The Experts below are selected from a list of 186 Experts worldwide ranked by ideXlab platform
Andrew Arnold - One of the best experts on this subject based on the ideXlab platform.
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Polyclonality of Parathyroid Tumors in Neonatal Severe HyperParathyroidism
Journal of Bone and Mineral Research, 2015Co-Authors: Kristin R. Corrado, Simone Caixeta De Andrade, Justin Bellizzi, Lília D'souza-li, Andrew ArnoldAbstract:Neonatal severe hyperParathyroidism (NSHPT) is a rare disorder characterized by major hypercalcemia, elevated Parathyroid hormone levels, and marked enlargement of multiple Parathyroid glands, usually associated with germline mutations in the calcium receptor gene CASR. However, little is known about the outgrowth of Parathyroid Tumors in NSHPT, including whether they represent monoclonal or polyclonal expansions. We sought to examine the clonality of Parathyroid tissues resected from a patient with NSHPT and biallelic CASR mutations. DNA from two distinct Parathyroid Tumors resected from a girl with NSHPT, plus polyclonal/monoclonal control samples, were subjected to analyses of clonality by two independent methods, X-chromosome inactivation analysis at the androgen receptor locus (HUMARA) and BAC array comparative genomic hybridization (CGH). Both Parathyroid Tumor samples revealed polyclonal patterns by X-inactivation analysis, with polyclonal and monoclonal controls yielding the expected patterns. Similarly, by BAC array CGH, neither Parathyroid sample contained monoclonal copy number changes and both appeared identical to the patient-matched polyclonal controls. Our observations provide direct experimental evidence that the markedly enlarged Parathyroid Tumors in the setting of NSHPT constitute polyclonal, generalized hyperplastic growths rather than monoclonal neoplasms. © 2015 American Society for Bone and Mineral Research.
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parafibromin immunoreactivity its use as an additional diagnostic marker for Parathyroid Tumor classification
Endocrine-related Cancer, 2007Co-Authors: Christofer C Juhlin, A Villablanca, Kerstin Sandelin, Felix Haglund, Jorgen Nordenstrom, Lars Forsberg, Robert Branstrom, Takao Obara, Andrew Arnold, Catharina LarssonAbstract:Parafibromin isa proteinproductderived fromthe hyperParathyroidism 2(HRPT2) Tumorsuppressor geneanditsinactivationhasbeencoupledtofamilialandsporadicformsofParathyroidmalignancy.In thisstudy,wehaveconductedimmunohistochemistryon33Parathyroidcarcinomas(22unequivocal and 11 equivocal) using four parafibromin antibodies directed to different parts of the protein. Furthermore, for a fraction of cases, the immunohistochemical results were compared with known HRPT2 mutational status. Our findings show that 68% (15 out of 22) of the unequivocal carcinomas exhibitedreducedexpressionofparafibrominwhilethe25sporadicadenomasusedascontrolswere entirelypositivefor parafibrominexpression.Additionally, three outof the six carcinomas withknown HRPT2mutationsshowedreducedexpressionofparafibromin.Usingallfourantibodies,comparable resultswereobtained onthe cellularlevelinindividual Tumorssuggesting that thereexistsnoepitope of choice in parafibromin immunohistochemistry. The results agree with the demonstration of a w60 kDa product preferentially in the nuclear fraction by western blot analysis. We conclude that parafibromin immunohistochemistry could be used as an additional marker for Parathyroid Tumor classification, where positive samples have low risk of malignancy, whereas samples with reduced expressioncouldbeeithercarcinomasorrarecasesofadenomaslikelycarryingan HRPT2mutation.
