Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P43146 (tumour suppressor)
5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene is responsible not only for VHL disease, but also for sporadic renal cell carcinoma and cerebellar haemangioblastoma. The distribution of VHL gene expression in the mouse embryo was recently studied by in situ hybridization, along with human VHL in 14-week-old fetal kidney: there was widely distributed expression in the former and expression in the tubules and blastema in the latter. Adult human tissue and other fetal organs were not examined. The present paper describes an in situ hybridization study to assess the function of the VHL gene in adult human tissues and in tissues of human fetus at 28 weeks of gestation. The expression of the VHL gene was limited to the adult and fetal brain and kidney, and the adult prostate. Nerve cells in adult and fetal brain were positive, including the cerebellar Purkinje cells. In adult and fetal kidney, the proximal tubular epithelium, the putative origin of the common type of renal cell carcinoma, showed intense signal, whereas the distal nephron, glomeruli, and nephrogenic blastema showed no significant signal. The prostate showed significant signal in the basal epithelium. The adrenal, pancreas, and epidydimis showed no significant signal, in spite of the frequent occurrence at these sites of neoplastic or hamartomatous lesions in VHL disease.
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PMID:Von Hippel-Lindau tumour suppressor gene. Localization of expression by in situ hybridization. 895 4

Renal cell carcinomas (RCC) develop as a consequence of somatic mutations of the von Hippel-Lindau (VHL) tumour suppressor gene. Recent epidemiological studies show that high and prolonged occupational exposures to trichloroethene (TRI) are associated with an increased incidence of RCC. Tumour tissues from 23 RCC patients with occupational histories of very high TRI exposure were analysed for somatic mutations within the VHL gene. DNA was isolated from microdissected tumour cells, amplified by polymerase chain reaction (PCR), and analysed in single strand conformation polymorphism (SSCP) and sequencing. RCC tissues of all 23 TRI exposed persons analysed thus far showed aberrations of the VHL gene, with 30% having aberrations in exon 1, 44% in exon 2, and 26% in exon 3. By comparison to much lower reported VHL mutation frequencies of 33-55% in TRI-unexposed RCC patients, these results indicate a specifically high mutation frequency at the VHL gene in TRI-exposed RCC patients; four of these aberrations have thus far been confirmed as VHL mutations by sequence analysis. This finding indicates the VHL gene being a susceptible and specific target in TRI induced renal carcinogenesis. Furthermore, the frequent involvement of exon 2 identifies potential 'hot spots' for this carcinogen. In addition to the available epidemiological studies the results are now further proof for human renal carcinogenicity induced by high occupational exposures to TRI.
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PMID:Renal cell carcinomas in trichloroethene (TRI) exposed persons are associated with somatic mutations in the von Hippel-Lindau (VHL) tumour suppressor gene. 913 12

A probable diagnosis of von Hippel-Lindau disease was made in a two generation family in which the proband had a phaeochromocytoma, renal cysts, and multiple cerebral cavernomas. His sister had multiple similar cerebral vascular lesions and his father died from renal carcinoma aged 42. Although the family did not satisfy the conventional diagnostic criteria for von Hippel-Lindau disease, an underlying germline mutation in the von Hippel-Lindau disease tumour suppressor gene was identified in the proband. Molecular genetic analysis not only confirmed the putative diagnosis of the disease in the proband but also showed that the cerebral vascular lesions segregated independently from the von Hippel-Lindau disease mutation. This report exemplifies how molecular genetic investigations can enhance the diagnosis and management of families with suspected von Hippel-Lindau disease, particularly when the manifestations, as in this family, are not typical.
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PMID:Independent segregation of von Hippel-Lindau disease and cerebral cavernomas. 940 11

