Aryl Hydrocarbon Receptor Interacting Protein (<i>AIP</i>) Mutations Occur Rarely in Sporadic Parathyroid Adenomas

Pardi, Elena; Marcocci, Claudio; Borsari, Simona; Saponaro, Federica; Torregrossa, Liborio; Tancredi, Mariella; Raspini, Benedetta; Basolo, Fulvio; Cetani, Filomena

doi:10.1210/jc.2012-4029

Cited by 32 publications

(19 citation statements)

References 36 publications

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“…One of the two mutation-positive patients had persistent hypercalcemia/hyperparathyroidism following surgery, suggestive of multi-gland disease. The same c.911G>A (R304Q) mutation was identified in both, unrelated patients and has been previously seen in several familial isolated pituitary adenoma kindreds and sporadic pituitary tumors (Pardi et al 2013). Homozygous inactivation of Aip in genetically engineered mice is embryonic lethal, and no parathyroid abnormalities were reported in Aip heterozygous knockout mice (Kang et al 2011).…”

Section: Parathyroid Adenomasupporting

confidence: 68%

Genetic and epigenetic changes in sporadic endocrine tumors: Parathyroid tumors

Costa-Guda

Arnold

2014

Molecular and Cellular Endocrinology

151

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Parathyroid neoplasia is most commonly due to benign parathyroid adenoma but rarely can be caused by malignant parathyroid carcinoma. Evidence suggests that parathyroid carcinomas rarely, if ever, evolve through an identifiable benign intermediate, with the notable exception of carcinomas associated with the familial hyperparathyroidism-jaw tumor syndrome. Several genes have been directly implicated in the pathogenesis of typical sporadic parathyroid adenoma; somatic mutations in the MEN1 tumor suppressor gene are the most frequent finding, and alterations in the Cyclin D1/PRAD1 oncogene are also firmly established molecular drivers of sporadic adenomas. In addition, good evidence supports mutation in the CDKN1B/p27 cyclin-dependent kinase inhibitor (CDKI) gene, and in other CDKI genes as contributing to disease pathogenesis in this context. Somatic defects in additional genes, including β-catenin, POT1 and EZH2 may contribute to parathyroid adenoma formation but, for most, their ability to drive parathyroid tumorigenesis remains to be demonstrated experimentally. Further, genetic predisposition to sporadic presentations of parathyroid adenoma appears be conferred by rare, and probably low-penetrance, germline variants in CDKI genes and, perhaps, in other genes such as CASR and AIP. The HRPT2 tumor suppressor gene is commonly mutated in parathyroid carcinoma.

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Section: Parathyroid Adenomasupporting

confidence: 68%

Genetic and epigenetic changes in sporadic endocrine tumors: Parathyroid tumors

Costa-Guda

Arnold

2014

Molecular and Cellular Endocrinology

151

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“…No N- RAS , H- RAS or K- RAS gene mutations were identified. Two germline AIP changes came to light among the acromegalic patients with DTC: one was a c.911G>A (R304Q) variant, which had previously been reported and considered a variant of uncertain significance [23], [29]; the other was a synonymous substitution c.144G>A (T48T), considered a rare neutral polymorphism [23].…”

Section: Resultsmentioning

confidence: 99%

AHR Over-Expression in Papillary Thyroid Carcinoma: Clinical and Molecular Assessments in a Series of Italian Acromegalic Patients with a Long-Term Follow-Up

