肿瘤患者外周血中的mRNA、miRNA、DNA甲基化特征模式及其与肿瘤微环境的调控网络

Mainly based on the various omics data for the non-small cell lung cancer（NSCLC）and chronic obstructive pulmonary disease(COPD), also taking the omics data for colorectal carcinoma and chronic ulcerative colitis and other tumors for comparision analysis, this project focuses on revealing the stable mRNA, miRNA and DNA methylation alternation patterns characterizing the peripheral whole blood of tumor patients in response to cancer damage, analyzing the difference between tumor patients and patients with inflammation in the molecular profiles of peripheral whole blood, constructing the network for the peripheral blood expression alternation pattern rugulated by the cytokines of the tumor microenvironment, studying the correlation between this network and aging genes, and extracting diagnosis tumor markers in the peripheral whole blood. We will produce the mRNA, miRNA and DNA methylation profiles of the peripheral blood for a set of NSCLC and COPD patients to further analyze the regulation mechnism of the altered gene expression in the tumor peripheral whole blood and to validate the tumor markers extracted from previously accumulated data sources. In order to greatly expand the range and the efficiency of the usage of omics data derived from different sources, we will develop robust gene rank based methods to identify differentially expressed genes between different disease states and to find reproducible diagnostic markers. For tackling the difficult problem of extracting tissue samples for human disease study, the results of this project could show lights on the investigation of the inflammation-cancer relationship and the mechanism of drug effect and disease prognosis via dynamic sampling from peripheral whole blood of tumor patients.

本课题以各类组学数据丰富的非小细胞肺癌与慢性阻塞性肺病为研究对象，辅以结肠癌与结肠炎等对比分析，论证肿瘤患者外周血中有稳定的癌损伤应答的mRNA、miRNA与DNA甲基化特征谱，并分析其与相应炎症患者的外周血特征谱的差异；建立肿瘤组织微环境中细胞因子调控外周血基因表达的网络模型并分析其与衰老相关基因的关联；据此提取肿瘤外周血诊断标志。拟采集一组结肺癌、肺炎患者全血中的mRNA、miRNA及DNA甲基化谱3维数据，进一步分析外周血基因表达调控机制并验证肿瘤标志。为扩展利用不同来源的数据比较相关疾病的范围，我们将利用基因表达水平或DNA甲基化水平在各样本内部的相对秩序关系，发展在跨实验室数据间识别差异基因及可重复的诊断标志的稳健方法。对于肿瘤研究中普遍面临的侵袭性组织取样受限难题，本课题的研究结果也可以为通过在外周血中采用多时点采样动态分析炎癌转化关系及药效预后机制等提供依据。

项目按计划完成了肿瘤患者外周血中的mRNA、miRNA和DNA甲基化特征模式分析，并分析了其与相应炎症患者的外周血特征谱的差异。包括：（1）相似的外周血白细胞亚群变化决定了肿瘤及炎症性疾病相似的血源性DNA甲基化改变。（2）在肺癌和肺炎疾病样本中观察到血液中具有相似的mRNA差异改变，主要反映了疾病状态下外周血中骨髓细胞和淋巴细胞比例变化。因此，通过比较癌症和正常样本差异的策略并不能为识别可区分癌症和炎症相关疾病的生物标志提供线索。（3）考虑到外周血组分的改变可以反映免疫微环境的免疫应答，我们证实了对外周血T细胞增殖过程中起关键作用的抗原提呈水平低同样和患者的差生存显著相关。表明能够反映肿瘤微环境的抗原提呈水平的外周T细胞的比例可能会成为非小细胞肺癌病人的预后标志物。（4）阿尔茨海默病（AD）是一种常见的和年龄相关的神经退行性疾病。我们发现，与年龄和AD都相关的外周全血DNA甲基化的改变能作为识别AD的生物标志物。.本项目已经发表论文32篇，其中SCI收录的31篇，还有两篇会议文章。对于肿瘤研究中普遍面临的侵袭性组织取样受限难题，本项目的研究成果为通过在外周血中采用多时间点采样动态分析炎癌转化关系及药效预后机制等提供了基础。

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