Mutations of the VHL tumour suppressor gene in renal carcinoma

Gnarra, James R.; Tory, Kálmán; Weng, Yongkai; Schmidt, Laura S.; Wei, Ming Hui; Li, H.; Latif, Farida; Liu, S.; Chen, F.; Duh, Fuh Mei; Lubensky, Irina A.; Duan, Delin; Florence, Charles D.; Pozzatti, Rudy; Walther, McClellan M.; Bander, Neil H.; Grossman, H. Barton; Brauch, Hiltrud; Pomer, S.; Brooks, James D.; Isaacs, William B.; Lerman, Michael I.; Zbar, Berton; Linehan, W. Marston

doi:10.1038/ng0594-85

Cited by 1,571 publications

(1,064 citation statements)

References 18 publications

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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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Section: Discussionsupporting

confidence: 63%

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

et al. 2004

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“…Thus, the epigenetic inactivation of HOXB13 is independent of the VHL status. This may help us to elucidate the tumorigenic mechanisms of RCCs that lack VHL inactivation, which constitute approximately 40% of the sporadic clear cell RCC cases (Foster et al, 1994;Gnarra et al, 1994;Herman et al, 1994;Shuin et al, 1994Shuin et al, , 1999. Notably, multivariate analysis of the clinicopathological parameters using a logistic regression model showed that HOXB13 methylation correlated significantly with tumor grade and microvessel invasion.…”

Section: Discussionmentioning

confidence: 99%

“…There are more than 30 000 newly diagnosed cases in the USA and 7000 occur in Japan every year. Previous studies revealed that the von Hippel-Lindau (VHL) gene is the major tumor suppressor gene that participates in the development of human RCC, as it is inactivated, mostly by genetic alterations, in about 60% of sporadic RCC cases (Foster et al, 1994;Gnarra et al, 1994;Herman et al, 1994;Shuin et al, 1994Shuin et al, , 1999. However, the tumorigenic mechanisms for the sporadic RCCs that lack VHL gene inactivation and the multi-step processes involved in RCC progression remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic inactivation of the candidate tumor suppressor gene HOXB13 in human renal cell carcinoma

Okuda¹,

Toyota

Ishida

et al. 2005

Oncogene

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Epigenetic alterations like DNA methylation and the resulting inactivation of cancer-related genes often contribute to the development of various cancers. To identify the genes that are silenced by aberrant methylation in renal cell carcinoma (RCC), we subjected two RCC lines to methylated CpG island amplification/representational difference analysis. This identified 27 CpG islands. Combined bisulfite restriction analysis of these CpG islands in primary RCC cases revealed that four were methylated in a tumor-specific manner. One of these was identified as the human homeo-box gene B13 (HOXB13) gene, but the remaining three CpG islands were not associated with known genes. The methylation frequencies of HOXB13 in primary RCC samples and lines were 30 and 73%, respectively. The methylation status of HOXB13 correlated with the loss of its expression both in RCC lines and primary tumors, and methyltransferase inhibitor treatment induced the recovery of its expression. Exogenous expression of HOXB13 in RCC cells that lacked endogenous HOXB13 expression suppressed colony formation and induced apoptotic features. Furthermore, HOXB13 methylation correlated positively with tumor grade and microvessel invasion. These results suggest that HOXB13 is a novel candidate tumor suppressor gene in RCC and that its inactivation may play an important role in both RCC tumorigenesis and progression.

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“…Over half of all sporadic clear cell RCCs carry biallelic inactivation of both VHL alleles (Foster et al, 1994;Gnarra et al, 1994;Shuin et al, 1994). However, the molecular pathway by which the VHL protein (pVHL) modulates the expression of target genes leading to tumorigenesis cannot be explained for all cases of clear cell RCC.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in the VHL gene, which is the first causative gene identified for VHL syndrome, are detectable in 30-60% of sporadic clear cell RCCs (Gnarra et al, 1994;Shuin et al, 1994;Schraml et al, 2002). Furthermore, inactivation of VHL through methylation or loss of heterozygosity (LOH) occurs frequently in clear cell RCC (Herman et al, 1994;Moch et al, 1998;Brauch et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Sporadic human renal tumors display frequent allelic imbalances and novel mutations of the HRPT2 gene

et al. 2006

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Inactivation of the HRPT2 gene encoding parafibromin was recently linked to the familial hyperparathyroidismjaw tumor syndrome. Patients with this syndrome carry an increased risk of parathyroid and renal tumors. To determine the relevance of HRPT2 for sporadic renal tumors, clear cell, papillary and chromophobe renal cell carcinomas as well as oncocytomas and Wilms tumors were analysed for HRPT2 gene alterations. Loss of heterozygosity (LOH) of HRPT2 was found in seven of 56 (12.5%) clear cell, three of 14 (21%) papillary, six of 10 (60%) chromophobe renal cell carcinomas, three of eight (38%) oncocytomas and four of 10 (40%) Wilms tumors. In addition, two novel HRPT2 point mutations, causing K34Q and R292K changes in parafibromin, were detected in one clear cell carcinoma and one Wilms tumor, respectively. These tumors displayed LOH of the remaining wild-type allele, but interestingly no von HippelLindau (VHL) mutation. Functional analysis revealed that the K34Q mutant species of parafibromin is, unlike wild-type protein, defective in suppressing cyclin D1 expression in vivo. Taken together, these results suggest that renal cancer-associated mutations in parafibromin occur in the absence of VHL mutation, which in turn may contribute to constitutively elevated cyclin D1 expression and abnormal cell proliferation.

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Mutations of the VHL tumour suppressor gene in renal carcinoma

Cited by 1,571 publications

References 18 publications

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

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

Epigenetic inactivation of the candidate tumor suppressor gene HOXB13 in human renal cell carcinoma

Sporadic human renal tumors display frequent allelic imbalances and novel mutations of the HRPT2 gene

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