Alterations in VHL as potential biomarkers in renal-cell carcinoma

Gossage, Lucy; Eisen, Tim

doi:10.1038/nrclinonc.2010.42

Cited by 154 publications

(125 citation statements)

References 75 publications

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“…We used a whole genome amplification step, because the yield of DNA extracted from the tumor cells in the cyst walls was frequently insufficient. The frequency of validated VHL mutations was 25%, which is somewhat below the mutation rates reported in clear cell renal cell carcinoma (reviewed in Gossage et al 13 ). The two missense mutations, c.194C4T and c.461C4T, have been described in both sporadic and hereditary clear cell renal cell carcinomas.…”

Section: Discussionmentioning

confidence: 72%

VHL mutations and dysregulation of pVHL- and PTEN-controlled pathways in multilocular cystic renal cell carcinoma

et al. 2011

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Multilocular cystic renal cell carcinoma is a rare renal cell carcinoma with an excellent prognosis. To clarify the relationship with typical clear cell renal cell carcinoma, we evaluated 15 cases of multilocular cystic renal cell carcinomas diagnosed according to the 2004 WHO classification. Von Hippel Lindau (VHL) gene mutations were determined by whole genome amplification and direct sequencing. Carbonic anhydrase 9 (CAIX), a hypoxiainducible factor (HIF) target, paired box gene 2 (PAX2), cyclin-dependent kinase inhibitor p27 and glycogen synthase kinase 3-b (GSK3b) were immunohistochemically evaluated as members of the VHL protein (pVHL)-and phosphatase and tensin homolog (PTEN)-controlled pathways. VHL mutations were identified in 3 of 12 (25%) tumors. Inactivated GSK3b, decreased PTEN expression and PAX2 positivity were observed in the vast majority of the multilocular cystic renal cell carcinomas. Strong nuclear staining of p27 was seen in 14 of 15 cases. Compared with multilocular cystic renal cell carcinomas, expression frequencies of PAX2, p-GSK3b, PTEN and CAIX were similar in a set of low-grade, early-stage clear cell renal cell carcinomas, whereas only 30% had strong p27 positivity. These results are consistent with the hypothesis that multilocular cystic renal cell carcinomas are related at the molecular level with clear cell renal cell carcinomas. Maintenance of a strong subcellular p27 expression in all multilocular cystic renal cell carcinomas analyzed may in part explain the excellent prognosis of these tumor patients.

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Section: Discussionmentioning

confidence: 72%

VHL mutations and dysregulation of pVHL- and PTEN-controlled pathways in multilocular cystic renal cell carcinoma

et al. 2011

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“…[13][14][15] Somatic alterations in the VHL gene alterations in kidney cancer have a potential for use as prognostic and predictive markers. 16 Other somatic mutations in kidney cancers have been documented in genes involved in histone modification, including SET domain containing 2 (SETD2), Jumonji/ARID domaincontaining protein 1C (JARID1C), as well as mutations in the histone H3 lysine 27 demethylase, and SWI/SNF chromatin remodeling complex gene, PBRM1. 17,18 In this study on ccRCC tumors, we observed that though present in tumors from only a proportion of patients, the multivariate analysis indicated that the TERT promoter mutations, in agreement with previous observations in different cancer types, can define poor cause-specific patient survival.…”

