Blood-based Proteomic Signatures Associated With MEN1-related Duodenopancreatic Neuroendocrine Tumor Progression

Purpose: Patients with multiple endocrine neoplasia type 1 (MEN1) are predisposed to develop duodenopancreatic neuroendocrine tumors (dpNETs), and metastatic dpNET is the primary cause of disease-related mortality. Presently, there is a paucity of prognostic factors that can reliably identify patients with MEN1-related dpNETS who are at high risk of distant metastasis. In the current study, we aimed to establish novel circulating molecular protein signatures associated with disease progression. <br> Experimental Design: Mass spectrometry-based proteomic profiling was conducted on plasmas procured through an international collaboration between MD Anderson Cancer Center, the National Institutes of Health, and the University Medical Center Utrecht from a cohort of 56 patients with MEN1 [14 with distant metastasis dpNETs (cases) and 42 with either indolent dpNETs or no dpNETs (controls)]. Findings were compared to proteomic profiles generated from serially collected plasmas from a mouse model of Men1-pancreatic neuroendocrine tumors (Men1fl/flPdx1- CreTg) and control mice (Men1fl/fl). <br> Results: A total of 187 proteins were found to be elevated in MEN1 patients with distant metastasis compared to controls, including 9 proteins previously associated with pancreatic cancer and other neuronal proteins. Analyses of mouse plasmas revealed 196 proteins enriched for transcriptional targets of oncogenic MYCN, YAP1, POU5F1, and SMAD that were associated with disease progression in Men1fl/flPdx1-CreTg mice. Cross-species intersection revealed 19 proteins positively associated with disease progression in both human patients and in Men1fl/flPdx1-CreTg mice. <br> Conclusions: Our integrated analyses identified novel circulating protein markers associated with disease progression in MEN1-related dpNET.

研究目的：多发性内分泌腺瘤1型（multiple endocrine neoplasia type 1, MEN1）患者易罹患十二指肠胰神经内分泌肿瘤（duodenopancreatic neuroendocrine tumors, dpNETs），而转移性dpNET是该类患者疾病相关死亡的首要诱因。目前，尚缺乏可可靠甄别MEN1相关dpNETs伴远处转移高风险患者的预后标志物。本研究旨在构建与疾病进展相关的新型循环分子蛋白特征谱。<br>实验设计：本研究依托MD安德森癌症中心、美国国立卫生研究院（National Institutes of Health, NIH）与乌得勒支大学医学中心的国际合作平台，收集了56例MEN1患者的血浆样本[其中14例伴远处转移dpNETs（病例组），42例为惰性dpNETs或无dpNETs（对照组）]，并对其开展基于质谱的蛋白质组学分析。同时将分析结果与Men1胰腺神经内分泌肿瘤小鼠模型（Men1fl/flPdx1-CreTg）及对照小鼠（Men1fl/fl）的连续采集血浆所获得的蛋白质组学谱进行比对。<br>结果：与对照组相比，伴远处转移的MEN1患者中共鉴定出187种上调蛋白，其中包含9种既往与胰腺癌相关的蛋白及其他神经源性蛋白。小鼠血浆分析显示，196种富集于致癌MYCN、YAP1、POU5F1与SMAD转录靶点的蛋白与Men1fl/flPdx1-CreTg小鼠的疾病进展显著相关。跨物种交叉分析表明，在人类患者与Men1fl/flPdx1-CreTg小鼠中，共有19种蛋白与疾病进展呈正相关。<br>结论：本研究的整合分析鉴定出与MEN1相关dpNET疾病进展相关的新型循环蛋白标志物。