COMBINED VHLH AND PTEN MUTATION CAUSES GENITAL TRACT CYSTADENOMA AND SQUAMOUS METAPLASIA

Institute of Cell Biology, ETH Zurich, Zurich, Switzerland; Institute of Surgical Pathology, Department of Pathology, University Hospital Zurich, Zurich, Switzerland; Génétique Oncologique EPHE, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, and CNRS FRE-2939, Institute de Cancerologie Gustave Roussy, Villejuif, France; Surgical Neurology Branch, NINDS, National Institutes of Health, Bethesda, MD, USA

^* To whom correspondence should be addressed. Email: wilhelm.krek{at}cell.biol.ethz.ch.

	Abstract

Patients with von Hippel-Lindau (VHL) disease develop tumours in a range of tissues but existing mouse models of Vhlh mutation have failed to reproduce these lesions. Epididymal cystadenomas arise frequently in VHL patients but VHL mutation alone is believed to be insufficient for tumour formation, implying a requirement for cooperating mutations in epididymal pathogenesis. Here we show that epididymal cystadenomas from VHL patients frequently also lack expression of the PTEN tumour suppressor and display activation of PI3K pathway signalling. Strikingly, while conditional inactivation of either Vhlh or Pten in epithelia of the mouse genital tract fails to produce a tumour phenotype, their combined deletion causes benign genital tract tumours with regions of squamous metaplasia and cystadenoma. The latter are histologically identical to lesions found in VHL patients. Importantly, these lesions are characterised by expansion of basal stem cells, high levels of expression and activity of HIF1 and HIF2 and dysregulation of PI3K signalling. Our studies suggest a model for cooperative tumour suppression in which inactivation of PTEN facilitates epididymal cystadenoma genesis initiated by loss of VHL.