Mutations in R-Loop metabolism genes as drivers of gastric carcinogenesis

Principal Investigators

Fellow

Keywords

Gastrointestinal cancer, bacterially induced carcinogenesis, Chromatin Immunoprecipitation, Cancer Genomics

Summary

Over 80% of gastric cancer cases are believed to arise in settings of chronic inflammation that is driven by persistent infection with the bacterial pathogen Helicobacter pylori. Malignant transformation progresses through a series of precursor lesions that manifest histologically as intestinal metaplasia, epithelial hyperplasia and dysplasia. Data from mouse models suggest that the development of epithelial hyperplasia is favored by T-helper-1 (Th1)-driven immune responses to the bacteria. Hyperproliferating epithelial cells in turn become susceptible to replication stress, which promotes DNA damage, the accumulation of mutations and (pre-)malignant transformation. With the funding provided by this grant, we have hired a bioinformatician, Dr. Peter Leary, who dedicates his time to the analysis of multi-omics datasets, both publicly available and generated in house, aiming to detect a signature of H. pylori infection in gastric cancer. To this end, we have annotated publicly available Cancer Genome Atlas (TCGA) gastric cancer data with the H. pylori status of the patient based on the presence of H. pylori DNA or RNA in non-human nucleic acid sequences in tumor versus adjacent non-tumor gastric tissue. H. pylori-positive and -negative cases will be compared with respect to their transcriptomes, mutational landscape and genetic subtype. The presence of non-H. pylori bacterial sequences will be assessed as well. Dr. Leary will additionally mine RNA-sequencing and chromatin immunoprecipitation datasets generated with antibodies against DNA damage markers such as gH2AX to determine sites of DNA damage in H. pylori-infected gastric epithelial cells and will integrate these data with mutational signatures of gastric cancer. In summary, we expect that the combined approaches will reveal how bacterial and genetic determinants act in concert to promote the early stages of malignant transformation in the stomach.