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analysis of the rad54 gene on chromosome 1p as a potential Tumor suppressor gene in Parathyroid adenomas
International Journal of Cancer, 1999Co-Authors: Tobias Carling, Yasuo Imanishi, Andrew ArnoldAbstract:Parathyroid adenomas causing primary hyperParathyroidism (pHPT) frequently exhibit allelic loss of DNA markers on the short arm of chromosome 1, indicating the presence of one or more Tumor-suppressor genes on 1p. Since the development of pHPT is enhanced in individuals exposed to ionizing radiation to the neck, it could be anticipated that genes involved in DNA repair and recombination may be special targets for mutation in Parathyroid Tumorigenesis, whether irradiation-associated or not. RAD54 is a member of a family of genes involved in such functions, and RAD54 knockout mice show increased sensitivity to ionizing radiation. The localization of the RAD54 gene to 1p32 has therefore elevated it to a most compelling candidate Parathyroid Tumor-suppressor gene. Twelve Parathyroid adenomas demonstrating allelic loss at chromosome 1p were selected from 55 Parathyroid adenomas previously analyzed for loss of heterozygosity using polymorphic microsatellite markers. All 18 exons of the RAD54 gene were fully analyzed by automated sequencing for detection of point mutations or micro-deletions in each Parathyroid adenoma. No mutational aberrations were detected in the RAD54 gene, strongly suggesting that complete somatic inactivation of RAD54 is infrequently, if ever, associated with the development of Parathyroid adenomas. Whether genes controlling DNA repair and recombination are involved in Parathyroid neoplasia remains to be determined. Int. J. Cancer 83:80–82, 1999. © 1999 Wiley-Liss, Inc.
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Molecular basis of hyperParathyroidism
Journal of Bone and Mineral Metabolism, 1997Co-Authors: Hideki Tahara, Andrew ArnoldAbstract:Several advances have been achieved toward an improved understanding of the molecular basis of human Parathyroid Tumorigenesis. One oncogene involved in the development of Parathyroid Tumors, PRAD1/cyclin D1 , has been discovered and is having a broad impact in oncology and cell-cycle biology. The general genomic locations of several novel putative Parathyroid Tumor suppressor genes have been identified, providing guideposts toward their specific identification. An already recognized Tumor suppressor gene, RB , or a close neighbor on 13q, has been linked to the pathogenesis of Parathyroid carcinomas. RET has been centrally implicated in MEN-2A, and investigators are on the verge of isolating the MEN1 gene, both of which are sure to have important basic and clinical implications relevant to Parathyroid and other endocrine diseases. Although mutations in the CASR gene itself play a critical role in familial disease, they do not appear to be involved in sporadic Parathyroid Tumorigenesis, and investigation of genes important for its regulation is warranted. Finally, new molecular genetic approaches will eventually permit the identification of additional Parathyroid Tumor-provoking genes and will begin to shed light upon other problems in Parathyroid biology, such as the relationship between abnormal Parathyroid cell proliferation and an altered setpoint in the mechanism linking extracellular calcium concentration to PTH secretion.
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Parathyroid Tumor suppressor on 1p analysis of the p18 cyclin dependent kinase inhibitor gene as a candidate
Journal of Bone and Mineral Research, 1997Co-Authors: Hideki Tahara, Alison P Smith, Maimoona A Zariwala, Yue Xiong, Andrew ArnoldAbstract:Loss of chromosome arm 1p DNA is the most common molecular defect thus far observed in human Parathyroid adenomas, suggesting that 1p is the location of a putative Tumor suppressor gene (or genes) whose inactivation contributes frequently to Parathyroid Tumorigenesis. To narrow the genomic location of this Tumor suppressor gene, we analyzed 25 sporadic Parathyroid adenomas for allelic loss of polymorphic DNA loci on chromosome 1 using 11 microsatellite markers not previously scored for this set of Tumors. Allelic loss on chromosome arm 1p DNA was observed in 8 of 25 adenomas. Marker deletion patterns showed some complexity, with the regions most commonly deleted in these Tumors being 1p36 and 1p35–p31. The 1p35–p31 region contains an excellent candidate Tumor suppressor gene, p18, whose product is a cell cycle regulator that inhibits the cyclin D1-associated kinase CDK6. Given that cyclin D1 is a Parathyroid oncogene, inactivation of an inhibitor of cyclin D1 function, like p18, might also cause excessive Parathyroid growth. To examine the involvement of p18 in Parathyroid Tumorigenesis, we analyzed 25 Parathyroid adenomas for mutations of the p18 coding exons by single strand conformational polymorphism analysis and sequencing. No point mutations were found in any of the 25 adenomas. These observations indicate that inactivating mutation of the p18 gene occurs uncommonly, if at all, in Parathyroid adenomas. In addition, the data raise the important possibility that more than a single Tumor suppressor gene on 1p could contribute to Parathyroid neoplasia.
Hideki Tahara - One of the best experts on this subject based on the ideXlab platform.
