Combined mutation of Vhl and Trp53 causes renal cysts and tumours in mice

Joachim Albers,Michal Rajski,Adriana Von Teichman,Ian J Frew,Wilhelm Krek,Peter J Wild,Peter Schraml,Désirée Schönenberger,Holger Moch,Sabine Harlander,Strahil Georgiev

doi:10.1002/emmm.201202231

Joachim Albers, Michal Rajski + Show 9 more

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https://doi.org/10.1002/emmm.201202231

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Abstract

The combinations of genetic alterations that cooperate with von Hippel–Lindau (VHL) mutation to cause clear cell renal cell carcinoma (ccRCC) remain poorly understood. We show that the TP53 tumour suppressor gene is mutated in approximately 9% of human ccRCCs. Combined deletion of Vhl and Trp53 in primary mouse embryo fibroblasts causes proliferative dysregulation and high rates of aneuploidy. Deletion of these genes in the epithelium of the kidney induces the formation of simple cysts, atypical cysts and neoplasms, and deletion in the epithelia of the genital urinary tract leads to dysplasia and tumour formation. Kidney cysts display a reduced frequency of primary cilia and atypical cysts and neoplasms exhibit a pro-proliferative signature including activation of mTORC1 and high expression of Myc, mimicking several cellular and molecular alterations seen in human ccRCC and its precursor lesions. As the majority of ccRCC is associated with functional inactivation of VHL, our findings suggest that for a subset of ccRCC, loss of p53 function represents a critical event in tumour development.

Highlights

Clear cell renal cell carcinoma accounts for approximately 80% of kidney tumours and thereby approximately 2.5% of all types of human malignancy
We show that TP53 is mutated in a subset of sporadic human clear cell renal cell carcinoma (ccRCC) and demonstrate genetically that Trp53 mutation allows Vhl null mouse embryo fibroblasts (MEFs) to escape senescence and proliferate in an immortalized manner
We show that combined deletion of Vhl and Trp53 in mice results in the formation of simple and atypical cysts, as well as neoplastic lesions in kidneys and causes tumours to form in other genital tract tissues

Summary

Introduction

Clear cell renal cell carcinoma (ccRCC) accounts for approximately 80% of kidney tumours and thereby approximately 2.5% of all types of human malignancy. The von Hippel–Lindau (VHL) tumour suppressor gene is mutated, deleted or epigenetically silenced in up to 85% of all sporadic cases of ccRCC (Maher, 2013). Germline inheritance of a single mutant allele of VHL gives rise to the dominantly inherited VHL familial cancer syndrome which predisposes to the formation of ccRCC, and to cystic lesions in the kidney and pancreas as (1) Institute of Physiology, University of Zurich, Zurich, Switzerland (2) Competence Center for Systems Physiology and Metabolic Diseases, ETH. Kidneys of patients with an inherited VHL mutation frequently display cystic lesions as well as ccRCC.

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