title: VHL mutations and their correlation with tumour cell proliferation, microvessel density, and patient prognosis in clear cell renal cell carcinoma.
abstract: Mutations of the von Hippel-Lindau (VHL) gene are considered critical for the initiation of clear cell renal cell carcinoma. The VHL protein is involved in regulation of the cell cycle and neo-vascularization. In this study, the association of VHL mutations with tumour cell proliferation, angiogenesis, and clinical outcome was analysed in 113 clear cell renal cell carcinomas. The degree of angiogenesis and tumour cell proliferation was immunohistochemically determined by counting microvessels (microvessel density, anti-CD34 antibody) and cells with proliferating activity (Ki-67 labelling index, MIB-1 antibody). Forty-eight different VHL sequence alterations were found in 38 of 113 patients (34%) by direct sequencing. Nineteen VHL mutations were frameshifts and nonsense mutations, predicted to change the open reading frame of VHL. These 'loss-of-function' mutations correlated with worse prognosis in univariate analysis (p=0.02). Tumour grade, stage, microvessel density, and tumour cell proliferation were not associated with VHL alterations. These findings may indicate that 'loss-of-function' VHL mutations are involved in the progression of a clear cell renal cell carcinoma subset, whereas regulation of angiogenesis and proliferation of renal carcinoma in vivo is apparently not directly influenced by VHL alterations.
authors.affiliation: Institute of Pathology, University of Basel, Schönbeinstrasse 40, CH-4031 Basel, Switzerland. Peter.Schraml@unibas.ch
authors.forename: Peter
authors.initials: P
authors.lastname: Schraml
authors.forename: Kirsten
authors.initials: K
authors.lastname: Struckmann
authors.forename: Florian
authors.initials: F
authors.lastname: Hatz
authors.forename: Stefan
authors.initials: S
authors.lastname: Sonnet
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kully
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mihatsch
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
mesh_terms: D000704:Analysis of Variance; D014408:Biomarkers, Tumor / Q000032:analysis*; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000235:genetics* / Q000401:mortality; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D019394:Ki-67 Antigen / Q000032:analysis; D007680:Kidney Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000401:mortality; D008025:Ligases / Q000235:genetics*; D009154:Mutation; D009389:Neovascularization, Pathologic; D016133:Polymerase Chain Reaction / Q000379:methods; D011379:Prognosis; D017422:Sequence Analysis, DNA; D015996:Survival Rate; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D008025:Ligases; C497446:VHL protein, human