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thoracoscopic excision for ectopic mediastinal Parathyroid Tumor
Biomedicine & Pharmacotherapy, 2002Co-Authors: Tetsuro Ishikawa, Naoyoshi Onoda, Yoshinari Ogawa, Tsutomu Takashima, Nobuo Matsunaga, Shinya Michigami, Terue Okamura, Hideki Tahara, Masaaki Inaba, Tatsuya NakataniAbstract:Ectopic Parathyroid adenoma or hyperplasia in the mediastinum are seen in a percentage of patients with hyperParathyroidism and have generally been treated by conventional open surgery. However, due to recent improvements in the ability of diagnostic imaging such as 99mTc-methoxyisobutylisonitrile (MIBI) scintigraphy to identify these lesions, we have been obtaining favorable results from thoracoscopic excision of mediastinal Parathyroid Tumors. In thoracoscopic surgery, three to four trocars were inserted between the fourth and seventh ribs from a lateral approach. Based on diagnostic imaging, Tumors were identified and excised by the shortest possible route. Surgery time for four consecutive patients ranged from 50 to 140 min, and hemorrhage volumes were small. No intra- or postoperative complications were observed, and the postoperative course for these patients has been uneventful. Analgesia was required only a few times for each patient. In the most recent patient, radioisotope-navigated thoracoscopic excision was performed using 99mTc-MIBI. When thoracoscopic excision was combined with radioisotope navigation, Tumor identification took less time, cutting the surgery time in half and ultimately placing less stress on the patient.
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putative Parathyroid Tumor suppressor on 1p independent molecular mechanisms of Tumorigenesis from 11q allelic loss
American Journal of Kidney Diseases, 2001Co-Authors: Yasuo Imanishi, Hideki TaharaAbstract:Abstract Multiple endocrine neoplasia type 1 (MEN1) gene was identified to be a Tumor suppressor that encodes menin, playing an important role in the development of MEN1-associated Tumors. Somatic MEN1 gene mutations also were detected in sporadic non-MEN1 endocrine Tumors. Frequent loss of chromosomal arm 1p has been reported in Parathyroid adenomas, suggesting the existence of putative Tumor-suppressor genes on 1p. In this study, we performed allelotyping of chromosomes 1p and 11q on 60 sporadic Parathyroid adenomas. Thirteen of 48 (27%) informative Tumors had allelic loss on 1p, and 18 of 50 (36%) had allelic loss on 11q. Ten of 18 Tumors with 11q allelic loss successfully completed the sequence of the MEN1 gene coding region and splice junctions, and 3 of 10 (30%) Tumors had no somatic mutation, indicating that other putative Tumor-suppressor genes on 11q may contribute to their Tumorigenesis. Frequency of allelic losses on 1p was significantly higher in Tumors without 11q allelic losses (7 of 11 informative Tumors [64%]) than in Tumors with 11q allelic losses (3 of 17 informative Tumors [18%]) by chi-square test (P = 0.0131; chi-square = 6.152). These observations suggested that putative Tumor-suppressor genes locate on 1p, and pathways of their Tumorigenesis are independent from inactivation of Tumor-suppressor genes on 11q. © 2001 by the National Kidney Foundation, Inc.
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Molecular basis of hyperParathyroidism
Journal of Bone and Mineral Metabolism, 1997Co-Authors: Hideki Tahara, Andrew ArnoldAbstract:Several advances have been achieved toward an improved understanding of the molecular basis of human Parathyroid Tumorigenesis. One oncogene involved in the development of Parathyroid Tumors, PRAD1/cyclin D1 , has been discovered and is having a broad impact in oncology and cell-cycle biology. The general genomic locations of several novel putative Parathyroid Tumor suppressor genes have been identified, providing guideposts toward their specific identification. An already recognized Tumor suppressor gene, RB , or a close neighbor on 13q, has been linked to the pathogenesis of Parathyroid carcinomas. RET has been centrally implicated in MEN-2A, and investigators are on the verge of isolating the MEN1 gene, both of which are sure to have important basic and clinical implications relevant to Parathyroid and other endocrine diseases. Although mutations in the CASR gene itself play a critical role in familial disease, they do not appear to be involved in sporadic Parathyroid Tumorigenesis, and investigation of genes important for its regulation is warranted. Finally, new molecular genetic approaches will eventually permit the identification of additional Parathyroid Tumor-provoking genes and will begin to shed light upon other problems in Parathyroid biology, such as the relationship between abnormal Parathyroid cell proliferation and an altered setpoint in the mechanism linking extracellular calcium concentration to PTH secretion.
