title: Absence of VHL gene alteration and high VEGF expression are associated with tumour aggressiveness and poor survival of renal-cell carcinoma.
abstract: BACKGROUND
  The von Hippel-Lindau gene (VHL) alteration, a common event in sporadic clear-cell renal-cell carcinoma (CCRCC), leads to highly vascularised tumours. Vascular endothelial growth factor (VEGF) is the major factor involved in angiogenesis, but the prognostic significance of both VHL inactivation and VEGF expression remain controversial. The aims of this study were to analyse the relationship between VHL genetic and epigenetic alterations, VHL expression and VEGF tumour or plasma expression, and to analyse their respective prognostic value in patients with CCRCC.
  
  
  METHODS
  A total of 102 patients with CCRCC were prospectively analysed. Alterations in VHL were determined by sequencing, Multiplex Ligation-dependent Probe Amplification (MLPA) and methylation-specific MLPA. Expression of pVHL and VEGF was determined by immunohistochemistry. Plasma VEGF was measured by enzyme-linked immunosorbent assay (ELISA).
  
  
  RESULTS
  VHL mutation, deletion and promoter methylation were identified in 70, 76 and 14 cases, respectively. Overall, at least one VHL-gene alteration occurred in 91 cases (89.2%). Both VEGF tumour and plasma expression appeared to be decreased in case of VHL alteration. Median progression-free survival and CCRCC-specific survival were significantly reduced in patients with wild-type VHL or altered VHL and high VEGF expression, which, therefore, represent two markers of tumour aggressiveness in CCRCC.
  
  
  CONCLUSIONS
  Stratifying CCRCCs according to VHL and VEGF status may help tailor therapeutic strategy.
authors.affiliation: Department of Urology, Rennes University Hospital, Rennes, France. jean-jacques.patard@univ-rennes1.fr
authors.forename: J-J
authors.initials: JJ
authors.lastname: Patard
authors.forename: N
authors.initials: N
authors.lastname: Rioux-Leclercq
authors.forename: D
authors.initials: D
authors.lastname: Masson
authors.forename: S
authors.initials: S
authors.lastname: Zerrouki
authors.forename: F
authors.initials: F
authors.lastname: Jouan
authors.forename: N
authors.initials: N
authors.lastname: Collet
authors.forename: C
authors.initials: C
authors.lastname: Dubourg
authors.forename: B
authors.initials: B
authors.lastname: Lobel
authors.forename: M
authors.initials: M
authors.lastname: Denis
authors.forename: P
authors.initials: P
authors.lastname: Fergelot
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D019175:DNA Methylation; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human