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

J Clin Endocrinol Metab. 2012 Oct;97(10):E1995-2005. doi: 10.1210/jc.2012-2303. Epub 2012 Aug 1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Telomere-Binding Proteins / genetics

Substances

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