Phenotypic Profiling and Molecular Mechanisms in Hyperparathyroidism-jaw Tumor Syndrome

Area of Science:

• Endocrinology
• Oncology
• Genetics

Background:

• Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is a rare inherited disorder characterized by primary hyperparathyroidism and an increased risk of parathyroid cancer, caused by germline mutations in the CDC73 gene.
• Management guidelines for HPT-JT syndrome are limited, necessitating further research into its natural history and molecular underpinnings.

Purpose of the Study:

• To characterize the natural history of HPT-JT syndrome.
• To correlate the genotype and histology of parathyroid tumors with parafibromin (encoded by CDC73) expression.
• To elucidate molecular changes downstream of CDC73 loss in HPT-JT syndrome.

Main Methods:

• Retrospective analysis of 68 patients from 29 kindreds with genetically confirmed HPT-JT syndrome.
• Independent review of uterine tumors from 2 patients and parafibromin immunostaining on parathyroid tumors from 19 patients (13 adenomas, 6 carcinomas).
• RNA-sequencing of 21 parathyroid samples (8 HPT-JT-related adenomas, 6 HPT-JT-related carcinomas, and 7 sporadic carcinomas).

Main Results:

• 81% of patients developed primary hyperparathyroidism, and 31% had parathyroid carcinoma. Uterine tumors occurred in 38% of females, often presenting as rare polypoid lesions.
• Specific CDC73 variants at the p.M1 residue were associated with a predisposition to kidney tumors.
• Parafibromin staining did not correlate with tumor histology or genotype, but RNA-sequencing revealed associations with transmembrane receptor protein tyrosine kinase signaling, mesodermal commitment, and cell-cell adhesion pathways in HPT-JT tumors.

Conclusions:

• Multiple, recurrent atypical adenomyomatous uterine polyps are characteristic of HPT-JT syndrome in women.
• Patients with CDC73 variants at p.M1 residue exhibit a predisposition to developing kidney tumors.
• Understanding the molecular pathways affected by CDC73 loss is crucial for managing HPT-JT syndrome.