Original ArticleComparative Genomic Hybridization Analysis of Human Parathyroid Tumors
Introduction
Primary hyperparathyroidism (pHPT) is a common endocrine disorder characterized by dysregulation and excessive secretion of parathyroid hormone (PTH) from one or more parathyroid glands. PTH excess may be produced by a parathyroid adenoma, parathyroid hyperplasia, or a parathyroid carcinoma. The chief biochemical manifestation of primary PTH excess is hypercalcemia. Approximately 100,000 new cases of pHPT per year are estimated in the United States [1]. Most patients with pHPT (80–85%) harbor a single adenoma; the other three glands are normal. About 15–20% of the patients with pHPT have hyperplasia that involves enlargement of all four parathyroid glands occurring sporadically or in conjunction with an inherited disorder such as multiple endocrine neoplasia (MEN) type 1 or 2. The rarest form of pHPT is parathyroid carcinoma with a single gland enlarged; this form is seen in well under 1% of all patients with pHPT [2]. The parathyroid adenoma is a solitary hyperfunctional benign monoclonal parathyroid tumor [1]. The carcinoma shows unrestrained growth, is often palpable, and usually presents with severe hypercalcemia. Additionally, the carcinoma tends to be locally invasive and has the ability to metastasize. Not enough evidence exists to show that parathyroid cancer usually arises from an adenoma.
Tumor cytogenetic analysis has so far not indicated the involvement of chromosomal target regions that could be intensively searched for direct-acting oncogenes or tumor-suppressor genes causing parathyroid lesions. A translocation between chromosomes 1 and 5 has been reported in a single parathyroid adenoma [3], but it is unclear whether this was an isolated random occurrence or will be characteristic of a distinct subset of adenomas. The cyclin D1 (PRAD1) oncogene is rearranged with the PTH gene and is thereby transcriptionally activated in a very small subset of parathyroid adenoma 4, 5. Loss of heterozygosity (LOH) analyses in parathyroid adenoma have detected allelic loss of chromosome 11q in 35–40%, LOH on chromosome arms 1p, 6q, 11p, and 15q in 30%, and allelic loss of 3q markers in 10% of cases 6, 7, 8, 9, 10, 11. Allelic loss of the retinoblastoma tumor-suppressor gene reported to be highly specific for parathyroid carcinoma 12, 13 also has been detected in 16% of parathyroid adenomas associated with aggressive clinical and histopathological features [14]. Allelic loss of the p53 tumor-suppressor gene was observed in parathyroid carcinoma from 2 of 6 genetically informative patients and not in parathyroid adenoma from 20 informative patients [15]. Analysis of gene amplification has not been reported in parathyroid cancer or adenoma. Analysis of both gains and losses of chromosomal regions is possible with comparative genomic hybridization (CGH), first described by Kallioniemi et al. [16]. We have used CGH to screen 10 frozen parathyroid adenoma samples, 1 frozen parathyroid carcinoma, and 9 paraffin-embedded parathyroid carcinoma samples.
Section snippets
Tissue Samples
Parathyroid adenoma samples were obtained from patients undergoing parathyroidectomy for the management of primary hyperparathyroidism at NIH. Patients exhibited accepted clinical features of sporadic parathyroid adenoma. No patient had MEN1 or a history of neck irradiation. All were hypercalcemic with elevated levels of parathyroid hormone. None of the adenomas had clinicopathological features of malignancy. After surgical removal, tissue was immediately frozen in liquid nitrogen and then
Results
We used CGH to identify DNA sequence copy number changes in 10 parathyroid adenomas and 10 parathyroid carcinomas.
Discussion
We performed CGH analysis of single gland parathyroid tumors, adenoma and parathyroid carcinoma, in an effort to scan the entire tumor genome for DNA sequence copy number changes. CGH has the power to perform a genomewide analysis of both loss and gain of chromosomal regions that may harbor genes involved in the pathogenesis of different tumors. Not much data are available for parathyroid carcinoma owing to the lack of sufficient amount and preservation of tissue. CGH analysis is possible in
Addendum
During the review process of the present investigation, a study describing CGH analysis of parathyroid adenomas was also published in J Clin Endocrinol Metab 83:1766–1770 (1998).
Acknowledgements
We thank Tim Veldman for assistance in chromosome identification.
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