PMID- 22575867
OWN - NLM
STAT- MEDLINE
DCOM- 20121106
LR  - 20230210
IS  - 1530-0285 (Electronic)
IS  - 0893-3952 (Print)
IS  - 0893-3952 (Linking)
VI  - 25
IP  - 7
DP  - 2012 Jul
TI  - Loss of ATRX or DAXX expression and concomitant acquisition of the alternative 
      lengthening of telomeres phenotype are late events in a small subset of MEN-1 
      syndrome pancreatic neuroendocrine tumors.
PG  - 1033-9
LID - 10.1038/modpathol.2012.53 [doi]
AB  - Approximately 45% of sporadic well-differentiated pancreatic neuroendocrine 
      tumors harbor mutations in either ATRX (alpha thalassemia/mental retardation 
      X-linked) or DAXX (death domain-associated protein). These novel tumor suppressor 
      genes encode nuclear proteins that interact with one another and function in 
      chromatin remodeling at telomeric and peri-centromeric regions. Mutations in 
      these genes are associated with loss of their protein expression and correlate 
      with the alternative lengthening of telomeres phenotype. Patients with multiple 
      endocrine neoplasia-1 (MEN-1) syndrome, genetically defined by a germ line 
      mutation in the MEN1 gene, are predisposed to developing pancreatic 
      neuroendocrine tumors and thus represent a unique model for studying the timing 
      of ATRX and DAXX inactivation in pancreatic neuroendocrine tumor development. We 
      characterized ATRX and DAXX protein expression by immunohistochemistry and 
      telomere status by telomere-specific fluorescence in situ hybridization in 109 
      well-differentiated pancreatic neuroendocrine lesions from 28 MEN-1 syndrome 
      patients. The study consisted of 47 neuroendocrine microadenomas (<0.5 cm), 50 
      pancreatic neuroendocrine tumors (>/=0.5 cm), and 12 pancreatic neuroendocrine 
      tumor lymph node metastases. Expression of ATRX and DAXX was intact in all 47 
      microadenomas, and none showed the alternative lengthening of telomeres 
      phenotype. ATRX and/or DAXX expression was lost in 3 of 50 (6%) pancreatic 
      neuroendocrine tumors. In all three of these, tumor size was >/=3 cm, and loss of 
      ATRX and/or DAXX expression correlated with the alternative lengthening of 
      telomeres phenotype. Concurrent lymph node metastases were present for two of the 
      three tumors, and each metastasis displayed the same changes as the primary 
      tumor. These findings establish the existence of ATRX and DAXX defects and the 
      alternative lengthening of telomeres phenotype in pancreatic neuroendocrine 
      tumors in the context of MEN-1 syndrome. The observation that ATRX and DAXX 
      defects and the alternative lengthening of telomeres phenotype occurred only in 
      pancreatic neuroendocrine tumors measuring >/=3 cm and their lymph node metastases 
      suggests that these changes are late events in pancreatic neuroendocrine tumor 
      development.
FAU - de Wilde, Roeland F
AU  - de Wilde RF
AD  - Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns 
      Hopkins University School of Medicine, Baltimore, MD, USA.
FAU - Heaphy, Christopher M
AU  - Heaphy CM
FAU - Maitra, Anirban
AU  - Maitra A
FAU - Meeker, Alan K
AU  - Meeker AK
FAU - Edil, Barish H
AU  - Edil BH
FAU - Wolfgang, Christopher L
AU  - Wolfgang CL
FAU - Ellison, Trevor A
AU  - Ellison TA
FAU - Schulick, Richard D
AU  - Schulick RD
FAU - Molenaar, I Quintus
AU  - Molenaar IQ
FAU - Valk, Gerlof D
AU  - Valk GD
FAU - Vriens, Menno R
AU  - Vriens MR
FAU - Borel Rinkes, Inne H M
AU  - Borel Rinkes IH
FAU - Offerhaus, G Johan A
AU  - Offerhaus GJ
FAU - Hruban, Ralph H
AU  - Hruban RH
FAU - Matsukuma, Karen E
AU  - Matsukuma KE
LA  - eng
GR  - P30 CA006973/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20120511
PL  - United States
TA  - Mod Pathol
JT  - Modern pathology : an official journal of the United States and Canadian Academy 
      of Pathology, Inc
JID - 8806605
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Co-Repressor Proteins)
RN  - 0 (DAXX protein, human)
RN  - 0 (Molecular Chaperones)
RN  - 0 (Nuclear Proteins)
RN  - EC 3.6.4.- (DNA Helicases)
RN  - EC 3.6.4.12 (ATRX protein, human)
RN  - EC 3.6.4.12 (X-linked Nuclear Protein)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/*biosynthesis
MH  - Adenoma/etiology/metabolism/pathology
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Carcinoma, Neuroendocrine/etiology/*metabolism/pathology
MH  - Co-Repressor Proteins
MH  - DNA Helicases/*biosynthesis
MH  - Female
MH  - Humans
MH  - Immunohistochemistry
MH  - In Situ Hybridization, Fluorescence
MH  - Male
MH  - Middle Aged
MH  - Molecular Chaperones
MH  - Multiple Endocrine Neoplasia Type 1/complications
MH  - Nuclear Proteins/*biosynthesis
MH  - Pancreatic Neoplasms/etiology/*metabolism/pathology
MH  - Phenotype
MH  - Telomere/metabolism/*pathology
MH  - X-linked Nuclear Protein
MH  - Young Adult
PMC - PMC3547622
MID - NIHMS429330
COIS- Disclosure/conflict of interest The authors declare no conflict of interest.
EDAT- 2012/05/12 06:00
MHDA- 2012/11/07 06:00
PMCR- 2013/01/17
CRDT- 2012/05/12 06:00
PHST- 2012/05/12 06:00 [entrez]
PHST- 2012/05/12 06:00 [pubmed]
PHST- 2012/11/07 06:00 [medline]
PHST- 2013/01/17 00:00 [pmc-release]
AID - S0893-3952(22)01711-2 [pii]
AID - 10.1038/modpathol.2012.53 [doi]
PST - ppublish
SO  - Mod Pathol. 2012 Jul;25(7):1033-9. doi: 10.1038/modpathol.2012.53. Epub 2012 May 
      11.