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Andrew Arnold - One of the best experts on this subject based on the ideXlab platform.
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analysis of cyp27b1 encoding 25 hydroxyvitamin d 1α hydroxylase as a candidate tumor Suppressor Gene in primary and severe secondary tertiary hyperparathyroidism
Journal of Bone and Mineral Research, 2009Co-Authors: Kelly Lauter, Andrew ArnoldAbstract:CYP27B1, encoding 25-hydroxyvitamin D-1α-hydroxylase, converts 25-hydroxyvitamin D to its active form, 1,25-dihydroxyvitamin D, and is expressed primarily in the kidney but also in nontraditional sites including the parathyroid glands. Whereas the role of locally produced 1,25-dihydroxyvitamin D is not yet clear, it is possible that it contributes importantly to vitamin D–mediated inhibition of parathyroid cell growth, so CYP27B1 can be considered a candidate parathyroid tumor Suppressor Gene in that its acquired inactivation in a parathyroid cell could confer a tumorigenic growth advantage. Expression of CYP27B1 has also been reported to be altered in parathyroid neoplasms. Because detection of inactivating mutations is the central criterion for validating a candidate tumor Suppressor, we directly sequenced the coding region and all splice sites of CYP27B1 in 31 sporadic parathyroid adenomas and 31 parathyroid tumors from patients with refractory secondary/tertiary hyperparathyroidism. No nonsense, frameshift, or other inactivating mutations were found, and there was no sign of homozygous deletion. Our findings indicate that CYP27B1 does not commonly serve as a classical tumor Suppressor Gene in the development of sporadic parathyroid adenomas or of refractory secondary/tertiary hyperparathyroidism.
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mutational analysis of cdkn1b a candidate tumor Suppressor Gene in refractory secondary tertiary hyperparathyroidism
Kidney International, 2008Co-Authors: Kelly Lauter, Andrew ArnoldAbstract:Most patients with refractory secondary/tertiary hyperparathyroidism have monoclonal parathyroid tumors. Inactivating mutations of CDKN1B, encoding the p27 cyclin-dependent kinase inhibitor, were reported to cause hyperparathyroidism in a multiple endocrine neoplasia type 1-like syndrome. Further, there was decreased expression of CDKN1B in parathyroid tumors of patients with chronic kidney disease. We sequenced the entire coding region and splice sites of CDKN1B in 50 parathyroid tumors from 35 patients to see if inactivating mutations could cause monoclonal tumoriGenesis in refractory secondary/tertiary hyperparathyroidism. No frameshift, nonsense, or other clearly inactivating mutations were found, nor was there evidence of homozygous deletion or loss of heterozygosity. The absence of clonal inactivating mutations suggests that CDKN1B is not a classical tumor-Suppressor Gene in secondary/tertiary parathyroid tumors.
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mutational analysis of the vitamin d receptor does not support its candidacy as a tumor Suppressor Gene in parathyroid adenomas
The Journal of Clinical Endocrinology and Metabolism, 2006Co-Authors: Elizabeth Hanna Samander, Andrew ArnoldAbstract:Context: The vitamin D receptor Gene (VDR) is a compelling candidate tumor Suppressor Gene for parathyroid adenomas based on existing evidence of the vitamin D system’s antiproliferative actions in parathyroid and other tissues, its reported inhibition of PTH Gene transcription, and the decreased expression of VDR mRNA and VDR protein observed in parathyroid adenomas. Objective: Because demonstration of intragenic mutations is required to establish the authenticity and primary role in pathoGenesis for any candidate tumor Suppressor Gene, we examined the VDR Gene in parathyroid adenomas for the presence of such mutations and other loss-of-function abnormalities. Methods and Results: Genomic DNA samples from 37 sporadic parathyroid adenomas and matched normal control DNA from the same individuals were subjected to direct sequencing of the entire VDR coding region and all intron-exon boundaries. No VDR coding region or junctional mutations were identified. The tumors were also analyzed for loss of heterozygo...
