Genetics and Epigenetics of Parathyroid Carcinoma

Abstract

Parathyroid carcinoma (PC) is an extremely rare malignancy, accounting less than 1% of all parathyroid neoplasms, and an uncommon cause of primary hyperparathyroidism (PHPT), characterized by an excessive secretion of parathyroid hormone (PTH) and severe hypercalcemia. As opposed to parathyroid hyperplasia and adenomas, PC is associated with a poor prognosis, due to a commonly unmanageable hypercalcemia, which accounts for death in the majority of cases, and an overall survival rate of 78-85% and 49-70% at 5 and 10 years after diagnosis, respectively. No definitively effective therapies for PC are currently available. The mainly employed treatment for PC is the surgical removal of tumoral gland(s). Post-surgical persistent or recurrent disease manifest in about 50% of patients. The comprehension of genetic and epigenetic bases and molecular pathways that characterize parathyroid carcinogenesis is important to distinguish malignant PCs from benign adenomas, and to identify specific targets for novel therapies. Germline heterozygote inactivating mutations of the CDC73 tumor suppressor gene, with somatic loss of heterozygosity at 1q31.2 locus, account for about 50-75% of familial cases; over 75% of sporadic PCs harbor biallelic somatic inactivation/loss of CDC73. Recurrent mutations of the PRUNE2 gene, a recurrent mutation in the ADCK1 gene, genetic amplification of the CCND1 gene, alterations of the PI3K/AKT/mTOR signaling pathway, and modifications of microRNA expression profile and gene promoter methylation pattern have all been detected in PC. Here, we review the current knowledge on gene mutations and epigenetic changes that have been associated with the development of PC, in both familial and sporadic forms of this malignancy.

Keywords: DNA methylation; epigenetic changes; gene mutation; long non-coding RNAs; microRNAs; molecular signatures; parathyroid carcinoma; tumor suppressor genes.

Figure 1

Main roles of parafibromin.

Figure 2

Deregulation of the Wnt/β-catenin signaling in PCs. Genetic and epigenetic aberrations detected in PC, altering the Wnt/β-catenin pathway, are highlighted in red. In the canonical Wnt/β-catenin pathway, the Wnt ligands initiate signaling by interacting, on the cell surface, with the Frizzled (FZD) receptor and the low density lipoprotein receptor-related protein 5/6 (LRP5/6) coreceptor. The ligand-activated FZD-LRP5/6 complex recruits, respectively, Dishevelled and AXIN2 intracellular proteins, preventing the constitutive destruction of cytosolic β-catenin by disassembling the β-catenin destruction complex, consisting of AXIN2, adenomatous polyposis coli (APC), glycogen synthase kinase3β (GSK3β) and casein kinase 1 (CK1), and ultimately leading to active β-catenin accumulation and nuclear translocation. In the nucleus, β-catenin binds and activates transcription factors of the lymphoid enhancer-binding factor (LEF)/T-cell factor (TCF) family, leading to the transcription of Wnt target genes (i.e. CCND1). DKK2 and SFRP proteins are natural extracellular inhibitors of the Wnt signaling, by respectively binding, and inactivating, the LRP5/6 coreceptor and the Wnt ligands. Figure created in BioRender.com, accessed on 10 January 2022.