PMID- 29486199
OWN - NLM
STAT- MEDLINE
DCOM- 20180718
LR  - 20240326
IS  - 1528-0012 (Electronic)
IS  - 0016-5085 (Print)
IS  - 0016-5085 (Linking)
VI  - 154
IP  - 8
DP  - 2018 Jun
TI  - Loss of Chromatin-Remodeling Proteins and/or CDKN2A Associates With Metastasis of 
      Pancreatic Neuroendocrine Tumors and Reduced Patient Survival Times.
PG  - 2060-2063.e8
LID - S0016-5085(18)30243-9 [pii]
LID - 10.1053/j.gastro.2018.02.026 [doi]
AB  - Despite prognostic grading and staging systems, it is a challenge to predict 
      outcomes for patients with pancreatic neuroendocrine tumors (PanNETs). Sequencing 
      studies of PanNETs have identified alterations in death domain-associated protein 
      (DAXX) and alpha-thalassemia/mental retardation X-linked chromatin remodeler 
      (ATRX). In tumors, mutations in DAXX or ATRX and corresponding loss of protein 
      expression correlate with shorter times of disease-free survival and 
      disease-specific survival of patients. However, DAXX or ATRX proteins were lost 
      in only 50% of distant metastases analyzed. We performed whole-exome sequencing 
      analyses of 20 distant metastases from 20 patients with a single nonsyndrome, 
      nonfunctional PanNET. We found distant metastases contained alterations in 
      multiple endocrine neoplasia type 1 (MEN1) (n = 8), ATRX (n = 5), DAXX (n = 5), 
      TSC2 (n = 3), and DEP domain containing 5 (DEPDC5) (n = 3). We found copy number 
      loss of cyclin dependent kinase inhibitor 2A (CDKN2A) in 15 metastases (75%) and 
      alterations in genes that regulate chromatin remodeling, including set domain 
      containing 2 (SETD2) (n = 4), AT-rich interaction domain 1A (ARID1A) (n = 2), 
      chromodomain helicase DNA binding protein 8 (CHD8) (n = 2), and DNA methyl 
      transferase 1 (DNMT1) (n = 2). In a separate analysis of 347 primary PanNETs, we 
      found loss or deletion of DAXX and ATRX, disruption of SETD2 function (based on 
      loss of H3 lysine 36 trimethylation), loss of ARID1A expression or deletions in 
      CDKN2A in 81% of primary PanNETs with distant metastases. Among patients with 
      loss or deletion of at least 1 of these proteins or genes, 39% survived 
      disease-free for 5 years and 44% had disease-specific survival times of 10 years. 
      Among patients without any of these alterations, 98% survived disease-free for 5 
      years and 95% had disease-specific survival times of 10 years. Therefore, primary 
      PanNETs with loss of DAXX, ATRX, H3 lysine 36 trimethylation, ARID1A, and/or 
      CDKN2A associate with shorter survival times of patients. Our findings indicate 
      that alterations in chromatin-remodeling genes and CDKN2A contribute to 
      metastasis of PanNETs.
CI  - Copyright (c) 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.
FAU - Roy, Somak
AU  - Roy S
AD  - Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania.
FAU - LaFramboise, William A
AU  - LaFramboise WA
AD  - Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania.
FAU - Liu, Ta-Chiang
AU  - Liu TC
AD  - Department of Pathology and Immunology, Washington University School of Medicine, 
      St. Louis, Missouri.
FAU - Cao, Dengfeng
AU  - Cao D
AD  - Department of Pathology and Immunology, Washington University School of Medicine, 
      St. Louis, Missouri.
FAU - Luvison, Alyssa
AU  - Luvison A
AD  - Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania.
FAU - Miller, Caitlyn
AU  - Miller C
AD  - Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania.
FAU - Lyons, Maureen A
AU  - Lyons MA
AD  - Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania.
FAU - O'Sullivan, Roderick J
AU  - O'Sullivan RJ
AD  - Department of Pharmacology and Chemical Biology, University of Pittsburgh, 
      Pittsburgh, Pennsylvania.
FAU - Zureikat, Amer H
AU  - Zureikat AH
AD  - Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania.
FAU - Hogg, Melissa E
AU  - Hogg ME
AD  - Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania.
FAU - Tsung, Allan
AU  - Tsung A
AD  - Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania.
FAU - Lee, Kenneth K
AU  - Lee KK
AD  - Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania.
FAU - Bahary, Nathan
AU  - Bahary N
AD  - Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania.
FAU - Brand, Randall E
AU  - Brand RE
AD  - Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania.
FAU - Chennat, Jennifer S
AU  - Chennat JS
AD  - Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania.
FAU - Fasanella, Kenneth E
AU  - Fasanella KE
AD  - Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania.
FAU - McGrath, Kevin
AU  - McGrath K
AD  - Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania.
FAU - Nikiforova, Marina N
AU  - Nikiforova MN
AD  - Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania.
FAU - Papachristou, Georgios I
AU  - Papachristou GI
AD  - Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania.
FAU - Slivka, Adam
AU  - Slivka A
AD  - Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania.
FAU - Zeh, Herbert J
AU  - Zeh HJ
AD  - Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania. Electronic address: zehxhx@upmc.edu.
FAU - Singhi, Aatur D
AU  - Singhi AD
AD  - Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania. Electronic address: singhiad@upmc.edu.
LA  - eng
GR  - P30 CA047904/CA/NCI NIH HHS/United States
GR  - R01 CA207209/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180302
PL  - United States
TA  - Gastroenterology
JT  - Gastroenterology
JID - 0374630
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (CDKN2A protein, human)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p16)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p18)
RN  - 0 (Nuclear Proteins)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Biomarkers, Tumor/*genetics
MH  - Chromatin Assembly and Disassembly/genetics
MH  - Cyclin-Dependent Kinase Inhibitor p16
MH  - Cyclin-Dependent Kinase Inhibitor p18/*genetics
MH  - DNA Copy Number Variations
MH  - Disease-Free Survival
MH  - Female
MH  - Humans
MH  - Kaplan-Meier Estimate
MH  - Male
MH  - Middle Aged
MH  - Mutation
MH  - Neuroendocrine Tumors/*genetics/mortality/pathology/surgery
MH  - Nuclear Proteins/*genetics
MH  - Pancreatectomy
MH  - Pancreatic Neoplasms/*genetics/mortality/pathology/surgery
MH  - Prognosis
MH  - Exome Sequencing
PMC - PMC5985217
MID - NIHMS964734
OTO - NOTNLM
OT  - Pancreas
OT  - Prognosis
OT  - Prognostic Factor
OT  - Risk
COIS- Disclosure/conflict of interest: The authors have no conflicts of interest to 
      declare.
EDAT- 2018/02/28 06:00
MHDA- 2018/07/19 06:00
PMCR- 2018/06/03
CRDT- 2018/02/28 06:00
PHST- 2017/07/13 00:00 [received]
PHST- 2018/02/01 00:00 [revised]
PHST- 2018/02/14 00:00 [accepted]
PHST- 2018/02/28 06:00 [pubmed]
PHST- 2018/07/19 06:00 [medline]
PHST- 2018/02/28 06:00 [entrez]
PHST- 2018/06/03 00:00 [pmc-release]
AID - S0016-5085(18)30243-9 [pii]
AID - 10.1053/j.gastro.2018.02.026 [doi]
PST - ppublish
SO  - Gastroenterology. 2018 Jun;154(8):2060-2063.e8. doi: 
      10.1053/j.gastro.2018.02.026. Epub 2018 Mar 2.