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rad51 as a candidate parathyroid tumour Suppressor Gene on chromosome 15q absence of somatic mutations
Clinical Endocrinology, 1999Co-Authors: Tobias Carling, Yasuo Imanishi, Randall D Gaz, Andrew ArnoldAbstract:OBJECTIVE Loss of heterozygosity (LOH) at chromosome 15q is frequent in parathyroid adenomas, but no tumour Suppressor Gene of importance to parathyroid tumour development has been isolated from this region. The RAD51 Gene has been localized to chromosome 15q and possesses regulatory functions involving DNA stability and cell proliferation, suggesting its possible role in tumoriGenesis. Additionally, mutations in the RAD51 Gene cause reduced resistance to ionizing radiation, which is a major risk factor for primary hyperparathyroidism. RAD51 was therefore analysed as a candidate tumour Suppressor Gene in a group of parathyroid adenomas for which mutations in a 15q tumour Suppressor should be most readily detectable. PATIENTS AND DESIGN From a total of 55 parathyroid adenomas, nine were selected based on their LOH pattern showing DNA loss at chromosome 15q in the vicinity of the RAD51 Gene. RAD51 mRNA expression was investigated by reverse transcription–polymerase chain reaction (RT-PCR), and sequence analysis of the entire coding region of the RAD51 cDNA was performed in all nine adenomas. RESULTS RAD51 mRNA expression was substantiated in all parathyroid adenomas. Compared with the normal RAD51 cDNA sequence, no point mutations or microdeletions could be found in the parathyroid tumor cDNA. CONCLUSION These observations suggest that somatic inactivating mutations of the RAD51 Gene are uncommonly, if ever, associated with parathyroid tumouriGenesis.
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loss of the retinoblastoma tumor Suppressor Gene in parathyroid carcinoma
The New England Journal of Medicine, 1994Co-Authors: Vincent L Cryns, Ann D Thor, Hong Ji Xu, Shi Xue Hu, Margaret E Wierman, Austin L Vickery, William F Benedict, Andrew ArnoldAbstract:Background The origin and molecular pathoGenesis of parathyroid carcinoma are unknown. This life-threatening cause of primary hyperparathyroidism cannot be reliably distinguished from its benign counterpart on the basis of histopathological features alone. Because the PRAD1, or cyclin D1, Gene, a cell-cycle regulator, has been implicated in a subgroup of benign parathyroid tumors, we examined the possibility that another cell-cycle regulator with possible functional links to PRAD1, the retinoblastoma tumor-Suppressor Gene (RB), might be involved in the molecular pathoGenesis of parathyroid carcinoma. Methods Parathyroid carcinomas from 9 patients and adenomas from 21 were studied for evidence of tumor-specific loss of RB Gene DNA (allelic loss) by analysis of four DNA polymorphisms and for evidence of altered expression of RB protein by immunohistochemical staining. Results All of 11 specimens from 5 patients with parathyroid carcinoma and informative DNA patterns and 1 of 19 specimens from 19 patients wi...
Eamonn R Maher - One of the best experts on this subject based on the ideXlab platform.
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vhl the story of a tumour Suppressor Gene
Nature Reviews Cancer, 2015Co-Authors: Lucy Gossage, Tim Eisen, Eamonn R MaherAbstract:Since the Von Hippel-Lindau (VHL) disease tumour Suppressor Gene VHL was identified in 1993 as the Genetic basis for a rare disorder, it has proved to be of wide medical and scientific interest. VHL tumour Suppressor protein (pVHL) plays a key part in cellular oxygen sensing by targeting hypoxia-inducible factors for ubiquitylation and proteasomal degradation. Early inactivation of VHL is commonly seen in clear-cell renal cell carcinoma (ccRCC), and insights gained from the functional analysis of pVHL have provided the foundation for the routine treatment of advanced-stage ccRCC with novel targeted therapies. However, recent sequencing studies have identified additional driver Genes that are involved in the pathoGenesis of ccRCC. As our understanding of the importance of VHL matures, it is timely to review progress from its initial description to current knowledge of VHL biology, as well as future prospects for novel medical treatments for VHL disease and ccRCC.
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the vhl tumour Suppressor Gene paradigm
Trends in Genetics, 1998Co-Authors: William G Kaelin, Eamonn R MaherAbstract:The VHL tumour-Suppressor Gene (TSG) has a critical 'gatekeeper' role in regulating growth and differentiation of human kidney cells, and inactivation of the VHL Gene is the most frequent Genetic event in human kidney cancer. There are many similarities between the Genetics of the VHL and retinoblastoma TSGs, but the VHL tumouriGenesis model is more complex. Here, we examine the current knowledge of the Genetics and functional aspects of the VHL TSG, and emphasize how the VHL Gene provides a paradigm that illustrates many aspects of TSG biology.
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molecular Genetic analysis of the von hippel lindau disease vhl tumour Suppressor Gene in gonadal tumours
European Journal of Cancer, 1995Co-Authors: Keith Foster, R J Osborne, R A Huddart, Nabeel A Affara, Malcolm A Fergusonsmith, Eamonn R MaherAbstract:Chromosome 3p allele loss is frequent in ovarian and testicular tumours. The von Hippel-Lindau (VHL) disease tumour Suppressor Gene maps to chromosome 3p25. Gonadal tumours may occur in patients with VHL disease, so somatic VHL Gene mutations might be involved in the pathoGenesis of sporadic gonadal tumours. To investigate this hypothesis, we screened 60 gonadal tumours (36 ovarian and 24 testicular) for VHL Gene mutations and chromosome 3p allele loss. Although 38% (10/26) of informative ovarian and 54% (7/13) of testicular tumours demonstrated 3p allele loss, no somatic VHL Gene mutations were detected in the 60 gonadal tumours analysed. This suggested that chromosome 3p tumour Suppressor Gene(s) other than VHL are involved in gonadal tumoriGenesis.
