Inactivation of the von Hippel–Lindau (
            <i>VHL</i>
            ) tumour suppressor gene and allelic losses at chromosome arm 3p in primary renal cell carcinoma: Evidence for a
            <i>VHL</i>
            ‐independent pathway in clear cell renal tumourigenesis

Clifford, Steven C.; Prowse, Amanda; Affara, Nabeel A.; Buys, Charles H.C.M.; Maher, Eamonn R.

doi:10.1002/(sici)1098-2264(199807)22:3<200::aid-gcc5>3.0.co;2-#

Cited by 242 publications

(150 citation statements)

References 34 publications

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“…This is consistent with the fact that in 70% of CC-RCC there is a constitutive activation of HIF, through VHL inactivation (Clifford et al, 1998). Nevertheless differences in HIF1a expression were seen between low-and high-grade CC-RCC.…”

Section: Discussionsupporting

confidence: 89%

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High-grade clear cell renal cell carcinoma has a higher angiogenic activity than low-grade renal cell carcinoma based on histomorphological quantification and qRT–PCR mRNA expression profile

et al. 2007

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Clear cell renal cell carcinoma (CC-RCC) is a highly vascularised tumour and is therefore an attractive disease to study angiogenesis and to test novel angiogenesis inhibitors in early clinical development. Endothelial cell proliferation plays a pivotal role in the process of angiogenesis. The aim of this study was to compare angiogenesis parameters in low nuclear grade (n ¼ 87) vs high nuclear grade CC-RCC (n ¼ 63). A panel of antibodies was used for immunohistochemistry: CD34/Ki-67, carbonic anhydrase IX, hypoxia-inducible factor-1a (HIF-1a) and vascular endothelial growth factor (VEGF). Vessel density (MVD -microvessel density), endothelial cell proliferation fraction (ECP%) and tumour cell proliferation fraction (TCP%) were assessed. mRNA expression levels of angiogenesis stimulators and inhibitors were determined by quantitative RT -PCR. High-grade CC-RCC showed a higher ECP% (P ¼ 0.049), a higher TCP% (P ¼ 0.009), a higher VEGF protein expression (Po0.001), a lower MVD (Po 0.001) and a lower HIF-1a protein expression (P ¼ 0.002) than low-grade CC-RCC. Growth factor mRNA expression analyses revealed a higher expression of angiopoietin 2 in low-grade CC-RCC. Microvessel density and ECP% were inversely correlated (Rho ¼ À0.26, P ¼ 0.001). Because of the imperfect association of nuclear grade and ECP% or MVD, CC-RCC was also grouped based on low/high MVD and ECP%. This analysis revealed a higher expression of vessel maturation and stabilisation factors (placental growth factor, PDGFB1, angiopoietin 1) in CC-RCC with high MVD, a group of CC-RCC highly enriched in low nuclear grade CC-RCC, with low ECP%. Our results suggest heterogeneity in angiogenic activity and vessel maturation of CC-RCC, to a large extent linked to nuclear grade, and, with probable therapeutic implications.

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Section: Discussionsupporting

confidence: 89%

“…Aberrations of the von Hippel-Lindau (VHL) tumour suppressor gene have been shown to be an early and distinct event in the development of CC-RCC (Kaelin, 2004). In up to 70% of CC-RCC, somatic VHL gene inactivation occurs (Clifford et al, 1998). The VHL gene product (pVHL) binds the hypoxia-inducible factor 1a (HIF-1a) in normoxic cells.…”

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confidence: 99%

High-grade clear cell renal cell carcinoma has a higher angiogenic activity than low-grade renal cell carcinoma based on histomorphological quantification and qRT–PCR mRNA expression profile

et al. 2007

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“…The most frequent genetic change in RCC is somatic inactivation of the VHL TSG (usually be mutation and loss, but promoter methylation may also occur), although VHL inactivation is specific for clear cell RCC (Foster et al, 1994;Gnarra et al, 1994;Clifford et al, 1998). Combining the results of the current study with previous investigations, frequent epigenetic changes (X20%) in RCC include promoter methylation of RASSF1A, TIMP3, DAPK, SLIT2, MT1G and GSTP1 (Esteller et al, 2001a;Nojima et al, 2001, Dreijerink et al, 2001Morrissey et al, 2001, Morris et al, 2003.…”

