Genotype-Phenotype Correlation Analysis Reveals an Increased Risk of Parathyroid Carcinoma in Patients with Large Germline CDC73 Genomic Alterations

Presentation Number: LB SAT 45
Date of Presentation: April 1st, 2017

Yulong Li*1, Jianhua Zhang1, Bin Guan2, James Welch1, Rashad M Riazuddin1 and William F Simonds1
1NIH, 2NIH, Bethesda, MD



Hyperparathyroidism-Jaw Tumor syndrome (HPT-JT), a rare familial form of hyperparathyroidism, is associated with germline mutations in CDC73 (formerly known as HRPT2) gene. Due to different penetration rates, patients can manifest parathyroid carcinoma, benign parathyroid disease (adenoma or hyperplasia), or no parathyroid disease. Genotype-phenotype correlation in patients with CDC73 germline mutation is currently unknown.


In this so far largest retrospective study, we analyzed 419 subjects with germline CDC73 mutations, of which 68 were from an NIH patient cohort and 351 were from previously published case reports/series. In total, there were 139 index cases. Based on whether the CDC73 mutation predicted significant protein structural changes, the subjects were divided into a large genomic alteration group (nonsense, frame-shift indels, gross deletions/insertions or splice site mutations) and a small genomic alteration group (missense, in-frame indels or non-coding region mutations). Kaplan-Meier time-to-event analysis was used to compare risk of parathyroid carcinoma and hypercalcemia between the two groups.


380 subjects (91%) harbored germline CDC73 mutations based on DNA analysis, and 39 subjects (9%) were presumed to have CDC73 mutations because they were either obligate carriers or affected family members of the an index case with documented CDC73 mutation. Most of CDC73 mutations (87%) were large genomic alterations, and the remainder (13%) were small genomic alterations. The mutations mostly mapped to the exonic regions of CDC73 gene encoding the N-terminal domain, which is remarkably different from distribution pattern of the CDC73 mutations present in the ExAC database. 77 subjects (18.4%) were diagnosed with parathyroid carcinoma, 252 subjects (60.1%) with benign parathyroid adenoma/hyperplasia, and 90 subjects (21.5%) with no evidence of parathyroid disease. Kaplan-Meier analysis showed that the subjects with large genomic alterations had a much higher risk of parathyroid carcinoma compared to those with small alterations (HR=13, 95% CI=6.58-25.69, P=0.0008), while no significant difference was found between two groups for risk of hyperparathyroidism. About 45% of subjects had multi-glandular parathyroid involvement based on surgical pathology, and no significant difference was found between patients with parathyroid carcinoma and benign parathyroid disease. A separate analysis of the index cases showed similar findings.


Our study demonstrates for the first time a correlation between the genotype of germline CDC73 mutation and the risk of developing parathyroid carcinoma. HPT-JT is a multi-glandular parathyroid disease. These findings have direct implications for clinical management.


Nothing to Disclose: YL, JZ, BG, JW, RMR, WFS