Fusobacterium Nucleatum-Induced Tumor Mutation Burden Predicts Poor Survival of Gastric Cancer Patients

SIMPLE SUMMARY: Gastric cancer is the fifth most common cancer in the world. An important risk factor in the development of alimentary tract cancers is the presence of pathogenic microbiota, such as Helicobacter pylori. We previously showed that sporadic infection of Fusobacterium nucleatum is associated with disease progression. Therefore, we examined the mutational landscape of F. nucleatum-positive, resected gastric cancer tissues using the Illumina TruSight Oncology 500 comprehensive panel to identify small nucleotide variants, small insertions and deletions, and unstable microsatellite sites. We identified a number of recurrent genetic aberrations, especially activating mutations of ERBB2, ERBB3, and PIK3CA and disrupted TP53. We found that the combination of F. nucleatum infection and high tumor mutational burden was a strong predictor of poor prognosis. Thus, F. nucleatum infection is correlated with increased accumulation of mutations and progression of gastric cancer, and these factors may be useful in the prognosis of this disease. ABSTRACT: Co-infection of Helicobacter pylori and Fusobacterium nucleatum is a microbial biomarker for poor prognosis of gastric cancer patients. Fusobacterium nucleatum is associated with microsatellite instability and the accumulation of mutations in colorectal cancer. Here, we investigated the mutation landscape of Fusobacterium nucleatum-positive resected gastric cancer tissues using Illumina TruSight Oncology 500 comprehensive panel. Sequencing data were processed to identify the small nucleotide variants, small insertions and deletions, and unstable microsatellite sites. The bioinformatic algorithm also calculated copy number gains of preselected genes and tumor mutation burden. The recurrent genetic aberrations were identified in this study cohort. For gene amplification events, ERBB2, cell cycle regulators, and specific FGF ligands and receptors were the most frequently amplified genes. Pathogenic activation mutations of ERBB2, ERBB3, and PIK3CA, as well as loss-of-function of TP53, were identified in multiple patients. Furthermore, Fusobacterium nucleatum infection is positively correlated with a higher tumor mutation burden. Survival analysis showed that the combination of Fusobacterium nucleatum infection and high tumor mutation burden formed an extremely effective biomarker to predict poor prognosis. Our results indicated that the ERBB2-PIK3-AKT-mTOR pathway is frequently activated in gastric cancer and that Fusobacterium nucleatum and high mutation burden are strong biomarkers of poor prognosis for gastric cancer patients.