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Context: Multiglandular and familial parathyroid disease constitute important fractions of primary hyperparathyroidism (PHPT). Germline missense variants of GCM2, a regulator of parathyroid development, were observed in familial isolated hyperparathyroidism and sporadic PHPT. However, as these previously reported GCM2 variants occur at relatively high frequencies in the population, understanding their potential clinical utility will require both additional penetrance data and functional evidence relevant to tumorigenicity. Objective: Determine the frequency of GCM2 variants of interest among patients with sporadic multigland or familial parathyroid disease and assess their penetrance. Design and Patients: DNA-encoding PHPT-associated GCM2 germline variants were polymerase chain reaction–amplified and sequenced from 107 patients with either sporadic multigland or suspected/confirmed familial parathyroid tumors. Results: GCM2 variants were observed in 9 of 107 cases (8.4%): Y282D in 4 patients (6.3%) with sporadic multigland disease; Y394S in 2 patients (11.1%) with familial PHPT and 3 (4.8%) with sporadic multigland disease. Compared with the general population, Y282D was enriched 5.9-fold in multigland disease, but its penetrance was very low (0.02%). Y394S was enriched 79-fold in sporadic multigland disease and 93-fold in familial PHPT, but its penetrance was low (1.33% and 1.04%, respectively). Conclusions: Observed in vitro–activating GCM2 variant alleles are significantly over-represented in PHPT patients with multiglandular or familial disease compared to the general population, yet penetrance values are very low; that is, most individuals with these variants in the population have a very low risk of developing PHPT. The potential clinical utility of detecting these GCM2 variants requires further investigation, including assessing their possible role as pathogenic/low-penetrance alleles. [ABSTRACT FROM AUTHOR]

Abstract Background The potential pathogenetic significance of mitochondrial DNA (mtDNA) mutations in tumorigenesis is controversial. We hypothesized that benign tumorigenesis of a slowly replicating tissue like the human parathyroid might constitute an especially fertile ground on which a selective advantage conferred by mtDNA mutation could be manifested and might contribute to the oxyphilic phenotype observed in a subset of parathyroid tumors. Methods We sought acquired mitochondrial DNA mutations by sequencing the entire 16.6 kb mitochondrial genome of each of thirty sporadic parathyroid adenomas (18 chief cell and 12 oxyphil cell), eight independent, polyclonal, parathyroid primary chief cell hyperplasias plus corresponding normal control samples, five normal parathyroid glands, and one normal thyroid gland. Results Twenty-seven somatic mutations were identified in 15 of 30 (9 of 12 oxyphil adenomas, 6 of 18 chief cell) parathyroid adenomas studied. No somatic mutations were observed in the hyperplastic parathyroid glands. Conclusion Features of the somatic mutations suggest that they may confer a selective advantage and contribute to the molecular pathogenesis of parathyroid adenomas. Importantly, the statistically significant differences in mutation prevalence in oxyphil vs. chief cell adenomas also suggest that mtDNA mutations may contribute to the oxyphil phenotype.

This report summarizes published data on parathyroid cancer, with the inclusion of topics discussed at MEN2019: 16th International Workshop on Multiple Endocrine Neoplasia, 27-29 March 2019, Houston, TX, USA. An expert panel on parathyroid cancer was constituted by the Steering Committee to address key questions in the field. The objectives were to recap open forum discussion of interested parties from multiple disciplines. The expert panel met in a closed session to consul t on the data to be highlighted on the evidence-based results and on the future directions. Preceding the Conference, members of the expert panel conducted an extensive literature search. All presentations were based upon the best peer-reviewed information taking into account the historical and current literature. Questions were developed by the expert panel on parathyroid carcinoma. A comprehensive literature search for relevant studies was undertaken. This report represents the expert panel's synthesis of the conference material placed in a context designed to be relevant to clinici ans and those engaged in cutting-edge studies of parathyroid carcinoma. This document not only provides a summary of our current knowledge but also places recent advances in its management into a context that should enhance future advances in our under standing of parathyroid carcinoma. [ABSTRACT FROM AUTHOR]

Loss of heterozygosity (LOH) or deletion of chromosome 3p is a frequent finding in enteropancreatic endocrine tumours (EPETs), suggesting the pathogenetic involvement of one or more tumour suppressor genes on 3p.PPARG, the gene encoding the gamma isoform of the peroxisome proliferator-activated receptor (PPARγ), is highly expressed in normal human pancreatic islet cells, is located at 3p25, and has been reported to sustain loss-of-function mutations in human colorectal carcinomas. Additionally, the development of islet cell hyperplasia in an islet cell-specificppargknockout mouse has further emphasized the attractiveness ofPPARGas a candidate gene important in the pathogenesis of EPETs. Therefore, we sought to examinePPARGfor intragenic inactivating mutations, the evidence needed to rigorously establish it as a tumour suppressor in EPETs.Twenty-three EPETs from 20 patients were examined for coding region mutations inPPARGand for LOH on 3p at microsatellite markers flankingPPARG.LOH on 3p was detected in tumours from six patients (30%), but no intragenic mutations were detected inPPARG, whether or not LOH was present.These findings strongly suggest thatPPARGdoes not commonly function as a classical tumour suppressor gene in the pathogenesis of EPETs. [ABSTRACT FROM AUTHOR]

Context: The molecular mechanisms underlying the pathogenesis of sporadic parathyroid adenomas are incompletely understood. Dysfunction of the Wnt signaling pathway is an established pathogenetic contributor to human tumorigenesis and, recently, the role of stabilizing mutations in beta-catenin, a cause of abnormal Wnt signaling, has been examined in parathyroid tumors with conflicting results., Objective: The objective of the present study was to determine the frequency of stabilizing mutations in exon 3 of CTNNB1, encoding beta-catenin, in a large series of parathyroid adenomas., Patients and Design: Ninety-seven sporadic parathyroid adenomas were examined for mutations in exon 3 of CTNNB1 by direct DNA sequencing., Results: No mutations were identified in any of the adenomas., Conclusions: The absence of stabilizing mutations of beta-catenin, including the previously reported S37A, encoded in CTNNB1 exon 3 among 97 tumors suggests that such mutations contribute rarely if at all to the development of sporadic parathyroid adenomas. A primary role for abnormal Wnt signaling in parathyroid tumor formation remains to be established.