title: Whole-exome sequencing studies of nonfunctioning pituitary adenomas.
abstract: BACKGROUND
  The tumorigenic role of genetic abnormalities in sporadic pituitary nonfunctioning adenomas (NFAs), which usually originate from gonadotroph cells, is unknown.
  
  
  OBJECTIVE
  The objective of the study was to identify somatic genetic abnormalities in sporadic pituitary NFAs.
  
  
  METHODS
  Whole-exome sequencing was performed using DNA from 7 pituitary NFAs and leukocyte samples obtained from the same patients. Somatic variants were confirmed by dideoxynucleotide sequencing, and candidate driver genes were assessed in an additional 24 pituitary NFAs.
  
  
  RESULTS
  Whole-exome sequencing achieved a high degree of coverage such that approximately 97% of targeted bases were represented by more than 10 base reads; 24 somatic variants were identified and confirmed in the discovery set of 7 pituitary NFAs (mean 3.5 variants/tumor; range 1-7). Approximately 80% of variants occurred as missense single nucleotide variants and the remainder were synonymous changes or small frameshift deletions. Each of the 24 mutations occurred in independent genes with no recurrent mutations. Mutations were not observed in genes previously associated with pituitary tumorigenesis, although somatic variants in putative driver genes including platelet-derived growth factor D (PDGFD), N-myc down-regulated gene family member 4 (NDRG4), and Zipper sterile-α-motif kinase (ZAK) were identified; however, DNA sequence analysis of these in the validation set of 24 pituitary NFAs did not reveal any mutations indicating that these genes are unlikely to contribute significantly in the etiology of sporadic pituitary NFAs.
  
  
  CONCLUSIONS
  Pituitary NFAs harbor few somatic mutations consistent with their low proliferation rates and benign nature, but mechanisms other than somatic mutation are likely involved in the etiology of sporadic pituitary NFAs.
authors: Academic Endocrine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7LJ, United Kingdom.
authors: Paul J
authors: PJ
authors: Newey
authors: M Andrew
authors: MA
authors: Nesbit
authors: Andrew J
authors: AJ
authors: Rimmer
authors: Rosie A
authors: RA
authors: Head
authors: Caroline M
authors: CM
authors: Gorvin
authors: Moustafa
authors: M
authors: Attar
authors: Lorna
authors: L
authors: Gregory
authors: John A H
authors: JA
authors: Wass
authors: David
authors: D
authors: Buck
authors: Niki
authors: N
authors: Karavitaki
authors: Ashley B
authors: AB
authors: Grossman
authors: Gilean
authors: G
authors: McVean
authors: Olaf
authors: O
authors: Ansorge
authors: Rajesh V
authors: RV
authors: Thakker
mesh_terms: D000236:Adenoma / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D010911:Pituitary Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D017422:Sequence Analysis, DNA / Q000379:methods; D059467:Transcriptome