Inactivation of tumour suppressor gene(s) (TSGs) on 3p appears to be a critical event in the pathogenesis of clear cell renal cell carcinoma (CC-RCC). Analysis of loss of heterozygosity (LOH) in sporadic RCC samples has implicated roles for TSGs in three specific regions of 3p in RCC development: (1) 3p12-p14, which includes the breakpoint of the familial t(3;8) constitutional translocation involved in hereditary RCC development and a recently cloned putative TSG, the FHIT gene: (2) 3p21.2-p21.3, a common region of deletion in many cancers including lung; and (3) 3p25-p26, which contains the von Hippel-Lindau (VHL) disease TSG. We and others have shown that most primary sporadic CC-RCCs contain somatic VHL gene mutations, clearly implicating inactivation of the VHL gene in the pathogenesis of CC-RCC. It is not known if CC-RCC without VHL gene mutations have alternative mechanisms of VHL gene inactivation or result from an alternative non-VHL pathway to RCC, e.g., inactivation of TSGs in 3p12-p21. We and others have reported hypermethylation and silencing of the VHL TSG in RCC from patients with VHL disease and in CC-RCC cell lines. However, the incidence and specificity of VHL methylation in primary sporadic RCC has not been defined. Therefore, we analysed methylation of the VHL, CDKN2, MYC, and H19 genes in primary RCC samples. Hypermethylation of the VHL promoter region was detected in 11% (11/99) of the primary RCCs analysed. In 10 of these tumours, there was no evidence of concomitant VHL gene mutation. VHL methylation was specific to CC-RCC (15%, 7/45) but was not detected in any non-CC tumours (n = 16). None of the 11 RCCs methylated at VHL had evidence of methylation at either CDKN2 or MYC (methylation at CDKN2 was, however, detected in 3%, or 1/33, of RCCs without VHL methylation). A normal methylation pattern at H19 was demonstrated in the three RCCs with methylated VHL analysed. Previous studies have suggested that, in addition to VHL, other 3p TSGs at 3p12-p14 and 3p21 may be involved in CC-RCC tumourigenesis. However, the interpretation of these studies has been difficult because information on VHL gene status has not been available for these data sets. Therefore, we investigated a subset of 55 sporadic RCCs (of known VHL gene methylation and mutation status) for LOH at polymorphic markers close to candidate TSG loci in the 3p14.2 and 3p21.2-p21.3 regions. Among tumours with LOH at one or more 3p markers, the incidence of 3p25 allele loss was higher in tumours with VHL alterations (mutation or methylation) than in those without. For tumours without detectable VHL alterations, the frequency of 3p14-p21 LOH was significantly higher than the frequency of 3p25-p26 LOH (93%, 13/14 vs. 43%, 6/14; P = 0.013), whereas, in RCC samples with VHL methylation or mutation, the frequency of 3p14-p21 LOH did not differ from that of sp25-p26 (72%, 18/25 vs. 59%, 13/22; P = 0.376). None of the 11 RCCs with 3p25 allele loss that were informative at 3p21 and 3p14 showed LOH at 3p25 only. These findings suggest that (1) VHL methylation is a specific and important event in the pathogenesis of CC-RCC; (2) in CC-RCC with 3p LOH but without VHL inactivation, mutations in TSGs at 3p14-p21 appear to have a primary role in tumourigenesis; and (3) inactivation of other 3p TSGs in addition to VHL may also be required for malignant transformation in tumours with VHL gene inactivation.
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PMID: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. 962 31

Acquired loss of the entire or parts of the short arm of chromosome 3 is a frequent aberration in renal cell carcinoma as well as in other tumour types, indicating the presence of at least one tumour suppressor gene on 3p. Previous studies have defined the distal and proximal ends of one critical region to reside between 3p21 and 3p11, and one gene involved in von Hippel-Lindau disease has been identified at 3p25. Experimental in vitro data has suggested a negative regulator of telomerase activity on chromosome 3. In the present study we investigated the relationship between telomerase activity and loss of heterozygosity (LOH) on 3p in a series of renal cell carcinomas. Telomerase activity was evaluated using the telomeric repeat amplification protocol assay and LOH, by analysis of 17 polymorphic microsatellite markers. Twenty-nine out of 45 tumours (64%) demonstrated telomerase activity and 37 tumours (82%) showed allelic loss of single or multiple areas of chromosome 3p. A significant correlation between LOH of at least one of three markers localised within 4 cM in the region of 3p21.2-3p14.2 and telomerase activity was demonstrated (p=0.0031), as well as for three distal markers within 3 cM at 3p24.3-3p24.1 (p=0.0287). These data suggest the presence of at least two genes with regulatory function on the expression of telomerase. These genes can encode proteins of importance for senescence and/or immortalisation or have a more direct effect on activation of telomerase.
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PMID:Loss of heterozygosity at chromosome 3p correlates with telomerase activity in renal cell carcinoma. 966 24

