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

Clear cell renal cell carcinomas (ccRCC) frequently exhibit inactivation of the VHL tumour suppressor gene and often harbour multiple copy number alterations in genes that regulate cell cycle progression. We show here that modelling these genetic alterations by combined renal epithelium-specific deletion of Vhl, Trp53 and Rb1 in mice caused ccRCC. These tumours 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 tumours responded differently to standard therapies for advanced human ccRCC, mimicking the range of clinical behaviours in the human disease. Inhibition of HIF-α transcription factors with Acriflavine as third line therapy had therapeutic effects in some tumours, providing pre-clinical 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.