학술논문
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
Document Type
Original Paper
Author
Joo, Jihoon E.; Chu, Yen Lin; Georgeson, Peter; Walker, Romy; Mahmood, Khalid; Clendenning, Mark; Meyers, Aaron L.; Como, Julia; Joseland, Sharelle; Preston, Susan G.; Diepenhorst, Natalie; Toner, Julie; Ingle, Danielle J.; Sherry, Norelle L.; Metz, Andrew; Lynch, Brigid M.; Milne, Roger L.; Southey, Melissa C.; Hopper, John L.; Win, Aung Ko; Macrae, Finlay A.; Winship, Ingrid M.; Rosty, Christophe; Jenkins, Mark A.; Buchanan, Daniel D.
Source
British Journal of Cancer. 130(5):728-740
Subject
Language
English
ISSN
0007-0920
1532-1827
1532-1827
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.