Integrated miRNAs profiling, DNA methylation, and RNA expression in gastroenteropancreatic neuroendocrine neoplasias [methylation]. Integrated miRNAs profiling, DNA methylation, and RNA expression in gastroenteropancreatic neuroendocrine neoplasias [methylation]

Background: Neuroendocrine neoplasms (NENs) are mutationally quiet, 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. Material and Methods: In total, 84 cancer-related miRNAs were analyzed in 84 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. Results: 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. Conclusion: 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 patient. Overall design: This study includes 85 paired tumor and non-tumor samples from 85 lung and GEP NEN patients. miRNAs profiling was performed in 84 patients, DNA methylation in 30 patients and RNA expressión in 63 patients. This dataset includes the DNA methylation data.

Background: 神经内分泌肿瘤（Neuroendocrine neoplasms, NENs）的突变特征相对静默，其发生与进展由表观遗传机制驱动。本研究旨在全面解析NEN的微小RNA（microRNA, miRNA）表达谱，并探索其下游靶基因及表观遗传调控机制。
Material and Methods: 本研究共分析了84例源自肺及胃肠胰（gastroenteropancreatic, GEP）来源的NEN样本中的84种癌相关miRNA，并通过单因素与多因素模型评估其预后价值。针对63例样本开展转录组学检测、30例样本开展甲基化组学检测，以预测miRNA靶基因、相关信号通路及调控性CpG位点。研究结果于癌症基因组图谱（The Cancer Genome Atlas, TCGA）队列及NEN细胞系中得到验证。
Results: 本研究鉴定出由8个miRNA组成的预后特征，可将患者分为三个预后亚组（5年生存率分别为80%、66%与36%）。该8-miRNA基因特征的表达水平与71个靶基因显著相关，这些靶基因参与PI3K-Akt及TNFα-NF-κB信号通路。其中28个靶基因与患者生存密切相关，并经计算机分析与体外实验验证。最终，本研究还鉴定出5个参与调控这8个miRNA表观遗传修饰的CpG位点。
Conclusion: 简言之，本研究鉴定出可预测肺及胃肠胰来源NEN患者生存情况的8-miRNA预后特征，并阐明了调控NEN患者预后的相关基因及表观遗传机制。
Overall design: 本研究共纳入85例肺及胃肠胰NEN患者的85对肿瘤与配对正常组织样本。其中84例患者接受miRNA表达谱检测，30例患者接受DNA甲基化检测，63例患者接受RNA表达检测。本数据集包含DNA甲基化数据。