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Clinical and molecular genetics of parathyroid neoplasms

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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 MEN1and 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.

Section snippets

Primary HPT: general concepts

Regulation of ionised calcium is achieved by secretion of the parathyroid hormone (PTH) (1–84) in response to changes in the ionised calcium within a relatively narrow physiologic range. Secretion of PTH is negatively regulated by the CaSR located on the surface of the parathyroid chief cells.*7, 8 PTH maintains the serum ionised calcium primarily by three mechanisms: stimulation of calcium re-absorption in the distal tubule of the kidney, stimulation of osteoclast resorption in the bone and

Tumour suppressors and the two-hit hypothesis

An important model for tumour development was proposed by Alfred Knudson based on his epidemiologic analysis of retinoblastoma nearly 40 years ago.13 Sporadic retinoblastoma is much more common than familial cases, yet the latter have a much earlier age of onset and more frequently affect both eyes. The ‘two-hit’ hypothesis of neoplasia, as proposed by Knudson, suggests that two events (or ‘hits’) in an affected cell confer a selective growth advantage, resulting in clonal expansion of its

Multiple endocrine neoplasia type 1 and the MEN1 gene

Multiple endocrine neoplasia type 1 (MEN1) is the most common familial cause of primary HPT, accounting for approximately 2% of all cases.14In general, the syndrome is rare, with a prevalence of 2–3 per 100 000. It is characterised by a predisposition to develop endocrine tumours in pituitary, parathyroid and enteropancreatic endocrine cells, although tumours in several other endocrine and non-endocrine tissues are also associated with the syndrome.15

Primary HPT is the most common endocrine

Molecular functions of menin

Menin, the protein encoded by the MEN1 gene, is a predominantly nuclear protein that is expressed throughout the body. It lacks homology to other proteins that might provide insight into its mechanism as a tumour suppressor. Based on its associations with other proteins, it appears that menin has roles in cellular proliferation, regulation of gene transcription, DNA replication and repair and control of the cell cycle. The pathways and interactions described below involving menin, however,

HPT-JT syndrome and the HRPT2 gene

HPT-JT is a rare autosomal-dominant familial cancer syndrome manifested by primary HPT, ossifying tumours of the maxilla and mandible that are histologically distinct from the osteoclastic brown tumours of primary HPT and less commonly, renal cysts and/or uterine tumours.53, 54, 55 Primary HPT is usually the presenting manifestation. Parathyroid carcinoma is present in approximately 15% of those with HPT.

A germline inactivating mutation of the HRPT2 gene can be demonstrated in more than half of

Molecular functions of parafibromin

Parafibromin is a ubiquitously expressed protein whose function as a tumour suppressor is not well understood. It is the human homologue of the yeast Cdc73 protein, which, in both yeast and humans, is part of the ribonucleic acid (RNA) polymerase II-regulatory Paf1 complex. The Paf1 complex associates with RNA polymerase II and appears to have roles in gene transcription mediated by histone methylation in the promoter and coding regions of specific genes.62 In human cell lines, endogenous

Familial hypocalciuric hypercalcaemia and the CASR gene

FHH is an autosomal-dominant trait usually causing mild HPT with relative hypocalciuria; hypercalcaemia in FHH is highly penetrant at all ages, even in the perinatal period.68 FHH cases usually remain hypercalcaemic following partial or subtotal PTX. Most cases of FHH result from a heterozygous loss-of-function mutation in the CASR gene on the long arm of chromosome 3 that encodes CaSR.69, 70, 71 Homozygous or compound heterozygous inheritance of two inactive CASR alleles classically results in

Familial isolated HPT

FIHP is a clinically defined syndrome in kindred with HPT but lacking the specific features of MEN1, HPT-JT or FHH. The majority of FIHP patients lack germline mutation of MEN1, HRPT2 or CASR.78, 79 A distinct genetic aetiology has not been defined, although a genomic screening of seven FIHP families has identified a suggestive 1.7-Mb region on chromosome 2.80

Oncogenes in parathyroid neoplasia

Oncogenes derive from naturally occurring genes called proto-oncogenes that positively regulate cell growth and/or proliferation. Oncogenes represent mutationally activated or overexpressed forms of proto-oncogenes that can induce neoplasia.

Germline-activating mutations in the RET (RET, rearranged during transfection) proto-oncogene are associated with three different endocrine tumour syndromes associated with thyroid C-cells: multiple endocrine neoplasia type 2A (MEN2A) and type 2B (MEN2B)

Potential role of other genes in parathyroid neoplasia

Mutations in several candidate genes, chosen because of their known importance in the regulation of parathyroid cell growth or hormonal secretion, have been examined for a possible role in parathyroid tumour formation. No somatic mutations in CASR have yet been found in studies of sporadic parathyroid adenomas and parathyroid cancers. Mutations in neither the VDR nor the vitamin-D-activating enzyme 25-hydroxyvitamin D-1-alpha-hydroxylase have so far been found in molecular analyses of sporadic

Acknowledgements

The authors thank Dr. Stephen J. Marx for critical reading of the manuscript and our colleagues Drs. Lee S. Weinstein, Monica C. Skarulis and Sunita K. Agarwal of the National Institute of Diabetes and Digestive and Kidney Diseases for their ongoing support and encouragement. The Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases supported this research.

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