Department of Surgery, University Medical Center Utrecht, PO box 85500, 3508 GA, Utrecht, The Netherlands.
Department of Internal Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
J Endocrinol Invest. 2018 Jun;41(6):655-661. doi: 10.1007/s40618-017-0783-y. Epub 2017 Nov 13.
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 and p18 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 p27 and p18 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 p27 was high in 57 (93%) PanNETs and 67% of the tumors showed low expression of p18 (67.3%). No association was found between expression of either p27 or p18 and clinic-pathological characteristics.
These findings indicate that loss of p18, but not p27, is a common event in the development of MEN1-related PanNETs. Restoration of p18 function through CDK4/6 inhibitors could be a therapeutic option for MEN1-related PanNETs.
胰腺神经内分泌肿瘤是多发性内分泌肿瘤 1 型（MEN1）的主要表现。这种肿瘤综合征是由 MEN1 基因种系突变引起的，该基因编码 menin。对这些肿瘤发病机制的深入了解可能为这些患者带来新的生物标志物和治疗靶点。有几条证据表明，p27 和 p18 在 MEN1 相关的动物模型中的肿瘤发展中起作用，但它们对人类 MEN1 相关的胰腺神经内分泌肿瘤发展的贡献尚不清楚。
在这项研究中，我们通过免疫组织化学方法对人类 MEN1 相关的 PanNETs 中的 p27 和 p18 的蛋白表达进行了特征描述。从包括 90%以上荷兰 MEN1 人群的全国性荷兰 MEN1 研究组数据库中，选择了接受胰腺手术的 MEN1 患者。构建了一个组织微阵列，包含了可用的石蜡组织块，其中 61 名 MEN1 患者的 PanNETs 适合进行分析。
p27 的表达在 57 个（93%）PanNETs 中较高，而 67%的肿瘤表现出 p18 的低表达（67.3%）。p27 或 p18 的表达与临床病理特征之间没有发现相关性。
这些发现表明，p18 的缺失，而不是 p27 的缺失，是 MEN1 相关的 PanNETs 发展中的常见事件。通过 CDK4/6 抑制剂恢复 p18 的功能可能是 MEN1 相关的 PanNETs 的一种治疗选择。
