Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma

N Engl J Med. 2003 Oct 30;349(18):1722-9. doi: 10.1056/NEJMoa031237.


Background: We looked for mutations of the HRPT2 gene, which encodes the parafibromin protein, in sporadic parathyroid carcinoma because germ-line inactivating HRPT2 mutations have been found in a type of familial hyperparathyroidism--hyperparathyroidism-jaw tumor (HPT-JT) syndrome--that carries an increased risk of parathyroid cancer.

Methods: We directly sequenced the full coding and flanking splice-junctional regions of the HRPT2 gene in 21 parathyroid carcinomas from 15 patients who had no known family history of primary hyperparathyroidism or the HPT-JT syndrome at presentation. We also sought to confirm the somatic nature of the identified mutations and tested the carcinomas for tumor-specific loss of heterozygosity at HRPT2.

Results: Parathyroid carcinomas from 10 of the 15 patients had HRPT2 mutations, all of which were predicted to inactivate the encoded parafibromin protein. Two distinct HRPT2 mutations were found in tumors from five patients, and biallelic inactivation as a result of a mutation and loss of heterozygosity was found in one tumor. At least one HRPT2 mutation was demonstrably somatic in carcinomas from six patients. Unexpectedly, HRPT2 mutations in the parathyroid carcinomas of three patients were identified as germ-line mutations.

Conclusions: Sporadic parathyroid carcinomas frequently have HRPT2 mutations that are likely to be of pathogenetic importance. Certain patients with apparently sporadic parathyroid carcinoma carry germ-line mutations in HRPT2 and may have the HPT-JT syndrome or a phenotypic variant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • DNA Mutational Analysis
  • Female
  • Germ-Line Mutation
  • Humans
  • Hyperparathyroidism / genetics*
  • Jaw Neoplasms / genetics
  • Loss of Heterozygosity
  • Male
  • Middle Aged
  • Mutation*
  • Parathyroid Neoplasms / genetics*
  • Proteins / genetics*
  • Syndrome
  • Tumor Suppressor Proteins


  • CDC73 protein, human
  • Proteins
  • Tumor Suppressor Proteins