Section: Discussionsupporting

confidence: 63%

SLIT2 promoter methylation analysis in neuroblastoma, Wilms' tumour and renal cell carcinoma

et al. 2004

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The 3p21.3 RASSF1A tumour suppressor gene (TSG) provides a paradigm for TSGs inactivated by promoter methylation rather than somatic mutations. Recently, we identified frequent promoter methylation without somatic mutations of SLIT2 in lung and breast cancers, suggesting similarities between SLIT2 and RASSF1A TSGs. Epigenetic inactivation of RASSF1A was first described in lung and breast cancers and subsequently in a wide range of human cancers including neuroblastoma, Wilms' tumour and renal cell carcinoma (RCC). These findings prompted us to investigate SLIT2 methylation in these three human cancers. We analysed 49 neuroblastomas (NBs), 37 Wilms' tumours and 48 RCC, and detected SLIT2 promoter methylation in 29% of NB, 38% of Wilms' tumours and 25% of RCC. Previously, we had demonstrated frequent RASSF1A methylation in the same tumour series and frequent CASP8 methylation in the NB and Wilms' tumour samples. However, there was no significant association between SLIT2 promoter methylation and RASSF1A or CASP8 methylation in NB and RCC. In Wilms' tumour, there was a trend for a negative association between RASSF1A and SLIT2 methylation, although this did not reach statistical significance. No associations were detected between SLIT2 promoter methylation and specific clinicopathological features in the tumours analysed. These findings implicate SLIT2 promoter methylation in the pathogenesis of both paediatric and adult cancers and suggest that further investigations of SLIT2 in other tumour types should be pursued. However, epigenetic inactivation of SLIT2 is less frequent than RASSF1A in the tumour types analysed.

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“…Our data support the second model and strongly suggest that cellular pathways involving the TSC genes provide an alternate pathway to clear cell renal carcinogenesis. Other studies in humans (35)(36)(37)(38)(39), rodents (40), and dogs (41) have also suggested the existence of pathways leading to clear cell renal carcinogenesis that do not involve mutations in the VHL genes. In contrast to these previous reports, in which the genetic components of the alternate pathways are unknown, all of the patients in our study are known to have TSC.…”

Section: Discussionmentioning

confidence: 96%

Mutational Analysis of the von Hippel Lindau Gene in Clear Cell Renal Carcinomas from Tuberous Sclerosis Complex Patients

et al. 2002

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Tuberous sclerosis complex (TSC) is an autosomaldominant disorder characterized by seizures, mental retardation, autism, and tumors of multiple organs. Renal disease in TSC includes angiomyolipomas, cysts, and renal cell carcinomas. It is known that somatic mutations in the von Hippel Lindau (VHL) tumor suppressor gene occur in most clear cell renal carcinomas. To determine whether TSCassociated clear cell carcinomas also contain VHL mutations, we analyzed six tumors for loss of heterozygosity in the VHL gene region of chromosome 3p and for mutations in the VHL gene. Four of the patients were women between the ages of 34 and 68 years, and two were males under the age of 21 years. The loss of heterozygosity analysis was performed using polymorphic microsatellite markers, and the mutational analysis was performed using direct sequencing. Chromosome 3p loss of heterozygosity was not detected, and no VHL mutations were identified. These findings suggest that mutations in the TSC1 and TSC2 genes lead to clear cell renal carcinogenesis via an alternate pathway not involving VHL mutations.

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Inactivation of the von Hippel–Lindau ( VHL ) tumour suppressor gene and allelic losses at chromosome arm 3p in primary renal cell carcinoma: Evidence for a VHL ‐independent pathway in clear cell renal tumourigenesis

Cited by 242 publications

References 34 publications

High-grade clear cell renal cell carcinoma has a higher angiogenic activity than low-grade renal cell carcinoma based on histomorphological quantification and qRT–PCR mRNA expression profile

High-grade clear cell renal cell carcinoma has a higher angiogenic activity than low-grade renal cell carcinoma based on histomorphological quantification and qRT–PCR mRNA expression profile

SLIT2 promoter methylation analysis in neuroblastoma, Wilms' tumour and renal cell carcinoma

Mutational Analysis of the von Hippel Lindau Gene in Clear Cell Renal Carcinomas from Tuberous Sclerosis Complex Patients

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