We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Whole-exome sequencing studies of nonhereditary (sporadic) parathyroid adenomas.
- Authors
Newey PJ; Nesbit MA; Rimmer AJ; Attar M; Head RT; Christie PT; Gorvin CM; Stechman M; Gregory L; Mihai R; Sadler G; McVean G; Buck D; Thakker RV; Newey, Paul J; Nesbit, M Andrew; Rimmer, Andrew J; Attar, Moustafa; Head, Rosie T; Christie, Paul T
- Abstract
<bold>Context: </bold>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.<bold>Objective: </bold>To identify genetic abnormalities in nonhereditary parathyroid adenomas by whole-exome sequence analysis.<bold>Design: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Publication
Journal of Clinical Endocrinology & Metabolism, 2012, Vol 97, Issue 10, pE1995
- ISSN
0021-972X
- Publication type
journal article
- DOI
10.1210/jc.2012-2303