VHL mutations and their correlation with tumour cell proliferation, microvessel density, and patient prognosis in clear cell renal cell carcinoma.
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.
Schraml
Peter
P
Institute of Pathology, University of Basel, Schönbeinstrasse 40, CH-4031 Basel, Switzerland. Peter.Schraml@unibas.ch
Struckmann
Kirsten
K
Hatz
Florian
F
Sonnet
Stefan
S
Kully
Charlotte
C
Gasser
Thomas
T
Sauter
Guido
G
Mihatsch
Michael J
MJ
Moch
Holger
H
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
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