Multiplex Ligation-Dependent Probe Amplification of Uveal Melanoma: Correlation with Metastatic Death

Damato, Bertil; Dopierała, Justyna; Klaasen, Annelies; Dijk, Marcory van; Sibbring, Julie; Coupland, Sarah E.

doi:10.1167/iovs.08-3165

Cited by 161 publications

(159 citation statements)

References 19 publications

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“…Approval for the study was obtained from the Health Research Authority (NRES REC ref 16/SW/0112), and all patients provided informed consent.…”

Section: Methodsmentioning

confidence: 99%

“…M3 is frequently accompanied by polysomy 8q, and increasing copies of 8q significantly correlate with reduced survival, in a dose‐dependent fashion 8, 10, 13, 14. 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.…”

Section: Introductionmentioning

confidence: 99%

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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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“…Approval for the study was obtained from the Health Research Authority (NRES REC ref 16/SW/0112), and all patients provided informed consent.…”

Section: Methodsmentioning

confidence: 99%

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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“…These alterations were initially identified by standard karyotypic analyses. 94 79,[125][126][127] and singlenucleotide polymorphisms (SNPs). 109,[128][129][130][131][132] The above-mentioned chromosomal alterations in primary UM are clinically relevant because of their correlation with the risk of metastatic death.…”

Section: Chromosomal Alterations In Primary Ummentioning

confidence: 99%

Molecular Pathology of Uveal Melanoma

Coupland

Lake

Damato

2014

Clinical Ophthalmic Oncology

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Like other cancers, uveal melanomas (UM) are characterised by an uncontrolled, clonal, cellular proliferation, occurring as a result of numerous genetic, and epigenetic aberrations. Signalling pathways known to be disrupted in UM include: (1) the retinoblastoma pathway, probably as a result of cyclin D1 overexpression; p53 signalling, possibly as a consequence of MDM2 overexpression; and the P13K/AKT and mitogen-activated protein kinase/extracellular signal-related kinase pathway pathways that are disturbed as a result of PTEN and GNAQ/11 mutations, respectively. Characteristic chromosomal abnormalities are common and include 6p gain, associated with a good prognosis, as well as 1p loss, 3 loss, and 8q gain, which correlate with high mortality. These are identified by techniques such as fluorescence in situ hybridisation, comparative genomic hybridisation, microsatellite analysis, multiplex ligationdependent probe amplification, and singlenucleotide polymorphisms. UM can also be categorised by their gene expression profiles as class 1 or class 2, the latter correlating with poor survival, as do BRCA1-associated protein-1 (BAP1) inactivating mutations. Genetic testing of UM has enhanced prognostication, especially when results are integrated with histological and clinical data. The identification of abnormal signalling pathways, genes and proteins in UM opens the way for target-based therapies, improving prospects for conserving vision and prolonging life.

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“…Loss of 1 copy of chromosome 3 (monosomy 3) is strongly associated with poor survival and metastatic disease in uveal melanoma, suggesting the presence of tumor suppressor gene on chro-mosome 3 (11,12). It remains unclear which genetic or environmental predisposing factors and cellular events are involved in the malignant transformation of normal uveal melanocytes to form uveal melanoma.…”

Section: Introductionmentioning

confidence: 99%

Status of RASSF1A in Uveal Melanocytes and Melanoma Cells

Calipel

Abonnet

Nicole

et al. 2011

Molecular Cancer Research

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RASSF1A gene, found at the 3p21.3 locus, is a tumor suppressor gene frequently hypermethylated in human cancers. In this study, we report that compared with melanocytes in normal choroid, RASSF1A is downregulated in uveal melanoma samples and in uveal melanoma cell lines. LOH at 3p21.3 was detected in 50% of uveal melanoma. Moreover, methylation of the RASSF1A promoter was detected in 35 of 42 tumors (83%) and RASSF1A was also weakly expressed at the mRNA level. These data indicate that LOH at the RASSF1A locus or RASSF1A promoter methylation may partly account for the suppression of RASSF1A expression observed in uveal melanoma. Furthermore, following ectopic expression in three RASSF1A-deficient melanoma cell lines (OCM-1, Mel270, and 92.1), RASSF1A weakly reduces cell proliferation and anchorage-independent growth of uveal melanoma cells without effect on ERK1/2 activation, cyclin D1 and p27Kip1 expression. This study explored biological functions and underlying mechanisms of RASSF1A in the ERK1/2 pathway in normal uveal melanocytes. We showed that siRNAmediated depletion of RASSF1A increased ERK1/2 activation, cyclin D1 expression, and also decreased p27Kip1 expression in normal uveal melanocytes. Moreover, that the depletion of RASSF1A induced senescence-associated b-galactosidase activity and increased p21 Cip1 expression suggests that RASSF1A plays a role in the escape of cellular senescence in normal uveal melanocytes. Interestingly, we found that RASSF1A was epigenetically inactivated in long-term culture of uveal melanocytes. Taken together, these data show that depletion of RASSF1A could be an early event observed during senescence of normal uveal melanocytes and that additional alterations are acquired during malignant transformation to uveal melanoma. Mol Cancer Res; 9(9);

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Multiplex Ligation-Dependent Probe Amplification of Uveal Melanoma: Correlation with Metastatic Death

Abstract: MLPA analysis of uveal melanoma predicts metastatic death if statistically insignificant losses of chromosome 3 are considered together with gains in 8q as well as clinical stage and histologic grade of malignancy.

Cited by 161 publications

References 19 publications

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

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

Molecular Pathology of Uveal Melanoma

Status of RASSF1A in Uveal Melanocytes and Melanoma Cells

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