Characterization of VHL missense mutations in sporadic clear cell renal cell carcinoma: hotspots, affected binding domains, functional impact on pVHL and therapeutic relevance

Razafinjatovo, Caroline; Bihr, Svenja; Mischo, Axel; Vogl, Ursula Maria; Schmidinger, Manuela; Moch, Holger; Schraml, Peter

doi:10.1186/s12885-016-2688-0

Cited by 53 publications

(61 citation statements)

References 54 publications

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“…The VHL gene product, pVHL, is a multi‐adaptor protein that binds more than 30 different binding partners . pVHL is a key component of the E3 ubiquitin ligase complex and is essential for the oxygen‐dependent ubiquitin‐mediated proteolytic degradation of HIF‐α .…”

Section: The Vhl Gene In Ccrccmentioning

confidence: 99%

“…These proteins are known to be important in metastatic processes . pVHL also interacts with several effector proteins that regulate cellular processes, including microtubule stability, activation of p53, neuronal apoptosis, cellular senescence and aneuploidy, ubiquitination of RNA polymerase II and regulation of nuclear factor kappa B (NF‐kB) activity …”

Section: The Vhl Gene In Ccrccmentioning

confidence: 99%

“…Therefore, details with regard to the molecular background of wt VHL ccRCC cases are limited. Several groups have stratified their data by VHL mutation types, and found that missense mutations may exert different effects on both pVHL stability and binding capability …”

Section: Ccrccs With Wild‐type Vhlmentioning

confidence: 99%

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Clear cell renal cell carcinoma with wild‐type von Hippel‐Lindau gene: a non‐existent or new tumour entity?

2018

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The current World Health Organisation (WHO) classification of renal tumours is based on characteristic histological features or specific molecular alterations. von Hippel‐Lindau (VHL) alteration is the hallmark of clear cell renal cell carcinoma (RCC). After identification of the MiT translocation family of tumours, clear cell papillary renal cancer and others, the group of ccRCC with wild‐type VHL is small. TCEB1 mutation combined with chromosome 8q loss is an emerging tumour entity with wild‐type VHL. Inactivation of TCEB1 increases HIF stabilisation via the same mechanism as VHL inactivation. Importantly, recent molecular analyses suggest the existence of another ‘VHL wild‐type’ evolutionary subtype of clear cell RCC in addition to TCEB1 mutated RCC and clear cell papillary renal cancer. These tumours are characterised by an aggressive behaviour, high tumour cell proliferation rate, elevated chromosomal instability and frequent presence of sarcomatoid differentiation. Future clinicopathological studies will have to provide data to determine whether TCEB1 tumours and clear cell RCC with wild‐type VHL are separate tumour entities or represent variants of a clear cell RCC tumour family.

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Section: The Vhl Gene In Ccrccmentioning

confidence: 99%

Section: The Vhl Gene In Ccrccmentioning

confidence: 99%

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Clear cell renal cell carcinoma with wild‐type von Hippel‐Lindau gene: a non‐existent or new tumour entity?

2018

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“…About 80%-90% of ccRCC tumors express a mutant form of pVHL, an E3 ubiquitin ligase (13)(14)(15). The mutant pVHL is unable to polyubiquitinate the transcription factor hypoxia-inducible factor (HIF), which regulates genes involved in angiogenesis, proliferation, metabolism, and invasion/metastasis pathways (16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

HIF2α-Targeted RNAi Therapeutic Inhibits Clear Cell Renal Cell Carcinoma

Wong

Cheng

Hamilton

et al. 2018

Molecular Cancer Therapeutics

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Targeted therapy against VEGF and mTOR pathways has been established as the standard-of-care for metastatic clear cell renal cell carcinoma (ccRCC); however, these treatments frequently fail and most patients become refractory requiring subsequent alternative therapeutic options. Therefore, development of innovative and effective treatments is imperative. About 80%-90% of ccRCC tumors express an inactive mutant form of the von Hippel-Lindau protein (pVHL), an E3 ubiquitin ligase that promotes target protein degradation. Strong genetic and experimental evidence supports the correlate that pVHL functional loss leads to the accumulation of the transcription factor hypoxia-inducible factor 2a (HIF2a) and that an overabundance of HIF2a functions as a tumorigenic driver of ccRCC. In this report, we describe an RNAi therapeutic for HIF2a that utilizes a targeting ligand that selectively binds to integrins avb3 and avb5 frequently overexpressed in ccRCC. We demonstrate that functional delivery of a HIF2a-specific RNAi trigger resulted in HIF2a gene silencing and subsequent tumor growth inhibition and degeneration in an established orthotopic ccRCC xenograft model.

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“…CC-RCC is the most prevalent subtype of RCC, accounting for ~80% of cases (3). Specific molecular mechanisms have been identified in RCC tumorigenesis, including von Hipple-Lindau gene mutation (4). Somatic mutation of this gene has been associated with the development of ~60% of sporadic CC-RCC (5).…”

Section: Introductionmentioning

confidence: 99%

Association of leptin, visfatin, apelin, resistin and adiponectin with clear cell renal cell carcinoma

Zhang

Zou

et al. 2016

Oncology Letters

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Abstract.Although an association between obesity and the occurrence of renal cell carcinoma (RCC) has been identified, the mechanism by which obesity functions to increase this risk of cancer remains unclear. Leptin, visfatin, apelin, resistin and adiponectin are peptide hormones secreted by adipocytes; it is considered that these may affect RCC development by exerting effects on proliferation, cell growth and inflammation. The aim of the present study was to investigate the association between the aforementioned adipokine genes and clear cell RCC (CC-RCC). The GSE6344 dataset was downloaded from the Gene Expression Omnibus database, and the relative expression levels of the adipokine genes were analyzed. To verify the results of the mRNA microarray, 77 paired samples of CC-RCC and corresponding adjacent normal tissue were allocated into two groups. The extraction of total RNA was conducted, and the mRNA expression of adipokine genes was analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The data from the GSE6344 dataset indicated that the expression of visfatin and apelin was upregulated (P<0.0001 and P<0.01, respectively), and adiponectin was downregulated (P<0.001) in the CC-RCC tissues compared with the adjacent normal tissues. The data from RT-qPCR demonstrated that visfatin and resistin gene expression was increased (P<0.01 and P<0.05, respectively) in the CC-RCC tissues. Furthermore, the mRNA expression level of leptin and adiponectin in the adjacent normal tissue was higher than those in the cancer tissue (P<0.01). The current study verifies that visfatin and adiponectin are associated with an increased risk of CC-RCC, which presents further insights into the molecular mechanisms of CC-RCC tumorigenesis.

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Characterization of VHL missense mutations in sporadic clear cell renal cell carcinoma: hotspots, affected binding domains, functional impact on pVHL and therapeutic relevance

Cited by 53 publications

References 54 publications

Clear cell renal cell carcinoma with wild‐type von Hippel‐Lindau gene: a non‐existent or new tumour entity?

Clear cell renal cell carcinoma with wild‐type von Hippel‐Lindau gene: a non‐existent or new tumour entity?

HIF2α-Targeted RNAi Therapeutic Inhibits Clear Cell Renal Cell Carcinoma

Association of leptin, visfatin, apelin, resistin and adiponectin with clear cell renal cell carcinoma

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