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Parathyroid carcinoma (PC) may occur as part of a complex hereditary syndrome or an isolated (i.e., non-syndromic) non-hereditary (i.e., sporadic) endocrinopathy. Studies of hereditary and syndromic forms of PC, which include the hyperparathyroidism-jaw tumor syndrome (HPT-JT), multiple endocrine neoplasia types 1 and 2 (MEN1 and MEN2), and familial isolated primary hyperparathyroidism (FIHP), have revealed some genetic mechanisms underlying PC. Thus, cell division cycle 73 (CDC73) germline mutations cause HPT-JT, and CDC73 mutations occur in 70% of sporadic PC, but in only ∼2% of parathyroid adenomas. Moreover, CDC73 germline mutations occur in 20%-40% of patients with sporadic PC and may reveal unrecognized HPT-JT. This indicates that CDC73 mutations are major driver mutations in the etiology of PCs. However, there is no genotype-phenotype correlation and some CDC73 mutations (e.g., c.679_680insAG) have been reported in patients with sporadic PC, HPT-JT, or FIHP. Other genes involved in sporadic PC include germline MEN1 and rearranged during transfection (RET) mutations and somatic alterations of the retinoblastoma 1 (RB1) and tumor protein P53 (TP53) genes, as well as epigenetic modifications including DNA methylation and histone modifications, and microRNA misregulation. This review summarizes the genetics and epigenetics of the familial syndromic and non-syndromic (sporadic) forms of PC.

Original publication




Journal article


Hum Mutat

Publication Date





1621 - 1648


CDC73, familial isolated primary hyperparathyroidism, genetic syndromes, hyperparathyroidism-jaw tumor syndrome, multiple endocrine neoplasia type 1, Adenoma, DNA Methylation, Epigenomics, Fibroma, Germ-Line Mutation, Humans, Hyperparathyroidism, Hyperparathyroidism, Primary, Jaw Neoplasms, MicroRNAs, Parathyroid Neoplasms, Proto-Oncogene Proteins, Retinoblastoma Binding Proteins, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases