Comprehensive molecular characterization of clear cell renal cell carcinoma

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doi:10.1038/nature12222

Cited by 2,742 publications

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“…We analyzed a recently obtained RNA-seq data set of 470 RCC samples and compared the data to 68 nontumor control kidney samples (28,31). Although SLFN5 was significantly overexpressed in RCC samples (t test, P value ϭ 2 ϫ 10 Ϫ6 ) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Human Schlafen 5 (SLFN5) Is a Regulator of Motility and Invasiveness of Renal Cell Carcinoma Cells

Sassano

Mavrommatis

Arslan

et al. 2015

Molecular and Cellular Biology

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We provide evidence that human SLFN5, an interferon (IFN)-inducible member of the Schlafen (SLFN) family of proteins, exhibits key roles in controlling motility and invasiveness of renal cell carcinoma (RCC) cells. Our studies define the mechanism by which this occurs, demonstrating that SLFN5 negatively controls expression of the matrix metalloproteinase 1 gene (MMP-1), MMP-13, and several other genes involved in the control of malignant cell motility. Importantly, our data establish that SLFN5 expression correlates with a better overall survival in a large cohort of patients with RCC. The inverse relationship between SLFN5 expression and RCC aggressiveness raises the possibility of developing unique therapeutic approaches in the treatment of RCC, by modulating SLFN5 expression. Interferons (IFNs) are cytokines with important antineoplastic activities and therefore are frequently utilized in the treatment of cancer (1-4). A malignancy that exhibits sensitivity to interferon treatment is renal cell carcinoma (RCC) (5). RCC is the most common type of kidney tumor in humans and is associated with high morbidity and mortality (6, 7). In general, patients with recurrent or advanced disease have limited treatment options and a very poor overall prognosis (7). The Schlafen (SLFN) family of genes includes several members that share structural homology and play regulatory roles in the control of cell cycle progression and cell growth arrest (8-12). There are several human and mouse genes that are members of the SLFN family (9, 11). Prior evidence has implicated members of the Schlafen family in the regulation of tumorigenesis (13)(14)(15)(16)(17)(18). Notably, expression of various members of this family is upregulated following treatment with type I IFNs (17-19), cytokines known to promote induction of antineoplastic, antiviral, and immunoregulatory effects (1-4). Despite the induction of human and mouse SLFN genes by IFNs, the precise mechanisms by which SLFNs mediate antineoplastic responses in different types of malignant human cells remain to be determined.In the present study, we provide evidence that the expression of human SLFN5 is inducible by type I IFN receptor. SLFN5, like other long SLFNs, is characterized by a large C-terminal extension, a DNA/RNA helicase domain, and a nuclear localization sequence (NLS) (9, 20). Although SLFN5 is induced in melanoma cells following IFN treatment (18), the role of SLFN5 in tumor progression is largely unknown.In efforts to define the functional implications of SLFN5 expression in malignant RCC cells, we found that SLFN5 repressed the motility and invasiveness of malignant renal cell carcinoma cells, by negatively controlling the expression of matrix metalloproteinase (MMP) genes, such as MMP-1 and MMP-13. Importantly, analysis of SLFN5 mRNA expression in a large number of samples from a cohort of RCC patients demonstrated that SLFN5 expression correlates with better overall survival of RCC patients. Altogether, our studies for the first time establish a mechanism by which...

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Section: Resultsmentioning

confidence: 99%

Human Schlafen 5 (SLFN5) Is a Regulator of Motility and Invasiveness of Renal Cell Carcinoma Cells

Sassano

Mavrommatis

Arslan

et al. 2015

Molecular and Cellular Biology

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“…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. Families with members carrying germline mutations in BAP1 have also been described, with individuals most often affected by mesothelioma, melanomas including UM, and renal cell carcinoma 28, 29.…”

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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“…We are pleased that de Velasco et al [1] have compared the performance of a 34‐gene model predictor (ClearCode34) developed by several authors [2] with our 8‐gene predictor [3] in an independent RNA‐sequencing dataset derived from frozen metastatic renal cell carcinoma (mRCC) samples [4]. We are also glad that that the authors have successfully reproduced our analyses as reported in reference [3].…”

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confidence: 74%