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William F Simonds - One of the best experts on this subject based on the ideXlab platform.
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genotype of cdc73 germline mutation determines risk of Parathyroid Cancer
Endocrine-related Cancer, 2020Co-Authors: Jianhua Zhang, Poorni R Adikaram, James Welch, Bin Guan, Lee S Weinstein, Haobin Chen, William F SimondsAbstract:Mutation of the CDC73 gene, which encodes parafibromin, has been linked with Parathyroid Cancer. However, no correlation between genotypes of germline CDC73 mutations and the risk of Parathyroid Cancer has been known. In this study, subjects with germline CDC73 mutations were identified from the participants of two clinical protocols at National Institutes of Health (Discovery Cohort) and from the literature (Validation Cohort). The relative risk of developing Parathyroid Cancer was analyzed as a function of CDC73 genotype, and the impact of representative mutations on structure of parafibromin was compared between genotype groups. A total of 419 subjects, 68 in Discovery Cohort and 351 in Validation Cohort, were included. In both cohorts, percentages of CDC73 germline mutations that predicted significant conformational disruption or loss of expression of parafibromin (referred as 'high-impact mutations') were significantly higher among the subjects with Parathyroid Cancers compared to all other subjects. The Kaplan-Meier analysis showed that high-impact mutations were associated with a 6.6-fold higher risk of Parathyroid carcinoma compared to low-impact mutations, despite a similar risk of developing primary hyperParathyroidism between two groups. Disruption of the C-terminal domain (CTD) of parafibromin is directly involved in predisposition to Parathyroid carcinoma, since only the mutations impacting this domain were associated with an increased risk of Parathyroid carcinoma. Structural analysis revealed that a conserved surface structure in the CTD is universally disrupted by the mutations affecting this domain. In conclusion, high-impact germline CDC73 mutations were found to increase risk of Parathyroid carcinoma by disrupting the CTD of parafibromin.
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Long-term remission of disseminated Parathyroid Cancer following immunotherapy.
Endocrine, 2019Co-Authors: Marta Sarquis, William F Simonds, Stephen J. Marx, Albert Beckers, Arthur R. Bradwell, Maria Aparecida Camargos Bicalho, Adrian F Daly, Daniela Betea, Eitan Friedman, Luiz De MarcoAbstract:Purpose Parathyroid Cancer is a rare tumor associated with poor prognosis particularly when disseminated. While chemotherapy and/or radiotherapy are of no clinical value in disseminated disease, immunotherapy should be considered. Subject and results A patient with CDC73-associated metastatic Parathyroid carcinoma was treated with combined anti-hPTH immunotherapy and surgery. Conclusions Following five courses of anti-hPTH immunotherapy and subsequent surgery, a 12-year long remission of disseminated Parathyroid Cancer is reported. This case further supports the ever-expanding spectrum of Cancers that may benefit from immunotherapy.
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Genetics of HyperParathyroidism, Including Parathyroid Cancer
Endocrinology and metabolism clinics of North America, 2017Co-Authors: William F SimondsAbstract:Primary hyperParathyroidism (HPT) is a metabolic disease caused by the excessive secretion of Parathyroid hormone from 1 or more neoplastic Parathyroid glands. HPT is largely sporadic, but it can be associated with a familial syndrome. The study of such families led to the discovery of tumor suppressor genes whose loss of function is now recognized to underlie the development of many sporadic Parathyroid tumors. Heritable and acquired oncogenes causing Parathyroid neoplasia are also known. Studies of somatic changes in Parathyroid tumor DNA and investigation of kindreds with unexplained familial HPT promise to unmask more genes relevant to Parathyroid neoplasia.
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Parathyroid Cancer and the CDC73 tumor suppressor gene
International Journal of Endocrine Oncology, 2014Co-Authors: William F SimondsAbstract:Parathyroid carcinoma (PC) is a rare endocrine neoplasm, usually causing severe primary hyperParathyroidism, that frequently causes death from unmanageable hypercalcemia. PC is frequently associated with somatic inactivating mutations of the CDC73 gene (previously called HRPT2), a gene discovered in association with the familial hyperParathyroidism-jaw tumor syndrome. DNA analysis for CDC73 mutation should be performed on all patients with seemingly sporadic PC since some 25% will carry a germline mutation. It is often difficult to make a firm diagnosis of PC by histopathology alone. That diagnosis often depends on the presence of local tissue invasion or distant metastases. If PC is suspected, en bloc resection at initial surgery is recommended. Medical therapy with cinacalcet, bisphosphonates or denosumab may temporarily ameliorate the hypercalcemia of inoperable PC.
