@article{246672ce6c5d44f786fbf1d512f89aab,
title = "Intratumoral presence of the genotoxic gut bacteria pks + E. coli, Enterotoxigenic Bacteroides fragilis, and Fusobacterium nucleatum and their association with clinicopathological and molecular features of colorectal cancer",
abstract = "Background: This study aimed to investigate clinicopathological and molecular tumour features associated with intratumoral pks+Escherichia coli (pks+E.coli+), pks+E.coli- (non-E.coli bacteria harbouring the pks island), Enterotoxigenic Bacteroides fragilis (ETBF) and Fusobacterium nucleatum (F. nucleatum). Methods: We screened 1697 tumour-derived DNA samples from the Australasian Colorectal Cancer Family Registry, Melbourne Collaborative Cohort Study and the ANGELS study using targeted PCR. Results: Pks+E.coli+ was associated with male sex (P < 0.01) and APC:c.835-8 A > G somatic mutation (P = 0.03). The association between pks+E.coli+ and APC:c.835-8 A > G was specific to early-onset CRCs (diagnosed<45years, P = 0.02). The APC:c.835-A > G was not associated with pks+E.coli- (P = 0.36). F. nucleatum was associated with DNA mismatch repair deficiency (MMRd), BRAF:c.1799T>A p.V600E mutation, CpG island methylator phenotype, proximal tumour location, and high levels of tumour infiltrating lymphocytes (Ps < 0.01). In the stratified analysis by MMRd subgroups, F. nucleatum was associated with Lynch syndrome, MLH1 methylated and double MMR somatic mutated MMRd subgroups (Ps < 0.01). Conclusion: Intratumoral pks+E.coli+ but not pks+E.coli- are associated with CRCs harbouring the APC:c.835-8 A > G somatic mutation, suggesting that this mutation is specifically related to DNA damage from colibactin-producing E.coli exposures. F. nucleatum was associated with both hereditary and sporadic MMRd subtypes, suggesting the MMRd tumour microenvironment is important for F. nucleatum colonisation irrespective of its cause.",
author = "Joo, {Jihoon E.} and Chu, {Yen Lin} and Peter Georgeson and Romy Walker and Khalid Mahmood and Mark Clendenning and Meyers, {Aaron L.} and Julia Como and Sharelle Joseland and Preston, {Susan G.} and Natalie Diepenhorst and Julie Toner and Ingle, {Danielle J.} and Sherry, {Norelle L.} and Andrew Metz and Lynch, {Brigid M.} and Milne, {Roger L.} and Southey, {Melissa C.} and Hopper, {John L.} and Win, {Aung Ko} and Macrae, {Finlay A.} and Winship, {Ingrid M.} and Christophe Rosty and Jenkins, {Mark A.} and Buchanan, {Daniel D.}",
note = "Funding Information: We thank the members of the Colorectal Oncogenomics Group (The University of Melbourne), in particular Emma Barrance. We thank the participants and staff from the ANGELS study, the Colon Cancer Family Registry (CCFR) and the Melbourne Collaborative Cohort Study (MCCS). We especially thank Maggie Angelakos, Samantha Fox, Allyson Templeton for facilitating CCFR resources and supporting this study. BML was supported by a Mid-Career Fellowship from the Victorian Cancer Agency (MRCF-18005). MCS is supported by a Level 3 Investigator Grant from the National Health and Medical Research Council, Australia, GNT2017325). DDB is supported by an NHMRC Investigator grant (GNT1194896) and the University of Melbourne Dame Kate Campbell Fellowship. The E. coli isolate provided was collected as part of the Controlling Superbugs study, funded by the Melbourne Genomics Health Alliance (supported by the State Government of Victoria). The Australasian Colon Cancer Family Registry (ACCFR) is supported in part by funding from the National Cancer Institute (NCI), National Institutes of Health (NIH) (award U01 CA167551). Support for case ascertainment was provided in part from the Victoria Cancer Registry (Australia). The content of this manuscript is solely the responsibility of the authors and does not necessarily reflect the views or policies of the NIH or any of the collaborating centres in the CCFR, nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government, any cancer registry, or the CCFR. Funding Information: We thank the members of the Colorectal Oncogenomics Group (The University of Melbourne), in particular Emma Barrance. We thank the participants and staff from the ANGELS study, the Colon Cancer Family Registry (CCFR) and the Melbourne Collaborative Cohort Study (MCCS). We especially thank Maggie Angelakos, Samantha Fox, Allyson Templeton for facilitating CCFR resources and supporting this study. BML was supported by a Mid-Career Fellowship from the Victorian Cancer Agency (MRCF-18005). MCS is supported by a Level 3 Investigator Grant from the National Health and Medical Research Council, Australia, GNT2017325). DDB is supported by an NHMRC Investigator grant (GNT1194896) and the University of Melbourne Dame Kate Campbell Fellowship. The E. coli isolate provided was collected as part of the Controlling Superbugs study, funded by the Melbourne Genomics Health Alliance (supported by the State Government of Victoria). The Australasian Colon Cancer Family Registry (ACCFR) is supported in part by funding from the National Cancer Institute (NCI), National Institutes of Health (NIH) (award U01 CA167551). Support for case ascertainment was provided in part from the Victoria Cancer Registry (Australia). The content of this manuscript is solely the responsibility of the authors and does not necessarily reflect the views or policies of the NIH or any of the collaborating centres in the CCFR, nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government, any cancer registry, or the CCFR. Publisher Copyright: {\textcopyright} The Author(s) 2024.",
year = "2024",
month = mar,
day = "23",
doi = "10.1038/s41416-023-02554-x",
language = "English",
volume = "130",
pages = "728--740",
journal = "British Journal of Cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",
number = "5",
}
