Clinical and molecular genetics of parathyroid neoplasms

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.

Figure 1. Role of cyclin D1, product of the CCND1/PRAD1 proto-oncogene, in cell cycle regulation

Chromosomal rearrangement in a subset of sporadic parathyroid adenomas, that positions the CCND1/PRAD1 proto-oncogene (normally activated by mitogenic signals) under the influence of parathyroid hormone gene promoter/enhancer elements [83-85], stimulates transcription of cyclin D1. Cyclin D expression is physiologically upregulated by mitogenic signals. Enhanced cyclin D expression results in increased complex formation between cyclin D and cyclin-dependent kinases 4 (CDK4) and 6 (CDK6). The retinoblastoma gene product, pRB, in its unphosphorylated state, normally binds to and sequesters the E2F family of transcription factors. Successive phosphorylation of pRB by CDK4 and CDK6 (bound to cyclin D) and CDK2 (bound to cyclin E) inhibits its ability to bind and sequester E2F. Upon its release from pRB, E2F becomes transcriptionally active and switches on multiple genes important for nucleotide synthesis, DNA replication and cell cycle progression from the G₁ phase into the S phase, including cyclin E. E2F-stimulated synthesis of cyclin A drives CDK2-mediated progression from S to G₂. Members of both the INK4 and Cip/Kip families of CDK inhibitors (CDKI) inhibit the function of cyclin D/ CDK4/6 complexes while members of the Cip/Kip family also inhibit cyclin E/ CDK2 and cyclin A/CDK2 complexes. The products of P53 and PTEN can strongly induce the expression of certain CDKI as shown. The CDKI also function in other phases of the cell cycle not shown here.