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The EIF4EBP3 translational repressor is a marker of CDC73 tumor suppressor haploinsufficiency in a Parathyroid Cancer syndrome
Cell Death & Disease, 2012Co-Authors: J. H. Zhang, E M Seigneur, A Loshakov, P S Connelly, L M Panicker, Pradeep K Dagur, M. Pandey, William F SimondsAbstract:Germline mutation of the tumor suppressor gene CDC73 confers susceptibility to the hyperParathyroidism-jaw tumor syndrome associated with a high risk of Parathyroid malignancy. Inactivating CDC73 mutations have also been implicated in sporadic Parathyroid Cancer, but are rare in sporadic benign Parathyroid tumors. The molecular pathways that distinguish malignant from benign Parathyroid transformation remain elusive. We previously showed that a hypomorphic allele of hyrax (hyx) , the Drosophila homolog of CDC73 , rescues the loss-of-ventral-eye phenotype of lobe , encoding the fly homolog of Akt1s1/ PRAS40. We report now an interaction between hyx and Tor , a central regulator of cell growth and autophagy, and show that eukaryotic translation initiation factor 4E-binding protein ( EIF4EBP ), a translational repressor and effector of mammalian target of rapamycin (mTOR), is a conserved target of hyx/CDC73 . Flies heterozygous for Tor and hyx , but not Mnn1 , the homolog of the multiple endocrine neoplasia type 1 ( MEN1 ) tumor suppressor associated with benign Parathyroid tumors, are starvation resistant with reduced basal levels of Thor/4E-BP . Human peripheral blood cell levels of EIF4EBP3 were reduced in patients with CDC73 , but not MEN1 , heterozygosity. Chromatin immunoprecipitation demonstrated occupancy of EIF4EBP3 by endogenous parafibromin. These results show that EIF4EBP3 is a peripheral marker of CDC73 function distinct from MEN1 -regulated pathways, and suggest a model whereby starvation resistance and/or translational de-repression contributes to Parathyroid malignant transformation.
Klaus-martin Schulte - One of the best experts on this subject based on the ideXlab platform.
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Oncologic Resection Achieving R0 Margins Improves Disease-Free Survival in Parathyroid Cancer
Annals of surgical oncology, 2014Co-Authors: Klaus-martin Schulte, Salvador J. Diaz-cano, N. Talat, G. Galata, Jackie Gilbert, J. Miell, Lc Hofbauer, Andreas Barthel, Stefan R. BornsteinAbstract:Background Parathyroid Cancer has a poor mid-term prognosis, often because of local recurrence, observed in half of all patients. Modern diagnostic workup increasingly enables a preoperative diagnosis of Parathyroid Cancer. There is limited evidence that more comprehensive oncologic surgery can reduce the risk of local recurrence. This study aims to identify the best specific surgical approach in Parathyroid Cancer.
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Diagnosis and management of Parathyroid Cancer
Nature reviews. Endocrinology, 2012Co-Authors: Klaus-martin Schulte, Nadia TalatAbstract:Parathyroid Cancer is a rare cause of primary hyperParathyroidism, but a missed diagnosis is often fatal. This Review highlights genetic, imaging and laboratory findings that can generate a preoperative diagnosis (or strong suspicion) of Parathyroid Cancer. The authors describe the management of these patients, which should include oncological resection and histological disease staging to predict prognosis and the need for adjuvant treatment.
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Classification of Parathyroid Cancer.
Annals of surgical oncology, 2012Co-Authors: Klaus-martin Schulte, Anthony J. Gill, Marcin Barczyński, Elias Karakas, Akira Miyauchi, Wolfram T. Knoefel, Celestino Pio Lombardi, Nadia Talat, Salvador J. Diaz-cano, Clive S. GrantAbstract:Purpose Parathyroid Cancer is rare and often has a poor outcome. There is no classification system that permits prediction of outcome in patients with Parathyroid Cancer. This study was designed to validate two prognostic classification systems developed by Talat and Schulte in 2010 (“Clinical Presentation, Staging and Long-term Evolution of Parathyroid Cancer,” Ann Surg Oncol 2010;17:2156–74) derived from a retrospective literature review of 330 patients.
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Lymph node involvement and surgical approach in Parathyroid Cancer.
