title: Bacterially-Associated Transcriptional Remodelling in a Distinct Genomic Subtype of Colorectal Cancer Provides a Plausible Molecular Basis for Disease Development.
abstract: The relevance of specific microbial colonisation to colorectal cancer (CRC) disease pathogenesis is increasingly recognised, but our understanding of possible underlying molecular mechanisms that may link colonisation to disease in vivo remains limited. Here, we investigate the relationships between the most commonly studied CRC-associated bacteria (Enterotoxigenic Bacteroides fragilis, pks+ Escherichia coli, Fusobacterium spp., afaC+ E. coli, Enterococcus faecalis & Enteropathogenic E. coli) and altered transcriptomic and methylation profiles of CRC patients, in order to gain insight into the potential contribution of these bacteria in the aetiopathogenesis of CRC. We show that colonisation by E. faecalis and high levels of Fusobacterium is associated with a specific transcriptomic subtype of CRC that is characterised by CpG island methylation, microsatellite instability and a significant increase in inflammatory and DNA damage pathways. Analysis of the significant, bacterially-associated changes in host gene expression, both at the level of individual genes as well as pathways, revealed a transcriptional remodeling that provides a plausible mechanistic link between specific bacterial colonisation and colorectal cancer disease development and progression in this subtype; these included upregulation of REG3A, REG1A and REG1P in the case of high-level colonization by Fusobacterium, and CXCL10 and BMI1 in the case of colonisation by E. faecalis. The enrichment of both E. faecalis and Fusobacterium in this CRC subtype suggests that polymicrobial colonisation of the colonic epithelium may well be an important aspect of colonic tumourigenesis.
authors.affiliation: Institute of Infectious Disease and Molecular Medicine & Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Katie S
authors.identifier: http://orcid.org/0000-0002-7801-1063
authors.initials: KS
authors.lastname: Lennard
authors.affiliation: Institute of Infectious Disease and Molecular Medicine & Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Ryan W
authors.initials: RW
authors.lastname: Goosen
authors.affiliation: Institute of Infectious Disease and Molecular Medicine & Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Jonathan M
authors.identifier: http://orcid.org/0000-0001-8988-9595
authors.initials: JM
authors.lastname: Blackburn
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D001441:Bacteroides fragilis / Q000472:pathogenicity; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000235:genetics; D015169:Colony Count, Microbial; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000382:microbiology* / Q000473:pathology; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D013293:Enterococcus faecalis / Q000472:pathogenicity; D054308:Enteropathogenic Escherichia coli / Q000472:pathogenicity; D005260:Female; D005673:Fusobacterium / Q000472:pathogenicity; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D007413:Intestinal Mucosa / Q000382:microbiology / Q000473:pathology; D037181:Lectins, C-Type / Q000096:biosynthesis / Q000235:genetics; D051847:Lithostathine / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000073718:Pancreatitis-Associated Proteins; D063150:Polycomb Repressive Complex 1 / Q000096:biosynthesis / Q000235:genetics; D059467:Transcriptome / Q000235:genetics*
chemical_list: D000951:Antigens, Neoplasm; C069077:BMI1 protein, human; D014408:Biomarkers, Tumor; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D037181:Lectins, C-Type; D051847:Lithostathine; D000073718:Pancreatitis-Associated Proteins; C497617:REG1A protein, human; C000612141:REG3A protein, human; D063150:Polycomb Repressive Complex 1