title: Molecular genetics and epigenetics of nonfamilial (sporadic) parathyroid tumours.
abstract: Primary hyperparathyroidism (pHPT) is a common endocrine disease characterized by excessive secretion of parathyroid hormone and an increased level of serum calcium. Overall, 80-85% of pHPT cases are due to a benign, single parathyroid adenoma (PA), and 15% to multiglandular disease (multiple adenomas/hyperplasia). Parathyroid carcinoma (PC) is rare, accounting for <0.5-1% of pHPT cases. Secondary hyperparathyroidism (sHPT) is a complication of renal failure, with the development of parathyroid tumours and hypercalcaemia. Recurrent mutations in the MEN1 gene have been confirmed by the whole-exome sequencing in 35% of PAs, suggesting that non-protein-coding genes, regulatory elements or epigenetic derangements may also have roles in the majority of PAs. DNA translocations with cyclin D1 overexpression occur in PAs (8%). In PCs, mutations in CDC73/HRPT2 are common. Activation of the WNT/β-catenin signalling pathway (accumulation of nonphosphorylated β-catenin) by an aberrantly truncated LRP5 receptor has been seen for the majority of investigated PAs and sHPT tumours, and possibly by APC inactivation through promoter methylation in PCs. Promoter methylation of several other genes and repressive histone H3 lysine 27 trimethylation by EZH2 of the HIC1 gene may also contribute to parathyroid tumorigenesis. It is possible that a common pathway exists for parathyroid tumour development. CCND1 (cyclin D1) and EZH2 overexpression, accumulation of nonphosphorylated β-catenin and repression of HIC1 have all been observed to occur in PAs, PCs and sHPT tumours. In addition, hypermethylation has been observed for the same genes in PAs and PCs (e.g. SFRP1, CDKN2A and WT1). Whether β-catenin represents a 'hub' in parathyroid tumour development will be discussed.
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Westin
mesh_terms: D044127:Epigenesis, Genetic; D006801:Humans; D049950:Hyperparathyroidism, Primary / Q000209:etiology / Q000235:genetics; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics; D009154:Mutation; D010282:Parathyroid Neoplasms / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D035683:MicroRNAs; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human
keywords: H3K27me3; adenoma; beta-catenin; cancer; hypermethylation and hyperparathyroidism