Identification of a diagnostic gene signature for the differentiation of the organ of origin for adeoncarcinomas at the esophagogastric junction (AEG).

鉴定食管胃交界处 (AEG) 腺癌起源器官分化的诊断基因特征。

• 批准号: 234328784
• 负责人: Privatdozent Dr. Jan Alexander Bornschein
• 金额: --
• 依托单位: Klinik und Poliklinik für Innere Medizin I
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/234328784?language=en
• 关键词: Identification; diagnostic; gene; signature; differentiation

In the current 7th edition of the TNM classification of the UICC adenocarcinomas at the esophagogastric junction (AEG) are regarded as one single entity resulting in uniform treatment algorithms. Organ of origin is either the distal esophagus or the proximal stomach. Epidemiological data point towards distinct mechanisms of carcinogenesis for each organ due to different biological risk factors that influence the prognosis of this malignant disease. Up to today, classification of the organ of origin is only done by certain morphological features like localisation of the man tumor mass or by surrogates like presence of Barretts metaplasia. A valid marker panel that allows the differentiation of tumors of esophageal or gastric origin, would not only facilitate epidemiological studies assessing the individual risk profile for AEG patients but could furthermore deliver the background for future approaches of individualized therapeutic algorithms.The introduction of tissue-based array-techniques enables the simultaneous analysis of the differential expression of a high number of different genes. For assessment and further evaluation of the by these techniques generated data computational, biostatistical methods a required. The systematic assessment of gene-gene-interactions in co-expression networks enabled the stratification into functional modules which are classified by functional and morphological criteria into clearly defined terms (gene ontology terms). Thus, it is not only possible to identify a specific gene signature that differentiates carcinomas by there organ of origin, but also to select these genes by functional criteria in order to identify candidate genes that are putative targets for therapeutic compounds. For the primary biostatistical analysis, it is not mandatory to generate de novo array data. One can also take access publicly available, already published array data sets.The proposed project comprises three main parts. Initially, publicly available data-sets are evaluated by biostatistical methods to demonstrate differential gene expression in adenocarcinomas of esophageal and gastric origin. Then, these data are used to generate a gene-signature that allows the differentiation of AEG by the site of origin via tissue-based array assessment. The second step includes the proof-of-principle confirmation of this gene-signature in a small subset of patients, before the main validation of the signature is performed in a large, independent cohort of patients with AEG.In a third step, the included target genes are further characterized concerning there molecular function in order to elucidate there putative role as therapeutic target. In an in vitro setting the modulatory effect of each gene on relevant signalling pathways will be assessed. This includes mainly regulatory pathways, responsible for cell proliferation and differentiation.

在目前的第7版UICC食管胃交界部腺癌(AEG)的TNM分类中，被认为是一个单一实体，从而导致了统一的治疗算法。起源于远端的食道或近端的胃。流行病学数据表明，由于影响这种恶性疾病预后的不同生物风险因素，每个器官的致癌机制不同。到目前为止，对起源器官的分类只能根据某些形态特征，如男性肿瘤肿块的定位或代用品，如Barretts化生的存在。一个有效的标记物小组，允许区分食道或胃源性肿瘤，不仅有助于流行病学研究评估AEG患者的个体风险概况，而且还可以为未来个体化治疗算法的方法提供背景。基于组织的阵列技术的引入使得能够同时分析大量不同基因的差异表达。为了评估和进一步评估由这些技术产生的数据，计算、生物统计方法是必需的。对共表达网络中基因-基因-相互作用的系统评估使其能够分层为功能模块，这些功能模块根据功能和形态标准被分类为明确定义的术语(基因本体论术语)。因此，不仅可以通过起源器官来识别区分癌症的特定基因标志，而且可以通过功能标准来选择这些基因，以便识别作为治疗化合物假定靶点的候选基因。对于初级生物统计分析，不强制生成从头开始的阵列数据。人们还可以获取公开可用的、已经发布的数组数据集。最初，公开可用的数据集通过生物统计学方法进行评估，以显示食管腺癌和胃腺癌的差异基因表达。然后，这些数据被用来生成基因签名，该签名允许通过基于组织的阵列评估来区分AEG的起源地。第二步包括在一小部分患者中对这一基因签名进行原则证明确认，然后在大量独立的AEG患者队列中执行签名的主要验证。在第三步中，进一步表征所包含的与分子功能有关的靶基因，以阐明作为治疗靶点的假定作用。在体外实验中，我们将评估每个基因对相关信号通路的调节作用。这主要包括调控通路，负责细胞的增殖和分化。