Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia.

Arnold, Andrew; Brown, Mark F.; Ureña, Pablo; Gaz, Randall D.; Sarfati, E.; Drüeke, Tilman B.

doi:10.1172/jci117890

Cited by 372 publications

(152 citation statements)

References 36 publications

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“…Seven solitary tumours repeatedly gave ratios suggesting a polyclonal origin. Besides admixture with normal tissue, a pattern suggestive of a polyclonal origin could also result from an aberrant pattern of DNA methylation or the presence of two clonal expansions with opposing X-chromosome inactivation patterns (12). Furthermore, a comparison of two independent methods for the study of X-chromosome inactivation reported con¯icting results in 10% of all cases evaluated (15).…”

Section: Discussionmentioning

confidence: 99%

Frequency of somatic MEN1 gene mutations in monoclonal parathyroid tumours of patients with primary hyperparathyroidism

Miedlich¹,

Krohn²,

Lamesch³

et al. 2000

European Journal of Endocrinology

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Objectives: Investigation of small numbers of parathyroid tumours by X-chromosome inactivation analysis suggests that the majority of them are monoclonal lesions most likely caused by a somatic mutation. Somatic mutations in the MEN1 gene located on chromosome 11q13 have recently been identi®ed in 12±17% of solitary parathyroid tumours in patients with sporadic primary hyperparathyroidism, and they may be the precipitating genetic defect leading to monoclonal cell proliferation in these tumours. Design: To determine the prevalence of MEN1 gene mutations in monoclonal parathyroid neoplasias we investigated 33 parathyroid tumours of patients with primary hyperparathyroidism for clonality and mutations in the MEN1 gene. Methods: X-chromosome inactivation analysis was used to assess the clonal status of the tumours, direct sequencing of the complete coding region was applied to identify mutations in the MEN1 gene. Results: Twenty-eight female patients (26 patients with solitary adenoma, 2 patients with hyperplasia) were informative for the polymorphism of the androgen receptor on the X-chromosome and could be tested for inactivation pattern. Nineteen of twenty-six (73%) solitary adenomas were monoclonal. Somatic mutations in the MEN1 gene were identi®ed in nine cases. Six of them were found in the relatively large second exon of the MEN1 gene (A49D, 193del36, 402delC, 482del22, 547delT, W126X). One was found in exon 5 (904del9), one in exon 7 (Y327X) and one in exon 9 (R415X). Of the monoclonal tumours, 5 out of 19 (26%) harboured a somatic MEN1 gene mutation. Conclusions: In summary, 73% of the solitary parathyroid adenomas were monoclonal. In 26% of the monoclonal tumours a somatic MEN1 gene mutation has been identifed. However, for 74% of monoclonal tumours of the parathyroids the underlying genetic defects are still not known.

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Section: Discussionmentioning

confidence: 99%

Frequency of somatic MEN1 gene mutations in monoclonal parathyroid tumours of patients with primary hyperparathyroidism

Miedlich¹,

Krohn²,

Lamesch³

et al. 2000

European Journal of Endocrinology

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“…Although genomic hybridization and loss of heterozygosity (LOH) studies have suggested the presence of an undiscovered parathyroid tumor suppressor gene on the X chromosome [11,24,25], and notwithstanding that ZFX deletion has led to tumorigenesis in an experimental liver cancer model in mice [26], it does not appear that ZFX is acting as a classic two-hit human tumor suppressor in parathyroid adenomas. In particular, we observed no mutations that would be expected to inactivate the ZFX gene product, such as early stop codons or frameshifts; in addition, none of the female patients' tumor samples that harbored a ZFX mutation showed LOH at the corresponding wild type locus.…”

Section: Discussionmentioning

confidence: 99%

Recurrent ZFX mutations in human sporadic parathyroid adenomas

Soong

Arnold

2014

Oncoscience

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ABSTRACT:The molecular abnormalities leading to sporadic parathyroid adenomas, a common type of human endocrine neoplasm, are heterogeneous and incompletely understood. Using whole exome and direct sequencing of parathyroid adenoma DNA samples, we identified recurrent somatic mutations in the ZFX gene. ZFX is a member of Krueppel C2H2 type zinc finger protein family, was initially described as a homolog of ZFY, and has been implicated as a transcription factor regulating embryonic stem cell renewal. The ZFX mutations we identified were strikingly specific, focused in each tumor on one encoded residue in a hotspot of two consecutive highly conserved arginine residues (R786/787; arginine to glutamine, threonine or leucine) in a zinc finger domain near the C-terminus of the protein. The intragenic specificity of these recurrently selected mutations, their confirmed expression within the tumors, the absence of loss of heterozygosity, and the absence of these mutations among over 4000 ZFX alleles in the dbSNP137 database, strongly suggest a novel role for ZFX as a human proto-oncogene. Further, these observations highlight the mutated zincfinger domain as a new focal point for understanding ZFX's normal and tumorigenic functions, and for development of molecularly-targeted therapeutics.

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“…In parathyroid cells, a rise in FM1-43 fluorescence occurred during incubation in a high (inhibitory) In patients with primary hyperparathyroidism, secretion of PTH continues uninhibited in the face of hypercalcaemia. Most patients with primary hyperparathyroidism have a single parathyroid adenoma whose cells are monoclonal [8][9][10], have a lower [Ca# + ] i in response to [Ca# + ] ext [11,12] and a higher set point (defined as the [Ca# + ] ext necessary for half-inhibition of PTH secretion) [13]. Cloning of the CaR from bovine parathyroid cells [2] and its isolation from human parathyroid adenomas [4] raised hopes that the molecular basis of primary hyperparathyroidism would be better understood.…”

Section: Introductionmentioning

confidence: 99%

Changes in cytoplasmic calcium determine the secretory response to extracellular cations in human parathyroid cells: a confocal microscopy study using FM1-43 dye

Mihai

Lai

Schofield

et al. 2000

Biochemical Journal

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Whether activation of the calcium receptor (CaR) modulates secretory events was investigated by real-time fluorescence and confocal microscopy using fura 2 and FM1-43 fluorescent dye. Two paradigms were used : human parathyroid cells, which are stimulated by a step from a high to a low extracellular calcium concentration ([Ca# + ] ext ), and rMTC6-23 cells, a rat medullary thyroid carcinoma cell line whose secretion is stimulated by an increase in [Ca# + ] ext . Parathyroid cells were dispersed from parathyroid adenomas removed from 18 patients with primary hyperparathyroidism. In both cell types, incubation with FM1-43 (2 µM) resulted in staining of the plasma membranes, which was rapidly increased following changes in [Ca# + ] ext known to stimulate secretion. A high [Ca# + ] ext and lanthanum (La$ + ) decreased the membrane-associated FM1-43 fluorescence. Prolonged incubation (5-30 min) in the presence of FM1-43 resulted in accumulation of the dye in the cytoplasm, its granular distribution suggesting targeting of the secretory compartment. These data suggest that FM1-43 fluorescence is determined by :

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Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia.

Cited by 372 publications

References 36 publications

Frequency of somatic MEN1 gene mutations in monoclonal parathyroid tumours of patients with primary hyperparathyroidism

Frequency of somatic MEN1 gene mutations in monoclonal parathyroid tumours of patients with primary hyperparathyroidism

Recurrent ZFX mutations in human sporadic parathyroid adenomas

Changes in cytoplasmic calcium determine the secretory response to extracellular cations in human parathyroid cells: a confocal microscopy study using FM1-43 dye

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