Identification of somatic mutations in parathyroid tumors using whole-exome sequencing

J Clin Endocrinol Metab. 2012 Sep;97(9):E1774-81. doi: 10.1210/jc.2012-1743. Epub 2012 Jun 27.


Context: The underlying molecular alterations causing sporadic parathyroid adenomas that drive primary hyperparathyroidism have not been thoroughly defined.

Objective: The aim of the study was to investigate the occurrence of somatic mutations driving tumor formation and progression in sporadic parathyroid adenoma using whole-exome sequencing.

Design: Eight matched tumor-constitutional DNA pairs from patients with sporadic parathyroid adenomas underwent whole-exome capture and high-throughput sequencing. Selected genes were analyzed for mutations in an additional 185 parathyroid adenomas.

Results: Four of eight tumors displayed a frame shift deletion or nonsense mutation in MEN1, which was accompanied by loss of heterozygosity of the remaining wild-type allele. No other mutated genes were shared among the eight tumors. One tumor harbored a Y641N mutation of the histone methyltransferase EZH2 gene, previously linked to myeloid and lymphoid malignancy formation. Targeted sequencing in the additional 185 parathyroid adenomas revealed a high rate of MEN1 mutations (35%). Furthermore, this targeted sequencing identified an additional parathyroid adenoma that contained the identical, somatic EZH2 mutation that was found by exome sequencing.

Conclusion: This study confirms the frequent role of the loss of heterozygosity of chromosome 11 and MEN1 gene alterations in sporadic parathyroid adenomas and implicates a previously unassociated methyltransferase gene, EZH2, in endocrine tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / genetics*
  • Cohort Studies
  • DNA Mutational Analysis
  • DNA, Neoplasm / genetics*
  • Enhancer of Zeste Homolog 2 Protein
  • Exons / genetics*
  • Humans
  • Multiple Endocrine Neoplasia Type 1 / genetics
  • Mutation / genetics*
  • Mutation / physiology
  • Parathyroid Neoplasms / genetics*
  • Polycomb Repressive Complex 2 / genetics
  • Polymerase Chain Reaction
  • Reproducibility of Results
  • Sequence Analysis, DNA*


  • DNA, Neoplasm
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2