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. Conclusion: Stratifying CCRCCs according to VHL and VEGF status may help tailor therapeutic strategy.

Mutations of the von Hippel–Lindau gene confer increased susceptibility to natural killer cells of clear-cell renal cell carcinoma

“…We report our original data providing evidence that mutant VHL, as found in most sporadic RCC, triggers NK cell activation. Although the correlation between VHL alteration in sporadic RCC and better survival is still controversial (Yao et al, 2002;Banks et al, 2006;Smits et al, 2008), the absence of VHL mutation is associated with tumor aggressiveness and poor survival (Patard et al, 2008(Patard et al, , 2009. Our evidence that NK cells are activated differently by targets that bear or not VHL mutations are consistent with earlier findings that suggest that somatic VHL alteration is associated with better cancer-specific survival among those patients presenting with early stage (pT1 and pT2) clear-cell RCC (Parker et al, 2005).…”

Overexpression of the polarity protein PAR‐3 in clear cell renal cell carcinoma is associated with poor prognosis

“…18 The cell lines were established as stable cell lines after 50 passages. The cells were dissociated and cultured in RPMI 1640 (Invitrogen) supplemented with 10% fetal calf serum (Sigma-Aldrich), 1% penicillin/streptomycin (Sigma-Aldrich) and 10 mM HEPES buffer at 37 C under 5% CO 2 .…”

Implication of VHL, ERK5, and HIF-1alpha in clear cell renal cell carcinoma: Molecular basis

“…This finding is usually present in ccRCC and makes it difficult to correlate increased expression of this protein with the clinical parameters because most tumors overexpress it. Nevertheless, some studies have found greater expression of the protein in tumors with distant metastasis [20]. One of the proteins activated by increased expression of HIF-1alpha is VEGF, a regulator, among other things, of angiogenesis.…”