title: VHL-gene deletion in single renal tubular epithelial cells and renal tubular cysts: further evidence for a cyst-dependent progression pathway of clear cell renal carcinoma in von Hippel-Lindau disease.
abstract: Inheritance of a mutant allele of the von Hippel-Lindau tumor suppressor gene predisposes affected individuals to develop renal cysts and clear cell renal cell carcinoma. Von Hippel-Lindau gene inactivation in single renal tubular cells has indirectly been showed by immunohistochemical staining for the hypoxia-inducible factor alpha target gene product carbonic anhydrase IX. In this study we were able to show von Hippel-Lindau gene deletion in carbonic anhydrase IX positive nonneoplastic renal tubular cells, in epithelial cells lining renal cysts and in a clear cell renal cell carcinoma of a von Hippel-Lindau patient. This was carried out by means of laser confocal microscopy and immunohistochemistry in combination with fluorescence in situ hybridization. Carbonic anhydrase IX negative normal renal tubular cells carried no von Hippel-Lindau gene deletion. Furthermore, recent studies have indicated that the von Hippel-Lindau gene product is necessary for the maintenance of primary cilia stability in renal epithelial cells and that disruption of the cilia structure by von Hippel-Lindau gene inactivation induces renal cyst formation. In our study, we show a significant shortening of primary cilia in epithelial cells lining renal cysts, whereas, single tubular cells with a von Hippel-Lindau gene deletion display to a far lesser extent signs of cilia shortening. Our in vivo results support a model in which renal cysts represent precursor lesions for clear cell renal cell carcinoma and arise from single renal tubular epithelial cells owing to von Hippel-Lindau gene deletion.
authors.affiliation: Department of Pathology, Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland. matteo.montani@usz.ch
authors.forename: Matteo
authors.initials: M
authors.lastname: Montani
authors.forename: Karl
authors.initials: K
authors.lastname: Heinimann
authors.forename: Adriana
authors.initials: A
authors.lastname: von Teichman
authors.forename: Thomas
authors.initials: T
authors.lastname: Rudolph
authors.forename: Aurel
authors.initials: A
authors.lastname: Perren
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
mesh_terms: D000328:Adult; D000951:Antigens, Neoplasm / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D002923:Cilia / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D004847:Epithelial Cells / Q000473:pathology*; D017353:Gene Deletion; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D052177:Kidney Diseases, Cystic / Q000235:genetics* / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D018613:Microscopy, Confocal; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D006623:von Hippel-Lindau Disease / Q000150:complications / Q000473:pathology
chemical_list: D000951:Antigens, Neoplasm; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C497446:VHL protein, human