PMID- 29903750
OWN - NLM
STAT- MEDLINE
DCOM- 20180820
LR  - 20190217
IS  - 1479-683X (Electronic)
IS  - 0804-4643 (Linking)
VI  - 179
IP  - 3
DP  - 2018 Sep
TI  - DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors 
      reveals a potential epigenetic target for treatment.
PG  - 153-160
LID - EJE-18-0195 [pii]
LID - 10.1530/EJE-18-0195 [doi]
AB  - OBJECTIVE: Epigenetic changes contribute to pancreatic neuroendocrine tumor 
      (PanNET) development. Hypermethylation of promoter DNA as a cause of tumor 
      suppressor gene silencing is a well-established oncogenic mechanism that is 
      potentially reversible and therefore an interesting therapeutic target. Multiple 
      endocrine neoplasia type 1 (MEN1) is the most frequent cause of inherited 
      PanNETs. The aim of this study was to determine promoter methylation profiles in 
      MEN1-related PanNETs. DESIGN AND METHODS: Methylation-specific multiplex 
      ligation-dependent probe amplification was used to assess promoter methylation of 
      56 tumor suppressor genes in MEN1-related (n = 61) and sporadic (n = 34) PanNETs. 
      Differences in cumulative methylation index (CMI), individual methylation 
      percentages and frequency of promoter hypermethylation between subgroups were 
      analyzed. RESULTS: We found promoter methylation of a large number of potential 
      tumor suppressor genes. CMI (median CMI: 912 vs 876, P = 0.207) was the same in 
      MEN1-related and sporadic PanNETs. We found higher methylation percentages of 
      CASP8 in MEN1-related PanNETs (median: 59% vs 16.5%, P = 0.002). In MEN1-related 
      non-functioning PanNETs, the CMI was higher in larger PanNETs (>2 cm) (median: 
      969.5 vs 838.5; P = 0.021) and in PanNETs with liver metastases (median: 1036 vs 
      869; P = 0.013). Hypermethylation of MGMT2 was more frequent in non-functioning 
      PanNETs compared to insulinomas (median: 44.7% vs 8.3%; P = 0.022). 
      Hypermethylation of the Von Hippel-Lindau gene promoter was observed in one 
      MEN1-related PanNET and was associated with loss of protein expression. 
      CONCLUSION: Promoter hypermethylation is a frequent event in MEN1-related and 
      sporadic PanNETs. Targeting DNA methylation could be of therapeutic value in MEN1 
      patients with advanced PanNETs.
CI  - (c) 2018 European Society of Endocrinology.
FAU - Conemans, E B
AU  - Conemans EB
AD  - Departments of Surgery, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
AD  - Departments of Internal Medicine, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
AD  - Departments of Section Endocrinology, Department of Internal Medicine, VU 
      University Medical Center, Amsterdam, The Netherlands.
FAU - Lodewijk, L
AU  - Lodewijk L
AD  - Departments of Surgery, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - Moelans, C B
AU  - Moelans CB
AD  - Department of Pathology, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - Offerhaus, G J A
AU  - Offerhaus GJA
AD  - Department of Pathology, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - Pieterman, C R C
AU  - Pieterman CRC
AD  - Departments of Internal Medicine, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - Morsink, F H
AU  - Morsink FH
AD  - Department of Pathology, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - Dekkers, O M
AU  - Dekkers OM
AD  - Departments of Endocrinology and Metabolism and Clinical Epidemiology, Leiden 
      University Medical Center, Leiden, The Netherlands.
FAU - de Herder, W W
AU  - de Herder WW
AD  - Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The 
      Netherlands.
FAU - Hermus, A R
AU  - Hermus AR
AD  - Department of Endocrinology, Radboud University Medical Center, Nijmegen, The 
      Netherlands.
FAU - van der Horst-Schrivers, A N
AU  - van der Horst-Schrivers AN
AD  - Department of Endocrinology, University Medical Center Groningen, Groningen, The 
      Netherlands.
FAU - Drent, M L
AU  - Drent ML
AD  - Departments of Section Endocrinology, Department of Internal Medicine, VU 
      University Medical Center, Amsterdam, The Netherlands.
FAU - Bisschop, P H
AU  - Bisschop PH
AD  - Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, 
      The Netherlands.
FAU - Havekes, B
AU  - Havekes B
AD  - Division of Endocrinology, Department of Internal Medicine, Maastricht University 
      Medical Center, Maastricht, The Netherlands.
FAU - Brosens, L A A
AU  - Brosens LAA
AD  - Department of Pathology, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - Dreijerink, K M A
AU  - Dreijerink KMA
AD  - Departments of Internal Medicine, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
AD  - Departments of Section Endocrinology, Department of Internal Medicine, VU 
      University Medical Center, Amsterdam, The Netherlands.
FAU - Borel Rinkes, I H M
AU  - Borel Rinkes IHM
AD  - Departments of Surgery, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - Timmers, H Th M
AU  - Timmers HTM
AD  - Regenerative Medicine Center and Center for Molecular Medicine, University 
      Medical Center Utrecht, Utrecht, The Netherlands.
AD  - German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research 
      Center (DKFZ) and Department of Urology, Medical Center-University of Freiburg, 
      Freiburg, Germany.
FAU - Valk, G D
AU  - Valk GD
AD  - Departments of Internal Medicine, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - Vriens, M R
AU  - Vriens MR
AD  - Departments of Surgery, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
LA  - eng
PT  - Journal Article
DEP - 20180614
PL  - England
TA  - Eur J Endocrinol
JT  - European journal of endocrinology
JID - 9423848
RN  - EC 2.3.2.27 (Von Hippel-Lindau Tumor Suppressor Protein)
RN  - EC 6.3.2.- (VHL protein, human)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - DNA Methylation/*genetics
MH  - Epigenesis, Genetic/*genetics
MH  - Female
MH  - Genes, Tumor Suppressor
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Multiple Endocrine Neoplasia Type 1/*genetics
MH  - Neuroendocrine Tumors/*genetics
MH  - Pancreatic Neoplasms/*genetics
MH  - Promoter Regions, Genetic/*genetics
MH  - Von Hippel-Lindau Tumor Suppressor Protein/genetics
EDAT- 2018/06/16 06:00
MHDA- 2018/08/21 06:00
CRDT- 2018/06/16 06:00
PHST- 2018/03/07 00:00 [received]
PHST- 2018/06/14 00:00 [accepted]
PHST- 2018/06/16 06:00 [pubmed]
PHST- 2018/08/21 06:00 [medline]
PHST- 2018/06/16 06:00 [entrez]
AID - EJE-18-0195 [pii]
AID - 10.1530/EJE-18-0195 [doi]
PST - ppublish
SO  - Eur J Endocrinol. 2018 Sep;179(3):153-160. doi: 10.1530/EJE-18-0195. Epub 2018 
      Jun 14.