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Parathyroid Tumor suppressor on 1p analysis of the p18 cyclin dependent kinase inhibitor gene as a candidate
Journal of Bone and Mineral Research, 1997Co-Authors: Hideki Tahara, Alison P Smith, Maimoona A Zariwala, Yue Xiong, Andrew ArnoldAbstract:Loss of chromosome arm 1p DNA is the most common molecular defect thus far observed in human Parathyroid adenomas, suggesting that 1p is the location of a putative Tumor suppressor gene (or genes) whose inactivation contributes frequently to Parathyroid Tumorigenesis. To narrow the genomic location of this Tumor suppressor gene, we analyzed 25 sporadic Parathyroid adenomas for allelic loss of polymorphic DNA loci on chromosome 1 using 11 microsatellite markers not previously scored for this set of Tumors. Allelic loss on chromosome arm 1p DNA was observed in 8 of 25 adenomas. Marker deletion patterns showed some complexity, with the regions most commonly deleted in these Tumors being 1p36 and 1p35–p31. The 1p35–p31 region contains an excellent candidate Tumor suppressor gene, p18, whose product is a cell cycle regulator that inhibits the cyclin D1-associated kinase CDK6. Given that cyclin D1 is a Parathyroid oncogene, inactivation of an inhibitor of cyclin D1 function, like p18, might also cause excessive Parathyroid growth. To examine the involvement of p18 in Parathyroid Tumorigenesis, we analyzed 25 Parathyroid adenomas for mutations of the p18 coding exons by single strand conformational polymorphism analysis and sequencing. No point mutations were found in any of the 25 adenomas. These observations indicate that inactivating mutation of the p18 gene occurs uncommonly, if at all, in Parathyroid adenomas. In addition, the data raise the important possibility that more than a single Tumor suppressor gene on 1p could contribute to Parathyroid neoplasia.
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genomic localization of novel candidate Tumor suppressor gene loci in human Parathyroid adenomas
Cancer Research, 1996Co-Authors: Hideki Tahara, Alison P Smith, Vincent L Cryns, A ArnoldAbstract:Only one oncogene, cyclin D1/PRAD1 , has an established role in Parathyroid Tumorigenesis, and Parathyroid Tumor suppressor genes on chromosome arms 1p and 11q, which still have not been identified, have also been implicated by loss of heterozygosity analysis. To investigate whether other putative Tumor suppressor genes are involved in the pathogenesis of Parathyroid adenomas, we performed a more comprehensive analysis of allelic losses in these Tumors. Using 39 polymorphic markers, we examined each chromosome arm, excluding the short arms of the acrocentric chromosomes. In 25 Parathyroid adenomas, frequent loss of heterozygosity, in > 25% of the informative cases, was observed on chromosome arms 6q (30%), 11p (27%), and 15q (35%), in addition to previously reported 1p (30%) and 11q (38%) allelic losses. To more specifically localize the smallest shared regions of molecular genetic deletion, we examined the following chromosomes in greater detail: chromosome 6 (9 additional markers), chromosome 11 (8 additional markers), and chromosome 15 (15 additional markers). The regions most commonly deleted in these Tumors were 6q22-23, 6q26-27, 11q13, 15q11-21, and 15q26-qter. All Tumors with 11p loss had patterns consistent with monosomy for chromosome 11. These findings provide novel evidence for the existence of Tumor suppressor genes on chromosome arms 6q and 15q that contribute commonly to the pathogenesis of Parathyroid adenomas.
Peyman Bjorklund - One of the best experts on this subject based on the ideXlab platform.
