Expression of p27Kip1 and p18Ink4c in human multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors
- 224 Downloads
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.
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.
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.
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.
KeywordsMultiple endocrine neoplasia type 1 Pancreatic neuroendocrine tumors Menin p27Kip1 p18Ink4c
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
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.
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.
For this type of study formal consent is not required.
- 2.Pieterman CR, Conemans EB, Dreijerink KM, de Laat JM, Timmers HT, Vriens MR et al (2014) Thoracic and duodenopancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: natural history and function of menin in tumorigenesis. Endocr Relat Cancer 21(3):R121–R142CrossRefPubMedGoogle Scholar
- 8.Schaaf L, Pickel J, Zinner K, Hering U, Hofler M, Goretzki PE et al (2007) Developing effective screening strategies in multiple endocrine neoplasia type 1 (MEN 1) on the basis of clinical and sequencing data of German patients with MEN 1. Exp Clin Endocrinol Diabetes 115(8):509–517CrossRefPubMedGoogle Scholar
- 24.Casparie M, Tiebosch AT, Burger G, Blauwgeers H, van de Pol A, van Krieken JH et al (2007) Pathology databanking and biobanking in The Netherlands, a central role for PALGA, the nationwide histopathology and cytopathology data network and archive. Cell Oncol 29(1):19–24PubMedPubMedCentralGoogle Scholar
- 29.Bosman FTCF, Hruban RH, Theisse ND (2010) WHO classification of tumours of the digestive system. International Agency for Research on Cancer (IARC), LyonGoogle Scholar
- 33.Lindberg D, Akerstrom G, Westin G (2008) Evaluation of CDKN2C/p18, CDKN1B/p27 and CDKN2B/p15 mRNA expression, and CpG methylation status in sporadic and MEN1-associated pancreatic endocrine tumours. Clin Endocrinol 68(2):271–277Google Scholar