PMID- 29134609
OWN - NLM
STAT- MEDLINE
DCOM- 20180928
LR  - 20181113
IS  - 1720-8386 (Electronic)
IS  - 0391-4097 (Linking)
VI  - 41
IP  - 6
DP  - 2018 Jun
TI  - Expression of p27(Kip1) and p18(Ink4c) in human multiple endocrine neoplasia type 
      1-related pancreatic neuroendocrine tumors.
PG  - 655-661
LID - 10.1007/s40618-017-0783-y [doi]
AB  - PURPOSE: Pancreatic neuroendocrine tumors are a major manifestation of multiple 
      endocrine neoplasia type 1 (MEN1). This tumor syndrome is caused by germline 
      mutations in MEN1, encoding menin. Insight into pathogenesis of these tumors 
      might lead to new biomarkers and therapeutic targets for these patients. Several 
      lines of evidence point towards a role for p27(Kip1) and p18(Ink4c) in 
      MEN1-related tumor development in animal models for MEN1, but their contribution 
      to human MEN1-related pancreatic neuroendocrine tumor development is not known. 
      METHODS: In this study, we characterized protein expression of p27(Kip1) and 
      p18(Ink4c) in human MEN1-related PanNETs by immunohistochemistry. From the 
      nationwide DutchMEN1 Study Group database including > 90% of the Dutch MEN1 
      population, MEN1-patients, who underwent pancreatic surgery, were selected. A 
      tissue micro-array was constructed with available paraffin tissue blocks, and 
      PanNETs from 61 MEN1 patients were eligible for analysis. RESULTS: Expression of 
      p27(Kip1) was high in 57 (93%) PanNETs and 67% of the tumors showed low 
      expression of p18(Ink4c) (67.3%). No association was found between expression of 
      either p27(Kip1) or p18(Ink4c) and clinic-pathological characteristics. 
      CONCLUSIONS: These findings indicate that loss of p18(Ink4c), but not p27(Kip1), 
      is a common event in the development of MEN1-related PanNETs. Restoration of 
      p18(Ink4c) function through CDK4/6 inhibitors could be a therapeutic option for 
      MEN1-related PanNETs.
FAU - Conemans, E B
AU  - Conemans EB
AD  - Department of Surgery, University Medical Center Utrecht, PO box 85500, 3508 GA, 
      Utrecht, The Netherlands.
AD  - Department of Internal Medicine, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - Raicu-Ionita, G M
AU  - Raicu-Ionita GM
AD  - Department of Pathology, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - Pieterman, C R C
AU  - Pieterman CRC
AD  - Department of Internal Medicine, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - Dreijerink, K M A
AU  - Dreijerink KMA
AD  - Department of Internal Medicine, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - Dekkers, O M
AU  - Dekkers OM
AD  - Department of Endocrinology and Metabolism and Department of Clinical 
      Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
FAU - Hermus, A R
AU  - Hermus AR
AD  - Department of Endocrinology, Radboud University Medical Center, Nijmegen, The 
      Netherlands.
FAU - de Herder, W W
AU  - de Herder WW
AD  - Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The 
      Netherlands.
FAU - Drent, M L
AU  - Drent ML
AD  - Department of Internal Medicine, Section Endocrinology, VU University Medical 
      Center, Amsterdam, The Netherlands.
FAU - van der Horst-Schrivers, A N A
AU  - van der Horst-Schrivers ANA
AD  - Department of Endocrinology, University Medical Center Groningen, Groningen, The 
      Netherlands.
FAU - Havekes, B
AU  - Havekes B
AD  - Department of Internal Medicine, Division of Endocrinology, Maastricht University 
      Medical Center, Maastricht, The Netherlands.
FAU - Bisschop, P H
AU  - Bisschop PH
AD  - Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, 
      The Netherlands.
FAU - Offerhaus, G J
AU  - Offerhaus GJ
AD  - Department of Pathology, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - Borel Rinkes, I H M
AU  - Borel Rinkes IHM
AD  - Department of Surgery, University Medical Center Utrecht, PO box 85500, 3508 GA, 
      Utrecht, The Netherlands.
FAU - Valk, G D
AU  - Valk GD
AD  - Department of Internal Medicine, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - Timmers, H Th M
AU  - Timmers HTM
AD  - Section Stem Cells, Regenerative Medicine Center and Center for Molecular 
      Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
FAU - Vriens, M R
AU  - Vriens MR
AD  - Department of Surgery, University Medical Center Utrecht, PO box 85500, 3508 GA, 
      Utrecht, The Netherlands. mvriens@umcutrecht.nl.
LA  - eng
PT  - Journal Article
DEP - 20171113
PL  - Italy
TA  - J Endocrinol Invest
JT  - Journal of endocrinological investigation
JID - 7806594
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (CDKN1B protein, human)
RN  - 0 (CDKN2C protein, human)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p18)
RN  - 147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Biomarkers, Tumor/*metabolism
MH  - Cyclin-Dependent Kinase Inhibitor p18/*metabolism
MH  - Cyclin-Dependent Kinase Inhibitor p27/*metabolism
MH  - Female
MH  - Follow-Up Studies
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Multiple Endocrine Neoplasia Type 1/*complications
MH  - Neuroendocrine Tumors/diagnosis/etiology/*metabolism
MH  - Pancreatic Neoplasms/diagnosis/etiology/*metabolism
MH  - Prognosis
MH  - Young Adult
OTO - NOTNLM
OT  - Menin
OT  - Multiple endocrine neoplasia type 1
OT  - Pancreatic neuroendocrine tumors
OT  - p18Ink4c
OT  - p27Kip1
EDAT- 2017/11/15 06:00
MHDA- 2018/10/03 06:00
CRDT- 2017/11/15 06:00
PHST- 2017/04/22 00:00 [received]
PHST- 2017/10/24 00:00 [accepted]
PHST- 2017/11/15 06:00 [pubmed]
PHST- 2018/10/03 06:00 [medline]
PHST- 2017/11/15 06:00 [entrez]
AID - 10.1007/s40618-017-0783-y [pii]
AID - 10.1007/s40618-017-0783-y [doi]
PST - ppublish
SO  - J Endocrinol Invest. 2018 Jun;41(6):655-661. doi: 10.1007/s40618-017-0783-y. Epub 
      2017 Nov 13.