癌、炎外周血CD4T细胞免疫功能损伤特征及个体化癌、炎鉴别诊断标志识别

As the proportions of myeloid and lymphoid cells increased and decreased respectively in peripheral whole blood of both cancer and inflammation, the differential mRNA signals observed in peripheral whole blood samples from cancer patients and from inflammatory patients compared to healthy controls were similar, all mainly reflecting the expression differences between myeloid cells and lymphoid cells. Therefore, it may be difficult for whole-blood gene expression signatures to distinguish cancer from inflammation. By analysing expression profiles of CD4 T cells for multiple cancer/inflammation, we found that the abnormal gene expression patterns and different dysfunctions exist in cancer and inflammation immune cells. Here, we will first show that the relative expression orderings of gene pairs are extensively stable in normal blood CD4 T cells, reflecting the coordinated gene expression in normal cells. Then, we will develop methods for identifying disease related pathways whose coordination of gene expression is significantly disturbed. We will apply the proposed methods to analyse the common difference of functional defect in cancer and information CD4 T cells and investigate whether there is a cancer specific signature that could discriminate cancer from inflammation (such as gastric cancer and gastritis). Finally, we will develop methods to identify discriminable biomarkers between cancer and inflammation based on personalized pathway analysis. Results of this research would have extensive theoretical and practical values for the investigation of functional defect characteristics in cancer immune peripheral blood cells and for the identification of biomarkers for diagnosis of cancer and inflammation.

由于癌、炎患者的外周血中都存在髓系细胞增加淋巴系细胞减少的现象，它们相对正常对照的基因差异表达信号高度相似，都主要反映髓系和淋巴系细胞间的差异，难以应用于鉴别癌、炎两类疾病。在预实验中，通过分析多种癌、炎疾病的外周血CD4T细胞等淋巴细胞的基因表达谱，我们发现癌、炎外周血免疫细胞存在完全不同的基因异常表达模式与功能特征。在本课题中，我们拟揭示在正常外周血CD4T细胞中基因表达的相对大小秩序关系存在广泛的稳定性（反映正常细胞中基因表达的协调关系），据此设计算法识别基因表达协调关系显著异常的疾病相关通路，应用于分析癌、炎外周血CD4T细胞的功能损伤共性差异特征及是否存在癌、炎（如胃癌与胃炎）特异的特征；最后，发展基于个体化通路分析的识别癌、炎鉴别标志的方法，应用于识别胃癌与胃炎的个体化鉴别标志。本课题的研究内容对探究肿瘤外周血免疫细胞功能损伤特征及识别癌、炎鉴别的分子标志兼具理论与应用价值。

炎癌转化是癌症研究的一个热点问题，也是一个难点问题。本项目从外周血CD4+T细胞出发分别从群体和个体的角度出发分析并比较了炎、癌外周血CD4+T细胞免疫功能损伤特征，并在此基础上识别炎、癌潜在预警标志。主要结果包括：（1）在群体上以基因间相对表达关系为基础识别疾病相关的异常改变通路，并分析癌、炎外周血CD4+ T细胞上异常改变的通路与疾病发生发展关系。 （2）以正常外周血CD4+T细胞作为研究对象，证实了不同个体CD4+T细胞中存在基因表达相对秩序关系高度稳定的基因对，并以此为基础上开发了识别个体化差异差异基因的算法。（3）基于（2）开发的算法，分别从群体水平和个体水平层面分析了癌、炎外周血CD4+ T细胞的免疫功能损伤特征，寻找潜在癌炎预警标记；（4）由于CD4+T细胞提取困难不易临床应用的特点，进一步提出从外周全血或外周血单核细胞中识别单个细胞的表达特征改变的方法，并用于癌、炎的预警标志的寻找。本项目提出的基于基因间相对表达相对秩序关系识别疾病相关的异常的通路和识别单个疾病样本中的个体化差异表达基因的方法，为通过血液材料分析炎癌关系提供了基础。