Combined mutation in Vhl, Trp53 and Rb1 causes clear cell renal cell carcinoma in mice

Harlander, Sabine; Schönenberger, Désirée; Toussaint, Nora C.; Prummer, Michael; Catalano, Antonella; Brandt, Laura P; Moch, Holger; Wild, Peter J.; Frew, Ian J.

doi:10.1038/nm.4343

Cited by 117 publications

(146 citation statements)

References 56 publications

(81 reference statements)

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“…Exome sequencing from Harlander et al revealed that mouse and human clear cell renal cell carcinomas exhibited recurrent mutations in genes associated with the primary cilium, which strongly suggested the correlation between abnormality of ciliary genes and tumor 6. Seven DEGs including TUBB3 , AURKA , CENPF , STIL , STK39 , RAB23 and OSR1 were identified in this study.…”

Section: Discussionsupporting

confidence: 68%

Analysis of potential genes associated with primary cilia in bladder cancer

Du¹,

Lü²,

Sheng³

et al. 2018

CMAR

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BackgroundDysfunction of primary cilia (PC), which could influence cell cycle and modulate cilia-related signaling transduction, has been reported in several cancers. However, there is no evidence of their function in bladder cancer (BLCA). This study was performed to investigate the presence of PC in BLCA and to explore the potential molecular mechanisms underlying the PC in BLCA.Patients and methodsThe presence of PC was assessed in BLCA and adjacent non-cancerous tissues. The gene expression dataset GSE52519 was employed to obtain differentially expressed genes (DEGs) associated with PC. The mRNA expression of the DEGs were confirmed by Gene Expression Profiling Interactive Analysis. The DEGs properties and pathways were analyzed by Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Genomatix software was used to predict putative transcription factor binding sites (TFBS) in the promoter region of DEGs, and the transcription factors were achieved according to the shared TFBS, which were supported by the ChIP-Sequence data.ResultsPC were found to be reduced in BLCA tissue samples in this study. Seven DEGs were observed to be associated with PC, and gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis indicated that these DEGs exhibited the properties and functions of PC, and that the Hedgehog signaling pathway probably participated in the pathogenesis and progression of BLCA. The mRNA expression of the seven DEGs in 404 BLCA and 28 normal tissue samples were analyzed, and five DEGs including CENPF, STIL, AURKA, STK39 and OSR1 were identified. Five TFBS including CREB, E2FF, EBOX, ETSF and HOXF in the promoter region of five DEGs were calculated and the transcription factors were obtained according to the shared TFBS.ConclusionPC were found to be reduced in BLCA, and the potential molecular mechanisms of PC in BLCA helped to provide novel diagnosis and therapeutic targets for BLCA.

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Section: Discussionsupporting

confidence: 68%

Analysis of potential genes associated with primary cilia in bladder cancer

Du¹,

Lü²,

Sheng³

et al. 2018

CMAR

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“…Reanalysis of the TCGA ccRCC data, focusing on cell cycle regulation, identified frequent copy number alterations of members of the p53 regulation and cell cycle checkpoint control clusters . Mutations in SWI–SNF members were not prevalent in this cohort, suggesting a different mechanism of oncogenesis.…”

Section: Cells Of Originmentioning

confidence: 81%

Clear cell carcinomas of the ovary and kidney: clarity through genomics

Wang

Cochrane

et al. 2018

The Journal of Pathology

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Clear cell ovarian carcinoma (CCOC) and clear cell renal cell carcinoma (ccRCC) both feature clear cytoplasm, owing to the accumulation of cytoplasmic glycogen. Genomic studies have demonstrated several mutational similarities between these two diseases, including frequent alterations in the chromatin remodelling SWI-SNF and cellular proliferation phosphoinositide 3-kinase-mammalian target of rapamycin pathways, as well as a shared hypoxia-like mRNA expression signature. Although many targeted treatment options have been approved for advanced-stage ccRCC, CCOC patients are still treated with conventional platinum and taxane chemotherapy, to which they are resistant. To determine the extent of similarity between these malignancies, we performed unsupervised clustering of mRNA expression data from these cancers. This review highlights the similarities and differences between these two clear cell carcinomas to facilitate knowledge translation within future research efforts. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…Though TP53 deletion or mutation is relatively uncommon in human ccRCC tumors, another study examined the effect of conditional Vhl , Trp53 , and Rb1 loss in the renal epithelium (utilizing Ksp -Cre), as changes in regulators of the p53 pathway and the G1/S cell cycle transition are frequently copy number modified according to The Cancer Genome Atlas (TCGA) data [49]. The authors found evidence of tumor onset as early as 7.5 months following triple knockout in a subset of mice, which were characterized by HIF-α and mTORC1 pathway activation by carbonic anhydrase 9 and phospho-4E-BP1 immunostaining, respectively.…”

Section: Genetic Mouse Models Of Renal Cell Carcinomamentioning

confidence: 99%

Genetic and metabolic hallmarks of clear cell renal cell carcinoma

Sanchez

Simon

2018

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

120

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Clear cell renal cell carcinoma (ccRCC) is a malignancy characterized by deregulated hypoxia-inducible factor signaling, mutation of several key chromatin modifying enzymes, and numerous alterations in cellular metabolism. Pre-clinical studies have historically been limited to cell culture models, however, the identification of critical tumor suppressors and oncogenes from large-scale patient sequencing data has led to several new genetically engineered mouse models with phenotypes reminiscent of ccRCC. In this review, we summarize recent literature on these topics and discuss how they inform targeted therapeutic approaches for the treatment of ccRCC.

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Combined mutation in Vhl, Trp53 and Rb1 causes clear cell renal cell carcinoma in mice

Cited by 117 publications

References 56 publications

Analysis of potential genes associated with primary cilia in bladder cancer

Analysis of potential genes associated with primary cilia in bladder cancer

Clear cell carcinomas of the ovary and kidney: clarity through genomics

Genetic and metabolic hallmarks of clear cell renal cell carcinoma

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