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

ABSTRACT 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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    • "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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    • "Although GNAQ/ 11 mutational status is not correlated with disease-free survival , these mutations are considered oncogenic drivers and consequently potential good targets for therapeutic intervention . Inactivating mutations of the tumor suppressor BAP1 occur in w85% of aggressive tumors and are associated with metastatic disease (Harbour et al., 2010). Recently, exome and whole genome sequencing of uveal melanomas identified recurrent mutations in SF3B1 (Furney et al., 2013; Harbour et al., 2013; Martin et al., 2013), which encodes a component of the spliceosome, and in the translation initiation factor EIF1AX (Martin et al., 2013). "
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    ABSTRACT: Uveal melanoma (UM) is the most common primary tumor of the eye in adults. There is no standard adjuvant treatment to prevent metastasis and no effective therapy in the metastatic setting. We have established a unique panel of 7 UM cell lines from either patient's tumors or patient-derived tumor xenografts (PDXs). This panel recapitulates the molecular landscape of the disease in terms of genetic alterations and mutations. All the cell lines display GNAQ or GNA11 activating mutations, and importantly four of them display BAP1 (BRCA1 associated protein-1) deficiency, a hallmark of aggressive disease. The mTOR pathway was shown to be activated in most of the cell lines independent of AKT signaling. mTOR inhibitor Everolimus reduced the viability of UM cell lines and significantly delayed tumor growth in 4 PDXs. Our data suggest that mTOR inhibition with Everolimus, possibly in combination with other agents, may be considered as a therapeutic option for the management of uveal melanoma.
    Molecular Oncology 12/2014; 74(19 Supplement). DOI:10.1016/j.molonc.2014.06.004 · 5.33 Impact Factor
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    • "The most significant single chromosomal marker of poor outcome in uveal melanoma is loss of one copy of chromosome 3 [4]–[8], while activating mutations in the alpha subunit of heterotrimeric G proteins, GNAQ or GNA11, are considered an early event in the development of the disease [9]. Recently, inactivating mutations in the tumor suppressor BRCA1-associated protein-1 (BAP1), located at 3p21.1, were shown to occur almost exclusively in metastatic uveal melanomas with monosomy 3 [10]. Finally, expression analysis has revealed two separate groups of uveal melanoma: class 1 tumors with low metastatic risk, and class 2 tumors, characterized by metastatic spread and worse prognosis [11], [12]. "
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    ABSTRACT: The transcriptional response promoted by hypoxia-inducible factors has been associated with metastatic spread of uveal melanoma. We found expression of hypoxia-inducible factor 1α (HIF-1α) protein in well-vascularized tumor regions as well as in four cell lines grown in normoxia, thus this pathway may be important even in well-oxygenated uveal melanoma cells. HIF-1α protein accumulation in normoxia was inhibited by rapamycin. As expected, hypoxia (1% pO2) further induced HIF-1α protein levels along with its target genes VEGF and LOX. Growth in hypoxia significantly increased cellular invasion of all 5 uveal melanoma lines tested, as did the introduction of an oxygen-insensitive HIF-1α mutant into Mel285 cells with low HIF-1α baseline levels. In contrast, HIF-1α knockdown using shRNA significantly decreased growth in hypoxia, and reduced by more than 50% tumor invasion in four lines with high HIF-1α baseline levels. Pharmacologic blockade of HIF-1α protein expression using digoxin dramatically suppressed cellular invasion both in normoxia and in hypoxia. We found that Notch pathway components, including Jag1-2 ligands, Hes1-Hey1 targets and the intracellular domain of Notch1, were increased in hypoxia, as well as the phosphorylation levels of Erk1-2 and Akt. Pharmacologic and genetic inhibition of Notch largely blocked the hypoxic induction of invasion as did the pharmacologic suppression of Erk1-2 activity. In addition, the increase in Erk1-2 and Akt phosphorylation by hypoxia was partially reduced by inhibiting Notch signaling. Our findings support the functional importance of HIF-1α signaling in promoting the invasive capacity of uveal melanoma cells in both hypoxia and normoxia, and suggest that pharmacologically targeting HIF-1α pathway directly or through blockade of Notch or Erk1-2 pathways can slow tumor spread.
    PLoS ONE 08/2014; 9(8):e105372. DOI:10.1371/journal.pone.0105372 · 3.23 Impact Factor
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