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Journal of Endocrinological Investigation

, Volume 41, Issue 6, pp 655–661 | Cite as

Expression of p27Kip1 and p18Ink4c in human multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors

  • E. B. Conemans
  • G. M. Raicu-Ionita
  • C. R. C. Pieterman
  • K. M. A. Dreijerink
  • O. M. Dekkers
  • A. R. Hermus
  • W. W. de Herder
  • M. L. Drent
  • A. N. A. van der Horst-Schrivers
  • B. Havekes
  • P. H. Bisschop
  • G. J. Offerhaus
  • I. H. M. Borel Rinkes
  • G. D. Valk
  • H. Th. M. Timmers
  • M. R. VriensEmail author
Original Article

Abstract

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 p27Kip1 and p18Ink4c 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 p27Kip1 and p18Ink4c 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 p27Kip1 was high in 57 (93%) PanNETs and 67% of the tumors showed low expression of p18Ink4c (67.3%). No association was found between expression of either p27Kip1 or p18Ink4c and clinic-pathological characteristics.

Conclusions

These findings indicate that loss of p18Ink4c, but not p27Kip1, is a common event in the development of MEN1-related PanNETs. Restoration of p18Ink4c function through CDK4/6 inhibitors could be a therapeutic option for MEN1-related PanNETs.

Keywords

Multiple endocrine neoplasia type 1 Pancreatic neuroendocrine tumors Menin p27Kip1 p18Ink4c 

Notes

Acknowledgements

We thank Annette H. Bruggink for her assistance in the tissue collection. We thank Domenico Castigliego and Lutske Lodewijk for their help with the construction of the TMA. We thank Folkert H. Morsink, Roel Broekhuizen and Radhika A. Varier for their advice on the optimization of procedures for immunohistochemistry.

Complicance with ethical standards

Funding

Gerlof D. Valk and Menno R. Vriens are the receivers of an unrestricted grant from Ipsen. Koen M. A. Dreijerink is supported by a fellowship from the Dutch Cancer Society (UU 2012 5370).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

For this type of study formal consent is not required.

Supplementary material

40618_2017_783_MOESM1_ESM.docx (22 kb)
Supplementary material 1 (DOCX 22 kb)

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Copyright information

© Italian Society of Endocrinology (SIE) 2017

Authors and Affiliations

  • E. B. Conemans
    • 1
    • 2
  • G. M. Raicu-Ionita
    • 3
  • C. R. C. Pieterman
    • 2
  • K. M. A. Dreijerink
    • 2
  • O. M. Dekkers
    • 4
  • A. R. Hermus
    • 5
  • W. W. de Herder
    • 6
  • M. L. Drent
    • 7
  • A. N. A. van der Horst-Schrivers
    • 8
  • B. Havekes
    • 9
  • P. H. Bisschop
    • 10
  • G. J. Offerhaus
    • 3
  • I. H. M. Borel Rinkes
    • 1
  • G. D. Valk
    • 2
  • H. Th. M. Timmers
    • 11
  • M. R. Vriens
    • 1
    Email author
  1. 1.Department of SurgeryUniversity Medical Center UtrechtUtrechtThe Netherlands
  2. 2.Department of Internal MedicineUniversity Medical Center UtrechtUtrechtThe Netherlands
  3. 3.Department of PathologyUniversity Medical Center UtrechtUtrechtThe Netherlands
  4. 4.Department of Endocrinology and Metabolism and Department of Clinical EpidemiologyLeiden University Medical CenterLeidenThe Netherlands
  5. 5.Department of EndocrinologyRadboud University Medical CenterNijmegenThe Netherlands
  6. 6.Department of Internal MedicineErasmus Medical CenterRotterdamThe Netherlands
  7. 7.Department of Internal Medicine, Section EndocrinologyVU University Medical CenterAmsterdamThe Netherlands
  8. 8.Department of EndocrinologyUniversity Medical Center GroningenGroningenThe Netherlands
  9. 9.Department of Internal Medicine, Division of EndocrinologyMaastricht University Medical CenterMaastrichtThe Netherlands
  10. 10.Department of Endocrinology and MetabolismAcademic Medical CenterAmsterdamThe Netherlands
  11. 11.Section Stem Cells, Regenerative Medicine Center and Center for Molecular MedicineUniversity Medical Center UtrechtUtrechtThe Netherlands

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