Molecular genetics of syndromic and non-syndromic forms of parathyroid carcinoma

Journal article

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 tumour 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 aetiology 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 tumour protein P53 (TP53) genes, as well as epigenetic modifications including DNA methylation and histone modifications, and microRNA mis-regulation. This review summarizes the genetics and epigenetics of the familial syndromic and non-syndromic (sporadic) forms of PC.

Authors: Cardoso, L; Stevenson, M; Thakker, R

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Wiley
• Journal: Human Mutation
• Volume: 38
• Issue: 12
• Pages: 1621–1648
• Publication date: 2017-09-25
• Acceptance date: 2017-09-04
• DOI: 10.1002/humu.23337
• ISSN: 1098-1004
• Keywords: multiple endocrine neoplasia type 1; CDC73; familial isolated primary hyperparathyroidism; hyperparathyroidism-jaw tumour syndrome; genetic syndromes