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

Nature Medicine volume 23, pages 869877 (2017) | Download Citation


Clear cell renal cell carcinomas (ccRCCs) frequently exhibit inactivation of the von Hippel–Lindau tumor-suppressor gene, VHL, and often harbor multiple copy-number alterations in genes that regulate cell cycle progression. We show here that modeling these genetic alterations by combined deletion of Vhl, Trp53 and Rb1 specifically in renal epithelial cells in mice caused ccRCC. These tumors arose from proximal tubule epithelial cells and shared molecular markers and mRNA expression profiles with human ccRCC. Exome sequencing revealed that mouse and human ccRCCs exhibit recurrent mutations in genes associated with the primary cilium, uncovering a mutational convergence on this organelle and implicating a subset of ccRCCs as genetic ciliopathies. Different mouse tumors responded differently to standard therapies for advanced human ccRCC, mimicking the range of clinical behaviors in the human disease. Inhibition of hypoxia-inducible factor (HIF)-α transcription factors with acriflavine as third-line therapy had therapeutic effects in some tumors, providing preclinical evidence for further investigation of HIF-α inhibition as a ccRCC treatment. This autochthonous mouse ccRCC model represents a tool to investigate the biology of ccRCC and to identify new treatment strategies.

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This work was supported by grants to I.J.F. from the Swiss National Science Foundation (PP00P3_128257), the European Research Council (260316) and the VHL Family Alliance. We are most grateful to Johannes Loffing (University of Zurich), Jürg Biber (University of Zurich) and the late Patrick Pollard (University of Oxford) for providing antibodies.

Author information


  1. Institute of Physiology, University of Zurich, Zurich, Switzerland.

    • Sabine Harlander
    • , Désirée Schönenberger
    • , Antonella Catalano
    • , Laura Brandt
    •  & Ian J Frew
  2. Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.

    • Sabine Harlander
    •  & Ian J Frew
  3. NEXUS Personalized Health Technologies, ETH Zurich, Zurich, Switzerland.

    • Nora C Toussaint
    •  & Michael Prummer
  4. SIB Swiss Institute of Bioinformatics, Zurich, Switzerland.

    • Nora C Toussaint
    •  & Michael Prummer
  5. BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.

    • Antonella Catalano
    •  & Ian J Frew
  6. Center for Translational Cell Research, Clinic of Internal Medicine I, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

    • Antonella Catalano
    •  & Ian J Frew
  7. Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.

    • Holger Moch
    •  & Peter J Wild


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I.J.F. and S.H. designed the study; S.H., D.S., A.C. and L.B. conducted experiments; N.C.T., M.P., I.J.F. and S.H. conducted bioinformatic analyses; P.J.W. and H.M. conducted pathological analyses; I.J.F. wrote the manuscript with input from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ian J Frew.

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–9.

Excel files

  1. 1.

    Supplementary Table 1

    RNA sequencing analysis of normal kidney cortices and mouse ccRCCs.

  2. 2.

    Supplementary Table 2

    Copy number variations in mouse ccRCCs.

  3. 3.

    Supplementary Table 3

    Collation of high impact mutations and high VAF SNVs in mouse ccRCC tumours.

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