Molecular profiling in primary hyperparathyroidism

Abstract

Primary hyperparathyroidism (HPT) is one of the most common endocrine disorders, defined by hypersecretion of parathormone. Primary HPT can be caused by adenoma, hyperplasia, and carcinoma. A great amount of mechanisms contribute to the pathogenesis of this disease, such as genetic predispositions because of the germline-inactivating mutations in the multiple endocrine neoplasia type 1 (MEN1) and HRPT2 tumor suppressor genes. Somatic mutations in these genes were found also in sporadic parathyroid neoplasias. Cell cycle regulators, growth factors, apoptosis-inducing ligands, death receptors, and other transmitter substances have also been implicated in the etiology of primary HPT. Parathyroid carcinoma is often misdiagnosed as parathyroid adenoma and long-term survival is conditioned by the extent of the primary surgical resection, therefore, of great interest is the discovery of definitive diagnostic markers for carcinoma. This article presents current state of knowledge of the molecular pathogenesis of primary HPT.

Clinicopathological correlates of hyperparathyroidism

“…Biochemically, a third-generation/second-generation PTH ratio >1 has been shown to help predict parathyroid malignancy prior to surgery by correlating with other clinical, biochemical and radiological findings 47 51 103–105. Although this method has not been widely accepted, it has been proposed based on the fact that most parathyroid carcinomas overproduce amino-PTH, which is recognised by third-generation but not second-generation PTH assays 47 51 81 103–105. However, rare ‘non-functioning’ parathyroid carcinomas have also been reported 42 47.…”

“…With the rise of circulating calcium levels, a classic endocrine feedback loop occurs, whereby the CaSRs and its signalling pathway are reactivated, silencing PTH secretion 7 33 80 141 168 169. In HPT, various alterations inactivating CaSR signalling pathway can occur, causing excess PTH secretion 7 11 13 33 42 78 81 141 166. Furthermore, if downregulation of CaSR persists over time, studies have shown that it can lead to aberrant cell growth and proliferation (thought to be related to aberrant Wnt/β-catenin and cyclin D1 signalling), suggesting that CaSR signalling may serve a tumour suppressor function in the parathyroid glands 7 11 33 42 78 81 141 152 166 170–172…”

“…Although the majority of cases do not have an identifiable risk factor, epidemiological studies suggest that a previous history of ionising radiation predisposes to the formation of sporadic parathyroid tumours 4 7 38 42. Somatic alterations in MEN1 and CCND1/PRAD1 genes have emerged as important drivers in the development of 25–40% of sporadic parathyroid adenomas 42 46 81 141 186 187…”

“…Although an inherited mutant copy of the MEN1 gene may be sufficient to cause multiglandular parathyroid disease (hyperplasia) and HPT (in MEN-1 syndrome or isolated familial HPT), an additional somatic inactivating mutation in the remaining copy of MEN1 (ie, the wild-type allele) is generally required for the development of sporadic parathyroid tumours (>25% in some series) 42 81 141. Alternatively, pure somatic mutations can result in bi-allelic inactivation of MEN1 , seen in some parathyroid adenomas 141 189 190.…”

Molecular pathways associated with transcriptional alterations in hyperparathyroidism

“…Mutations in the MEN1 tumor suppressor gene and alterations in the CCND1 (cyclin D1/PRAD1) oncogene represent the major driver in sporadic parathyroid tumorigenesis. Cell cycle regulators (including CDC73 aka HRPT2), growth factors, apoptosis-inducing ligands, death receptors, and other transmitter substances have also been implicated in the pathogenesis (19,20). Although there is an abundance of data examining the gene expression profiles of parathyroid adenoma, few studies have been performed in comparing gene expressions of pHPT with sHPT tissues.…”