World journal of surgery, 2010Co-Authors: Klaus-martin Schulte, Nadia Talat, John Miell, Caje Moniz, Prakash Sinha, Salvador J. Diaz-canoAbstract:Background The best surgical approach to Parathyroid Cancer is disputed. Recommendations vary and are built on incoherent evidence. High rates of recurrence and death require an in-depth review of underlying findings.
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clinical presentation staging and long term evolution of Parathyroid Cancer
Annals of Surgical Oncology, 2010Co-Authors: Nadia Talat, Klaus-martin SchulteAbstract:Background Parathyroid Cancer is rare and often fatal. This review provides an in-depth analysis of 330 clinical cases reported in detail. These data are used to inform a proposal for a hitherto lacking TNM staging system.
Lee S Weinstein - One of the best experts on this subject based on the ideXlab platform.
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genotype of cdc73 germline mutation determines risk of Parathyroid Cancer
Endocrine-related Cancer, 2020Co-Authors: Jianhua Zhang, Poorni R Adikaram, James Welch, Bin Guan, Lee S Weinstein, Haobin Chen, William F SimondsAbstract:Mutation of the CDC73 gene, which encodes parafibromin, has been linked with Parathyroid Cancer. However, no correlation between genotypes of germline CDC73 mutations and the risk of Parathyroid Cancer has been known. In this study, subjects with germline CDC73 mutations were identified from the participants of two clinical protocols at National Institutes of Health (Discovery Cohort) and from the literature (Validation Cohort). The relative risk of developing Parathyroid Cancer was analyzed as a function of CDC73 genotype, and the impact of representative mutations on structure of parafibromin was compared between genotype groups. A total of 419 subjects, 68 in Discovery Cohort and 351 in Validation Cohort, were included. In both cohorts, percentages of CDC73 germline mutations that predicted significant conformational disruption or loss of expression of parafibromin (referred as 'high-impact mutations') were significantly higher among the subjects with Parathyroid Cancers compared to all other subjects. The Kaplan-Meier analysis showed that high-impact mutations were associated with a 6.6-fold higher risk of Parathyroid carcinoma compared to low-impact mutations, despite a similar risk of developing primary hyperParathyroidism between two groups. Disruption of the C-terminal domain (CTD) of parafibromin is directly involved in predisposition to Parathyroid carcinoma, since only the mutations impacting this domain were associated with an increased risk of Parathyroid carcinoma. Structural analysis revealed that a conserved surface structure in the CTD is universally disrupted by the mutations affecting this domain. In conclusion, high-impact germline CDC73 mutations were found to increase risk of Parathyroid carcinoma by disrupting the CTD of parafibromin.
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HRPT2, a Marker of Parathyroid Cancer
The New England journal of medicine, 2003Co-Authors: Lee S Weinstein, William F SimondsAbstract:Primary hyperParathyroidism is a state of excess secretion of Parathyroid hormone and hypercalcemia, often with skeletal and renal complications. The disease usually results from a single parathyro...
Piero Berti - One of the best experts on this subject based on the ideXlab platform.
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A reappraisal of the Rb1 gene abnormalities in the diagnosis of Parathyroid Cancer
Clinical endocrinology, 2004Co-Authors: Filomena Cetani, Elena Pardi, Paolo Viacava, Giada Di Pollina, Giovanni Fanelli, A Picone, Simona Borsari, Elisabetta Gazzerro, Paolo Miccoli, Piero BertiAbstract:Summary OBJECTIVES Some histological features may suggest the malignant nature of a Parathyroid tumour. However, the diagnosis of Parathyroid Cancer can only be definitively established in the presence of local invasion or metastases. DESIGN We further investigated the role of the retinoblastoma gene (Rb1) and the breast Cancer susceptibility gene (BRCA2) in the differential diagnosis between benign and malignant Parathyroid tumours by evaluating loss of heterozygosity (LOH) at these loci and Rb protein (pRb) immunohistochemistry. PATIENTS AND MEASUREMENTS Fifty-three Parathyroid adenomas from patients with sporadic primary hyperParathyroidism (PHPT) and 10 Parathyroid Cancer specimens were studied. Microsatellite polymorphisms at the Rb1 and BRCA2 loci were polymerase chain reaction (PCR) amplified from each patient’s paired tumour and leucocyte DNA samples, using oligonucleotide primers flanking the repeat sequence. Immunohistochemical staining of pRb was carried out using a monoclonal antibody. RESULTS All but one of the 53 tumour‐leucocyte pairs was informative for at least one of the three polymorphic markers of the Rb1 gene. Fifteen adenomas (28·8%) showed LOH. Regarding the BRCA2 gene, 46 tumour‐ leucocyte pairs were informative and LOH was present in eight (17·4%). All six carcinomas had LOH for at least one marker at the Rb1 locus. LOH for the BRCA2 microsatellite was found in three of the five informative primary tumour samples. Immunohistochemical analysis revealed that all adenomas were positive and the number of pRb-positive cells varied significantly among different samples. The mean percentage of stained cells was 15·7%. Eleven of the 30 (36·7%) adenomas showed sparse positive staining, 13 (43·3%) intermediate staining and six (20%) extensive staining. All Parathyroid Cancers were entirely negative for pRb immunostaining. CONCLUSIONS Inactivation of the Rb1 gene is a common event in Parathyroid tumorigenesis. Retention of heterozygosity seems to exclude Parathyroid malignancy, which is suggested by the combined finding of LOH and lack of protein expression.
