Deletion of 11q23 and Cyclin D1 Overexpression Are Frequent Aberrations in Parathyroid Adenomas

Abstract

Hyperparathyroidism may result from parathyroid hyperplasia or adenoma, or rarely from parathyroid carcinoma. Pericentromeric inversion of chromosome 11 that results in activation of the PRAD1/cyclin D1 gene and tumor suppressor gene loss have been described as genetic abnormalities in the evolution of parathyroid neoplasms. We studied tissue samples taken from primary parathyroid hyperplasia, parathyroid adenoma, and histologically normal parathyroid tissue by comparative genomic hybridization, fluorescent in situ hybridization, and immunohistochemistry for cyclin D1. DNA copy number changes were infrequent in primary hyperplasia (4 of 24, 17%), but common in adenomas (10 of 16, 63%; P ‫؍‬ 0.0059). The most common change was deletion of the entire chromosome 11 or a part of it, with a minimal common region at 11q23. This change was present in five (31%) adenomas and two (8%) primary hyperplasias. Fluorescent in situ hybridization confirmed the presence of both MEN1 alleles located at 11q13 despite deletion of 11q23 in all three cases studied. Cyclin D1 was overexpressed in six (40%) of the 15 adenomas studied, whereas none of the 27 hyperplasias (P ‫؍‬ 0.0010) nor the five histologically normal tissue samples overexpressed cyclin D1. Either DNA copy number loss or cyclin D1 overexpression was present in 13 (81%) of the 16 adenomas. We conclude that DNA copy number loss and cyclin D1 overexpression are common in parathyroid adenomas. The region 11q23 is frequently lost in parathyroid adenomas and occasionally in parathyroid hyperplasias, and this suggests the possibility that a tumor suppressor gene that is important in their pathogenesis is present on 11q23. Hyperparathyroidism may be caused by parathyroid gland hyperplasia or adenoma, or very rarely by parathyroid carcinoma. The clinical manifestations of hyperparathyroidism vary, but the patient may present with recurrent nephrolithiasis, mental changes, peptic ulcers, and sometimes with extensive bone resorption. The annual incidence is estimated to be 0.03% in patients older than 60, but the estimated prevalence including undiscovered asymptomatic patients is 1 to 2% or higher. The diagnosis is made primarily on clinical grounds and presence of elevated serum parathyroid hormone, which is usually associated with elevated serum calcium levels and urine calcium excretion. Primary hyperparathyroidism is usually caused by a single parathyroid adenoma, but multiglandular parathyroid hyperplasia accounts for ϳ10 to 15% of primary hyperparathyroidism.

Distinction in gene expression profiles demonstrated in parathyroid adenomas by high-density oligoarray technology

“…In the extended series of 17 adenomas, Cyclin D1 was over-expressed (. twofold) in 24% of the cases, which is in good agreement with the reported immunohistochemistry results (20,21). Notably, in the four adenomas with Cyclin D1 over-expression, the level was largely increased compared with the normal parathyroid (4-to 36-fold), suggesting its relevance for tumor development.…”

“…Cyclin D1 over-expression is in agreement with the protein over-expression previously detected by immunohistochemistry in parathyroid adenomas (20,21). A pericentric inversion with breakpoints at 11q13 and 11p15 is suggested to bring the Cyclin D1 oncogene under the influence of the 5 0 -regulatory sequences of the PTH gene (9), which results in dramatic over-expression of Cyclin D1.…”

Involvement of the MEN1 gene locus in familial isolated hyperparathyroidism

“…However, we cannot exclude involvement of mutations in other regions of MEN1, such as intronic or regulatory parts. Furthermore, the existence of a possible second parathyroid gene in 11q is supported by the LOH outside MEN1 in families 3 and 4, and by distal 11q deletions in sporadic parathyroid tumours (28). In contrast, the loss of 11 could represent a secondary alteration occurring after the inactivation of the predisposing disease gene.…”

Chromosomal imbalances identified by comparative genomic hybridization in sporadic parathyroid adenomas

“…Based upon the reported results and in contrast with PAs, PT hyperplasias show scarce chromosomal gains or losses, hindering the establishment of a common profile. The only significant recurrent chromosomal aberration appears to be loss of 11q in less than 10% of cases (25).…”

“…Four previously published reports have studied sporadic PAs by CGH (22)(23)(24)(25). They found chromosomal imbalances in 62 to 90% of cases.…”