Whole-exome sequencing studies of nonhereditary (sporadic) parathyroid adenomas.

Abstract

CONTEXT:

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.

OBJECTIVE:

To identify genetic abnormalities in nonhereditary parathyroid adenomas by whole-exome sequence analysis.

DESIGN:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Paul J Newey, M Andrew Nesbit, Andrew J Rimmer, Moustafa Attar, Rosie T Head, Paul T Christie, Caroline M Gorvin, Michael Stechman, Lorna Gregory, Radu Mihai, Greg Sadler, Gil McVean, David Buck, Rajesh V Thakker
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 97 Issue 10 Pg. E1995-2005 (Oct 2012) ISSN: 1945-7197 [Electronic] United States
• PMID: 22855342 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCND1 protein, human
• POT1 protein, human
• Shelterin Complex
• Telomere-Binding Proteins
• Cyclin D1

Topics

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