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Genetic analyses of the HRPT2 gene in primary hyperParathyroidism: germline and somatic mutations in familial and sporadic Parathyroid tumors.
The Journal of clinical endocrinology and metabolism, 2004Co-Authors: Filomena Cetani, Elena Pardi, Paolo Viacava, Simona Borsari, Elisabetta Gazzerro, Giada Dipollina, Luisella Cianferotti, Elena Ambrogini, Giacomo Colussi, Piero BertiAbstract:We investigated the involvement of the HRPT2 gene by loss of heterozygosity analysis and direct sequencing in a kindred with hyperParathyroidism-jaw tumor syndrome (HPT-JT) and three kindreds with familial isolated primary hyperParathyroidism (FIHP). Seven patients with sporadic Parathyroid Cancers and 35 with Parathyroid adenomas with no family history of primary hyperParathyroidism or HPT-JT were also studied. A germline heterozygous substitution G to A was found in the donor splice site of intron 1 in one of the three FIHP families. No mutations were identified in the HPT-JT kindred. A somatic HRPT2 mutation was found in four of seven patients with Parathyroid Cancers, two of which were unreported frameshift mutations (195insT and 195insA) in exon 2. Consistent with recent findings, two of seven patients with sporadic Parathyroid Cancer had germline mutations. Four adenomas showed loss of heterozygosity at HRPT2, whereas a somatic HRPT2 mutation was found in one. In conclusion, we provide additional evidence for a strong association between HRPT2 gene mutations and sporadic Parathyroid Cancer. The finding that two of the seven patients with sporadic Parathyroid Cancer carried an HRPT2 germline mutation suggests that they might have occult HPT-JT. Our results also confirm the need for testing HRPT2 gene in FIHP families.
Filomena Cetani - One of the best experts on this subject based on the ideXlab platform.
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cdc73 mutational status and loss of parafibromin in the outcome of Parathyroid Cancer
Endocrine connections, 2013Co-Authors: Filomena Cetani, Elena Pardi, Simona Borsari, Paolo Miccoli, Maria Rosa Pelizzo, Chiara Banti, P Viacava, Liborio Torregrossa, Fulvio Basolo, Massimo RuggeAbstract:Inactivating mutations of the CDC73 tumor suppressor gene have been reported in Parathyroid carcinomas (PC), in association with the loss of nuclear expression of the encoded protein, parafibromin. The aim of this study was to further investigate the role of the CDC73 gene in PC and evaluate whether gene carrier status and/or the loss of parafibromin staining might have an effect on the outcome of the disease. We performed genetic and immunohistochemical studies in Parathyroid tumor samples from 35 patients with sporadic PC. Nonsense or frameshift CDC73 mutations were detected in 13 samples suitable for DNA sequencing. Six of these mutations were germline. Loss of parafibromin expression was found in 17 samples. The presence of the CDC73 mutation as well as the loss of parafibromin predicted a high likelihood of subsequent recurrence and/or metastasis (92.3%, PZ0.049 and 94.1%, PZ0.0017 respectively), but only the latter was associated with a decreased overall 5- and 10-year survival rates (59%, PZ0.107, and 23%, PZ0.0026 respectively). The presence of both the CDC73 mutation and loss of parafibromin staining compared with their absence predicted a lower overall survival at 10- (18 vs 84%, PZ0.016) but not at 5-year follow-up. In conclusion, loss of parafibromin staining, better than CDC73 mutation, predicts the clinical outcome and mortality rate. The added value of CDC73 mutational analysis is the possibility of identifying germline mutations, which will prompt the screening of other family members.