Section: Discussionmentioning

confidence: 99%

TERT promoter mutations in clear cell renal cell carcinoma

Hosen

Rachakonda

Heidenreich

et al. 2014

Intl Journal of Cancer

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We screened promoter region of the telomerase reverse transcriptase (TERT) for activating somatic mutations in 188 tumors from patients with clear cell renal cell carcinoma (ccRCC). Twelve tumors (6.4%) carried a mutation within the core promoter region of the gene. The mutations were less frequent in high grade tumors compared to low grade tumors [odds ratio (OR) 5 0.15, 95% confidence interval (CI) 5 0.03-0.72, p 5 0.02]. Multivariate analysis for cause specific survival showed statistically significant poor outcome in patients with TERT promoter mutations [hazard ratio (HR) 5 2.90, 95% CI 5 1.13-7.39, p 5 0.03]. A common polymorphism (rs2853669) within the locus seemed to act as a modifier of the effect of the mutations on patient survival as the noncarriers of the variant allele with the TERT promoter mutations showed worst survival (HR 5 3.34, 95% CI 5 1.24-8.98, p 5 0.02). We also measured relative telomere length (RTL) in tumors and difference between tumors with and without the TERT promoter mutations was not statistically significant. Similarly, no difference in patient survival based on RTL in tumors was observed. Our study showed a relatively low frequency of TERT promoter mutations in ccRCC. Nevertheless, patients with the mutations, particularly in the absence of the rs2853669 variant showed the worst disease-specific survival. Thus, it is possible that the TERT promoter mutations define a small subset of tumors with an aggressive behavior.The human telomerase reverse transcriptase (TERT) gene encodes the catalytic subunit of telomerase, a ribonucleoprotein complex that maintains genomic integrity through de novo synthesis of telomere repeat units at chromosomal ends.1 Activation of telomerase is dependent on a number of factors in which the transcriptional regulation of the TERT gene constitutes a rate limiting step. The TERT promoter harbors binding sites for a number of transcriptional activators and repressors and is considered to be the most important regulatory element for telomerase expression.2 Since initial discovery, activating somatic mutations in the promoter region in the TERT gene have been reported in many cancers.3, 4 The promoter mutations result in creation of binding sites for the E-twenty Six (ETS)/ternary complex factors (TCFs) transcription factors located mainly at two residues at 2124C > T (G > A) and 2146C > T (G > A) from the ATG start site in the TERT promoter. The mutations in the TERT promoter result in increased TERT expression and have been shown to be associated with more advanced forms of malignant diseases. In primary cutaneous melanoma the mutations were associated with increased patient age, increased tumor thickness and tumor ulceration. 5In bladder cancer and gliomas, the mutations were associated with risk of tumor recurrence and poor survival. 6,7 In thyroid cancer, the TERT promoter mutations were more frequent in advanced tumors. 4 In follicular thyroid cell-derived carcinomas, the TERT promoter mutations have been shown to be associated with increased age a...

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“…The pathology of ccRCC is tightly associated with aberrant elevation of HIF signaling resulted from VHL deficiency (32). PML, however, negatively regulates HIF expression through mTOR repression (3,19).…”

Section: Scp-pml Axis Downregulates Hif Signaling In Ccrccmentioning

confidence: 99%

“…ccRCC can occur sporadically (>96%) or hereditarily (<4%). Almost all hereditary ccRCC and most sporadic ccRCC are characterized by loss/ inactivation of the von Hippel-Lindau (VHL) tumor-suppressor gene (32). VHL is a substrate-binding subunit of Cullin 2 ubiquitin ligase that targets HIF1/2a for degradation.…”

Section: Introductionmentioning

confidence: 99%

SCP Phosphatases Suppress Renal Cell Carcinoma by Stabilizing PML and Inhibiting mTOR/HIF Signaling

Lin

Chen

et al. 2014

Cancer Research

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The tumor-suppressor protein promyelocytic leukemia (PML) is aberrantly degraded in multiple types of human cancers through mechanisms that are incompletely understood. Here, we show that the phosphatase SCP1 and its isoforms SCP2/3 dephosphorylate PML at S518, thereby blocking PML ubiquitination and degradation mediated by the prolyl isomerase Pin1 and the ubiquitin ligase KLHL20. Clinically, SCP1 and SCP3 are downregulated in clear cell renal cell carcinoma (ccRCC) and these events correlated with PMLS518 phosphorylation, PML turnover, and high-grade tumors. Restoring SCP1-mediated PML stabilization not only inhibited malignant features of ccRCC, including proliferation, migration, invasion, tumor growth, and tumor angiogenesis, but also suppressed the mTOR-HIF pathway. Furthermore, blocking PML degradation in ccRCC by SCP1 overexpression or Pin1 inhibition enhanced the tumor-suppressive effects of the mTOR inhibitor temsirolimus. Taken together, our results define a novel pathway of PML degradation in ccRCC that involves SCP downregulation, revealing contributions of this pathway to ccRCC progression and offering a mechanistic rationale for combination therapies that jointly target PML degradation and mTOR inhibition for ccRCC treatment. Cancer Res; 74(23); 6935-46. Ó2014 AACR.

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Alterations in VHL as potential biomarkers in renal-cell carcinoma

Cited by 154 publications

References 75 publications

VHL mutations and dysregulation of pVHL- and PTEN-controlled pathways in multilocular cystic renal cell carcinoma

VHL mutations and dysregulation of pVHL- and PTEN-controlled pathways in multilocular cystic renal cell carcinoma

TERT promoter mutations in clear cell renal cell carcinoma

SCP Phosphatases Suppress Renal Cell Carcinoma by Stabilizing PML and Inhibiting mTOR/HIF Signaling

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