RT Journal Article SR Electronic T1 Patients with mesenchymal tumours and high Fusobacteriales prevalence have worse prognosis in colorectal cancer (CRC) JF Gut JO Gut FD BMJ Publishing Group Ltd and British Society of Gastroenterology SP 1600 OP 1612 DO 10.1136/gutjnl-2021-325193 VO 71 IS 8 A1 Salvucci, Manuela A1 Crawford, Nyree A1 Stott, Katie A1 Bullman, Susan A1 Longley, Daniel B A1 Prehn, Jochen H M YR 2022 UL http://gut.bmj.com/content/71/8/1600.abstract AB Objectives Transcriptomic-based subtyping, consensus molecular subtyping (CMS) and colorectal cancer intrinsic subtyping (CRIS) identify a patient subpopulation with mesenchymal traits (CMS4/CRIS-B) and poorer outcome. Here, we investigated the relationship between prevalence of Fusobacterium nucleatum (Fn) and Fusobacteriales, CMS/CRIS subtyping, cell type composition, immune infiltrates and host contexture to refine patient stratification and to identify druggable context-specific vulnerabilities.Design We coupled cell culture experiments with characterisation of Fn/Fusobacteriales prevalence and host biology/microenviroment in tumours from two independent colorectal cancer patient cohorts (Taxonomy: n=140, colon and rectal cases of The Cancer Genome Atlas (TCGA-COAD-READ) cohort: n=605).Results In vitro, Fn infection induced inflammation via nuclear factor kappa-light-chain-enhancer of activated B cells/tumour necrosis factor alpha in HCT116 and HT29 cancer cell lines. In patients, high Fn/Fusobacteriales were found in CMS1, microsatellite unstable () tumours, with infiltration of M1 macrophages, reduced M2 macrophages, and high interleukin (IL)-6/IL-8/IL-1β signalling. Analysis of the Taxonomy cohort suggested that Fn was prognostic for CMS4/CRIS-B patients, despite having lower Fn load than CMS1 patients. In the TCGA-COAD-READ cohort, we likewise identified a differential association between Fusobacteriales relative abundance and outcome when stratifying patients in mesenchymal (either CMS4 and/or CRIS-B) versus non-mesenchymal (neither CMS4 nor CRIS-B). Patients with mesenchymal tumours and high Fusobacteriales had approximately twofold higher risk of worse outcome. These associations were null in non-mesenchymal patients. Modelling the three-way association between Fusobacteriales prevalence, molecular subtyping and host contexture with logistic models with an interaction term disentangled the pathogen–host signalling relationship and identified aberrations (including NOTCH, CSF1-3 and IL-6/IL-8) as candidate targets.Conclusion This study identifies CMS4/CRIS-B patients with high Fn/Fusobacteriales prevalence as a high-risk subpopulation that may benefit from therapeutics targeting mesenchymal biology.Data are available in a public, open access repository. Processing and analysis code along with bacterium estimates with corresponding clinical and molecular datasets for the Taxonomy and TCGA-COAD-READ cohorts included in this study are publicly available and archived at Zenodo (https://10.5281/zenodo.4019142). Bacterium estimates include Fusobacterium nucleatum load (Taxonomy cohort) and Fusobacteriales relative abundance, along with higher resolution estimates at genus, family and species taxonomic ranks, (TCGA-COAD-READ cohort).