VHL Tumor Suppressor Gene Alterations Associated With Good Prognosis in Sporadic Clear-Cell Renal Carcinoma

Yao, Masahiro; Yoshida, Minoru; Kishida, Takeshi; Nakaigawa, Noboru; M, Baba; Kobayashi, Kazuki; Miura, Takeshi; Moriyama, Masatoshi; Nagashima, Yoji; Nakatani, Yukio; Kubota, Yoshinobu; Kondo, Keiichi

doi:10.1093/jnci/94.20.1569

Cited by 225 publications

(148 citation statements)

References 26 publications

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“…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).…”

Section: Mutated Vhl Rcc Cells and Nk Cell Activationsupporting

confidence: 89%

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

et al. 2011

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The tumor suppressor gene von Hippel-Lindau (VHL) is involved in the development of sporadic clear-cell renal cell carcinoma (RCC). VHL interferes with angiogenesis and also controls cell adhesion and invasion. Therapies that target VHL-controlled genes are currently being evaluated in RCC patients. RCC is a immunogenic tumor and treatment with interleukin-2 (IL2) or interferon (IFN)-a results in regression in some patients. We used two renal tumor cell lines (RCC6 and RCC4) carrying VHL loss-of-function mutations to investigate the role of mutant VHL in susceptibility to natural killer (NK) cellmediated lysis. The RCC6 and RCC4 cell lines were transfected with the wild-type gene to restore the function of VHL. The presence of the gene in RCC cells downregulated hypoxia-inducible factor (HIF)-1a and subsequently decreased vascular endothelial growth factor (VEGF) production. Relative to control transfectants and parental cells, pVHL-transfected cell lines activated resting and IL2-activated NK cells less strongly, as assessed by IFNc secretion, NK degranulation and cell lysis. NKG2A, a human leukocyte antigen (HLA)-Ispecific inhibitory NK receptor, controls the lysis of tumor targets. We show that HLA-I expression in RCC-pVHL cells is stronger than that in parental and controls cells, although the expression of activating receptor NK ligands remains unchanged. Blocking NKG2A/HLA-I interactions substantially increased lysis of RCC-pVHL, but had little effect on the lysis of VHL-mutated RCC cell lines. In addition, in response to IFNa, the exponential growth of RCC-pVHL was inhibited more than that of RCC-pE cells, indicating that VHL mutations may be involved in IFNa resistance. These results indicate that a decreased expression of HLA-I molecules in mutated VHL renal tumor cells sensitizes them to NK-mediated lysis. These results suggest that combined immunotherapy with antiangiogenic drugs may be beneficial for patients with mutated VHL.

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Section: Mutated Vhl Rcc Cells and Nk Cell Activationsupporting

confidence: 89%

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

et al. 2011

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“…Few studies have addressed the issue of clinical impacts of somatic VHL alterations in sporadic RCCs reporting, however, conflicting results [2,15,26]. Brauch et al [2] have showed a significant association between VHL alterations (mutation and methylation) and advanced RCC tumor stage.…”

Section: Discussionmentioning

confidence: 99%

“…This SNP leads to a proline to serine substitution at codon 582 [13,14]. Although C1772T has been shown not to affect the hydroxylation process [15], it might confer susceptibility to RCC and its presence has been demonstrated to correlate with the development of metastases [14]. Here, we evaluated the prognostic significance of such SNP in ccRCC patients.…”

Section: Introductionmentioning

confidence: 99%

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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VHL Tumor Suppressor Gene Alterations Associated With Good Prognosis in Sporadic Clear-Cell Renal Carcinoma

Abstract: The VHL alteration status may provide useful prognostic information, as a biomolecular marker, for patients with stage I-III clear-cell RCC who have undergone nephrectomy.

Cited by 225 publications

References 26 publications

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

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