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The histone methyltransferase EZH2, an oncogene common to benign and malignant Parathyroid Tumors
Endocrine-related Cancer, 2014Co-Authors: Jessica Svedlund, Peyman Bjorklund, Goran Akerstrom, Elham Barazeghi, Peter Stålberg, Per Hellman, Gunnar WestinAbstract:Primary hyperParathyroidism (pHPT) resulting from Parathyroid Tumors is a common endocrine disorder with incompletely understood etiology. In renal failure, secondary hyperParathyroidism (sHPT) occurs with multiple Tumor development as a result of calcium and vitamin D regulatory disturbance. The aim of this study was to investigate a potential role of the histone 3 lysine 27 methyltransferase EZH2 in Parathyroid Tumorigenesis. Parathyroid Tumors from patients with pHPT included adenomas and carcinomas. Hyperplastic Parathyroid glands from patients with HPT secondary to uremia and normal Parathyroid tissue specimens were included in this study. Quantitative RT-PCR, western blotting, bisulfite pyrosequencing, colony formation assay, and RNA interference were used. EZH2 was overexpressed in a subset of the benign and in all malignant Parathyroid Tumors as determined by quantitative RT-PCR and western blotting analyses. Overexpression was explained by EZH2 gene amplification in a large fraction of Tumors. EZH2 depletion by RNA interference inhibited sHPT-1 Parathyroid cell line proliferation as determined by tritium‐ thymidine incorporation and colony formation assays. EZH2 depletion also interfered with the Wnt/b-catenin signaling pathway by increased expression of growth-suppressive AXIN2, a negative regulator of b-catenin stability. Indeed, EZH2 contributed to the total level of aberrantly accumulated transcriptionally active (nonphosphoylated) b-catenin in the Parathyroid Tumor cells. To our knowledge EZH2 gene amplification presents the first genetic aberration common to Parathyroid adenomas, secondary hyperplastic Parathyroid glands, and Parathyroid carcinomas. This supports the possibility of a common pathway in Parathyroid Tumor development.
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expression and somatic mutations of sdhaf2 sdh5 a novel endocrine Tumor suppressor gene in Parathyroid Tumors of primary hyperParathyroidism
Endocrine, 2010Co-Authors: Peyman Bjorklund, Lee F Starker, Alberto Delgadoverdugo, Robert Udelsman, Tobias CarlingAbstract:To investigate the SDHAF2 gene and its effect on primary hyperParathyroidism. Parathyroid Tumors causing primary hyperParathyroidism (pHPT) are one of the more common endocrine neoplasias. Loss of heterozygosity at chromosome 11q13 is the most common chromosomal aberration in Parathyroid Tumors occurring in about 40% of sporadic Tumors. Only 15–19% display somatic mutations in the MEN1 gene, which suggest that this chromosomal region may harbor additional genes of importance in Parathyroid Tumor development. The SDHAF2 (formerly SDH5) gene is a recently identified neuroendocrine Tumor suppressor gene at this locus, and inherited mutations of the SDHAF2 gene has been linked to familial paraganglioma. We demonstrate that the SDHAF2 gene is expressed in Parathyroid tissue using RT-PCR. Because detection of inactivating mutations is the major criterion for validating a candidate Tumor suppressor, we used automated sequencing of the coding region and intron/exon boundaries in 80 sporadic Parathyroid adenomas from patients with pHPT. A known polymorphisms (A to G substitution; rs879647) was identified in 9/80 Parathyroid Tumors but no Tumor-specific somatic mutational aberrations, such as nonsense, frameshift, or other inactivating mutations were identified. The SDHAF2 gene is expressed in Parathyroid tissue. However, somatic mutations of the SDHAF2 Tumor suppressor gene are unlikely to frequently contribute to Parathyroid Tumor development in sporadic pHPT.
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Molecular Genetics of Parathyroid Disease
World Journal of Surgery, 2009Co-Authors: Gunnar Westin, Peyman Bjorklund, Goran AkerstromAbstract:Background Primary hyperParathyroidism (HPT) is often caused by a benign Parathyroid Tumor, adenoma; less commonly by multiglandular Parathyroid disease/hyperplasia; and rarely by Parathyroid carcinoma. Patients with multiple Tumors require wider exploration to avoid recurrence and have increased risk for hereditary disease. Secondary HPT is a common complication of renal failure. Improved knowledge of the molecular background of Parathyroid Tumor development may help select patients for appropriate surgical treatment and can eventually provide new means of treatment. The present contribution summarizes more recent knowledge of Parathyroid molecular genetics. Methods A literature search and review was made to evaluate the level of evidence concerning molecular biology and genetics of primary, secondary, and familial HPT according to criteria proposed by Sackett, with recommendation grading by Heinrich et al. Results Most Parathyroid adenomas and hyperplastic glands are monoclonal lesions. Cyclin D1 gene (CCND1) translocation and oncogene action occur in 8% of adenomas; cyclin D1 overexpression is seen in 20% to 40% of Parathyroid adenomas and in 31% of secondary hyperplastic glands. Somatic loss of one MEN1 allele is seen in 25% to 40% of sporadic Parathyroid adenomas, half of which have inactivating mutation of the remaining allele. Inactivating somatic HRPT2 mutations are common in Parathyroid carcinoma, often causing decreased expression of the protein parafibromin involved in cyclin D1 regulation. Aberrant regulation of Wnt/β-catenin signaling may be important for Parathyroid Tumor development. Conclusions Molecular genetic studies of Parathyroid Tumors are well designed basic experimental studies providing strong level III evidence, with data frequently confirmed by subsequent studies.
