately 20% of cases of MPM (118) and linkage analysis demonstrated that germ-line mutations in BAP1 are associated with familial MPM (16). The BAP1 gene encodes a ubiquitin hydrolase that functions as a catalytic unit of the polycomb repressive deubiquitinase complex crucial for regulating gene expression and facilitating DNA repair (119,120 (122).…”

Section: Targeting Epigenetic Regulatorsmentioning

confidence: 99%

“…Prior chest radiation therapy or occupational radiation also increases the risk for developing mesothelioma (9)(10)(11)(12)(13)(14)(15). Familial variants of mesothelioma exist as well: for example, two families with strong family history of mesothelioma without an associated history of exposure to asbestos or other mineral fibers were found to have familial mutations in BRCA associated protein 1 (BAP1), a tumor suppressor gene, that either affects the gene's promoter or forms a premature stop codon (16). Somatic mutations of BAP-1 have also been identified in 57-63% of cases (17).…”

Section: Introductionmentioning

confidence: 99%

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Novel systemic therapy against malignant pleural mesothelioma

Mancuso

Neal

2017

Transl. Lung Cancer Res.

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Malignant pleural mesothelioma is an aggressive tumor of the pleura with an overall poor prognosis. Even with surgical resection, for which only a subset of patients are eligible, long term disease free survival is rare. Standard first-line systemic treatment consists of a platinum analog, an anti-metabolite, and sometimes anti-angiogenic therapy, but there is currently no well-established standard therapy for refractory or relapsed disease. This review focuses on efforts to develop improved systemic therapy for the treatment of malignant pleural mesothelioma (MPM) including cytotoxic systemic therapy, a variety of tyrosine kinase inhibitors and their downstream effector pathways, pharmacologic targeting of the epigenome, novel approaches to target proteins expressed on mesothelioma cells (such as mesothelin), arginine depletion therapy, and the emerging role of immunotherapy. Overall, these studies demonstrate the challenges of improving systemic therapy for MPM and highlight the need to develop therapeutic strategies to control this disease.

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Section: Targeting Epigenetic Regulatorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel systemic therapy against malignant pleural mesothelioma

Mancuso

Neal

2017

Transl. Lung Cancer Res.

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“…Somatic inactivating mutations have been found at high incidence in uveal melanomas, clear cell renal carcinoma, and pleural malignant mesotheliomas (1,82,86). Germline mutations have been linked to a tumor predisposition syndrome for melanocytic tumors and mesothelioma (252,274). BAP1 gene deletion in mice is embryonically lethal, but conditional knockout mice develop a myeloid disorder resembling chronic myelomonocytic leukemia (CMML) (57).…”

Section: Figurementioning

confidence: 99%

Deubiquitylases From Genes to Organism

Clague

Barsukov

Coulson

et al. 2013

Physiological Reviews

358

383

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Ubiquitylation is a major posttranslational modification that controls most complex aspects of cell physiology. It is reversed through the action of a large family of deubiquitylating enzymes (DUBs) that are emerging as attractive therapeutic targets for a number of disease conditions. Here, we provide a comprehensive analysis of the complement of human DUBs, indicating structural motifs, typical cellular copy numbers, and tissue expression profiles. We discuss the means by which specificity is achieved and how DUB activity may be regulated. Generically DUB catalytic activity may be used to 1) maintain free ubiquitin levels, 2) rescue proteins from ubiquitin-mediated degradation, and 3) control the dynamics of ubiquitin-mediated signaling events. Functional roles of individual DUBs from each of five subfamilies in specific cellular processes are highlighted with an emphasis on those linked to pathological conditions where the association is supported by whole organism models. We then specifically consider the role of DUBs associated with protein degradative machineries and the influence of specific DUBs upon expression of receptors and channels at the plasma membrane.

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“…[11][12][13] Inactivating somatic and germline BAP1 mutations have been identified in a variety of cancers, including malignant pleural mesotheliomas, cutaneous melanoma, atypical cutaneous melanocytic tumors, meningioma, lung adenocarcinoma, and renal cell carcinoma. [14][15][16][17][18][19] The number of reported cancer-prone families with germline BAP1 mutations is rising and suggesting a BAP1 cancer syndrome. However, the prevalence of germline BAP1 mutations in uveal melanoma patients is low compared with BAP1 mutations of somatic origin.…”

mentioning

confidence: 99%

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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Germline BAP1 mutations predispose to malignant mesothelioma

Cited by 928 publications

References 29 publications

Novel systemic therapy against malignant pleural mesothelioma

Novel systemic therapy against malignant pleural mesothelioma

Deubiquitylases From Genes to Organism

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

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