Intratumoural pks+ Escherichia coli is associated with risk of metachronous colorectal cancer and adenoma development in people with Lynch syndrome

Background The adverse gut microbiome may underlie the variability in risks of colorectal cancer (CRC) and metachronous CRC in people with Lynch syndrome (LS). The role of pks+/- Escherichia coli (pks+/- E. coli), Enterotoxigenic Bacteroides fragilis (ETBF), and Fusobacterium nucleatum (Fn) in CRCs and adenomas in people with LS is unknown. Methods A total of 358 LS cases, including 386 CRCs, 90 adenomas, 195 normal colonic mucosa DNA from the Australasian Colon Cancer Family Registry were tested using multiplex TaqMan qPCR. Logistic regression was used to compare the intratumoural prevalence of each bacteria in Lynch CRCs with 1336 sporadic CRCs. Cox proportional-hazards regression estimated the associations of each bacteria with the risk of metachronous CRC and neoplasia. Findings Pks+ E. coli (odds ratio [95% confidence interval] = 1.60 [1.08-2.35], P = 0.017), pks- E. coli (3.87 [2.58-5.80], P < 0.001) and Fn (19.47 [13.32-28.87], P < 0.001) were significantly enriched in LS CRCs when compared with sporadic CRCs. Pks+ E. coli in the initial CRC was associated with an increased risk of metachronous CRC (hazard ratio [95% confidence interval] = 2.32 [1.29-4.17], P = 0.005) and metachronous colorectal neoplasia (1.51 [1.02-2.23], P = 0.040) when compared with CRCs without pks+ E. coli. Interpretation Pks+ E. coli, pks- E. coli, and Fn are enriched within LS CRCs, suggesting possible roles in CRC development in LS. Having intratumoural pks+ E. coli is associated with increased risk of metachronous CRC, suggesting that, if validated, people with LS might benefit from pks+ E. coli screening and eradication. Funding This work was funded by an NHMRC Investigator grant (GNT1194896) and a Cancer Australia/Cancer Council NSW co-funded grant (GNT2012914). Copyright (c) 2025 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).