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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 p27Kip1and p18Ink4cin 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 p27Kip1and p18Ink4cin 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 p27Kip1was 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 p27Kip1or p18Ink4cand 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 p18Ink4cfunction through CDK4/6 inhibitors could be a therapeutic option for MEN1-related PanNETs.