Identification of risk genes for gastric cancer

• Applicants: Privatdozent Dr. Michael Knapp; Professor Dr. Florian Lordick; Professor Dr. Johannes Schumacher; Professor Dr. Marino Venerito
• Subject Area: Human Genetics
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 275016020

Gastric adenocarcinoma represents the fifth most common cancer in Germany. In most cases the etiology is multifactorial and, in addition to environmental influences, genetic factors play a role in the disease development. Genetic risk factors can be identified through genome-wide association studies (GWAS) using large case-control cohorts. Accordingly, the number of identified risk genes clearly depends on the size of GWAS samples. The risk genes can be further used for system biology studies in order to identify cellular networks of interacting proteins in which GWAS risk genes are enriched. The applicants have established an international research network called STAR (http://star-project.md/) with the purpose of deciphering the genetic and cell biological causes of GC. Therefore, a biobank has been set up with GC patients of European descent.The aim of the proposed project is the identification of genetic risk variants for GC. [A] Molecular genetic work: (i) Using the biobank from STAR (4,000 patients) we will perform a stage-1 GWAS and will identify the first genetic risk variants for GC in the European population. (ii) In addition, a trans-ancestry meta-analysis using GC GWAS data from two Asian studies will be carried out (8,000 patients). This will enable the identification of trans-ethnic GC risk variants. (iii) Furthermore, a meta-analysis incorporating GWAS data from a sample with adenocarcinoma of the gastroesophageal junction will be done (7,000 patients). This should lead to the identification of common genetic risk variants for adenocarcinomas of the upper gastrointestinal tract. (iv) The GWAS data will also be compared to GWAS results for H. pylori infection, which will help us to identify genetic risk variants for H. pylori infection and GC. The most associated genetic risk variants and corresponding genes will then be studied on the bioinformatic level. Thus, we will gain first insights into pathophysiologically relevant cellular networks underlying GC. With phenotypic data of patients and GWAS variants, we will finally perform genotype-phenotype and genotype-environmental analyses, which will define biologically-based GC subtypes. [B] Recruitment work: In parallel, we will extend the biobank of STAR. Besides DNA samples, we anticipate also to collect tissue samples obtained from different parts of the stomach during diagnostic gastroscopy or surgery. The biobank will be used for a stage-2 GWAS and cell biological studies, which both will be subject of future applications.The identified risk variants and genes will make an important contribution in the elucidation of the pathophysiology of GC. This will lead to the identification of new therapeutic targets and biomarkers for the diagnosis and prevention.

• DFG Programme: Research Grants