PMID- 22855342
OWN - NLM
STAT- MEDLINE
DCOM- 20121218
LR  - 20220129
IS  - 1945-7197 (Electronic)
IS  - 0021-972X (Print)
IS  - 0021-972X (Linking)
VI  - 97
IP  - 10
DP  - 2012 Oct
TI  - Whole-exome sequencing studies of nonhereditary (sporadic) parathyroid adenomas.
PG  - E1995-2005
LID - 10.1210/jc.2012-2303 [doi]
AB  - CONTEXT: 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. DESIGN: 
      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 ( approximately 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.
FAU - Newey, Paul J
AU  - Newey PJ
AD  - Academic Endocrine Unit, Nuffield Department of Clinical Medicine, University of 
      Oxford, and Department of Surgery, John Radcliffe Hospital, Oxford University 
      Hospitals Trust, Oxford, UK.
FAU - Nesbit, M Andrew
AU  - Nesbit MA
FAU - Rimmer, Andrew J
AU  - Rimmer AJ
FAU - Attar, Moustafa
AU  - Attar M
FAU - Head, Rosie T
AU  - Head RT
FAU - Christie, Paul T
AU  - Christie PT
FAU - Gorvin, Caroline M
AU  - Gorvin CM
FAU - Stechman, Michael
AU  - Stechman M
FAU - Gregory, Lorna
AU  - Gregory L
FAU - Mihai, Radu
AU  - Mihai R
FAU - Sadler, Greg
AU  - Sadler G
FAU - McVean, Gil
AU  - McVean G
FAU - Buck, David
AU  - Buck D
FAU - Thakker, Rajesh V
AU  - Thakker RV
LA  - eng
GR  - G1000467/2010/MRC_/Medical Research Council/United Kingdom
GR  - G0601423/MRC_/Medical Research Council/United Kingdom
GR  - G1000467/MRC_/Medical Research Council/United Kingdom
GR  - G9825289/MRC_/Medical Research Council/United Kingdom
GR  - 91070/MRC_/Medical Research Council/United Kingdom
GR  - 090532/Z/09/Z/WT_/Wellcome Trust/United Kingdom
GR  - G9825289/2004/MRC_/Medical Research Council/United Kingdom
GR  - 090532/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120801
PL  - United States
TA  - J Clin Endocrinol Metab
JT  - The Journal of clinical endocrinology and metabolism
JID - 0375362
RN  - 0 (CCND1 protein, human)
RN  - 0 (POT1 protein, human)
RN  - 0 (Shelterin Complex)
RN  - 0 (Telomere-Binding Proteins)
RN  - 136601-57-5 (Cyclin D1)
SB  - IM
MH  - Adenoma/*genetics
MH  - Aged
MH  - Aged, 80 and over
MH  - Cyclin D1/genetics
MH  - DNA Mutational Analysis/*methods
MH  - Exome/genetics
MH  - Female
MH  - Genetic Variation/genetics
MH  - Humans
MH  - Hyperparathyroidism, Primary/*genetics
MH  - Male
MH  - Middle Aged
MH  - Multiple Endocrine Neoplasia Type 1/*genetics
MH  - Parathyroid Neoplasms/*genetics
MH  - Shelterin Complex
MH  - Telomere-Binding Proteins/genetics
PMC - PMC4446457
EDAT- 2012/08/03 06:00
MHDA- 2012/12/19 06:00
PMCR- 2013/10/01
CRDT- 2012/08/03 06:00
PHST- 2012/08/03 06:00 [entrez]
PHST- 2012/08/03 06:00 [pubmed]
PHST- 2012/12/19 06:00 [medline]
PHST- 2013/10/01 00:00 [pmc-release]
AID - jc.2012-2303 [pii]
AID - 12-2303 [pii]
AID - 10.1210/jc.2012-2303 [doi]
PST - ppublish
SO  - J Clin Endocrinol Metab. 2012 Oct;97(10):E1995-2005. doi: 10.1210/jc.2012-2303. 
      Epub 2012 Aug 1.