Frequent Mutation of
            <i>BAP1</i>
            in Metastasizing Uveal Melanomas

Harbour, J. William; Onken, Michael D.; Roberson, Elisha D.O.; Duan, Shenghui; Cao, Li; Worley, Lori A.; Matatall, Katie A.; Helms, Cynthia; Bowcock, Anne M.

doi:10.1126/science.1194472

Cited by 1,227 publications

(1,172 citation statements)

References 24 publications

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“…Accumulative evidence has reported the diverse roles of ubiquitination in different biological activities and its great importance in the pathogenesis of various cancers, including melanoma 11. For example, the inactivating somatic mutations of BAP1 , a nuclear ubiquitin carboxyl‐terminal hydrolase (UCH), were frequently detected in metastasizing uveal melanomas, and melanoma cell with BAP1 gene deficiency grew as multi‐cellular non‐adherent spheroids with rounded epithelioid morphology, paralleled with increased metastatic capacity 26, 27. In addition, the mutation of ubiquitin ligase FBXW7 resulted in hyper‐activation of Notch1 signalling and subsequent sustained proliferation of melanoma cells by up‐regulation of cell‐cycle mediators 28, 29, 30.…”

Section: Discussionmentioning

confidence: 99%

Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

Guo

Pei

et al. 2018

J Cellular Molecular Medi

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Melanoma is the most malignant skin cancer with increasing incidence worldwide. Although innovative therapies such as BRAF inhibitor and immune checkpoint inhibitor have gained remarkable advances, metastatic melanoma remains an incurable disease for its notorious aggressiveness. Therefore, further clarification of the underlying mechanism of melanoma pathogenesis is critical for the improvement of melanoma therapy. Ubiquitination is an important regulatory event for cancer hallmarks and melanoma development, and the deubiquitinating enzymes including ubiquitin‐specific peptidase (USP) families are greatly implicated in modulating cancer biology. Herein, we first found that the expression of the deubiquitinase USP4 was significantly up‐regulated in melanoma tissues and cell lines. Furthermore, although USP4 knockdown had little impact on melanoma cell proliferation, it could increase the sensitivity to DNA damage agent cisplatin. We subsequently showed that USP4 regulated cisplatin‐induced cell apoptosis via p53 signalling. More importantly, USP4 could accentuate the invasive and migratory capacity of melanoma cells by promoting epithelial‐mesenchymal transition. Altogether, our results demonstrate that the up‐regulated USP4 plays an oncogenic role in melanoma by simultaneously suppressing stress‐induced cell apoptosis and facilitating tumour metastasis.

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Section: Discussionmentioning

confidence: 99%

Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

Guo

Pei

et al. 2018

J Cellular Molecular Medi

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“…Translocations and copy-number changes have also been investigated using paired-end sequencing coupled with the aforementioned structural variation callers, e.g., Breakdancer, GASV, BreakSeq. Following the identification of somatic variants in genome-wide studies, investigators have performed large scale resequencing projects to determine whether the gene is mutated at a statistically significant frequency in the cancer subtype, and if so, what the underlying biological mechanism might be [110–113]. …”

Section: Mps Applications In Mutation Analysismentioning

confidence: 99%

Direct mutation analysis by high-throughput sequencing: From germline to low-abundant, somatic variants

Gundry

Vijg

2012

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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DNA mutations are the source of genetic variation within populations. The majority of mutations with observable effects are deleterious. In humans mutations in the germ line can cause genetic disease. In somatic cells multiple rounds of mutations and selection lead to cancer. The study of genetic variation has progressed rapidly since the completion of the draft sequence of the human genome. Recent advances in sequencing technology, most importantly the introduction of massively parallel sequencing (MPS), have resulted in more than a hundred-fold reduction in the time and cost required for sequencing nucleic acids. These improvements have greatly expanded the use of sequencing as a practical tool for mutation analysis. While in the past the high cost of sequencing limited mutation analysis to selectable markers or small forward mutation targets assumed to be representative for the genome overall, current platforms allow whole genome sequencing for less than $5,000. This has already given rise to direct estimates of germline mutation rates in multiple organisms including humans by comparing whole genome sequences between parents and offspring. Here we present a brief history of the field of mutation research, with a focus on classical tools for the measurement of mutation rates. We then review MPS, how it is currently applied and the new insight into human and animal mutation frequencies and spectra that has been obtained from whole genome sequencing. While great progress has been made, we note that the single most important limitation of current MPS approaches for mutation analysis is the inability to address low-abundance mutations that turn somatic tissues into mosaics of cells. Such mutations are at the basis of intra-tumor heterogeneity, with important implications for clinical diagnosis, and could also contribute to somatic diseases other than cancer, including aging. Some possible approaches to gain access to low-abundance mutations are discussed, with a brief overview of new sequencing platforms that are currently waiting in the wings to advance this exploding field even further.

