Abstract
Various studies have presented clinical or in vitro evidence linking bacteria to colorectal cancer, but these bacteria have not previously been concurrently quantified by qPCR in a single cohort. We quantify these bacteria (Fusobacterium spp., Streptococcus gallolyticus, Enterococcus faecalis, Enterotoxigenic Bacteroides fragilis (ETBF), Enteropathogenic Escherichia coli (EPEC), and afaC- or pks-positive E. coli) in paired tumour and normal tissue samples from 55 colorectal cancer patients. We further investigate the relationship between a) the presence and b) the level of colonisation of each bacterial species with site and stage of disease, age, gender, ethnicity and MSI-status. With the exception of S. gallolyticus, we detected all bacteria profiled here in both tumour and normal samples at varying frequencies. ETBF (FDR = 0.001 and 0.002 for normal and tumour samples) and afaC-positive E. coli (FDR = 0.03, normal samples) were significantly enriched in the colon compared to the rectum. ETBF (FDR = 0.04 and 0.002 for normal and tumour samples, respectively) and Fusobacterium spp. (FDR = 0.03 tumour samples) levels were significantly higher in late stage (III/IV) colorectal cancers. Fusobacterium was by far the most common bacteria detected, occurring in 82% and 81% of paired tumour and normal samples. Fusobacterium was also the only bacterium that was significantly higher in tumour compared to normal samples (p = 6e-5). We also identified significant associations between high-level colonisation by Fusobacterium and MSI-H (FDR = 0.05), age (FDR = 0.03) or pks-positive E. coli (FDR = 0.01). Furthermore, we exclusively identified atypical EPEC in our cohort, which has not been previously reported in association with colorectal cancer. By quantifying colorectal cancer-associated bacteria across a single cohort, we uncovered inter- and intra-individual patterns of colonization not previously recognized, as well as important associations with clinicopathological features, especially in the case of Fusobacterium and ETBF.
Highlights
A causal link between specific pathogens and numerous cancers has been firmly established
18 adenocarcinoma samples were selected from archival FFPE specimens that had previously been screened for microsatellite instability (MSI) by immunohistochemistry of the mismatch repair genes MLH1, MSH2 and MSH6; these patients were referred for MSI testing because colorectal cancer (CRC) was diagnosed under the age of 50 and/or in two or more first or second degree relatives with an HNPCC-related tumor, regardless of age
There are an increasing number of reports in the literature of specific bacteria enriched in CRC patients compared to healthy controls
Summary
A causal link between specific pathogens and numerous cancers has been firmly established. 16S rRNA profiling of colorectal cancer (CRC) paired tumour and normal biopsies has revealed that while only 3% of biopsy specimens from healthy controls contained any type of bacteria, ~90% of patients with adenomas or carcinomas had 103–105 bacteria in both malignant and macroscopically normal samples [13]. This clearly demonstrates the susceptibility of these patients to colonisation of the normally sterile colonic epithelium–– in existing tumour tissue, and in the surrounding macroscopically normal tissue, which may suggest a pre-existing risk to colonisation/infection
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