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

• Published in: Journal of endocrinological investigation 2018-06, Vol.41 (6), p.655-661
• Main Authors: Conemans, E. B., Raicu-Ionita, G. M., Pieterman, C. R. C., Dreijerink, K. M. A., Dekkers, O. M., Hermus, A. R., de Herder, W. W., Drent, M. L., van der Horst-Schrivers, A. N. A., Havekes, B., Bisschop, P. H., Offerhaus, G. J., Borel Rinkes, I. H. M., Valk, G. D., Timmers, H. Th. M., Vriens, M. R.
• Format: Article
• Language: English
• Subjects: Animal models; Biomarkers; Cyclin-dependent kinase 4; Cyclin-dependent kinase inhibitor p27; Endocrinology; Immunohistochemistry; Medicine; Medicine & Public Health; Metabolic Diseases; Multiple endocrine neoplasia; Mutation; Neuroendocrine tumors; Original Article; Pancreas; Paraffin; Surgery; Therapeutic applications; Tumors
• ISSN: 1720-8386; 0391-4097; 1720-8386
• DOI: 10.1007/s40618-017-0783-y

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.