Microbiome–Genome Crosstalk in Colorectal Cancer: Colibactin Signatures and Fusobacterium nucleatum in Epidemiology, Driver Selection, and Translation

Colibactin, a genotoxin produced by <i>pks</i>⁺<i>E. coli</i>, imprints highly specific mutational signatures SBS88 and ID18 in colorectal cancer (CRC) and even in normal colonic crypts. Population-scale analyses show these signatures are enriched in early-onset CRC, vary geographically, and are imprinted early during tumor evolution, where probabilistic attribution indicates that colibactin contributes to a measurable fraction of <i>APC</i> driver mutations in colibactin-positive cancers. Beyond colibactin, <i>Fusobacterium nucleatum</i> exerts clade-specific effects on tumor ecology and therapy response, with data supporting both chemoresistance and sensitization to anti-<i>PD-1</i> in microsatellite stable (MSS) CRC. This article covers mechanistic, genomic, and molecular epidemiology evidence, outlines analytic standards for signature detection (whole-genome sequencing (WGS)/whole-exome sequencing (WES), single-sample fitting, and limits at low mutation counts), and charts translational paths spanning noninvasive screening (stool metagenomics + mutational signatures in tissue/circulating tumor DNA (ctDNA)), risk stratification, and microbial-targeted interventions (antibiotics, phages, <i>ClbP</i> inhibitors). Framing microbiome-genome crosstalk as a tractable axis enables testable clinical hypotheses for precision oncology.