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
Affiliations: Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands | Department of Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands | Translational Cancer Research Group, Lab Pathology University of Antwerp/University Hospital Antwerp, Edegem; Oncology Center, General Hospital St. Augustinus, Wilrijk, Belgium | Department of Pathology, University Hospital of Leuven, Leuven, Belgium | Department of Urology, University Hospital of Leuven, Leuven, Belgium
Note: [] Corresponding author: M.M. Baldewijns, Department of Pathology, AZ Maastricht, P. Debyelaan 25, NL 6229 HX Maastricht, The Netherlands. Tel.: +31 433876612; Fax: +31 433876613; E-mail: [email protected].
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.