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A reappraisal of the Rb1 gene abnormalities in the diagnosis of Parathyroid Cancer
Clinical endocrinology, 2004Co-Authors: Filomena Cetani, Elena Pardi, Paolo Viacava, Giada Di Pollina, Giovanni Fanelli, A Picone, Simona Borsari, Elisabetta Gazzerro, Paolo Miccoli, Piero BertiAbstract:Summary OBJECTIVES Some histological features may suggest the malignant nature of a Parathyroid tumour. However, the diagnosis of Parathyroid Cancer can only be definitively established in the presence of local invasion or metastases. DESIGN We further investigated the role of the retinoblastoma gene (Rb1) and the breast Cancer susceptibility gene (BRCA2) in the differential diagnosis between benign and malignant Parathyroid tumours by evaluating loss of heterozygosity (LOH) at these loci and Rb protein (pRb) immunohistochemistry. PATIENTS AND MEASUREMENTS Fifty-three Parathyroid adenomas from patients with sporadic primary hyperParathyroidism (PHPT) and 10 Parathyroid Cancer specimens were studied. Microsatellite polymorphisms at the Rb1 and BRCA2 loci were polymerase chain reaction (PCR) amplified from each patient’s paired tumour and leucocyte DNA samples, using oligonucleotide primers flanking the repeat sequence. Immunohistochemical staining of pRb was carried out using a monoclonal antibody. RESULTS All but one of the 53 tumour‐leucocyte pairs was informative for at least one of the three polymorphic markers of the Rb1 gene. Fifteen adenomas (28·8%) showed LOH. Regarding the BRCA2 gene, 46 tumour‐ leucocyte pairs were informative and LOH was present in eight (17·4%). All six carcinomas had LOH for at least one marker at the Rb1 locus. LOH for the BRCA2 microsatellite was found in three of the five informative primary tumour samples. Immunohistochemical analysis revealed that all adenomas were positive and the number of pRb-positive cells varied significantly among different samples. The mean percentage of stained cells was 15·7%. Eleven of the 30 (36·7%) adenomas showed sparse positive staining, 13 (43·3%) intermediate staining and six (20%) extensive staining. All Parathyroid Cancers were entirely negative for pRb immunostaining. CONCLUSIONS Inactivation of the Rb1 gene is a common event in Parathyroid tumorigenesis. Retention of heterozygosity seems to exclude Parathyroid malignancy, which is suggested by the combined finding of LOH and lack of protein expression.
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Genetic analyses of the HRPT2 gene in primary hyperParathyroidism: germline and somatic mutations in familial and sporadic Parathyroid tumors.
The Journal of clinical endocrinology and metabolism, 2004Co-Authors: Filomena Cetani, Elena Pardi, Paolo Viacava, Simona Borsari, Elisabetta Gazzerro, Giada Dipollina, Luisella Cianferotti, Elena Ambrogini, Giacomo Colussi, Piero BertiAbstract:We investigated the involvement of the HRPT2 gene by loss of heterozygosity analysis and direct sequencing in a kindred with hyperParathyroidism-jaw tumor syndrome (HPT-JT) and three kindreds with familial isolated primary hyperParathyroidism (FIHP). Seven patients with sporadic Parathyroid Cancers and 35 with Parathyroid adenomas with no family history of primary hyperParathyroidism or HPT-JT were also studied. A germline heterozygous substitution G to A was found in the donor splice site of intron 1 in one of the three FIHP families. No mutations were identified in the HPT-JT kindred. A somatic HRPT2 mutation was found in four of seven patients with Parathyroid Cancers, two of which were unreported frameshift mutations (195insT and 195insA) in exon 2. Consistent with recent findings, two of seven patients with sporadic Parathyroid Cancer had germline mutations. Four adenomas showed loss of heterozygosity at HRPT2, whereas a somatic HRPT2 mutation was found in one. In conclusion, we provide additional evidence for a strong association between HRPT2 gene mutations and sporadic Parathyroid Cancer. The finding that two of the seven patients with sporadic Parathyroid Cancer carried an HRPT2 germline mutation suggests that they might have occult HPT-JT. Our results also confirm the need for testing HRPT2 gene in FIHP families.
