Analysis of Activating GCM2 Sequence Variants in Sporadic Parathyroid Adenomas.
J Clin Endocrinol Metab 2019 Jun 01; 104(6):1948-1952.

Abstract

CONTEXT

Sporadic, solitary parathyroid adenoma is the most common cause of primary hyperparathyroidism (PHPT). Apart from germline variants in certain cyclin-dependent kinase inhibitor genes and occasionally in MEN1, CASR, or CDC73, little is known about possible genetic variants in the population that may confer increased risk for development of typical sporadic adenoma. Transcriptionally activating germline variants, especially within in the C-terminal conserved inhibitory domain (CCID) of glial cells missing 2 (GCM2), encoding a transcription factor required for parathyroid gland development, have recently been reported in association with familial and sporadic PHPT.

OBJECTIVE

To evaluate the potential role of specific GCM2 activating variants in sporadic parathyroid adenoma.

DESIGN AND PATIENTS

Regions encoding hyperparathyroidism-associated, activating GCM2 variants were PCR amplified and sequenced in genomic DNA from 396, otherwise unselected, cases of sporadic parathyroid adenoma.

RESULTS

Activating GCM2 CCID variants (p.V382M and p.Y394S) were identified in six of 396 adenomas (1.52%), and a hyperparathyroidism-associated GCM2 non-CCID activating variant (p.Y282D) was found in 20 adenomas (5.05%). The overall frequency of tested activating GCM2 variants in this study was 6.57%, approximately threefold greater than their frequency in the general population.

CONCLUSIONS

The examined, rare CCID variants in GCM2 were enriched in our cohort of patients and appear to confer a moderately increased risk of developing sporadic solitary parathyroid adenoma compared with the general population. However, penetrance of these variants is low, suggesting that the large majority of individuals with such variants will not develop a sporadic parathyroid adenoma.

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Authors+Show Affiliations

Riccardi ACenter for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut.
Aspir TCenter for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut.
Shen LCenter for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut.
Kuo CLBiostatistics Center, Connecticut Institute for Clinical and Translational Science, University of Connecticut, Farmington, Connecticut.
Brown TCYale Endocrine Neoplasia Laboratory, Department of Surgery, Yale School of Medicine, New Haven, Connecticut.
Korah RYale Endocrine Neoplasia Laboratory, Department of Surgery, Yale School of Medicine, New Haven, Connecticut.
Murtha TDYale Endocrine Neoplasia Laboratory, Department of Surgery, Yale School of Medicine, New Haven, Connecticut.
Bellizzi JCenter for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut.
Parham KDivision of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Connecticut School of Medicine, Farmington, Connecticut.
Carling TYale Endocrine Neoplasia Laboratory, Department of Surgery, Yale School of Medicine, New Haven, Connecticut.
Costa-Guda JCenter for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut. Center for Regenerative Medicine and Skeletal Development, University of Connecticut School of Dental Medicine, Farmington, Connecticut.
Arnold ACenter for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut. Division of Endocrinology and Metabolism, University of Connecticut School of Medicine, Farmington, Connecticut.

MeSH

Cohort StudiesDNA Mutational AnalysisFemaleGain of Function MutationGenetic Predisposition to DiseaseGerm-Line MutationHumansHyperparathyroidism, PrimaryMaleNuclear ProteinsParathyroid GlandsParathyroid NeoplasmsParathyroidectomyPolymorphism, Single NucleotideProtein DomainsTranscription Factors

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30624640