Germline and somatic mutations in cyclin-dependent kinase inhibitor genes CDKN1A, CDKN2B, and CDKN2C in sporadic parathyroid adenomas

Horm Cancer. 2013 Oct;4(5):301-7. doi: 10.1007/s12672-013-0147-9. Epub 2013 May 29.


The molecular pathogenesis of sporadic parathyroid adenomas is incompletely understood. The possible role of cyclin-dependent kinase inhibitor (CDKI) genes was raised by recognition of cyclin D1 as a parathyroid oncogene, identification of rare germline mutations in CDKI genes in patients with multiple endocrine neoplasia type 1; that in rodents, mutation in Cdkn1b caused parathyroid tumors; and subsequently through identification of rare predisposing germline sequence variants and somatic mutation of CDKN1B, encoding p27(kip1), in sporadic human parathyroid adenoma. We therefore sought to determine whether mutations/variants in the other six CDKI genes CDKN1A, CDKN1C, CDKN2A, CDKN2B, CDKN2C, and CDKN2D, encoding p21, p57, p14(ARF)/p16, p15, p18, and p19, respectively, contribute to the development of typical parathyroid adenomas. In a series of 85 sporadic parathyroid adenomas, direct DNA sequencing identified alterations in five adenomas (6 %): Two contained distinct heterozygous changes in CDKN1A, one germline and one of undetermined germline status; one had a CDKN2B germline alteration, accompanied by loss of the normal allele in the tumor (LOH); two had variants of CDKN2C, one somatic and one germline with LOH. Abnormalities of three of the mutant proteins were readily demonstrable in vitro. Thus, germline mutations/rare variants in CDKN1A, CDKN2B, and CDKN2C likely contribute to the development of a significant subgroup of common sporadic parathyroid adenomas, and somatic mutation in CDKN2C further suggests a direct role for CDKI alteration in conferring a selective growth advantage to parathyroid cells, providing novel support for the concept that multiple CDKIs can play primary roles in human neoplasia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / genetics*
  • Adenoma / metabolism
  • Aged
  • Aged, 80 and over
  • Base Sequence
  • Cell Culture Techniques
  • Cyclin-Dependent Kinase Inhibitor Proteins / genetics*
  • Cyclin-Dependent Kinase Inhibitor Proteins / metabolism
  • Cyclin-Dependent Kinase Inhibitor p15 / genetics
  • Cyclin-Dependent Kinase Inhibitor p15 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p18 / genetics
  • Cyclin-Dependent Kinase Inhibitor p18 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Germ-Line Mutation*
  • HEK293 Cells
  • Humans
  • Hyperparathyroidism, Primary / genetics
  • Hyperparathyroidism, Primary / metabolism
  • Hyperparathyroidism, Primary / surgery
  • Middle Aged
  • Mutation, Missense*
  • Parathyroid Neoplasms / genetics*
  • Parathyroid Neoplasms / metabolism


  • CDKN1A protein, human
  • CDKN2B protein, human
  • CDKN2C protein, human
  • Cyclin-Dependent Kinase Inhibitor Proteins
  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p18
  • Cyclin-Dependent Kinase Inhibitor p21