Identification of Somatic Mutations in Parathyroid Tumors Using Whole-Exome Sequencing

Cromer, M. Kyle; Starker, Lee F.; Choi, Murim; Udelsman, Robert; Nelson‐Williams, Carol; Lifton, Richard P.; Carling, Tobias

doi:10.1210/jc.2012-1743

Cited by 142 publications

(137 citation statements)

References 43 publications

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“…Parathyroid adenomas, the most common cause of PHPT, are considered clonal proliferations of a transformed parathyroid cell that has acquired proliferative or survival advantage due to one of several genetic abnormalities including the PRAD1 translocation or mutations in the genes encoding menin, P53, and P27 (3)(4)(5)(6)(7). Regardless of type, most authors consider parathyroid tumors clonal (8,9) although intratumoral heterogeneity has been observed and polyclonality of microdissected parathyroid adenomas has been reported (10,11).…”

mentioning

confidence: 99%

Functional and genetic studies of isolated cells from parathyroid tumors reveal the complex pathogenesis of parathyroid neoplasia

Shi

Hogue

Dixit

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Parathyroid adenomas, the main cause of primary hyperparathyroidism (PHPT), are thought to result from clonal expansion of tumor cells and to be insensitive to normal calcium feedback due to the loss of the calcium-sensing receptor (CASR). Utilizing flow cytometric analysis to isolate and individually study oxyphil cells, chief cells, and lymphocytes from resected parathyroid tumors and glands, we now report previously unrecognized heterogeneity in these tissues with respect to calcium responsiveness, CASR expression, and clonal origin of parathyroid tumors. Such heterogeneity of parathyroid adenomas likely reflects the complex etiopathogenesis and clinical heterogeneity of PHPT.

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mentioning

confidence: 99%

Functional and genetic studies of isolated cells from parathyroid tumors reveal the complex pathogenesis of parathyroid neoplasia

Shi

Hogue

Dixit

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…However, these derangements occur, collectively, in a minority of these tumors [2,3,7], and even when present are likely to cooperate with other driver lesions; thus multiple additional targets for tumorigenic mutation and future therapeutics undoubtedly exist. Indeed, studies of the genomes of parathyroid adenomas using a variety of methods have revealed a complex and heterogeneous landscape of chromosomal and DNA sequence level changes [8][9][10][11][12][13]. Identification of novel, recurrently altered genes has been difficult due to a low frequency of mutation observed in candidate genes and the limited number of cases examined [8,9].…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, studies of the genomes of parathyroid adenomas using a variety of methods have revealed a complex and heterogeneous landscape of chromosomal and DNA sequence level changes [8][9][10][11][12][13]. Identification of novel, recurrently altered genes has been difficult due to a low frequency of mutation observed in candidate genes and the limited number of cases examined [8,9]. For example, EZH2 mutation was observed in 1 of 8 adenoma exomes, and overall in 2/193 adenomas after direct sequencing of additional samples [8].…”

Section: Introductionmentioning

confidence: 99%

“…Identification of novel, recurrently altered genes has been difficult due to a low frequency of mutation observed in candidate genes and the limited number of cases examined [8,9]. For example, EZH2 mutation was observed in 1 of 8 adenoma exomes, and overall in 2/193 adenomas after direct sequencing of additional samples [8]. Thus, to shed more light on the molecular pathogenesis of this disorder, we subjected a larger cohort consisting of 19 pairs of parathyroid adenoma and matched germline DNA to whole exome sequencing.…”

Section: Introductionmentioning

confidence: 99%

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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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“…Surprisingly, genetic evidence argues against such a progression for parathyroid carcinoma. Genomic and genetic alterations common in benign parathyroid adenomas, most prominently loss of chromosome 11q and accompanying mutation of MEN1, which occur in 35% of parathyroid adenomas [2][3][4][5][6][7][8] , are rarely, if ever, seen in parathyroid cancer [3,4,8,9] . The clearly distinguishable patterns of genomic and genetic alterations present in parathyroid adenomas versus carcinomas suggests that parathyroid cancer most commonly arises de novo, rather than evolving from a preexisting benign adenoma [8] .…”

Section: Genetic Alterations In Parathyroid Cancermentioning

confidence: 99%

Parathyroid carcinoma

Costa-Guda¹

2018

JTGG

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Parathyroid carcinoma is a rare but clinically-aggressive tumor. While most cases are sporadic, parathyroid cancer is overrepresented in hyperparathyroidism-jaw tumor syndrome, or rarely other heritable syndromes. Evidence suggests that sporadic parathyroid carcinomas rarely, if ever, evolve through an identifiable benign tumor intermediate. A few genes have been directly implicated in the pathogenesis of sporadic parathyroid cancer; somatic (and less common germline) mutations in the CDC73 tumor suppressor gene are the most frequent finding and the only firmly established molecular drivers of parathyroid cancer. Alterations in other important human cancer genes, including CCND1 /cyclin D1, PIK3CA , MTOR and PRUNE2 have also been described in parathyroid cancer, however their abilities to drive malignant parathyroid tumorigenesis remains to be demonstrated experimentally.

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Identification of Somatic Mutations in Parathyroid Tumors Using Whole-Exome Sequencing

Abstract: This study confirms the frequent role of the loss of heterozygosity of chromosome 11 and MEN1 gene alterations in sporadic parathyroid adenomas and implicates a previously unassociated methyltransferase gene, EZH2, in endocrine tumorigenesis.

Cited by 142 publications

References 43 publications

Functional and genetic studies of isolated cells from parathyroid tumors reveal the complex pathogenesis of parathyroid neoplasia

Functional and genetic studies of isolated cells from parathyroid tumors reveal the complex pathogenesis of parathyroid neoplasia

Recurrent ZFX mutations in human sporadic parathyroid adenomas

Parathyroid carcinoma

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