Abstract

Purpose

Duodenopancreatic neuroendocrine tumors (dpNETs) frequently occur in patients with Multiple Endocrine Neoplasia Type 1 (MEN1), and metastatic dpNET is the primary cause of disease-related mortality. There is a need for biomarkers that can identify patients with MEN1-related dpNETs that are at high risk of developing distant metastasis. Polyamines have tumor promoting roles in several cancer types. We hypothesized that MEN1-dpNET-related disease progression is associated with elevated levels of circulating polyamines.

Experimental Design

Through an international collaboration between MD Anderson Cancer Center (MDACC), the National Institutes of Health (NIH), and the University Medical Center Utrecht (UMCU), plasma polyamine levels were assessed using mass spectrometry in a total of 84 patients with MEN1 (20 with distant metastatic dpNETs (cases) and 64 with either indolent dpNETs or no dpNETs (controls)). A mouse model of MEN1-pNET, Men1 ^fl/flPdx1-Cre ^Tg, was used to test time-dependent changes in plasma polyamines associated with disease progression.

Results

A 3-marker plasma polyamine signature (3MP: n-acetylputrescine, acetylspermidine, and diacetylspermidine) distinguished patients with metastatic dpNETs from controls in an initial set of plasmas from the three participating centers. The fixed 3MP yielded an AUC of 0.84 (95% CI: 0.62-1.00) with 66.7% sensitivity at 95% specificity for distinguishing cases from controls in an independent test set from MDACC. In Men1 ^fl/flPdx1-Cre ^Tg mice, the 3MP was elevated early and remained high during disease progression.

Conclusions

Our findings provide a basis for prospective testing of blood-based polyamines as a potential means for monitoring patients with MEN1 for harboring or developing aggressive disease.

中文翻译：

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与 MEN1 十二指肠神经内分泌肿瘤进展相关的基于血液的多胺特征

摘要

目的

十二指肠胰腺神经内分泌肿瘤 (dpNETs) 经常发生在多发性内分泌肿瘤 1 型 (MEN1) 患者中，转移性 dpNET 是疾病相关死亡的主要原因。需要能够识别具有发生远处转移高风险的 MEN1 相关 dpNET 患者的生物标志物。多胺在几种癌症类型中具有促进肿瘤的作用。我们假设 MEN1-dpNET 相关疾病进展与循环多胺水平升高有关。

实验设计

通过 MD 安德森癌症中心 (MDACC)、美国国立卫生研究院 (NIH) 和乌得勒支大学医学中心 (UMCU) 之间的国际合作，使用质谱法评估了总共 84 名 MEN1 患者的血浆多胺水平 (20有远处转移性 dpNETs（病例）和 64 个有惰性 dpNETs 或没有 dpNETs（对照））。MEN1-pNET 小鼠模型Men1 ^fl/fl Pdx1-Cre ^Tg用于测试与疾病进展相关的血浆多胺的时间依赖性变化。

结果

在三个参与中心的初始血浆组中，3 标记血浆多胺特征（3MP：n-乙酰腐胺、乙酰亚精胺和二乙酰亚精胺）将转移性 dpNET 患者与对照组区分开来。固定的 3MP 产生的 AUC 为 0.84（95% CI：0.62-1.00），灵敏度为 66.7%，特异性为 95%，用于在来自 MDACC 的独立测试集中区分病例与对照。在Men1 ^fl/fl Pdx1-Cre ^Tg小鼠中，3MP 早期升高并在疾病进展期间保持高水平。

结论

我们的研究结果为前瞻性测试基于血液的多胺作为监测 MEN1 患者是否存在或发展为侵袭性疾病的潜在手段提供了基础。