Von Hippel-Lindau (VHL) disease is a dominantly inherited multisystem family cancer syndrome predisposing to retinal and central nervous system haemangioblastomas, renal carcinoma, phaeochromocytoma, pancreatic islet cell tumours and endolymphatic sac tumours. In addition, renal, pancreatic and epididymal cysts occur. Morbidity and mortality from VHL disease can be reduced by the identification and surveillance of affected individuals and at-risk relatives so that complications are diagnosed at an early presymptomatic stage. The detailed mapping and subsequent isolation of the VHL tumour suppressor gene has enabled molecular genetic analysis in families and patients with definite or possible VHL disease. Initially, linked DNA markers were used in informative families to modify individual risks and then to make appropriate alterations in surveillance programs. However, currently most DNA analysis involves the characterisation of germline mutations. World-wide, mutations have been identified in almost 500 families (including 132 in our laboratory). These studies have revealed considerable heterogeneity both in the type and in the location of mutations within the VHL gene. In our experience, most recurrent mutations result from de novo mutations at hypermutable sequences, although a founder effect for the Tyr98His ('Black Forest') mutation has been reported in German and American families. Although many mutations are predicted to impair the ability of pVHL to combine with the elongin regulatory subunits, analysis of genotype-phenotype relationships suggests that the VHL protein has multiple and tissue specific functions. Calculation of tumour risks for different classes of VHL mutations has provided important prognostic information especially with respect to the likelihood of phaeochromocytoma. However, there is evidence that retinal involvement does not correlate with allelic heterogeneity, but that the variability in retinal angiomatosis is influenced by modifier gene effects. VHL gene mutation analysis also provides a basis for investigating the genetic basis of familial phaeochromocytoma and renal cell carcinoma, and apparently isolated retinal angiomas. Results to date suggest that a substantial proportion of patients with familial pheochromocytoma have VHL gene mutations but in contrast, most familial clusters of clear cell renal cell carcinoma (RCC) without evidence of VHL do not have germline VHL mutations.
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PMID:Molecular genetic analysis of von Hippel-Lindau disease. 968 54

Renal cell carcinomas (RCCs) with sarcomatoid transformation show the most malignant behaviour of all renal carcinoma types. In this study, comparative genomic hybridization was used to screen for losses and gains of DNA sequences along all chromosome arms in 12 sarcomatoid (S) RCCs. On average, there were 8.6 aberrations per tumour. DNA sequence losses (5.2 +/- 4.4) were slightly more frequent than gains (3.4 +/- 2.6). DNA gains most often involved chromosomes 17 (33 per cent), 7, and 8q (25 per cent each). High-level co-amplification involving 11q22-23 and 7p21-22 in one SRCC was not present in adjacent non-sarcomatous tumour areas, raising the possibility of oncogene involvement at these loci for sarcomatoid transformation. DNA losses were most prevalent at 13q (75 per cent) and 4q (50 per cent), suggesting that inactivation of tumour suppressor genes at chromosomes 13q and 4q may be linked to sarcomatoid growth of RCC. It is concluded that SRCCs are genetically highly complex. Chromosomes 13q, 4q, 7p21-22, and 11q22-23 may carry genes with relevance for sarcomatoid growth in RCC.
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PMID:Comparative genomic hybridization reveals frequent chromosome 13q and 4q losses in renal carcinomas with sarcomatoid transformation. 982 36

