The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma

Bott, Matthew; Brevet, Marie; Taylor, Barry S.; Shimizu, Shigeki; Itö, Tatsuo; Wang, Lu; Creaney, Jenette; Lake, Richard; Zakowski, Maureen F.; Reva, Boris; Sander, Chris; Delsite, Robert; Powell, Simon N.; Zhou, Qin; Shen, Ronglai; Olshen, Adam B.; Rusch, Valerie W.; Ladanyi, Marc

doi:10.1038/ng.855

Cited by 609 publications

(663 citation statements)

References 34 publications

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“…Somatic BAP1 mutations have been described in other cancers, such as malignant pleural mesotheliomas and cutaneous melanoma, and the absence of BAP1 expression in mesotheliomas has been demonstrated by immunohistochemistry. 15 In contrast to our uveal melanoma cohort, 25% of the mesotheliomas without a BAP1 mutation did not display any immunohistochemistry staining for BAP1.…”

Section: Discussioncontrasting

confidence: 78%

“…[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.…”

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confidence: 99%

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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: Discussioncontrasting

confidence: 78%

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confidence: 99%

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

et al. 2014

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“…Immunohistochemical scoring of BAP1 expression was performed similar to those published previously. 17,29 Assessment of BAP1 was done blinded to any other patient data including outcome. Intact or "positive" expression of BAP1 was defined as nuclear staining within tumor cells, using stromal cells as a positive internal control.…”

Section: Fluorescence In Situ Hybridizationmentioning

confidence: 99%

“…[16][17][18][19][20] Integrative analysis of mutations and somatic copy-number alterations has revealed frequent inactivation in CDKN2A, NF2, and BAP1. Moreover, the status of these three genes has significant prognostic implications.…”

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confidence: 99%

The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma

et al. 2016

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Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion for patients with malignant peritoneal mesothelioma has resulted in improved disease control and increased survival. Despite these results, there are significant perioperative risks associated with this aggressive procedure that necessitate consideration of prognostic markers during patient selection. The molecular pathogenesis of peritoneal mesothelioma remains relatively unknown, but extrapolation of findings from their pleural counterpart would suggest frequent alterations in CDKN2A, NF2, and BAP1. Homozygous deletions in CDKN2A portend a worse overall survival in peritoneal mesothelioma. However, the prevalence and prognostic significance of NF2 and BAP1 abnormalities has not been studied. Dual-color fluorescence in situ hybridization using CDKN2A and NF2 locus-specific probes and BAP1 immunohistochemistry identified homozygous CDKN2A deletions (n = 25, 29%), hemizygous NF2 loss (n = 30, 35%), and/or loss of BAP1 protein expression (n = 49, 57%) in 68 of 86 (79%) peritoneal mesotheliomas. Homozygous CDKN2A deletions or hemizygous NF2 loss correlated with shorter progressionfree survival (Po 0.02) and poor overall survival (Po 0.03). Moreover, the significance of these findings was cumulative. Patients harboring both homozygous CDKN2A deletions and hemizygous NF2 loss had a 2-year progression-free survival rate of 9% with a median of 6 months (Po 0.01) and overall survival rate of 18% with a median of 8 months (Po 0.01). By multivariate analysis, combined homozygous CDKN2A deletions and hemizygous NF2 loss was a negative prognostic factor for both progression-free survival and overall survival, independent of patient age, peritoneal cancer index, completeness of cytoreduction, and extent of invasion. In contrast, loss of BAP1 was not associated with clinical outcome. In summary, homozygous deletions in CDKN2A and hemizygous loss of NF2 as detected by fluorescence in situ hybridization would confer a poor clinical outcome and may guide future treatment decisions for patients with peritoneal mesothelioma.

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“…In the case of A20, chromosomal deletions and inactivating mutations have been found in several lymphoma subtypes (Honma et al, 2009;Novak et al, 2009), whereas point mutations and deletions in BAP1 have been described in breast and lung cancer (Jensen et al, 1998;Harbour et al, 2010). Furthermore, BAP1-inactivating mutations have been identified in 84% of metastasizing uveal melanomas (Harbour et al, 2010) and in 23% of malignant pleural mesotheliomas (Bott et al, 2011). Regarding DUBs with oncogenic roles, somatic mutations in USP6 and USP28 have been found in different human malignancies.…”

Section: Genetic or Functional Alterations Of Dubs In Cancermentioning

confidence: 99%

Deubiquitinases in cancer: new functions and therapeutic options

et al. 2011

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Deubiquitinases (DUBs) have fundamental roles in the ubiquitin system through their ability to specifically deconjugate ubiquitin from targeted proteins. The human genome encodes at least 98 DUBs, which can be grouped into 6 families, reflecting the need for specificity in their function. The activity of these enzymes affects the turnover rate, activation, recycling and localization of multiple proteins, which in turn is essential for cell homeostasis, protein stability and a wide range of signaling pathways. Consistent with this, altered DUB function has been related to several diseases, including cancer. Thus, multiple DUBs have been classified as oncogenes or tumor suppressors because of their regulatory functions on the activity of other proteins involved in tumor development. Therefore, recent studies have focused on pharmacological intervention on DUB activity as a rationale to search for novel anticancer drugs. This strategy may benefit from our current knowledge of the physiological regulatory mechanisms of these enzymes and the fact that growth of several tumors depends on the normal activity of certain DUBs. Further understanding of these processes may provide answers to multiple remaining questions on DUB functions and lead to the development of DUB-targeting strategies to expand the repertoire of molecular therapies against cancer.

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The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma

Cited by 609 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

The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma

Deubiquitinases in cancer: new functions and therapeutic options

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