The Gastric Cancer Microbiome

Helicobacter Pylori infection is recognised as an established risk factor for developing gastric cancer, although only 3% of infected patients develop gastric cancer. Previous sequencing-based studies have indicated changes in the gastric mucosal microbiota along the carcinogenic cascade. Gastric cancer is characterised by significant heterogeneity with respect to anatomical, histopathological, and molecular features, in addition to epidemiological heterogeneity. The relationship between these clinical and pathological factors and the intratumoural gastric cancer microbiome has not previously been systematically examined. Furthermore, current investigations of the gastric cancer microbiome are predominantly culture-independent studies, limiting interpretations to associations alone.

The work presented within this thesis investigated the intratumoural microbiome of established gastric cancer through use of existing databases and prospectively collected gastric cancer tumour tissue.

Using two large sequencing databases, the 100,000 Genomes Project and the Cancer Genome Atlas, the gastric cancer microbiome was characterised and the relationships between the microbiome and clinicopathological variables were explored. Microsatellite instability, low pathological depth of invasion, intestinal histological phenotype, and non-Asian origin were all associated with increased microbial abundance and alpha diversity.

Prospectively collected gastric cancer samples were used to investigate methods of characterising the microbiome through culture-dependent and culture-independent methods. Bacterial isolations were performed from five gastric tumour samples, resulting in the greatest number of bacterial genera isolated from any gastric cancer study.

A bioreactor model was developed, capable of supporting gastric cancer microbiota in continuous culture. This model was used to explore the impact of pH on the intratumoural gastric cancer community, demonstrating an increase in lactic acid bacilli at lower pH. Measured metabolites produced by the microbial communities differed to what has previously been observed by the production of colonic microbiota.

The findings presented in this thesis indicate that the gastric cancer microbiota differs according to clinicopathological factors which should be accounted for in future research. Different methodological approaches were explored and refined; culture-dependent and culture-independent methods are complimentary and should be used to further progress the understanding of the role of the microbiome in gastric cancer.