PSUN363 GCM2 variants in Parathyroid Carcinoma
Authors: Costa-Guda Jessica , Arnold Andrew 
Published: November 2022

Abstract
Germline, in vitro activating GCM2 variants are notably overrepresented in patients with primary hyperparathyroidism (PHPT), in both the familial and sporadic settings. While increased compared with the general population, most individuals with such variants in the population have a very low risk of developing PHPT. However, for those individuals who do develop PHPT, the degree to which harboring such a variant might impact the disease severity remains unclear. An increased likelihood of multigland involvement and a lower rate of biochemical cure has been reported in GCM2variant-positive patients as compared with variant-negative patients. In the context of familial isolated primary hyperparathyroidism, one individual with a GCM2 Y394S variant was reported to have developed parathyroid carcinoma (Guan, 2016) and another developed parathyromatosis (Koh, 2021). In another family, carrying I383M, parathyroid carcinoma was seen in one individual and atypical adenoma in another (Canaff, 2022). No GCM2 variants were noted in two other kindreds which included at least one individual with parathyroid carcinoma, for which other known causes of FIHP had already been ruled out (Cetani, 2019). Rare GCM2 variants were reported in three patients with sporadic parathyroid carcinoma: two with K388E (Song, 2020) and one with V382M (Canaff, 2022). V382M was also observed in a patient with atypical adenoma (Song, 2020). No GCM2 variants have been reported in whole exome sequencing (WES) studies of parathyroid carcinoma. However, in 45% of reported cases subjected to WES, germline variants were specifically filtered out during data analysis. In the remaining reported cases for which germline DNA was unavailable, filtering would have excluded common variants, such as Y282D, but rare GCM2 variants may have been detectable. We sought to determine the frequency of GCM2 germline variants of interest in a series of 15 sporadic parathyroid carcinomas by direct DNA sequencing. No sequence variants were identified within the C-terminal conserved inhibitory domain (CCID) of GCM2, nor was the PHPT-associated Y282D variant found in any of our samples. Across all studies to date, GCM2 CCID variants have been detected in 3 of 48 (6.25%) sporadic parathyroid carcinomas and Y282D in 4 of 56 (7.14%) of cases. Our results demonstrating a dearth of GCM2 variants in individuals with parathyroid carcinoma, combined with the absence of malignancy in the overwhelming majority of patients harboring PHPT-associated GCM2 variants, suggest individuals in the general population with such variants are at exceedingly low risk of developing parathyroid carcinoma. However, some very rare variants, such as I383M, might be show higher penetrance. Given the potential implications for surveillance/monitoring approaches and/or surgical decision making, the hypothesis that in certain genetic and/or environmental contexts GCM2 variants may be associated with more severe clinical phenotypes merits further investigation.
Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.