William G Kaelin - One of the best experts on this subject based on the ideXlab platform.
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Genetic and functional studies implicate hif1α as a 14q kidney cancer Suppressor Gene
Cancer Discovery, 2011Co-Authors: Chuan Shen, Rameen Beroukhim, Steven E Schumacher, Jing Zhou, Michelle Chang, Sabina Signoretti, William G KaelinAbstract:Kidney cancers often delete chromosome 3p, spanning the VHL tumor Suppressor Gene, and chromosome 14q, which presumably harbors one or more tumor Suppressor Genes. pVHL inhibits the HIF transcription factor and HIF2α is a kidney cancer oncoprotein. Here we identify focal, homozygous, deletions of the HIF1α locus on 14q in clear cell renal carcinoma cell lines. Wild-type HIF1α, but not the products of these altered loci, suppress renal carcinoma growth. Conversely, downregulation of HIF1α in HIF1α-proficient lines promote tumor growth. HIF1α activity is diminished in 14q deleted kidney cancers and all of the somatic HIF1α mutations identified in kidney cancers tested to date are loss of function. Therefore HIF1α has the credentials of a kidney cancer Suppressor Gene.
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the von hippel lindau tumor Suppressor Gene
Experimental Cell Research, 2001Co-Authors: Keiichi Kondo, William G KaelinAbstract:Germline mutations of the von Hippel-Lindau tumor Suppressor Gene (VHL) in humans causes a hereditary cancer syndrome characterized by the development of retinal and central nervous system hemangioblastomas. Other tumors associated with von Hippel-Lindau disease include clear cell renal carcinomas and pheochromocytomas. Tumor development in this setting is due to functional loss of the remaining wild-type VHL allele. Biallelic VHL inactivation is also common in nonhereditary hemangioblastomas and clear cell renal carcinomas, in keeping with Knudson's 2-Hit Model of carcinoGenesis. The VHL Gene product, pVHL, is a component of an E3 ubiquitin ligase that targets the alpha subunits of the HIF (hypoxia-inducible factor) transcription factor for destruction in the presence of oxygen. Consequently, tumor cells lacking pVHL overproduce the products of HIF target Genes such as vascular endothelial growth factor and transforming growth factor alpha. pVHL has been implicated in a variety of processes that are central to carcinoGenesis including cell-cycle control, differentiation, extracellular matrix formation and turnover, and angioGenesis.
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the vhl tumour Suppressor Gene paradigm
Trends in Genetics, 1998Co-Authors: William G Kaelin, Eamonn R MaherAbstract:The VHL tumour-Suppressor Gene (TSG) has a critical 'gatekeeper' role in regulating growth and differentiation of human kidney cells, and inactivation of the VHL Gene is the most frequent Genetic event in human kidney cancer. There are many similarities between the Genetics of the VHL and retinoblastoma TSGs, but the VHL tumouriGenesis model is more complex. Here, we examine the current knowledge of the Genetics and functional aspects of the VHL TSG, and emphasize how the VHL Gene provides a paradigm that illustrates many aspects of TSG biology.
Taro Shuin - One of the best experts on this subject based on the ideXlab platform.
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somatic mutations of the von hippel lindau tumor Suppressor Gene in sporadic central nervous system hemangioblastomas
Cancer Research, 1994Co-Authors: Hiroshi Kanno, Keiichi Kondo, Isao Yamamoto, Satoshi Fujii, Soichiro Torigoe, Naoki Sakai, Masahiko Hosaka, Taro ShuinAbstract:Hemangioblastoma is one of the benign tumors in the central nervous system. It is often associated with the von Hippel-Lindau (VHL) disease, a well known hereditary tumor syndrome. It is believed that inactivation of both alleles of VHL tumor Suppressor Gene is essential in the tumorigenic processes in hemangioblastomas associated with VHL disease. The molecular basis for the development of sporadic hemangioblastomas is not known. Here, we analyzed 13 cases of primary sporadic hemangloblastomas for somatic mutations of VHL Gene with single strand conformational polymorphism analyses of the tumor DNAs. We detected abnormal single strand conformational polymorphism pattern in 7 tumors (54%). Of these 7 possibly mutated tumors, we successfully characterized 3 tumors by direct sequencing. We were unable to sequence 4 tumors because of the poor quality of DNA obtained from paraffin blocks. Somatic mutations in the 3 tumors were 2 missense mutations and 1 microdeletion. These mutations were observed in 1 tumor in exon 1 and 2 tumors in exon 2. Our results suggest that mutations of VHL tumor Suppressor Gene are involved in the development of at least 20% of sporadic central nervous system hemangioblastomas.
