title: Whole-exome sequencing studies of nonhereditary (sporadic) parathyroid adenomas.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.affiliation: Academic Endocrine Unit, Nuffield Department of Clinical Medicine, University of Oxford, and Department of Surgery, John Radcliffe Hospital, Oxford University Hospitals Trust, Oxford, UK.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Newey
authors.forename: M Andrew
authors.initials: MA
authors.lastname: Nesbit
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Rimmer
authors.forename: Moustafa
authors.initials: M
authors.lastname: Attar
authors.forename: Rosie T
authors.initials: RT
authors.lastname: Head
authors.forename: Paul T
authors.initials: PT
authors.lastname: Christie
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Gorvin
authors.forename: Michael
authors.initials: M
authors.lastname: Stechman
authors.forename: Lorna
authors.initials: L
authors.lastname: Gregory
authors.forename: Radu
authors.initials: R
authors.lastname: Mihai
authors.forename: Greg
authors.initials: G
authors.lastname: Sadler
authors.forename: Gil
authors.initials: G
authors.lastname: McVean
authors.forename: David
authors.initials: D
authors.lastname: Buck
authors.forename: Rajesh V
authors.initials: RV
authors.lastname: Thakker
mesh_terms: D000236:Adenoma / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D019938:Cyclin D1 / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods*; D059472:Exome / Q000235:genetics; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D049950:Hyperparathyroidism, Primary / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics*; D010282:Parathyroid Neoplasms / Q000235:genetics*; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins / Q000235:genetics
chemical_list: C530104:CCND1 protein, human; C440849:POT1 protein, human; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D019938:Cyclin D1