Frequent Mutation of BAP1 in Metastasizing Uveal Melanomas

Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
Science (Impact Factor: 33.61). 11/2010; 330(6009):1410-3. DOI: 10.1126/science.1194472
Source: PubMed


Metastasis is a defining feature of malignant tumors and is the most common cause of cancer-related death, yet the genetics
of metastasis are poorly understood. We used exome capture coupled with massively parallel sequencing to search for metastasis-related
mutations in highly metastatic uveal melanomas of the eye. Inactivating somatic mutations were identified in the gene encoding
BRCA1-associated protein 1 (BAP1) on chromosome 3p21.1 in 26 of 31 (84%) metastasizing tumors, including 15 mutations causing premature protein termination
and 5 affecting its ubiquitin carboxyl-terminal hydrolase domain. One tumor harbored a frameshift mutation that was germline
in origin, thus representing a susceptibility allele. These findings implicate loss of BAP1 in uveal melanoma metastasis and
suggest that the BAP1 pathway may be a valuable therapeutic target.

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    • "Current literature suggests that the deactivation of the tumor-suppressor gene BAP1 (chr. 3p21.1) in UM occurs via a two-step process: loss of one copy of the gene and mutation of the other allele (Koopmans et al. 2014; Harbour et al. 2010). BAP1 mutations are reported to result in the loss of protein nuclear localization and hence loss of function (Ventii et al. 2008). "
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    ABSTRACT: The liver is the organ usually affected by metastatic uveal melanoma (MUM). Current treatments are almost always ineffective and mortality remains high. In this study, copy number variations (CNVs) were identified in 12 metastatic and five matched primary UMs (PUMs). Our data revealed a wide spectrum of genetic alterations in MUM. Most common were amplifications of chromosome (chr.) 8q; alterations on chr. 3 included monosomy, isodisomy and large regions of homozygosity (ROH). Genomic profiles of PUM-MUM pairs varied in their degree of similarity and complexity. However, within the pairs, 135 genes were consistently altered. Protein expression of C-MYC and BAP1 was examined by immunohistochemistry (IHC); a positive association between IHC and CNVs was seen for C-MYC. This comprehensive catalogue of CNVs associated with MUM should facilitate the identification of key alterations that drive tumor growth. This would have the potential to select urgently-needed novel, targeted, therapeutic regimens. This article is protected by copyright. All rights reserved.
    Pigment Cell & Melanoma Research 11/2015; DOI:10.1111/pcmr.12433 · 4.62 Impact Factor
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    • "The cloning and identification of somatic mutations of the BAP1 tumor suppressor gene in lung and breast cancer cells were first reported by the Rauscher laboratory [7]. Subsequently, BAP1 somatic mutations were discovered in MM [8] [9] and metastasizing UMs [5]. We reported the discovery of germline mutations of BAP1 in two families with multiple MMs, one of which had two family members with UMs (one also having MM), as well as in two additional cases having both MM and UM [9]. "
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    ABSTRACT: We report a high-risk cancer family with multiple mesotheliomas, cutaneous melanomas, basal cell carcinomas, and meningiomas segregating with a germline nonsense mutation in BAP1 (c.1938T>A; p.Y646X). Notably, most (four of five) mesotheliomas were peritoneal rather than the usually more common pleural form of the disease, and all five mesothelioma patients also developed second or third primary cancers, including two with meningiomas. Another family member developed both cutaneous melanoma and breast cancer. Two family members had basal cell carcinomas, and six others had melanocytic tumors, including four cutaneous melanomas, one uveal melanoma, and multiple benign melanocytic tumors. The family resides in a subtropical area, and several members had suspected exposure to asbestos either occupationally or in the home. We hypothesize that the concurrence of a genetic predisposing factor and environmental exposure to asbestos and UV irradiation contributed to the high incidence of multiple cancers seen in this family, specifically mesothelioma and various skin tumors, respectively.
    Cancer letters 09/2015; DOI:10.1016/j.canlet.2015.09.011 · 5.62 Impact Factor
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    • "h et al . ( 2013 ) Ubiquitin C - terminal hydrolases ( UCH ) BAP1 H2AK119ub H2AX Promotes DSB repair . Sensitization : IR and PARP inhibitors Cell cycle progression ; transcription Bap1 - knockout is embryonic lethal ; Bap1 deletion in adulthood results in HSC defects and myeloid transformation . Human tumor suppressor Nishikawa et al . ( 2009 ) , Harbour et al . ( 2010 ) , Scheuermann et al . ( 2010 ) , Bott et al . ( 2011 ) , Dey et al . ( 2012 ) , Peña - Llopis et al . ( 2012 ) , Carbone et al . ( 2013 ) , Ismail et al . ( 2014 ) , Nishi et al . ( 2014 ) , Yu et al . ( 2014 ) JAMM / MPM+ metallo - proteases BRCC36 , ( BRCC3 ) K63 - ub , H2A - K63 - ub , IFNAR1 Restrict DNA end resection ; limits HR "
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    ABSTRACT: Ubiquitination is a reversible protein modification broadly implicated in cellular functions. Signaling processes mediated by ubiquitin are crucial for the cellular response to DNA double-strand breaks (DSBs), one of the most dangerous types of DNA lesions. In particular, the DSB response critically relies on active ubiquitination by the RNF8 and RNF168 ubiquitin ligases at the chromatin, which is essential for proper DSB signaling and repair. How this pathway is fine-tuned and what the functional consequences are of its deregulation for genome integrity and tissue homeostasis are subject of intense investigation. One important regulatory mechanism is by reversal of substrate ubiquitination through the activity of specific deubiquitinating enzymes (DUBs), as supported by the implication of a growing number of DUBs in DNA damage response (DDR) processes. Here, we discuss the current knowledge of how ubiquitin-mediated signaling at DSBs is controlled by deubiquitinating enzymes, with main focus on DUBs targeting histone H2A and on their recent implication in stem cell biology and cancer.
    Frontiers in Genetics 09/2015; 08(September 2015):Article 282. DOI:10.3389/fgene.2015.00282
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