Somatic VHL alteration and its impact on prognosis in patients with clear cell renal cell carcinoma

Kim, J. H.; Kim, H. Y.; Jung, Chul Won; Lee, S.-H.; Kim, K.; Kim, W. S.; Park, Y. S.; Im, Young‐Hyuck; Kang, Woodae; Park, K.

doi:10.1200/jco.2005.23.16_suppl.4602

Cited by 35 publications

(59 citation statements)

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“…Several other studies, however, were not able to correlate VHL status to clinicopathological parameters or prognosis (Brauch et al, 2000;Kim et al, 2005;Smits et al, 2008), and others linked VHL alteration with more advanced tumour stages (Schraml et al, 2002). These discrepancies may be partially explained by recruitment bias with an insufficient number of small incidental tumours, or the fact that TNM grouping was used and not separated in T, N and M stage.…”

Section: Discussionmentioning

confidence: 62%

Absence of VHL gene alteration and high VEGF expression are associated with tumour aggressiveness and poor survival of renal-cell carcinoma

et al. 2009

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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.

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Section: Discussionmentioning

confidence: 62%

Absence of VHL gene alteration and high VEGF expression are associated with tumour aggressiveness and poor survival of renal-cell carcinoma

et al. 2009

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“…When assessing the VHL mutational status in our cohort, we found that VHL coding sequence was mutated in 51 % of cases, with exon 1 being the most mutated, as already shown in a previous study [8]. A wide discrepancy exists in literature about the VHL mutation frequency in ccRCC, ranging between 21 and 66 % [22,23], which may be explained by the different ethnic origin of the populations recruited in the different studies or, more importantly, by the differential efficiency of the technical approaches applied (for example Sanger sequencing is more sensitive than SSCP).…”

Section: Discussionmentioning

confidence: 50%

“…Although not involved in the process of hydroxylation [14], this SNP may confer susceptibility to renal cancerogenesis and progression. Supporting this hypothesis, Kim et al [8] showed that the Pro582Ser change contributes to the development of metastases. When comparing the distribution of this SNP in our cohort with the 1000 Genome Project data, we found that the T allele frequency was higher in the ccRCC patients compared with the healthy subjects.…”

Section: Discussionmentioning

confidence: 65%

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VHL and HIF-1α: gene variations and prognosis in early-stage clear cell renal cell carcinoma

et al. 2014

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Von Hipple-Lindau gene (VHL) inactivation represents the most frequent abnormality in clear cell renal cell carcinoma (ccRCC). Hypoxia-inducible factor-1a (HIF-1a) expression is regulated by O 2 level. In normal O 2 conditions, VHL binds HIF-1a and allows HIF-1a proteasomal degradation. A single-nucleotide polymorphism (SNP) has been found located in the oxygen-dependent degradation domain at codon 582 (C1772T, rs11549465, Pro582Ser). In hypoxia, VHL/HIF-1a interaction is abolished and HIF-1a activates target genes in the nucleus. This study analyzes the impact of genetic alterations and protein expression of VHL and the C1772T SNP of HIF-1a gene (HIF-1a) on prognosis in early-stage ccRCC (pT1a, pT1b, and pT2). Mutational analysis of the entire VHL sequence and the genotyping of HIF-1a C1772T SNP were performed together with VHL promoter methylation analysis and loss of heterozygosis (LOH) analysis at (3p25) locus. Data obtained were correlated with VHL and HIF-1a protein expression and with tumor-specific survival (TSS). VHL mutations, methylation status, and LOH were detected in 51, 11, and 12 % of cases, respectively. Our results support the association between biallelic alterations and/or VHL silencing with a worse TSS. Moreover, we found a significant association between the HIF-1a C1772C genotype and a worse TSS. The same association was found when testing the presence of HIF-1a protein in the nucleus. Our results highlight the role of VHL/HIF-1a pathway in RCC and support the molecular heterogeneity of earlystage ccRCC. More important, we show the involvement of HIF-1a C1772T SNP in ccRCC progression.

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“…Diese Daten sind jedoch äußerst widersprüchlich. Während einige Arbeiten eine VHL-abhängige Prognose postulieren [14,20], konnten andere Studien keine Assoziation zwischen VHLFunktion/Mutation und Überleben von kNZK-Patienten erkennen [1,8] versprechend und verdeutlichen die Mög-lichkeiten von Genexpressionanalysen in der Pathologie [6]. Studien über den Zusammenhang zwischen VHL-Mutationen und Genexpressionsmuster fehlen jedoch bisher in der Literatur.…”

Section: Diskussionunclassified

Von-Hippel-Lindau-Gen-Mutationstypen

Luu¹,

Fischer

Teichman³

et al. 2008

Pathologe

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Somatic VHL alteration and its impact on prognosis in patients with clear cell renal cell carcinoma

Cited by 35 publications

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Absence of VHL gene alteration and high VEGF expression are associated with tumour aggressiveness and poor survival of renal-cell carcinoma

Absence of VHL gene alteration and high VEGF expression are associated with tumour aggressiveness and poor survival of renal-cell carcinoma

VHL and HIF-1α: gene variations and prognosis in early-stage clear cell renal cell carcinoma

Von-Hippel-Lindau-Gen-Mutationstypen

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