Identification of rare and penetrant germline mutations for gastric cancer

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As with other common cancers gastric cancer is multifactorial or monogenic in origin. However, the only monogenic form of gastric cancer identified to date is Hereditary Diffuse Gastric Cancer (HDGC), which is caused by highly penetrant mutations in the gene CDH1 (E-cadherin) and restricted to patients with a histopathologically diffuse type of gastric cancer according to the Lauren classification. In recent years, further candidate genes for monogenic forms of gastric cancer have been identified via Whole-Exome Sequencing (WES) approaches. However, in all these studies only CDH1-negative HDGC patients were analyzed and/or the Next Generation Sequencing (NGS) was limited to predefined groups of genes of known oncological relevance.Through work conducted over the past years, the applicants have established the prerequisites for the proposed research and have established the international research network STAR (http://star-project.md/). The aim of STAR is to elucidate the genetic and cell-biological causes of gastric cancer. The STAR Biobank contains biomaterials from > 5,100 European gastric cancer patients, and is an optimal resource for the identification of the entire spectrum of common and rare gene variants and mutations underlying gastric cancer. The applicants now hypothesize that rare, and as yet unidentified, pathogenic gene mutations contribute to gastric cancer in a monogenic manner. The identification of those mutations is of major clinical relevance. Due to their high penetrance, such monogenic forms would have implications for the clinical management of both affected patients and healthy carriers. In order to identify rare and penetrant germline mutations, samples of 300 gastric cancer patients with an extreme early onset (< 45 years) will be subjected to WES. The selection of this cohort was based on a power analysis and the fact, that early age at onset cases are highly enriched among monogenic cancer types. In all patients the presence of CDH1 mutations has been excluded. The WES will be carried out at the West German Genome Center using most modern NGS technology. The applicants will then conduct the bioinformatics work-up using state-of-the-art methods, incl. modern Burden tests in order to prioritize genes and mutations for subsequent analysis. Finally, the applicants will confirm all identified mutations using Sanger sequencing. The generated data will be further analyzed in follow-up projects. The identified cancer genes will be investigated in the entire STAR gastric cancer cohort, which is detailed clinically characterized. These analyses will help to determine the contribution of the identified cancer genes to gastric cancer in detail, and whether this is dependent on the age of disease onset. In addition, first functional studies of new monogenic disease genes will be carried out in order to characterize the respective cellular dysfunction.