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Genetic abnormalities, such as those of multiple endocrine neoplasia type 1 (MEN1) and Cyclin D1 (CCND1) genes, occur in <50% of nonhereditary (sporadic) parathyroid adenomas.To identify genetic abnormalities in nonhereditary parathyroid adenomas by whole-exome sequence analysis.Whole-exome sequence analysis was performed on parathyroid adenomas and leukocyte DNA samples from 16 postmenopausal women without a family history of parathyroid tumors or MEN1 and in whom primary hyperparathyroidism due to single-gland disease was cured by surgery. Somatic variants confirmed in this discovery set were assessed in 24 other parathyroid adenomas.Over 90% of targeted exons were captured and represented by more than 10 base reads. Analysis identified 212 somatic variants (median eight per tumor; range, 2-110), with the majority being heterozygous nonsynonymous single-nucleotide variants that predicted missense amino acid substitutions. Somatic MEN1 mutations occurred in six of 16 (∼35%) parathyroid adenomas, in association with loss of heterozygosity on chromosome 11. However, no other gene was mutated in more than one tumor. Mutations in several genes that may represent low-frequency driver mutations were identified, including a protection of telomeres 1 (POT1) mutation that resulted in exon skipping and disruption to the single-stranded DNA-binding domain, which may contribute to increased genomic instability and the observed high mutation rate in one tumor.Parathyroid adenomas typically harbor few somatic variants, consistent with their low proliferation rates. MEN1 mutation represents the major driver in sporadic parathyroid tumorigenesis although multiple low-frequency driver mutations likely account for tumors not harboring somatic MEN1 mutations.

Original publication

DOI

10.1210/jc.2012-2303

Type

Journal article

Journal

The journal of clinical endocrinology and metabolism

Publication Date

10/2012

Volume

97

Pages

E1995 - E2005

Addresses

Academic Endocrine Unit, Nuffield Department of Clinical Medicine, University of Oxford, and Department of Surgery, John Radcliffe Hospital, Oxford University Hospitals Trust, Oxford, UK.

Keywords

Humans, Adenoma, Multiple Endocrine Neoplasia Type 1, Parathyroid Neoplasms, Cyclin D1, Telomere-Binding Proteins, DNA Mutational Analysis, Aged, Aged, 80 and over, Middle Aged, Female, Male, Hyperparathyroidism, Primary, Genetic Variation, Exome