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activated β catenin in the novel human Parathyroid Tumor cell line shpt 1
Biochemical and Biophysical Research Communications, 2007Co-Authors: Peyman Bjorklund, Goran Akerstrom, Gunnar WestinAbstract:Misregulation of the Wnt/beta-catenin signalling pathway is involved in the development and progression of many cancers. Recently, we presented evidence for aberrant accumulation of non-phosphorylated (stabilized) beta-catenin in benign Parathyroid Tumors from patients with primary hyperParathyroidism (pHPT) or HPT secondary to uremia (sHPT). Here we have used a human Parathyroid hormone (PTH)-producing cell line (sHPT-1), established from a hyperplastic Parathyroid gland removed at operation of a patient with sHPT, to further investigate the potential importance of beta-catenin in Parathyroid Tumorigenesis. Our studies demonstrate that efficient and specific knockdown of beta-catenin by small interfering RNA (siRNA) markedly decreased endogenous beta-catenin transcriptional activity as well as expression of the Wnt/beta-catenin target genes cyclin D1 and c-myc, known to be overexpressed in a substantial fraction of Parathyroid Tumors. Furthermore, siRNA to beta-catenin inhibited cellular growth and induced cell death. Growth and survival of the Parathyroid Tumor cells are thus dependent on maintained expression level of beta-catenin. The Wnt/beta-catenin signalling pathway, and beta-catenin in particular, presents a potential therapeutic target for HPT.
Tobias Carling - One of the best experts on this subject based on the ideXlab platform.
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expression and somatic mutations of sdhaf2 sdh5 a novel endocrine Tumor suppressor gene in Parathyroid Tumors of primary hyperParathyroidism
Endocrine, 2010Co-Authors: Peyman Bjorklund, Lee F Starker, Alberto Delgadoverdugo, Robert Udelsman, Tobias CarlingAbstract:To investigate the SDHAF2 gene and its effect on primary hyperParathyroidism. Parathyroid Tumors causing primary hyperParathyroidism (pHPT) are one of the more common endocrine neoplasias. Loss of heterozygosity at chromosome 11q13 is the most common chromosomal aberration in Parathyroid Tumors occurring in about 40% of sporadic Tumors. Only 15–19% display somatic mutations in the MEN1 gene, which suggest that this chromosomal region may harbor additional genes of importance in Parathyroid Tumor development. The SDHAF2 (formerly SDH5) gene is a recently identified neuroendocrine Tumor suppressor gene at this locus, and inherited mutations of the SDHAF2 gene has been linked to familial paraganglioma. We demonstrate that the SDHAF2 gene is expressed in Parathyroid tissue using RT-PCR. Because detection of inactivating mutations is the major criterion for validating a candidate Tumor suppressor, we used automated sequencing of the coding region and intron/exon boundaries in 80 sporadic Parathyroid adenomas from patients with pHPT. A known polymorphisms (A to G substitution; rs879647) was identified in 9/80 Parathyroid Tumors but no Tumor-specific somatic mutational aberrations, such as nonsense, frameshift, or other inactivating mutations were identified. The SDHAF2 gene is expressed in Parathyroid tissue. However, somatic mutations of the SDHAF2 Tumor suppressor gene are unlikely to frequently contribute to Parathyroid Tumor development in sporadic pHPT.
