Ecp% Endothelial Cell Proliferation Fraction Hif Hypoxia-inducible Transcription Factor Mvd Microvessel Density Rcc Renal Cell Carcinoma Tcp% Tumour Cell Proliferation Fraction Vegf Vascular Endothelial Growth Factor Vhl Von Hippel–lindau

Different angiogenic potential in low and high grade sporadic clear cell renal cell carcinoma is not related to alterations in the von Hippel–Lindau gene Abstract. Background: von Hippel–Lindau (VHL) inactivation is common in sporadic clear cell renal cell carcinomas (ccRCC). pVHL is part of the ubiquitin ligase complex that targets the alpha subunits of hypoxia-inducible transcription factor (HIF) for degradation under well-oxygenated conditions. In the absence of wild-type pVHL, as observed in VHL patients and most sporadic ccRCCs, constitutive upregulation of HIF results in transcriptional activation of angiogenesis-related genes, such as VEGF. Differences in angiogenic activity within the group of ccRCCs were reported and strong genotype-phenotype correlations were found in patients with VHL disease, raising a question about the importance of VHL inactivation status in angiogenic behaviour and tumour progression. Methods: To address this question, we investigated the influence of VHL mutation (direct sequencing)/hypermethylation (methylation-specific PCR) on angiogenesis/tumour parameters (immunohistochemistry) in 150 patients with sporadic ccRCC. Results: We found no significant association between VHL mutation or methylation and angiogenesis/tumour parameters. Conclusion: These data indicate that tumour progression and angiogenesis are not directly influenced by VHL alterations and that additional genetic/epigenetic events should be considered to explain the diverse angiogenic and proliferative behaviour during tumour progression. Abbreviations CAIX carbonic anhydrase IX CcRCC clear cell renal cell carcinoma 372 M.M. Baldewijns et al. / Low and high grade sporadic clear cell renal cell carcinoma