Expression of p27(KiP1)and p18(Ink4c) in human multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors

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 Dutch MEN1 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.