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Molecular pathology of Parathyroid Tumors
Trends in Endocrinology and Metabolism, 2001Co-Authors: Tobias CarlingAbstract:Primary hyperParathyroidism (pHPT), generally caused by a monoclonal Parathyroid adenoma, is a common endocrinopathy. Until recently, the genesis of the disease was poorly understood but during the past decade the molecular pathology of Parathyroid Tumor development has begun to be unveiled. This review summarizes recent advances in our understanding of genetic predisposition to pHPT, and the role of vitamin D receptor gene (VDR) variants in development of the disease. It has been shown that the multiple endocrine neoplasia Tumor suppressor gene (MEN1) is mutated in Parathyroid adenomas, and overexpression of the cyclin D1 oncogene [PRAD1 (Parathyroid adenoma 1)] seems to contribute to Parathyroid Tumorigenesis. Several familal hyperParathyroid disorders have been studied, and the identification and characterization of the disease-causing genes have contributed to our understanding of Parathyroid physiology and pathophysiology.
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analysis of the rad54 gene on chromosome 1p as a potential Tumor suppressor gene in Parathyroid adenomas
International Journal of Cancer, 1999Co-Authors: Tobias Carling, Yasuo Imanishi, Andrew ArnoldAbstract:Parathyroid adenomas causing primary hyperParathyroidism (pHPT) frequently exhibit allelic loss of DNA markers on the short arm of chromosome 1, indicating the presence of one or more Tumor-suppressor genes on 1p. Since the development of pHPT is enhanced in individuals exposed to ionizing radiation to the neck, it could be anticipated that genes involved in DNA repair and recombination may be special targets for mutation in Parathyroid Tumorigenesis, whether irradiation-associated or not. RAD54 is a member of a family of genes involved in such functions, and RAD54 knockout mice show increased sensitivity to ionizing radiation. The localization of the RAD54 gene to 1p32 has therefore elevated it to a most compelling candidate Parathyroid Tumor-suppressor gene. Twelve Parathyroid adenomas demonstrating allelic loss at chromosome 1p were selected from 55 Parathyroid adenomas previously analyzed for loss of heterozygosity using polymorphic microsatellite markers. All 18 exons of the RAD54 gene were fully analyzed by automated sequencing for detection of point mutations or micro-deletions in each Parathyroid adenoma. No mutational aberrations were detected in the RAD54 gene, strongly suggesting that complete somatic inactivation of RAD54 is infrequently, if ever, associated with the development of Parathyroid adenomas. Whether genes controlling DNA repair and recombination are involved in Parathyroid neoplasia remains to be determined. Int. J. Cancer 83:80–82, 1999. © 1999 Wiley-Liss, Inc.
Lee F Starker - One of the best experts on this subject based on the ideXlab platform.
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expression and somatic mutations of sdhaf2 sdh5 a novel endocrine Tumor suppressor gene in Parathyroid Tumors of primary hyperParathyroidism
Endocrine, 2010Co-Authors: Peyman Bjorklund, Lee F Starker, Alberto Delgadoverdugo, Robert Udelsman, Tobias CarlingAbstract:To investigate the SDHAF2 gene and its effect on primary hyperParathyroidism. Parathyroid Tumors causing primary hyperParathyroidism (pHPT) are one of the more common endocrine neoplasias. Loss of heterozygosity at chromosome 11q13 is the most common chromosomal aberration in Parathyroid Tumors occurring in about 40% of sporadic Tumors. Only 15–19% display somatic mutations in the MEN1 gene, which suggest that this chromosomal region may harbor additional genes of importance in Parathyroid Tumor development. The SDHAF2 (formerly SDH5) gene is a recently identified neuroendocrine Tumor suppressor gene at this locus, and inherited mutations of the SDHAF2 gene has been linked to familial paraganglioma. We demonstrate that the SDHAF2 gene is expressed in Parathyroid tissue using RT-PCR. Because detection of inactivating mutations is the major criterion for validating a candidate Tumor suppressor, we used automated sequencing of the coding region and intron/exon boundaries in 80 sporadic Parathyroid adenomas from patients with pHPT. A known polymorphisms (A to G substitution; rs879647) was identified in 9/80 Parathyroid Tumors but no Tumor-specific somatic mutational aberrations, such as nonsense, frameshift, or other inactivating mutations were identified. The SDHAF2 gene is expressed in Parathyroid tissue. However, somatic mutations of the SDHAF2 Tumor suppressor gene are unlikely to frequently contribute to Parathyroid Tumor development in sporadic pHPT.
