Mice deleted for cell division cycle 73 gene develop parathyroid and uterine tumours: model for the hyperparathyroidism-jaw tumour syndrome

B T Teh,K J Bradley,P Wang,A A C Reed,K E Lines,B O Williams,S Manek,G V Walls,B Harding,M R Bowl,J Jeyabalan,R V Thakker,P J Newey,M Stevenson,J Chen

doi:10.1038/onc.2017.43

Abstract

The hyperparathyroidism-jaw tumour (HPT-JT) syndrome is an autosomal dominant disorder characterized by occurrence of parathyroid tumours, often atypical adenomas and carcinomas, ossifying jaw fibromas, renal tumours and uterine benign and malignant neoplasms. HPT-JT is caused by mutations of the cell division cycle 73 (CDC73) gene, located on chromosome 1q31.2 and encodes a 531 amino acid protein, parafibromin. To facilitate in vivo studies of Cdc73 in tumourigenesis we generated conventional (Cdc73+/−) and conditional parathyroid-specific (Cdc73+/L/PTH-Cre and Cdc73L/L/PTH-Cre) mouse models. Mice were aged to 18-21 months and studied for survival, tumour development and proliferation, and serum biochemistry, and compared to age-matched wild-type (Cdc73+/+ and Cdc73+/+/PTH-Cre) littermates. Survival of Cdc73+/− mice, when compared to Cdc73+/+ mice was reduced (Cdc73+/−=80%; Cdc73+/+=90% at 18 months of age, P<0.05). Cdc73+/−, Cdc73+/L/PTH-Cre and Cdc73L/L/PTH-Cre mice developed parathyroid tumours, which had nuclear pleomorphism, fibrous septation and increased galectin-3 expression, consistent with atypical parathyroid adenomas, from 9 months of age. Parathyroid tumours in Cdc73+/−, Cdc73+/L/PTH-Cre and Cdc73L/L/PTH-Cre mice had significantly increased proliferation, with rates >fourfold higher than that in parathyroid glands of wild-type littermates (P<0.0001). Cdc73+/−, Cdc73+/L/PTH-Cre and Cdc73L/L/PTH-Cre mice had higher mean serum calcium concentrations than wild-type littermates, and Cdc73+/− mice also had increased mean serum parathyroid hormone (PTH) concentrations. Parathyroid tumour development, and elevations in serum calcium and PTH, were similar in males and females. Cdc73+/− mice did not develop bone or renal tumours but female Cdc73+/− mice, at 18 months of age, had uterine neoplasms comprising squamous metaplasia, adenofibroma and adenomyoma. Uterine neoplasms, myometria and jaw bones of Cdc73+/− mice had increased proliferation rates that were 2-fold higher than in Cdc73+/+ mice (P<0.05). Thus, our studies, which have established mouse models for parathyroid tumours and uterine neoplasms that develop in the HPT-JT syndrome, provide in vivo models for future studies of these tumours.

Highlights

Mutations of the cell division cycle 73 (CDC73) gene (OMIM #607393), which is located on chromosome 1q31.2 and encodes a 531 amino acid protein called parafibromin, are associated with hereditary and non-hereditary forms of parathyroid carcinomas and the hyperparathyroidism-jaw tumour (HPT-JT) syndrome (OMIM #145001).[1,2,3] HPT-JT, an autosomal dominant disorder, is characterized by the occurrence of parathyroid tumours, and ossifying fibromas of the jaw which occur in ~ 30% of HPT-JT patients (Table 1).[1,4,5,6] The parathyroid tumours are usually parathyroid adenomas (PAs) but may be atypical parathyroid adenomas (APAs) or parathyroid carcinomas (PCs) in 415% of HPT-JT patients
75% of the parathyroid tumours were APAs, and these Cdc73+/ − mice with the conditional Cdc73+/L/PTHCre and Cdc73L/L/parathyroid hormone (PTH)-Cre mice provide important in vivo models for this rare but difficult to treat human neoplasm
These parathyroid tumours and uterine neoplasms had a lack of nuclear expresison of parafibromin, consistent with a tumour suppressor role for Cdc[73], and similar to the findings reported in HPT-JT associated tumours in man.[36]

Summary

Introduction

Mutations of the cell division cycle 73 (CDC73) gene (OMIM #607393), which is located on chromosome 1q31.2 and encodes a 531 amino acid protein called parafibromin, are associated with hereditary and non-hereditary forms of parathyroid carcinomas and the hyperparathyroidism-jaw tumour (HPT-JT) syndrome (OMIM #145001).[1,2,3] HPT-JT, an autosomal dominant disorder, is characterized by the occurrence of parathyroid tumours, and ossifying fibromas of the jaw which occur in ~ 30% of HPT-JT patients (Table 1).[1,4,5,6] The parathyroid tumours are usually parathyroid adenomas (PAs) but may be atypical parathyroid adenomas (APAs) or parathyroid carcinomas (PCs) in 415% of HPT-JT patients. Other tumours that may arise in o2% of HPT-JT patients are Hürthle cell thyroid adenomas, pancreatic adenocarcinomas and mixed germ cell testicular tumours.[4,5,7,8] CDC73 loss of heterozygosity (LOH) has been observed in HPT-JT associated tumours, thereby indicating a likely tumour suppressor role for CDC73.1 A tumour suppressor role for CDC73 is further supported by reports that the majority of CDC73 mutations are predicted to result in a functional loss of parafibromin, and that some HPT-JT tumours and non-hereditary PCs harbour both germline and somatic mutations, consistent with the Knudson 'two-hit' hypothesis.[10,11,12]

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Conclusion