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

• Applicant: Privatdozent Dr. Jan Alexander Bornschein
• Subject Area: Gastroenterology
• Term: from 2012 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 234328784

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.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professorin Dr. Rebecca C. Fitzgerald