神经内分泌肿瘤(NENs)的突变很少(每Mb的突变数很低)，其发展和进展主要由表观遗传机制驱动。我们旨在全面表征NENs的微小RNA(miRNA)谱，并探索下游靶点和它们的表观遗传调控。共分析了来自肺部和胃肠胰(GEP)起源的85个NEN样本中的84种癌症相关miRNA，并通过单变量和多变量模型评估其预后价值。进行了转录组学(N=63)和甲基组学(N=30)以预测miRNA靶基因、信号通路和调节CpG位点。结果在癌症基因组图谱(TCGA)的队列和NEN细胞系中得到了验证。我们确定了一个包含八个miRNA的标志，将患者分为三个预后组(5年生存率为80%、66%和36%)。八种miRNA基因标志的表达与PI3K-Akt和TNFα-NF-kB信号通路中的71个靶基因相关。其中28个与生存相关，并在体内和体外进行了验证。最后，我们确定了五个与这八个miRNA的表观遗传调控有关的CpG位点。简而言之，我们确定了一个8-miRNA标志，能够预测GEP和肺NEN患者的生存率，并确定了驱动患者预后的基因和调节机制。本文受版权保护。保留所有权利。

Neuroendocrine neoplasms (NENs) are mutationally quiet (low number of mutations/Mb), and epigenetic mechanisms drive their development and progression. We aim to comprehensively characterize the microRNA (miRNA) profile of NENs, and explore downstream targets and their epigenetic modulation. In total, 84 cancer-related miRNAs were analyzed in 85 NEN samples from lung and gastroenteropancreatic (GEP) origin, and their prognostic value was evaluated by univariate and multivariate models. Transcriptomics (N=63) and methylomics (N=30) were performed to predict miRNA target genes, signaling pathways and regulatory CpG sites. Findings were validated in The Cancer Genome Atlas (TCGA) cohorts and in NEN cell lines. We identified a signature of eight miRNAs that stratified patients in three prognostic groups (5-year survival of 80%, 66% and 36%). Expression of the eight-miRNA gene signature correlated with 71 target genes involved in PI3K-Akt and TNFα-NF-kB signaling. Of these, 28 were associated with survival and validated in silico and in vitro. Finally, we identified five CpG sites involved in the epigenetic regulation of these eight miRNAs. In brief, we identified an 8-miRNA signature able to predict survival of patients with GEP and lung NENs, and identified genes and regulatory mechanisms driving prognosis in NEN patients.This article is protected by copyright. All rights reserved.