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

Abstract

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.

Keywords: CDC73; familial isolated primary hyperparathyroidism; genetic syndromes; hyperparathyroidism-jaw tumor syndrome; multiple endocrine neoplasia type 1.

Figure 1

A genetic testing approach to patients with parathyroid carcinoma. PC, parathyroid carcinoma; APA, atypical parathyroid adenoma; PA, parathyroid adenoma; pHPT, primary hyperparathyroidism; HPT‐JT, hyperparathyroidism‐jaw tumor; FIHP, familial isolated primary hyperparathyroidism; MEN1, multiple endocrine neoplasia type 1; MEN2, multiple endocrine neoplasia type 2; FHH, familial hypocalciuric hypercalcemia

Figure 2

Schematic representation of the genomic organization of the human CDC73 gene, parafibromin protein, and its functions. (A) Upper panel, schematic representation of genomic structure of cell division cycle 73 (CDC73) comprising 17 exons. ATG and TGA represent the initiation and stop codons, respectively. Sites of CDC73 mutations associated with sporadic and familial parathyroid carcinoma (PC) are shown (^S somatic mutation; ^G germline mutation; ^ND not defined; white, dotted line boxes, CDC73 mutations associated with sporadic PC; gray, full line boxes, CDC73 mutations associated with syndromic or hereditary forms of PC, where ^¶ means hyperparathyroidism‐jaw tumor and ^§ means familial isolated primary hyperparathyroidism). (B) Middle panel, schematic representation of parafibromin protein structure and known functional domains. CDC73 encodes a 531‐amino acid protein, whose C‐terminal domain shares 27% homology with the yeast CDC73 (CDC73 core homology domain). The nuclear localization signal (NLS) is encoded by exon 5, the evolutionary conserved polymerase‐associated factor 1 (Paf1) complex‐binding domain (Paf1 complex BD) by exons 7–14, the Gli binding domain (Gli BD) by exons 7–11, and the β‐catenin interaction binding domain (β‐catenin BD) and the SV40 large T antigen binding domain (SV40 LTA BD) by exons 7 and 8. (C) Lower panel, schematic representation of parafibromin functions. Parafibromin is a component of the Paf1 protein complex, which regulates chromatin remodeling and gene expression via histone modification. Parafibromin also regulates cell growth, via cyclin D1 and Wnt signaling, and embryonic development via genes involved in cell growth and survival. H19, H19 fetal liver mRNA; IGF1 and IGF2, insulin‐like growth factor 1 and 2; IGFBP4, insulin‐like growth factor binding protein 4; HMGA1 and HMGA2, high mobility AT‐hook 1 and 2; HMGCS2, 3‐hydroxy‐3‐methylglutaryl‐Coenzyme A synthase 2

Figure 3

Molecular mechanisms of parathyroid carcinoma. LOH, loss of heterozygosity