Article

Clinical and molecular genetics of parathyroid neoplasms.

Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg. 10 Room 8C-101, 10 Center Dr. MSC 1752 Bethesda, MD 20892-1752, USA.
Best Practice & Research: Clinical Endocrinology & Metabolism (Impact Factor: 4.91). 06/2010; 24(3):491-502. DOI: 10.1016/j.beem.2010.01.003
Source: PubMed

ABSTRACT Primary hyperparathyroidism (HPT) results from the excessive secretion of parathyroid hormone from parathyroid tumours. While most HPT is sporadic, it is associated with a familial syndrome in a minority of cases. The study of these syndromes has helped define the pathophysiology of both familial and sporadic parathyroid neoplasms. Investigation of kindred with multiple endocrine neoplasia type 1 (MEN1) and the hyperparathyroidism-jaw tumour syndrome (HPT-JT) led to the discovery of the tumour suppressor genes MEN1 and HRPT2. We now recognise that somatic mutations in MEN1 and HRPT2 tumour suppressor genes are frequent events in sporadic parathyroid adenomas and carcinomas, respectively. Parathyroid tumours in the MEN2A syndrome result from mutational activation of the RET oncogene. The CCND1/PRAD1 oncogene was discovered by analysis of sporadic parathyroid tumours. Studies of familial isolated HPT and analysis of chromosomal loss and gain in parathyroid tumours suggest that other genes relevant to parathyroid neoplasia await identification.

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    Surgical Oncology 06/2014; DOI:10.1016/j.suronc.2014.03.005 · 2.37 Impact Factor
  • Source
    Therapeutic advances in endocrinology and metabolism 10/2010; 1(5):191-6. DOI:10.1177/2042018810389646
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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 the 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 the study. Quantitative RT-PCR, Western blotting, bisulfite pyrosequencing, colony formation assay, and RNA interference was 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 analysis. 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 assay. EZH2 depletion also interfered with the Wnt/β-catenin signaling pathway by increased expression of growth-suppressive Axin 2, a negative regulator of β-catenin stability. Indeed, EZH2 contributed to the total level of aberrantly accumulated transcriptionally active (nonphosphylated) β-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.
    Endocrine Related Cancer 11/2013; DOI:10.1530/ERC-13-0497 · 4.91 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Parathyroid carcinoma is a rare form of endocrine malignancy accounting for only a small minority of cancer cases. Due to the rarity of this cancer, there are no generalized guidelines for its management; however, surgery remains to be the mainstay therapy. The purpose of this article is to review and summarize the available literature on parathyroid carcinoma, while discussing proposed staging systems and the role of available adjuvant therapies.
    Surgical Oncology 06/2014; DOI:10.1016/j.suronc.2014.03.005 · 2.37 Impact Factor
  • Source
    Therapeutic advances in endocrinology and metabolism 10/2010; 1(5):191-6. DOI:10.1177/2042018810389646
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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 the 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 the study. Quantitative RT-PCR, Western blotting, bisulfite pyrosequencing, colony formation assay, and RNA interference was 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 analysis. 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 assay. EZH2 depletion also interfered with the Wnt/β-catenin signaling pathway by increased expression of growth-suppressive Axin 2, a negative regulator of β-catenin stability. Indeed, EZH2 contributed to the total level of aberrantly accumulated transcriptionally active (nonphosphylated) β-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.
    Endocrine Related Cancer 11/2013; DOI:10.1530/ERC-13-0497 · 4.91 Impact Factor

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