et al. 2014

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AimAcromegaly reportedly carries an increased risk of malignant and benign thyroid tumors, with a prevalence of thyroid cancer of around 3–7%. Germline mutations in the aryl-hydrocarbon receptor (AHR) interacting protein (AIP) have been identified in familial forms of acromegaly. The molecular and endocrine relationships between follicular thyroid growth and GH-secreting pituitary adenoma have yet to be fully established. Our aim was to study the prevalence of differentiated thyroid cancer (DTC) in acromegaly, focusing on the role of genetic events responsible for the onset of thyroid cancer.MethodsGermline mutations in the AIP gene were assessed in all patients; BRAF and H-N-K RAS status was analyzed by direct sequencing in thyroid specimens, while immunohistochemistry was used to analyze the protein expression of AIP and AHR. A set of PTCs unrelated to acromegaly was also studied.Results12 DTCs (10 papillary and 2 follicular carcinomas) were identified in a cohort of 113 acromegalic patients. No differences in GH/IGF-1 levels or disease activity emerged between patients with and without DTC, but the former were older and more often female. BRAF V600E was found in 70% of the papillary thyroid cancers; there were no RAS mutations. AIP protein expression was similar in neoplastic and normal cells, while AHR protein was expressed more in PTCs carrying BRAF mutations than in normal tissue, irrespective of acromegaly status.ConclusionsThe prevalence of DTC in acromegaly is around 11% and endocrinologists should bear this in mind, especially when examining elderly female patients with uninodular goiter. The DTC risk does not seem to correlate with GH/IGF-1 levels, while it may be associated with BRAF mutations and AHR over-expression. Genetic or epigenetic events probably play a part in promoting thyroid carcinoma.

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“…Other genetic abnormalities have been detected in a small proportion of parathyroid adenomas, including mutations in CDC73 (REFS 82,83 ), CDKN1B 84 and AIP 85 . Interestingly, mutations were germline in two patients with CDKN1B mutations and in one carrying a mutation in AIP Contradictory results have been reported on the presence of CTNNB1 (encoding β-catenin) mutations involving serine/threonine phosphorylation 86,87 .…”

Section: Mechanisms/pathophysiologymentioning

confidence: 99%

Primary hyperparathyroidism

Bilezikian

Cusano

Khan

et al. 2016

Nat Rev Dis Primers

Self Cite

209

166

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Primary hyperparathyroidism (PHPT) is a common disorder in which parathyroid hormone (PTH) is excessively secreted from one or more of the four parathyroid glands. A single benign parathyroid adenoma is the cause in most people. However, multiglandular disease is not rare and is typically seen in familial PHPT syndromes. The genetics of PHPT is usually monoclonal when a single gland is involved and polyclonal when multiglandular disease is present. The genes that have been implicated in PHPT include proto-oncogenes and tumour-suppressor genes. Hypercalcaemia is the biochemical hallmark of PHPT. Usually, the concentration of PTH is frankly increased but can remain within the normal range, which is abnormal in the setting of hypercalcaemia. Normocalcaemic PHPT, a variant in which the serum calcium level is persistently normal but PTH levels are increased in the absence of an obvious inciting stimulus, is now recognized. The clinical presentation of PHPT varies from asymptomatic disease (seen in countries where biochemical screening is routine) to classic symptomatic disease in which renal and/or skeletal complications are observed. Management guidelines have recently been revised to help the clinician to decide on the merits of a parathyroidectomy or a non-surgical course. This Primer covers these areas with particular attention to the epidemiology, clinical presentations, genetics, evaluation and guidelines for the management of PHPT.

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Aryl Hydrocarbon Receptor Interacting Protein (AIP) Mutations Occur Rarely in Sporadic Parathyroid Adenomas

Abstract: The AIP gene is rarely involved in parathyroid adenomas, but the germline nature of the mutations suggests that it might predispose to primary hyperparathyroidism. MEN1 gene alterations occur in a substantial proportion of sporadic parathyroid adenomas.

Cited by 32 publications

References 36 publications

Genetic and epigenetic changes in sporadic endocrine tumors: Parathyroid tumors

Genetic and epigenetic changes in sporadic endocrine tumors: Parathyroid tumors

AHR Over-Expression in Papillary Thyroid Carcinoma: Clinical and Molecular Assessments in a Series of Italian Acromegalic Patients with a Long-Term Follow-Up

Primary hyperparathyroidism

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