Fig. 2.

Schematic presentation of common molecular genetic aberrancies in parathyroid adenoma (PA; left) and carcinoma (PC; right). Green arrows represent activating events (such as activating mutations and/or protein overexpression) while red arrows depict deleterious events (inactivating mutations, downregulation or epigenetic silencing). Germline RET oncogenic mutations lead to activation of an intracellular Erk-RAS cascade followed by initiation of gene transcription and increased proliferation. Similarly, germline and somatic MEN1 inactivating mutations affect the regulation of the JunD transcription regulator. Moreover, germline and somatic CDC73 mutations affect epigenetic, transcriptional and cell cycle programs, underlying the development of both PAs and PCs. Additional mechanisms underlying the development of small subsets of PAs include mutational or epigenetic silencing of various cyclin-dependent kinase inhibitors (CDKIs) and up-regulation of cyclin D1 through a chromosomal inversion or via additional unknown mechanisms. Activating mutations in mitochondrial DNA (particularly NADH dehydrogenase gene family orthologs) and CTNNB1 (encoding beta-catenin) could underly the development of PA cases, although their specific roles as driver gene events are debated. For PCs, inactivating CDC73 gene mutations or promoter hypermethylation leads to the downregulation of parafibromin (PFIB), which regulates epigenetic, transcriptional and cell cycle programs. Depletion of additional cell cycle regulators (P53 and pRB) is also a recurrent theme in PC. Moreover, APC is in its normal state a negative regulator of the Wnt pathway, thereby inhibiting beta-catenin in the absence of upstream signaling from Frizzled type of membrane-bound receptors. Hypermethylation of the APC promoter has been demonstrated in PCs, thereby enhancing the Wnt pathway output—but APC also has DNA-binding capacity on its own and could possibly act independently from beta-catenin. Created with BioRender.com.