Various genetic changes are involved in human renal cell carcinomas (RCCs). However, the molecular events related to other cytomorphological subtypes of RCC are not well known, apart from the relationship between the von Hippel-Lindau tumour suppressor gene and clear cell subtype RCC. We examined the overexpression of several growth factor receptors immunohistochemically and analyzed their relationship to the cytomorphological characters in 120 cases of RCCs. These receptors included c-met proto-oncogene product (c-MET), epidermal growth factor receptor (EGFR) and transforming growth factor beta receptor II (TGFbetaR). The overexpression of c-MET was detected in all cases (20/20) of the tubulo-papillary growth type and 78.3% (18/23) of chromophilic cell subtype, resulting in a very significant associations between c-MET overexpression and tubulo-papillary growth RCCs (P<0.0001), c-MET and chromophilic subtype RCCs (P<0.0001), and c-MET and EGFR (P<0.0001). EGFR overexpression was significantly associated with the compact growth RCCs (49/89, P<0.0001), clear cell subtype RCCs (P<0.005) and the overexpression of TGFbetaR (P<0.0001). These results strongly suggest a close correlation between the overexpression of c-MET and development of the chromophilic subtype of RCC with papillary growth pattern. EGFR expression is closely related to the pathogenesis of the clear cell subtype of RCC with compact growth pattern. The overexpression of c-MET, EGFR, and TGFbetaR may have roles that are individually significant in the morphogenesis of RCC.
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PMID:Overexpression of c-met proto-oncogene associated with chromophilic renal cell carcinoma with papillary growth. 987 Jun 83

Small amounts of free DNA circulate in both healthy and diseased human plasma/serum, and increased concentrations of DNA are present in the plasma of cancer patients. Characteristics of tumour DNA have been found in genetic material extracted from the plasma of cancer patients. These features include decreased strand stability and the presence of specific oncogene, tumour suppressor gene and microsatellite alterations. Point mutations of the ras genes have been detected in the plasma DNA of patients suffering from haematopoetic malignancies, colorectal and pancreatic cancer, sometimes prior to clinical diagnosis. Rearranged immunoglobulin heavy chain DNA has been found in the plasma of patients with non-Hodgkins lymphoma and acute B cell leukaemia. Microsatellite instability, expressed either as a new allele or a loss of one allele (LOH) occurs in the plasma and serum DNA of patients suffering from head and neck, lung and renal cell cancer. The results obtained in many different cancers have opened a new research area indicating that plasma DNA might eventually be a suitable target for the development of non-invasive diagnostic, prognostic and follow-up tests for cancer.
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PMID:Detection of circulating tumour DNA in the blood (plasma/serum) of cancer patients. 1050 46

Papillary renal cell carcinomas (RCCs) have characteristic clinical and morphological features that separate them from the more common clear cell RCCs. The details of the molecular changes in papillary RCC progression are not well understood. In this study, four highly polymorphic microsatellite markers [D9S970 (9p12-9p13), D9S171 (9p13), D9S1748 (9p21) and D9S156 (9p21)] were used to determine the frequency and prognostic significance of 9p deletions in 37 papillary RCCs. Allelic deletions were detected in eight cases (22%). The highest rate of loss of heterozygosity (LOH) was observed in 6 of 29 informative patients (21%) at the D9S171 locus on 9p13. Only two patients displayed allelic loss at D9S1748, which resides in close proximity to p16(INK4). Two of 24 informative papillary RCCs (8%) showed LOH for D9S970. LOH at D9S171 (9p13) was associated with short patient survival (p=0.008), independently of tumour grade and stage. These data suggest a tumour suppressor gene centromeric to 9p21 that may contribute to papillary RCC progression.
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PMID:Allelic loss at the D9S171 locus on chromosome 9p13 is associated with progression of papillary renal cell carcinoma. 1069 95


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