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“…Further abnormalities described in UM include loss of 1p, which is associated with poor prognosis in the context of M3 15, and gains on 6p, which, in the absence of additional chromosomal abnormalities, correspond with a good prognosis 16, 17. More recently, mutations occurring in UM have been identified in several genes, including GNAQ , GNA11 , BAP1 , SF3B1 , EIF1AX , PLCB4 , and CYSLTR2 11, 18, 19, 20, 21, 22. In particular, inactivating BAP1 mutations are associated with a poor outcome, being present in ∼84% of all UMs that went on to produce metastases 19, 23, 24.…”

Section: Introductionmentioning

confidence: 99%

“…More recently, mutations occurring in UM have been identified in several genes, including GNAQ , GNA11 , BAP1 , SF3B1 , EIF1AX , PLCB4 , and CYSLTR2 11, 18, 19, 20, 21, 22. In particular, inactivating BAP1 mutations are associated with a poor outcome, being present in ∼84% of all UMs that went on to produce metastases 19, 23, 24. BAP1 mutations similarly correspond with a significantly worse prognosis in renal clear cell carcinoma 25 and cholangiocarcinoma 26, whilst in mesothelioma BAP1 inactivation is associated with a good prognosis 27.…”

Section: Introductionmentioning

confidence: 99%

Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma

Farquhar

Thornton

Coupland

et al. 2017

The Journal of Pathology CR

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Uveal melanoma (UM) is a rare aggressive intraocular tumour with a propensity for liver metastases, occurring in ∼50% of patients. The tumour suppressor BAP1 is considered to be key in UM progression. Herein, we present the largest study to date investigating cellular expression patterns of BAP1 protein in 165 UMs, correlating these patterns to prognosis. Full clinical, histological, genetic, and follow‐up data were available for all patients. BAP1 gene sequencing was performed on a subset of 26 cases. An independent cohort of 14 UMs was examined for comparison. Loss of nuclear BAP1 (nBAP1) protein expression was observed in 54% (88/165) UMs. nBAP1 expression proved to be a significant independent prognostic parameter: it identified two subgroups within monosomy 3 (M3) UM, which are known to have a high risk of metastasis. Strikingly, nBAP1‐positiveM3 UMs were associated with prolonged survival compared to nBAP1‐negative M3 UMs (Log rank, p = 0.014). nBAP1 protein loss did not correlate with a BAP1 mutation in 23% (6/26) of the UMs analysed. Cytoplasmic BAP1 protein (cBAP1) expression was also observed in UM: although appearing ‘predominantly diffuse’ in most nBAP1‐negative UM, a distinct ‘focal perinuclear’ expression pattern – localized immediately adjacent to the cis Golgi – was seen in 31% (18/59). These tumours tended to carry loss‐of‐function BAP1 mutations. Our study demonstrates loss of nBAP1 expression to be the strongest prognostic marker in UM, confirming its importance in UM progression. Our data suggest that non‐genetic mechanisms account for nBAP1 loss in a small number of UMs. In addition, we describe a subset of nBAP1‐negative UM, in which BAP1 is sequestered in perinuclear bodies, most likely within Golgi, warranting further mechanistic investigation.

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Frequent Mutation of BAP1 in Metastasizing Uveal Melanomas

Cited by 1,227 publications

References 24 publications

Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

Direct mutation analysis by high-throughput sequencing: From germline to low-abundant, somatic variants

Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma

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