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.

A role for TET2 in parathyroid carcinoma

“…PCs (approximately 70%), and parafibromin-negative immunostaining has been suggested as a marker for PC, although some studies reported this to be less useful (Tan et al 2004, Iacobone et al 2005, DeLellis et al 2008, Sharretts & Simonds 2010, Guarnieri et al 2012, Cetani et al 2013, Gill 2014, Westin 2016. Lost expression of the APC tumor suppressor gene has been suggested to occur in PCs through epigenetic inactivation by DNA methylation of the APC promoter region (Svedlund et al 2010).…”

Epigenetic Alterations in Parathyroid Cancers

“…Wnt/β-catenin is potentially deregulated in PCas by loss of parafibromin, which is a member of the polymerase II complex interacting with β-catenin [36]. Therefore, Wnt/β-catenin deregulation has been suggested as a “hub” of parathyroid tumorigenesis [37] (Figure 1). Indeed, accumulation of β-catenin is controversial in PCas, with studies reporting constitutive accumulation of active unphosphorylated β-catenin [26] and others failing in the detection of total β-catenin at the nuclear level [38].…”

“…Schematic representation of the molecules involved in the Wnt/β-catenin signaling in the inactive (left) and active (right) state: molecules, whose expression may be affected by genetic and epigenetic modifications in PCas, are indicated. The Wnt/β-catenin deregulation has been suggested as a “hub” of parathyroid tumorigenesis [37]. DKK1, Dickkopf 1; DVL, disheveled segment polarity protein; SFRP, secreted frizzled related protein; CKI, cyclin-dependent kinase inhibitor; GSK3, glycogen synthase kinase 3 β; TCF/LEF1, transcription factor 7/lymphoid enhancer binding factor 1; HIC1, hypermethylated in cancer 1; WT1, Wilms tumor 1; RASSF1A, Ras-association domain family 1; LRP-5, low density lipoprotein (LDL) receptor related protein 5; LRP-6, low density lipoprotein (LDL) receptor related protein 6; CDC73, cell division cycle 73; APC, WNT signaling pathway regulator; WNT, wingless-type ; ub, ubiquitination; ⊥, inhibitory effect.…”

Endocrine tumors associated with the vagus nerve

“…These mutations are commonly found in young patients with clinically non-familial PHPT (Starker, et al 2012). Other parathyroid tumors may be due to activation of the WNT/β-catenin signaling pathway (Westin 2016). Inactivating mutations of the CDC73 tumor suppressor gene have been reported in hyperparathyroidism–jaw tumor (HPT–JT) syndrome-related adenomas and parathyroid carcinomas, in association with the loss of nuclear expression of the encoded protein, parafibromin.…”