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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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2024年1月10日

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  • Jihoon E. Joo,
  • Yen Lin Chu,
  • Peter Georgeson,
  • Romy Walker,
  • Khalid Mahmood,
  • Mark Clendenning,
  • Aaron L. Meyers,
  • Julia Como,
  • Sharelle Joseland,
  • Susan G. Preston,
  • Natalie Diepenhorst,
  • Julie Toner,
  • Danielle J. Ingle,
  • Norelle L. Sherry,
  • Andrew Metz,
  • Brigid M. Lynch,
  • Roger L. Milne,
  • Melissa C. Southey,
  • John L. Hopper,
  • Aung Ko Win,
  • Finlay A. Macrae,
  • Ingrid M. Winship,
  • Christophe Rosty,
  • Mark A. Jenkins,
  • Daniel D. Buchanan

摘要

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.