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frequent somatic mutations and loss of heterozygosity of the von hippel lindau tumor Suppressor Gene in primary human renal cell carcinomas
Cancer Research, 1994Co-Authors: Taro Shuin, Farida Latif, Soichiro Torigoe, Masahiko Hosaka, Kelichi Kondo, Takeshi Kishida, Yoshinobu Kubota, Yoji Nagashima, Hitoshi Kitamura, Berton ZbarAbstract:Abstract We analyzed 47 primary sporadic human renal cell carcinomas (39 clear cell and 8 non-clear cell) for mutations of the von Hippel-Lindau (VHL) tumor Suppressor Gene using the polymerase chain reaction and single strand conformational polymorphism analysis of DNA. All of the positive cases in single strand conformational polymorphism analyses were further characterized by direct sequencing. Somatic mutations were detected in 22 (56%) of 39 clear cell renal carcinomas including 15 deletions, 3 insertions, 3 missense mutations, and 1 nonsense mutation. Nineteen of these mutations predicted to produce truncation of the VHL protein. These mutations mainly occurred in the last one-third region of exons 1, 2, and 3. In addition, loss of heterozygosity of the VHL Gene was observed in 16 (84%) of 19 informative clear cell renal carcinomas. No somatic mutations were detected in 8 non-clear cell carcinomas. These results show that the VHL tumor Suppressor Gene is one of the major tumor Suppressor Genes in human renal cell carcinomas, especially in the clear cell subtype renal cell carcinoma. Clear cell carcinoma might be distinguished from other pathological types of renal cell carcinomas by molecular Genetic techniques.
Kelly Lauter - One of the best experts on this subject based on the ideXlab platform.
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analysis of cyp27b1 encoding 25 hydroxyvitamin d 1α hydroxylase as a candidate tumor Suppressor Gene in primary and severe secondary tertiary hyperparathyroidism
Journal of Bone and Mineral Research, 2009Co-Authors: Kelly Lauter, Andrew ArnoldAbstract:CYP27B1, encoding 25-hydroxyvitamin D-1α-hydroxylase, converts 25-hydroxyvitamin D to its active form, 1,25-dihydroxyvitamin D, and is expressed primarily in the kidney but also in nontraditional sites including the parathyroid glands. Whereas the role of locally produced 1,25-dihydroxyvitamin D is not yet clear, it is possible that it contributes importantly to vitamin D–mediated inhibition of parathyroid cell growth, so CYP27B1 can be considered a candidate parathyroid tumor Suppressor Gene in that its acquired inactivation in a parathyroid cell could confer a tumorigenic growth advantage. Expression of CYP27B1 has also been reported to be altered in parathyroid neoplasms. Because detection of inactivating mutations is the central criterion for validating a candidate tumor Suppressor, we directly sequenced the coding region and all splice sites of CYP27B1 in 31 sporadic parathyroid adenomas and 31 parathyroid tumors from patients with refractory secondary/tertiary hyperparathyroidism. No nonsense, frameshift, or other inactivating mutations were found, and there was no sign of homozygous deletion. Our findings indicate that CYP27B1 does not commonly serve as a classical tumor Suppressor Gene in the development of sporadic parathyroid adenomas or of refractory secondary/tertiary hyperparathyroidism.
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mutational analysis of cdkn1b a candidate tumor Suppressor Gene in refractory secondary tertiary hyperparathyroidism
Kidney International, 2008Co-Authors: Kelly Lauter, Andrew ArnoldAbstract:Most patients with refractory secondary/tertiary hyperparathyroidism have monoclonal parathyroid tumors. Inactivating mutations of CDKN1B, encoding the p27 cyclin-dependent kinase inhibitor, were reported to cause hyperparathyroidism in a multiple endocrine neoplasia type 1-like syndrome. Further, there was decreased expression of CDKN1B in parathyroid tumors of patients with chronic kidney disease. We sequenced the entire coding region and splice sites of CDKN1B in 50 parathyroid tumors from 35 patients to see if inactivating mutations could cause monoclonal tumoriGenesis in refractory secondary/tertiary hyperparathyroidism. No frameshift, nonsense, or other clearly inactivating mutations were found, nor was there evidence of homozygous deletion or loss of heterozygosity. The absence of clonal inactivating mutations suggests that CDKN1B is not a classical tumor-Suppressor Gene in secondary/tertiary parathyroid tumors.